Thyroid & parathyroid

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Thyroid & parathyroid

Authors: Shipra Agarwal, M.D., F. Zahra Aly, M.D., Ph.D., Zubair W. Baloch, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D., Anthony Chi, M.D., Ph.D., Sara Conway, M.D., Nadine Demko, M.D., C.M., M.Sc., Livia Florianova, M.D., M.Sc., Julie Guilmette, M.D., Hanni Gulwani, M.B.B.S., Momin Iqbal, M.D., M.B.B.S., Shahid Islam, M.D., Ph.D., Xiaoyin "Sara" Jiang, M.D., Rachel Jug, M.B.B.Ch., B.A.O., Mehmet Kefeli, M.D., Jonathan K. Lai, M.D., Virginia A. LiVolsi, M.D. (Deceased), Jijgee Munkhdelger, M.D., Ph.D., Diana Murro Lin, M.D., Truong Phan Xuan Nguyen, M.D., Nat Pernick, M.D., David Poller, M.D., Marc Pusztaszeri, M.D., Monika Roychowdhury, M.D., Swati Satturwar, M.D., Ayana Suzuki, C.T., Huy Gia Vuong, M.D., Ph.D., Shuanzeng (Sam) Wei, M.D., Ph.D., Bin Xu, M.D., Ph.D., Sheren Younes, M.D., Ph.D., Xiaofeng Zhao, M.D., Ph.D., Jianhong Zhou, M.D.

Editorial Board Members: Andrey Bychkov, M.D., Ph.D., Bonnie Choy, M.D., Marc Pusztaszeri, M.D., Molly Housley Smith, D.M.D., Bin Xu, M.D., Ph.D.

Deputy Editors-in-Chief: Andrey Bychkov, M.D., Ph.D., Kelly Magliocca, D.D.S., M.P.H., Nat Pernick, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

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Editorial Board oversight: Marc Pusztaszeri, M.D. (last reviewed March 2023)

Superpage Topics

Acute / infectious thyroiditis Adequacy AJCC / TNM Staging Amiodarone induced hyperthyroidism Amyloid goiter Anaplastic thyroid carcinoma Anatomy Anatomy & histology-parathyroid Angiosarcoma Aplasia / hypoplasia AUS Autoimmune thyroiditis Benign Bethesda system diagnostic categories Black / pigmented thyroid Branchial pouch / cleft anomalies C cell hyperplasia Calcification Children Clear cell Clear cell change Columnar cell Congenital hypothyroidism Cribriform-morular thyroid carcinoma Crystals Differentiated high grade thyroid carcinoma / high grade differentiated thyroid carcinoma (HGDTC) Diffuse follicular Diffuse sclerosing DiGeorge syndrome Dyshormonogenetic goiter Ectopic parathyroid tissue Ectopic thyroid tissue Embryology Encapsulated Encapsulated follicular Endemic goiter Features to report Fibromatosis / fasciitis-like FNA-general Focal lymphocytic thyroiditis Follicular adenoma Follicular adenoma with papillary architecture (pending) Follicular neoplasm Follicular thyroid carcinoma Follicular variant Frozen section Frozen section-parathyroid FT-UMP (pending) Graves disease Grossing Hashimoto thyroiditis Hashimoto-fibrous Histology Hobnail Hyalinizing trabecular tumor Hyperparathyroidism Hyperthyroidism Hypothyroidism Intrathyroidal thymic carcinoma Invasive EFVPTC Langerhans cell histiocytosis Lateral aberrant thyroid Lymphoepithelial cyst Lymphoma Lysosomal storage diseases Macrofollicular Malakoplakia Malignant Medullary thyroid carcinoma Microcarcinoma Mixed medullary-follicular tumors Molecular pathology basics Molecular pathology-practical Molecular testing in FNA Mucoepidermoid carcinoma NIFTP Oncocytic Oncocytic (Hürthle cell) tumors Oncocytic neoplasm Other nonneoplastic parathyroid Palpation thyroiditis Papillary thyroid carcinoma - classic Papillary thyroid carcinoma overview Parasitic nodule Parathyroid adenoma Parathyroid carcinoma Parathyroid gland hyperplasia Parathyroid tissue Plasma cell granuloma Plasmacytoma Poorly differentiated thyroid carcinoma Postoperative spindle cell nodule Radiation thyroiditis References Riedel thyroiditis Sarcoidosis Sarcoma Sclerosing mucoepidermoid carcinoma with eosinophilia Secretory carcinoma SETTLE Silent thyroiditis Solid / trabecular Solid cell nests / ultimobranchial body remnants Solitary fibrous tumor Solitary papillary hyperplastic nodule Solitary thyroid nodule Solitary thyroid nodule Squamous cell carcinoma Staging-parathyroid Subacute thyroiditis Suspicious for malignancy Tall cell Teratoma Thymic tissue Thyroblastoma (pending) Thyroglossal duct carcinoma Thyroglossal duct cyst Thyroid cancer-general Thyroid follicular nodular disease (multinodular goiter) Thyroid inclusions Thyroid metastases Toxic goiter Ultrasound Unsatisfactory Warthin-like WDT-UMP WHO classification

Acute / infectious thyroiditis

Table of Contents

Definition / general

Also called acute thyroiditis
Via blood or direct seeding from upper respiratory infections, causes sudden onset of pain and glandular enlargement
Risk factors: malnourished infant, debilitated elderly, immunosuppression, trauma
Often Streptococcus haemolyticus, Streptococcus pneumoniae, Staphylococcus aureus; gram negative bacteria associated with trauma; also Pneumocystis jiroveci in HIV+ patients with low CD4 counts (Mycoses 2007;50:443)

Clinical features

Rarely is suppurative (Pediatr Emerg Care 2008;24:764)
May be associated with pyriform sinus fistula (Pediatr Surg Int 2007;23:779)

Diagnosis

Usually based on serologic tests

Case reports

23 year old woodcutter with blastomycosis (Thyroid 2008;18:659)
31 year old woman with Aspergillus and end stage AIDS (Postgrad Med J 2001;77:336)
With septic emboli from endocarditis (Postgrad Med J 2008;84:445)
Renal transplant recipient with Salmonella infection complicated with suppurative thyroiditis and ruptured aortic mycotic aneurysm (Transplant Proc 2008;40:3759)
Odontogenic origin (Minerva Stomatol 2007;56:461)
Allescheria boydii thyroiditis in posttransplant patient (Arch Pathol Lab Med 1978;102:158)

Treatment

Drainage, antibiotics, fistulectomy

Gross description

Normal or slightly enlarged thyroid gland
May have suppurative areas

Gross images

Images hosted on other servers:

Aspergillus septic foci

Microscopic (histologic) description

Neutrophils, possibly microabscesses and tissue necrosis
Fungi are associated with necrosis, acute inflammation and granulomas

Cytology images

Images hosted on other servers:

Aspergillus

Nocardia

Stains

Gram stain or GMS / PAS may help identify bacteria or fungi; use ISH or IHC for viruses

Differential diagnosis

Ischemic necrosis
Subacute thyroiditis

Adequacy

Table of Contents

Definition / general

Assessment of adequacy is the first step in the evaluation of a thyroid fine needle aspiration (FNA) sample (Clark: Thyroid Cytopathology, 1st Edition, 2005)
- Rapid, low magnification review of all cytologic slides by pathologist or cytotechnologist
- Rapid on site evaluation helps assess adequacy after sampling; if smear is inadequate, the thyroid nodule can be reaspirated immediately
Factors influencing adequacy (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2018):
- Nature of the nodule (location, size, cystic component)
- Skills of operator and reader
- Technical setup (gauge size, ultrasound guidance, etc.)
- Criteria of adequacy

Essential features

Adequate specimen should contain ≥ 6 groups of well visualized follicular cells (≥ 10 per cluster)
A minimum number of follicular cells is not required for samples with cytologic atypia or if inflammation or abundant colloid are present

Diagnosis

FNA smear should contain ≥ 6 groups of well visualized follicular cells (≥ 10 cells/group), preferably on a single slide
Exceptions (a minimum number of follicular cells is not required)
- Solid nodules with cytologic atypia, which qualify into categories III - VI
- Solid nodules with inflammation are considered benign (Diagn Cytopathol 2008;36:407, Diagn Cytopathol 2008;36:161)
  - Only numerous inflammatory cells
  - Lymphocytic thyroiditis, thyroid abscess or granulomatous thyroiditis
  - Nodules with abundant colloid are placed in the benign category even in the absence of follicular epithelium (Endocr Res 2015;40:215)
Same criteria of adequacy are applicable to thyroid liquid based preparations; however, some differences between conventional smears and liquid based preparations should be considered (Kakudo: Thyroid FNA Cytology, 2nd Edition, 2019):
- Liquid based preparation contains increased amount of follicular cells, especially cell clusters and atypical cells
- Decreased background components (fresh blood, watery colloid and inflammatory cells)

Cytology description

Adequate quantity / cellularity as per criteria above
Satisfactory quality (fixation and staining)

Cytology images

Contributed by Ayana Suzuki, C.T.

Adequate with macrofollicles

Adequate with thick colloid only

Adequate with atypical cells

Adequate with thyroiditis

Inadequate / blood obscured

Nondiagnostic dried or acellular

Images hosted on other servers:

Inadequate / blood obscured

Nondiagnostic dried or acellular

Videos

Thyroid fine needle aspiration and smearing techniques

Essential thyroid cytopathology

Board review style question #1

Which cytologic appearance of thyroid FNA specimen is classified as adequate?

3 groups with 10 follicular cells
Abundant thick colloid only
Air dried specimen without any atypical cells
Foamy histiocytes only
Respiratory epithelium only

Board review style answer #1

B. Abundant thick colloid

When the aspirated material contains only abundant thick colloid and no follicular epithelium, it is qualified as adequate. Colloid may have variable appearance. It is important to recognize a substance as a colloid, not blood. 3 groups with 10 benign follicular cells are not sufficient to be qualified as diagnostic per the current criteria.

Comment Here

Reference: Adequacy

AJCC / TNM Staging

Table of Contents

Definition / general

AJCC / TNM staging is used for predicting disease specific survival
Clinical staging is based on inspection / palpation and imaging (ultrasound, PET / CT, etc.) of thyroid gland and regional lymph nodes
Pathologic staging (pTNM) is based on all information used for clinical staging plus histologic examination plus surgeon's description of gross unresected tumor
Any information obtained within the first 4 months after thyroid surgery should be used to refine the N and M status
AJCC 8th edition (Amin: AJCC Cancer Staging Manual, 8th Edition, 2017) is effective from January 1, 2018
Other staging systems also exist (Ann Surg 2007;245:366, Endocr Relat Cancer 2007;14:29)

Essential features

T, N and M categories are the mainstay for predicting survival in patients with thyroid cancer
Age (cutoff of 55 years) is an essential variable for AJCC staging of differentiated thyroid cancer

TNM definitions

Primary tumor (pT) for papillary, follicular, poorly differentiated, Hürthle cell and anaplastic thyroid carcinomas:

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor ≤ 2 cm in greatest dimension limited to the thyroid
- T1a: Tumor ≤ 1 cm in greatest dimension limited to the thyroid
- T1b: Tumor > 1 cm but ≤ 2 cm in greatest dimension limited to the thyroid
T2: Tumor > 2 cm but ≤ 4 cm in greatest dimension limited to the thyroid
T3*: Tumor > 4 cm limited to the thyroid or gross extrathyroidal extension invading only strap muscles
- T3a*: Tumor > 4 cm limited to the thyroid
- T3b*: Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid or omohyoid muscles) from a tumor of any size
T4: Includes gross extrathyroidal extension into major neck structures
- T4a: Gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus or recurrent laryngeal nerve from a tumor of any size
- T4b: Gross extrathyroidal extension invading prevertebral fascia or encasing carotid artery or mediastinal vessels from a tumor of any size

Primary tumor (pT) for medullary thyroid carcinomas:

TX - T3: Definitions are similar to the above
T4: Advanced disease
- T4a: Moderately advanced disease; tumor of any size with gross extrathyroidal extension into the nearby tissues of the neck, including subcutaneous soft tissue, larynx, trachea, esophagus or recurrent laryngeal nerve
- T4b: Very advanced disease; tumor of any size with extension toward the spine or into nearby large blood vessels, invading the prevertebral fascia or encasing the carotid artery or mediastinal vessels

Regional lymph node (pN):

NX: Regional lymph nodes cannot be assessed
N0: No evidence of regional lymph node metastasis
- N0a*: One or more cytologic or histologically confirmed benign lymph nodes
- N0b*: No radiologic or clinical evidence of locoregional lymph node metastasis
N1*: Metastasis to regional nodes
- N1a*: Metastasis to level VI or VII (pretracheal, paratracheal, prelaryngeal / Delphian or upper mediastinal) lymph nodes; this can be unilateral or bilateral disease
- N1b*: Metastasis to unilateral, bilateral or contralateral lateral neck lymph nodes (levels I, II, III, IV or V) or retropharyngeal lymph nodes

Distant metastasis (M):

M0: No distant metastasis
M1: Distant metastasis

* All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest tumor determines the classification)

AJCC prognostic stage grouping

Differentiated thyroid cancer:

	Age at diagnosis < 55 years
Stage I:	any T	any N	M0
Stage II:	any T	any N	M1
	Age at diagnosis ≥ 55 years
Stage I:	T1	N0 / NX	M0
	T2	N0 / NX	M0
Stage II:	T1	N1	M0
	T2	N1	M0
	T3a / T3b	any N	M0
Stage III:	T4a	any N	M0
Stage IVA:	T4b	any N	M0
Stage IVB:	any T	any N	M1

Medullary thyroid cancer:

Stage I:	T1	N0	M0
Stage II:	T2	N0	M0
	T3	N0	M0
Stage III:	T1 - 3	N1a	M0
Stage IVA:	T4a	any N	M0
	T1 - 3	N1b	M0
Stage IVB:	T4b	any N	M0
Stage IVC:	any T	any N	M1

Anaplastic thyroid cancer:

Stage IVA:	T1 - T3a	N0 / NX	M0
Stage IVB:	T1 - T3a	N1	M0
	T3b	any N	M0
	T4	any N	M0
Stage IVC:	any T	any N	M1

Major changes in the AJCC / TNM 8th edition

Differentiated thyroid cancer (Thyroid 2017;27:751):

Age cutoff used for staging was increased from 45 to 55 years at diagnosis
Minimal extrathyroidal extension detected only on histologic examination was removed from the definition of T3 disease and therefore has no impact on either T category or overall stage
N1 disease no longer upstages a patient to stage III; if the patient's age is < 55 years at diagnosis, N1 disease is stage I; if age is ≥ 55 years, N1 disease is stage II
T3a is a new category for tumors > 4 cm confined to the thyroid gland
T3b is a new category for tumors of any size demonstrating gross extrathyroidal extension into strap muscles (sternohyoid, sternothyroid, thyrohyoid or omohyoid muscles)
Level VII lymph nodes, previously classified as lateral neck lymph nodes (N1b), were reclassified as central neck lymph nodes (N1a) to be more anatomically consistent and because level VII presented significant coding difficulties for tumor registrars, clinicians and researchers
In differentiated thyroid cancer, the presence of distant metastases in older patients is classified as stage IVB disease rather than stage IVC disease; distant metastasis in anaplastic thyroid cancer continues to be classified as stage IVC disease

Anaplastic thyroid cancer (CA Cancer J Clin 2018;68:55):

Unlike previous editions where all anaplastic thyroid cancers were classified as T4 disease, anaplastic cancers will now use the same T definitions as differentiated thyroid cancer
Intrathyroidal disease is stage IVA, gross extrathyroidal extension or cervical lymph node metastases are stage IVB and distant metastases are stage IVC

Diagrams / tables

Scroll to see all images:

Contributed by Andrey Bychkov, M.D., Ph.D.

AJCC / TNM charts

Images hosted on other servers:

Levels of the cervical lymph nodes

TNM sketches

T1N0

T2N0

T3N0 and T1N1

T3N1

T1M1

T2M1

Staging charts

Stage I, < 55 yo

Stage I, 55 yo

Stage II, < 55 yo

Stage II, > 55 yo

Stage III

Stage IVA

Stage IVB

Anaplastic cancer, stage IVA

Anaplastic cancer, stage IVB

Anaplastic cancer, stage IVC

Medullary cancer, stage I

Medullary cancer, stage II

Medullary cancer, stage III

Medullary cancer, stage IVA

Medullary cancer, stage IVB

Medullary cancer, stage IVC

Videos

Advanced thyroid carcinoma

Thyroid carcinoma

Staging thyroid cancer

Staging of medullary thyroid cancer

Staging animation

Board review style question #1

50 year old woman presented with widely invasive follicular thyroid carcinoma penetrating thyroid capsule and strap muscles (confirmed on thyroidectomy) and spinal metastasis (confirmed by imaging and biopsy). What is the clinical stage as per the AJCC / TNM 8th edition?

Stage I
Stage II
Stage III
Stage IVA
Stage IVC

Board review style answer #1

B. Stage II. Despite the advanced disease, this patient is qualified as having stage II because her age is less than 55 years. Age at presentation is a critical prognostic characteristic in well differentiated thyroid carcinoma.

Comment Here

Reference: Thyroid & parathyroid - Staging

Board review style question #2

Histopathological examination of total thyroidectomy specimen revealed conventional papillary thyroid carcinoma in the right lobe (1.8 cm), with minimal extrathyroidal extension (perithyroidal fat), microscopically involved posterior resection margin and micrometastasis in the single perithyroidal lymph node (0.2 cm). What are the correct pT and pN categories?

pT1N0
pT1aN1a
pT1bN1a
pT2N1a
pT3N1a

Board review style answer #2

C. pT1bN1a. T1b describes a tumor > 1 cm but ≤ 2 cm in greatest dimension limited to the thyroid. Minimal extrathyroidal extension was removed from the definition of T3 disease in the AJCC / TNM 8th edition and therefore has no impact on T category. Metastasis to the central lymph nodes qualifies as N1a.

Comment Here

Reference: Thyroid & parathyroid - Staging

Additional references

Features to report, Ultrasonography 2017;36:292

Amiodarone induced hyperthyroidism

Table of Contents

Definition / general

Amiodarone is an antiarrhythmic medication for atrial and ventricular tachyarrhythmias, and less commonly for ischemic heart disease and congestive heart failure; also used for fetal tachycardia (Arch Cardiovasc Dis 2008;101:619, eMedicine)
Contains 37% iodine by weight, and structurally resembles thyroxine, which interferes with thyroid hormone metabolic pathways, causing hypo- or hyperthyroidism
The relative frequency of amiodarone induced hypothyroidism (AIH) and amiodarone induced thyrotoxicosis (AIT) depends on the iodine status of the population
- In populations with iodine deficiency, amiodarone induced thyrotoxicosis is more common
- Conversely, in the United States, amiodarone induced hypothyroidism is more common (Proc (Bayl Univ Med Cent) 2008;21:382)
AIT is classified in two subtypes, type 1 AIT and type 2 AIT
Distinguishing between the two subtypes is important as both arise in different settings and have different treatments (Case Rep Med 2014;2014:231651)

Essential features

Amiodarone induced thyrotoxicosis (AIT) is classified in two subtypes (Case Rep Med 2014;2014:231651)
Type 1 AIT arises in thyroid glands with preexisting disease (Jod-Basedow phenomenon)
Type 2 AIT develops in a previously normal thyroid gland due to a destructive amiodarone induced inflammatory process
Presents with worsening cardiac arrhythmia, recurrent atrial fibrillation and palpitations (NCBI - Amiodarone Induced Thyrotoxicosis)
Diagnosis requires correlation of clinical, imaging and laboratory findings
Histologically, type 1 AIT has features of preexisting disease; type 2 AIT shows involuted follicles filled with desquamated vacuolated epithelial cells, scattered inflammatory infiltrate composed of foamy macrophages and lymphocytes, and fibrosis (Proc (Bayl Univ Med Cent) 2008;21:382, Pathol Int 2008;58:55)

Epidemiology

More frequent in males than in females (3:1)
Occurs in 3% of patients treated with amiodarone in North America, increasing to 10% in countries with low iodine dietary intake (NCBI - Amiodarone Induced Thyrotoxicosis)

Sites

In addition to the thyroid gland, amiodarone can affect the lungs, liver, cornea and skin (Pathol Int 2008;58:55, Cutan Ocul Toxicol 2017;36:98 )

Pathophysiology

Thyrotoxicosis is due to amiodarone's iodine content and structural resemblance to thyroxine
Amiodarone has pharmacological properties enabling its toxicity (Can J Cardiol 2009;25:421), including:
- Lipophilia, promoting accumulation in adipose tissue, cardiac and skeletal muscle, and thyroid
- Inhibition of thyroidal T4 and T3 production and release within the first two weeks of treatment (Wolff-Chaikoff effect)
- Direct toxicity to cultured thyroid cells exposed to media with concentrations above those normally found in patients

Clinical features

Associated with worsening cardiac arrhythmia with recurrence of atrial fibrillation and palpitations (NCBI - Amiodarone Induced Thyrotoxicosis)
May occur suddenly in patients treated with amiodarone for several years, likely due to its long half life, lipid solubility and accumulation in almost all tissue
Type 1 amiodarone induced thyrotoxicosis:
- Occurs with preexisting thyroid disease, due to iodine induced excess thyroid hormone synthesis
- Microscopic changes are due primarily to preexisting disease
Type 2 amiodarone induced thyrotoxicosis:
- Develops as an inflammatory process in a normal thyroid (NCBI - Amiodarone Induced Thyrotoxicosis)
- Due to destructive thyroiditis (Endocr Rev 2001;22:240)
Amiodarone is probably the cause of thyroid cell damage in some patients, and follicular disruption (with consequent release of iodothyronines into the circulation) is likely to be an important contributor to associated thyrotoxicosis (Am J Surg Pathol 1987;11:197)

Diagnosis

Based on clinical, laboratory and imaging correlations

Laboratory

To confirm the diagnosis of amiodarone induced thyrotoxicosis, it is necessary to demonstrate a suppressed serum TSH associated with an increase in serum free T3 and free T4 levels in a patient treated with amiodarone (NCBI - Amiodarone Induced Thyrotoxicosis)
In type 1: increased T4 / T3 due to destructive thyroiditis, in addition to increased levels of antibodies to thyroglobulin and TPO
In type 2: elevated levels of IL6; 8% also have increased levels of antibodies to thyroglobulin and TPO

Radiology description

Color flow Doppler ultrasonography is useful to differentiate between type 1 and type 2 (NCBI - Amiodarone Induced Thyrotoxicosis, World J Surg 2006;30:1957)
Type 1:
- Increased intrathyroidal vascular flow
- Normal or raised radioactive iodine update
- Tc sestamibi thyroid scan shows a diffusely increased uptake and retention in an enlarged thyroid gland (Clin Nucl Med 2016;41:566)
Type 2:
- Reduced or absent vascular flow
- Low or absent radioactive iodine update

Case reports

59 year old man with type 2 disease and papillary thyroid carcinoma (Arch Pathol Lab Med 2004;128:807)
64 year old woman with nodular goiter (Ann Pharmacother 2009;43:134)
65 year old man with fatal amiodarone induced thyrotoxicosis (J Med Case Rep 2007;1:134)
66 year old man with thyrotoxicosis (Arch Pathol Lab Med 2003;127:e275)
66 year old man with medically refractory amiodarone induced thyrotoxicosis requiring thyroidectomy (Proc (Bayl Univ Med Cent) 2008;21:382)

Treatment

Differs for type 1 and 2 amiodarone induced thyrotoxicosis (Minerva Endocrinol 2008;33:213)
Up to 20% of mild cases spontaneously resolve (NCBI - Amiodarone Induced Thyrotoxicosis)
Type 1: treat with high doses of thioamides to block synthesis of thyroid hormones
- Potassium perchlorate can also be combined to increased sensitivity to thioamides
- Once the thyroid function is normalized, hyperthyroidism can be treated by either radioactive iodine or thyroidectomy depending on its severity
Type 2: treat with prednisone; thionamides are generally not useful
Clinically, "mixed" AIT is common, in which patients seems to be respond only to therapy with both thioamides and glucocorticoids (Proc (Bayl Univ Med Cent) 2008;21:382)
Dronedarone is an alternative but less effective antiarrhythmic agent without the adverse thyroid effects (Clin Endocrinol (Oxf) 2009;70:2)

Gross description

Type 2 amiodarone induced thyrotoxicosis:

Firm in consistency, normal shape (Case Reports in Endocrinology 2015; Article ID 416145)
Homogeneous "beefy red" parenchyma (Arch Pathol Lab Med 2004;128:807)

Microscopic (histologic) description

Associated with type 1 amiodarone induced thyrotoxicosis: changes are those of preexisting disease, usually multinodular goiter
Associated with type 2 amiodarone induced thyrotoxicosis: often with no history of thyroid disorder
- Randomly distributed disrupted follicles filled with desquamated vacuolated epithelial cells, foamy macrophages and scattered lymphocytes, involutional changes, fibrosis
- Associated with hypothyroidism: involuted follicles with flattened follicular cells, dilated lumina with dense colloid; also small numbers of damaged follicles infiltrated by macrophages (Pathol Int 2008;58:55)

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Amiodarone thyroiditis

Images hosted on other servers:

Amiodarone induced thyrotoxicosis

Electron microscopy description

Prominent cytoplasmic vacuoles with lipid
Also prominent lysosomes with lamellar configuration (Lloyd: Endocrine Diseases, 1st Edition, 2002)
It is speculated that this may result from impairment of lysosome function

Additional references

J Intensive Care Med 2015;30:179, Bol Asoc Med P R 2013;105:47

Amyloid goiter

Table of Contents

Definition / general

First reported in 1855 (Rokitansky: A Manual Of Pathological Anatomy; Vol: I, 2008)
Defined as a diffuse clinically apparent enlargement of the thyroid gland due to widespread amyloid deposits (von Eisenberg: Ueber einen Fall von Amyloid-Kropf, 1904)
Rare entity
Diagnosis often made at autopsy (Am J Clin Pathol 1995;104:306)
Patients usually have normal thyroid function tests (euthyroid); minority have hyperthyroidism, hypothyroidism or thyroid autoantibodies

Terminology

Also known as amyloid tumor of thyroid

Epidemiology

Median age 54 years, range 23 - 75 years
In adolescence associated with juvenile arthritis or familial Mediterranean fever
Males > females

Etiology

Due to systemic amyloidosis (majority arise in secondary AA amyloidosis)
Secondary AA amyloidosis occurs as a result of chronic inflammatory conditions such as rheumatoid arthritis, Crohn's disease, familial Mediterranean fever, osteomyelitis or tuberculosis, resulting in increase in serum amyloid protein
Also reported in dialysis dependent chronic renal failure patients as a result of beta-2-microglobulin accumulation (Case Rep Endocrinol 2012;2012:741754)

Clinical features

Nontender, diffuse enlargement of gland over weeks to months
May have obstructive symptoms of dyspnea, hoarseness, dysphagia
Patients usually have normal thyroid function tests (euthyroid); minority have hyperthyroidism or hypothyroidism

Diagnosis

Fine needle aspiration cytology
Thyroidectomy for definitive diagnosis

Laboratory

Majority have normal thyroid function tests (euthyroid)
Minority have hyperthyroidism, hypothyroidism or thyroid autoantibodies

Radiology description

Ultrasound: enlargement with high echogenicity and very fine homogenous echotexture similar to ground glass appearance (J Clin Ultrasound 1994;22:239)

Case reports

30 year old man with chronic kidney disease (Anal Quant Cytopathol Histpathol 2014;36:241)
40 year old man with parathyroid involvement (Arch Pathol Lab Med 2000;124:281)
46 year old man, a renal allograft recipient, with transthyretin type (Endocr Pathol 2008;19:66)
48 year old woman with multiple myeloma (Arch Pathol Lab Med 1990;114:429)
58 year old woman with diffuse fatty infiltration in amyloid goiter (Pathol Int 2007;57:449)
61 year old woman with diffuse thyroid enlargement (Case #247)
Case with Castleman disease (Arch Pathol Lab Med 1989;113:542)

Treatment

Treatment of underlying systemic amyloidosis
Thyroidectomy to relieve pressure symptoms
Treat associated hypothyroidism, which may cause cardiomyopathy, gastrointestinal involvement (leading to malabsorption of oral therapy) and abnormal circulating immunoglobulins, which may interfere with hormone assays or hormone function (Head Neck 1995;17:343)

Gross description

Depending on the amount of amyloid deposited, thyroid gland can be soft, hard, diffuse or nodular
Bilateral and diffusely enlarged gland with inhomogeneous nodules, whitish tan / light brown or pale yellow

Gross images

AFIP images

Enlarged and bosselated with salmon cut surface

Images hosted on other servers:

Lipomatosis and amyloidosis

Microscopic (histologic) description

Diffuse deposition of amorphus eosinophilic fibrillary material in perifollicular and perivascular regions, may replace thyroid follicles
Other associated findings: fatty metaplasia, foreign body giant cell reaction, squamous metaplasia or focal lymphocytic thyroiditis

Microscopic (histologic) images

Contributed by Nazar M. T. Jawhar, M.D.

Various images

Case #247 and AFIP images

Amyloid and inflammatory cells

Apple green birefringence

Images hosted on other servers:

Birefringent apple green staining under polarized light

Cytology description

Dense amorphus clumps of extracellular material or irregularly shaped fragments with scalloped and pointed edges
The amorphous fragments stain eosinophilic on Papanicolaou stain, magenta colored on Giemsa and deep blue with Diff-Quick cytology stain

Positive stains

Congo red shows salmon color and apple green dichroism with polarized light
The type of fibril can be determined by immunochemical staining using specific antibodies (AL and AA)

Negative stains

Calcitonin, thyroglobulin

Differential diagnosis

Medullary thyroid carcinoma: calcitonin+ tumor cells present
Microscopic deposition of amyloid within the thyroid occurs in 59 - 92% of patients with amyloidosis; this frequency is similar between AL and AA amyloidosis (Q J Med 1974;43:127) but is not considered part of the amyloid goiter discussed here

Board review style question #1

Which statement about amyloid goiter of the thyroid is false?

Can be seen in renal transplant patients on dialysis
Commonly seen in males
Is associated with medullary thyroid carcinoma
Microscopically shows diffuse deposition of amyloid
Rarely presents with dysphagia, dysphonia or dyspnea

Board review style answer #1

C. Is associated with medullary thyroid carcinoma. Amyloid goiter is not associated with medullary thyroid carcinoma. It is defined as amyloid deposits in thyroid associated with a goiter, but not with a malignant neoplasm.

Comment Here

Reference: Amyloid goiter

Anaplastic thyroid carcinoma

Table of Contents

Definition / general

The most aggressive follicular cell derived thyroid malignancy composed of undifferentiated cells
Total or near total loss of follicular cell differentiation
Concomitant with previous history of differentiated thyroid carcinoma
Clinically, a rapidly enlarging neck mass with survival < 6 months in most cases

Essential features

Composed of undifferentiated, pleomorphic, mitotically active tumor cells, that may show focal follicular cell differentiation morphologically or immunohistochemically
Develops from progression of differentiated thyroid carcinoma (DTC) or de novo
Rapidly growing, widely invasive thyroid mass needing multimodal treatment, still with near 100% disease specific mortality

Terminology

Synonym: undifferentiated thyroid carcinoma (Endocr Relat Cancer 2022;30:e220293)

ICD coding

ICD-O: 8020/3 - carcinoma, undifferentiated, NOS
ICD-10: C73 - malignant neoplasm of thyroid gland
ICD-11: 2D10.3 - undifferentiated carcinoma of thyroid gland

Epidemiology

Rare, 1 - 2% of all thyroid malignancies
Incidence: 0.9 - 1.2 cases per 1,000,000 population (Am J Transl Res 2019;11:5888, World J Otorhinolaryngol Head Neck Surg 2018;5:34)
Age: > 50 years in most; median: 68 years (Thyroid 2020;30:1505)
F:M = 1 - 2:1

Sites

Either lobe or isthmus of thyroid gland
Anaplastic transformation can be seen in local and distant metastases of DTC

Pathophysiology

May arise de novo or from dedifferentiation from DTC, such as papillary thyroid carcinoma, follicular thyroid carcinoma, oncocytic carcinoma of the thyroid
Accumulation of genetic events, commonly TP53 and TERT promoter

Etiology

2 pathways: develops from pre-existing DTC or de novo (Endocr Pathol 2022;33:27)
Radiation exposure and iodine deficiency in 10% of cases

Diagrams / tables

Images hosted on other servers:

Molecular landscape

Treatment of stage IVA - B

Treatment of stage IVC

Clinical features

Rapidly enlarging, fixed neck mass (Endocrinol Metab Clin North Am 2019;48:269)
Compression symptoms (e.g., pain, dysphonia, dysphagia, dyspnea, cough)
Symptoms related to distant metastases, in ~60% of cases (Thyroid 2020;30:1505)
Prior history of surgery for DTC or concurrent DTC in > 50% of cases (Thyroid 2020;30:1505)

Diagnosis

Anaplastic thyroid carcinoma (ATC) is a clinicopathological diagnosis to be corroborated with radiology; confirmation on histopathology or cytopathology supplemented by immunohistochemistry or molecular analysis is essential
Diagnostic workup (Thyroid 2021;31:337)
- Fine needle aspiration cytology (FNAC)
  - Can be supplemented by immunohistochemistry and BRAF evaluation
- Core biopsy, if FNAC does not have adequate cellularity for diagnosis or for ancillary testing
- Ultrasonography of neck for evaluation of the thyroid mass and assessment of cervical node involvement
- Staging of disease using ¹⁸F FDG PET / CT (whole body); if unavailable, computed tomography (CT) / magnetic resonance imaging (MRI) of neck, chest, abdomen and pelvis
- MRI or CT brain with contrast for brain metastases

Laboratory

Blood tests and biochemistry: complete blood count with differential, blood chemistry, thyroid function tests, Tg and Tb antibody (Thyroid 2021;31:337)
- Part of clinical workup but changes are not specific to ATC
Optional, liquid biopsy to assess mutational profile or monitor treatment response

Radiology description

Sonography
- Large, hypoechoic, solid, irregular mass with heterogeneous echogenicity, invading surrounding neck structures (J Ultrasound Med 2016;35:1873)
Computed tomography scan
- Large ill defined mass, heterogeneous, isodense or slightly hyperdense relative to skeletal muscle, with areas of necrosis, dense amorphous nodular calcification and infiltration of adjoining organs (AJR Am J Roentgenol 1990;154:1079, Acta Radiol 2008;49:321)

Radiology images

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Neck CT, FDG PET scan, sonography

Neck CT

CT for staging

FDG PET before / after therapy

Prognostic factors

Poor prognosis, mortality > 90%
- Median survival: 5 - 6 months
- 1 year survival: 10 - 20%
- 5 year survival: 5 - 10% (Clin Oncol (R Coll Radiol) 2010;22:486, J Natl Compr Canc Netw 2015;13:1140)
- Only marginal improvement with multimodal therapy
Poor prognostic indicators (Thyroid 2020;30:1505, Thyroid 2021;31:337, Endocr Pathol 2022;33:27)
- Older patient age (> 60 - 65 years)
- Acute symptoms
- Leukocytosis
- Absence of DTC
- Presence of nodal or distant metastasis
- Larger tumor size (> 5 - 7 cm)
- Tumor with gross extrathyroidal extension
- TERT promoter mutations
- Concomitant BRAF / RAS and TERT promoter mutations
- EIF1AX mutation, chromosome 13q loss and 20q gains (Endocr Pathol 2016;27:205)
Better clinical outcome (Thyroid 2021;31:337, Head Neck 2016;38:E2083, Thyroid 2020;30:1505, Thyroid 2016;26:404)
- Younger age
- Lower comorbidity score (Charlson / Deyo comorbidity score of 0)
- Absent nodal disease and metastasis
- Smaller tumor size
- Minor ATC component: defined arbitrarily as < 10% ATC component along with DTC
- Encapsulation
- Absent extrathyroidal extension
ATC with excellent outcome is likely to be a misdiagnosed case of PTC with unusual morphology (Endocr J 2016;63:441)

Case reports

44 year old woman diagnosed with ATC with rhabdoid phenotype (Diagn Cytopathol 2020;48:1125)
44 year old woman with Epstein-Barr virus (EBV) associated lymphoepithelioma-like thyroid carcinoma (Diagn Pathol 2018;13:39)
51 year old man with ATC arising from tall cell variant of papillary thyroid carcinoma (Case Rep Endocrinol 2017;2017:4581626)
53 year old man with ATC (J Clin Diagn Res 2017;11:ED03)
61 year old woman with anaplastic transformation of papillary thyroid carcinoma found at pleural metastasis (Head Neck Pathol 2017;11:162)
63 year old man with ATC showing chondrosarcomatous differentiation (Diagn Pathol 2020;15:89)
64 year old man with metastatic ATC in complete remission (Endocr Pathol 2020;31:77)
67 year old woman with osteoclastic variant of ATC (J Cancer Res Ther 2019;15:704)
72 year old man with BRAF V600E positive ATC (Diagn Cytopathol 2021;49:150)
75 year old man with a history of malignant melanoma develops ATC with rhabdoid features (Diagn Cytopathol 2019;47:1232)

Treatment

Based on American Thyroid Association and National Comprehensive Cancer Network guidelines, usually multimodal therapy (Thyroid 2021;31:337, NCCN: NCCN Guidelines - Thyroid Carcinoma [Accessed 14 August 2023])
- Surgery, if resectable
- Radiotherapy with or without chemotherapy
- Targeted therapy
  - Dabrafenib and trametenib, if BRAF V600E mutated
  - Crizotinib, ceritinib, alectinib, in case of ALK fusions
  - Pralsetinib, selpercatinib, in case of RET fusions
  - Larotrectinib, entrectinib, in case of NTRK fusions
- Checkpoint inhibitor (e.g., pembrolizumab)
  - High PD-L1 expression or ≥ 10 MB mutations/Mb

Clinical images

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Fungating neck mass

Gross description

Large mass (often > 5 cm) with ill defined margins that infiltrate adjoining skeletal muscle and trachea
Cut surface is tan, fleshy, may be variegated; hemorrhage, necrosis (Endocr Pathol 2022;33:27)

Gross images

Contributed by Shipra Agarwal, M.D., Mark R. Wick, M.D. and AFIP

Variegated, fleshy

Large, tan, fleshy mass with hemorrhage

Metastases to stomach with ulcerated center

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Diffusely infiltrative, fleshy

Gray-white, fleshy

Frozen section description

Rarely used
Sometimes may be helpful to assess adequacy of diagnostic tissue, besides margins and tumor extent (Thyroid 2021;31:337)
May not be diagnostic if only necrotic or inflammatory areas are sampled

Microscopic (histologic) description

Marked cellular pleomorphism
- Bizarre, hyperchromatic nuclei
Prominent mitotic activity
- Atypical mitoses
Necrosis, usually extensive
- Accompanied by acute inflammatory infiltrate, tumor associated macrophages
Invasion
- Deep infiltration of adjacent structures such as trachea / larynx and esophagus, fibroadipose tissue and skin
- Vascular invasion
- Very rarely encapsulated (Thyroid 2020;30:1505)
Coexistent DTC (papillary thyroid carcinoma, follicular thyroid carcinoma, oncocytic carcinoma of thyroid) or poorly differentiated thyroid carcinoma (PDTC) (Thyroid 2020;30:1505, Ann Surg 2000;231:329)
Heterologous differentiation: bone, with or without cartilage
Common patterns: epithelioid / squamoid, spindle / sarcomatoid, giant cell and pleomorphic; occur singly or in combination (Endocr Pathol 2022;33:27)
- Epithelioid / squamoid: tumor nests with abundant eosinophilic cytoplasm, appear squamoid, may show keratinization
- Spindle / sarcomatoid: malignant spindle cells simulating pleomorphic sarcoma
- Pleomorphic: highly pleomorphic tumor cells, having bizarre nuclei and prominent nucleoli, some with multiple nuclei
- Giant cell: numerous multinucleated giant cells, which can be cancer cells or macrophages
Rare patterns (Endocr Pathol 2022;33:27)
- Squamous cell carcinoma pattern
  - Focal or diffuse squamous phenotype (previously primary squamous cell carcinoma of thyroid) (Endocr Pathol 2022;33:27)
- Paucicellular
  - Mimics Riedel thyroiditis
  - Abundant fibrotic stroma, chronic inflammatory cell infiltrate
  - Few atypical spindle cells
- Angiomatoid
  - Irregular channels within tumor cell islands mimicking blood vessels
  - May contain red blood cells
  - Mimics angiosarcoma
- Rhabdoid
  - Rhabdoid cells
  - Eccentric nucleus, paranuclear inclusion, prominent nucleoli
- Lymphoepithelioma-like
  - Sheets of tumor cells infiltrated by dense infiltrate of lymphocytes and plasma cells (Int J Endocrinol 2014;2014:790834)
  - Mimics intrathyroidal thymic carcinoma

Microscopic (histologic) images

Contributed by Shipra Agarwal, M.D., Shuanzeng Wei, M.D., Ph.D., Stephen J. Schultenover, M.D. and AFIP

Malignant spindle cells

Nuclear hyperchromasia and pleomorphism

Squamoid cells

Tumor giant cells

Angiomatoid pattern

Neck muscle infiltration

Angioinvasion

Associated papillary thyroid carcinoma

Anaplastic carcinoma and adjacent papillary thyroid carcinoma

Anaplastic carcinoma with necrosis and inflammation

Malignant spindle cells

AE1 / AE3

CK903

Keratin stains many mesenchymal-like tumor cells

Thyroglobulin stain

Virtual slides

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Epithelioid pattern, ATC

Sarcomatoid pattern, ATC

Cytology description

Cellular or less commonly, sparse aspirate (Endocr Pathol 2022;33:27)
Marked nuclear pleomorphism
Epithelioid and spindle cells, osteoclast-like tumor giant cells
Necrosis
Mixed with acute inflammatory cells
DTC component may be present
Usually classified as Bethesda VI

Cytology images

Contributed by Shipra Agarwal, M.D. and Ayana Suzuki, C.T.

Necroinflammatory
background

Atypical mitoses

Epithelioid pattern

Sarcomatoid variant

Differentiated thyroid carcinoma component

Pleomorphism

Positive stains

PAX8
- Immunopositivity varies with the histologic pattern: up to 100% of the squamoid and 50 - 60% of the sarcomatoid (Semin Diagn Pathol 2015;32:305)
- More likely to be positive in the presence of a DTC component
- Higher rate of positivity (60 - 80%) with less specific polyclonal antibody (Hum Pathol 2011;42:1873)
- ~50 - 60% when using monoclonal antibody (Virchows Arch 2020;476:431)
Cytokeratin (50 - 70%) (Thyroid 2020;30:1505)
Aberrant p53 expression (Thyroid 2020;30:1505)
BRAF VE1 antibody detects BRAF V600E mutant protein (Cancers (Basel) 2020;12:596)
Ki67 labeling index > 30%, often > 50%
Epithelial membrane antigen and vimentin are frequently positive but have no role in diagnostic workup

Negative stains

Markers of thyroid follicular cells: TTF1 and thyroglobulin
- Positive in coexisting DTC and PDTC, if present
Markers of parafollicular cells: calcitonin, chromogranin, synaptophysin
CD45
S100, HMB45, melanA
CK20
Reference: Semin Diagn Pathol 2015;32:305

Molecular / cytogenetics description

Genes involved in MAP kinase pathway
- BRAF V600E (40 - 70%) (Thyroid 2021;31:337)
- RAS mutations (15 - 40%)
TERT promoter mutations (55 - 75%) (Endocrinol Metab Clin North Am 2019;48:269)
E1F1AX mutation (10%) (Thyroid 2021;31:337)
Mutations of MMR genes (MLH1, PMS2, MSH2 and MSH6) (5 - 10%) (Thyroid 2021;31:337)
Mutations of DNA repair genes: ATM mutation (10%) (Thyroid 2020;30:1505, Thyroid 2021;31:337)
Mutations involving tumor suppressor genes
- TP53 mutation (30 - 70%) (Endocrinol Metab Clin North Am 2019;48:269, Thyroid 2021;31:337, Endocr Pathol 2016;27:205)
- NF2 mutation (12%) (Thyroid 2020;30:1505, Clin Cancer Res 2018;24:3059)
- NF1 mutation (10%)
- RB1 mutation (10%)
- MEN1 mutation
Alterations in cell cycle genes (CDKN2A, CDKN2B, CCNE1) (Thyroid 2020;30:1505, Clin Cancer Res 2018;24:3059)
Mutations in genes of PI3K / AKT pathway
- PIK3CA mutations (10 - 20%) (Endocr Pathol 2022;33:27, Thyroid 2021;31:337)
- PTEN mutation (10 - 15%)
- AKT1, AKT2 mutations (< 5%)
Gene fusions: RET, NTRK
ALK mutations, ALK fusions

Molecular / cytogenetics images

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Hierarchical clustering

Genetic alterations

Involved molecular pathways

Recurrent MSK-IMPACT derived copy number alterations

Increased mutation burden

Videos

Cytology of ATC

Management of ATC

Sample pathology report

Thyroid, total thyroidectomy:
- Anaplastic thyroid carcinoma, epithelioid pattern, 12 cm, replacing the entire specimen (see synoptic report)
- It is dedifferentiating from papillary thyroid carcinoma, classical subtype
- Gross extrathyroidal extension into adjoining skeletal muscles
- Multiple lymphovascular emboli and perineural invasion are present
- 4 of the 5 lymph nodes dissected from the specimen are involved by tumor
- AJCC stage IVB (pT3bN1Mx)
- Immunohistochemically, the tumor cells are positive for pan-CK, PAX8, VE1 and p53 but are negative for TTF1 and TG; the Ki67 labeling index is 35%
Thyroid, needle biopsy:
- Anaplastic thyroid carcinoma, spindle cell pattern
- Immunohistochemically, the tumor cells are positive for pan-CK, vimentin and p53 but are negative for PAX8, p40 and VE1; the Ki67 labeling index is 55%
- Findings corroborate with but are not specific for the above diagnosis; a clinicoradiological correlation is advised
Thyroid, fine needle cytology:
- Malignant (Bethesda diagnostic category VI): anaplastic thyroid carcinoma, pleomorphic pattern
- Immunohistochemistry performed on cell block shows that the tumor cells are positive for pan-CK and PAX8 but are negative for VE1
- The findings corroborate with but are not specific for the above diagnosis; a clinicoradiological correlation is advised

Differential diagnosis

Poorly differentiated thyroid carcinoma (Thyroid 2021;31:337, Nat Rev Endocrinol 2017;13:644):
- Small uniform cells arranged as nests and trabeculae
- Lesser nuclear pleomorphism, atypia and mitotic activity
- Patchy necrosis thyroglobulin, TTF1 positive
Riedel thyroiditis:
- Absent atypia, mitoses
Squamous cell carcinoma of head and neck:
- Absent DTC component
- Site specific clinical features and radiology
- PAX8 negative
Medullary thyroid carcinoma:
- Amyloid
- Stippled chromatin
- Chromogranin, synaptophysin, calcitonin, carcinoembryonic antigen immunopositivity
Non-Hodgkin lymphoma:
- LCA positive and cytokeratin negative
- Lineage specific immunoprofile
- Absent DTC component
Squamous metaplasia in differentiated thyroid tumors and chronic thyroiditis:
- Absence of nuclear pleomorphism, mitosis, necrosis and a large invasive front
- Low Ki67 index, usually
- Angiosarcoma:
  - PAX8 negative
  - Absent DTC component
- Pleomorphic sarcoma:
  - Cytokeratin and PAX8 negative
  - Lineage specific immunoprofile
  - Absent DTC component
- Spindle epithelial tumor with thymus-like differentiation (SETTLE):
  - Less pleomorphism
  - Smooth muscle actin positive
- Intrathyroid thymic carcinoma (CASTLE; carcinoma showing thymus-like element):
  - Less pleomorphism
  - Vesicular nuclei
  - CD5, CD117 positive
- Metastatic carcinoma:
  - Usually PAX8 negative, unless originated from PAX8 positive tissue (kidney)
  - Primary site specific immunoprofile
  - Absent DTC component
- Metastatic malignant melanoma:
  - PAX8 negative
  - S100, HMB45, melanA positive
  - Absent DTC component

Board review style question #1

Anaplastic thyroid carcinoma
Follicular thyroid carcinoma
Metastatic carcinoma to thyroid gland
Papillary thyroid carcinoma
Spindle epithelial tumor with thymus-like differentiation

Board review style answer #1

A. Anaplastic thyroid carcinoma. Anaplastic thyroid carcinoma typically presents with a short duration history of a rapidly enlarging neck mass, with symptoms secondary to compression of adjacent structures, such as pain, dysphonia, dysphagia, dyspnea and cough. Lymph node and distant metastases are common. Cytological examination reveals a pleomorphic tumor cell population, including bizarre forms, dispersed in a necrotic and inflammatory background. Mitotic activity is frequent and atypical mitotic forms common. Answer B is incorrect because follicular thyroid carcinoma, on cytology, shows a microfollicular architecture and lacks marked cellular pleomorphism and extensive necrosis. Answer C is incorrect because the clinical presentation of hoarseness of voice, a rapidly enlarging neck mass and radiology revealing distant metastases are indicative of a thyroid primary. Answer D is incorrect because papillary thyroid carcinoma, on cytological evaluation, lacks cellular pleomorphism and extensive necrosis. Instead, classic papillary thyroid carcinoma shows follicular cells arranged as papillae, sheets and fragments showing typical nuclear features. Answer E is incorrect because spindle epithelial tumor with thymus-like elements is characterized by low grade spindle cells and an amyloid-like material with or without an epithelial component.

Comment Here

Reference: Anaplastic thyroid carcinoma

Board review style question #2

TTF1 negative, thyroglobulin negative, CD5 positive, CD117 positive
TTF1 negative, thyroglobulin negative, PAX8 positive, cytokeratin positive
TTF1 negative, thyroglobulin negative, S100 positive, HMB45 positive
TTF1 positive, thyroglobulin negative, PAX8 negative, calcitonin positive
TTF1 positive, thyroglobulin positive, PAX8 positive, vimentin negative

Board review style answer #2

B. TTF1 negative, thyroglobulin negative, PAX8 positive, cytokeratin positive. Anaplastic thyroid carcinoma (ATC) is usually immunonegative for TTF1 and thyroglobulin but expresses PAX8; cytokeratin is variably positive. Answer E is incorrect because vimentin can also be variably positive in ATC but in this case thyroglobulin is positive as well. Answer D is incorrect because calcitonin is immunopositive in medullary thyroid carcinoma. Answer A is incorrect because CD5 and CD117 are positive in intrathyroidal thymic carcinoma. Answer C is incorrect because S100 and HMB45 are positive in malignant melanoma.

Comment Here

Reference: Anaplastic thyroid carcinoma

Anatomy

Table of Contents

Definition / general

Thyroid gland is a bilobed organ in the lower half of anterior neck, which is composed of two bulky lateral lobes joined by a thin isthmus
Location
- Anterior region of the neck, midway between thyroid cartilage and suprasternal notch (level of C5 - T1 vertebrae)
- Immediately anterior to larynx and trachea, being attached to anterior trachea by loose connective tissue
- Two lobes lie on both sides of larynx and trachea, reaching the lower halves of thyroid cartilage and covering II - IV tracheal rings
- Isthmus lies across the trachea anteriorly, below the level of cricoid cartilage (II - III tracheal rings)
Shape of adult thyroid resembles a butterfly or a capital H, with each lobe having pointed upper and blunted lower poles
Practical implications for pathologists
- Grossing of surgical thyroid specimens, which are submitted as a single lobe (lobectomy), lobe with isthmus (hemithyroidectomy) or the whole gland (total thyroidectomy); other procedures are subtotal thyroidectomy and neck dissection
- Evaluation of the organ on autopsy
- Thyroid FNA by interventional cytopathologist, often combined with ultrasound
Historical aspects
- English name for thyroid gland is derived from the Greek thyreoeidos (Thyreos = shield, eidos = form); German word Schilddrüse means "shield gland"
- Leonardo Da Vinci (1452 - 1519) is credited as the first to draw thyroid gland as an anatomical organ, although "glands" in the neck corresponding to the thyroid (mainly pathologically enlarged) were known for thousands of years (Clin Anat 2011;24:1)
- The gland was named thyroid by Thomas Wharton (1614 - 1673) because of its proximity to the thyroid cartilage (Wharton, Adenographia: sive glandularum totius corporis descriptio)

Diagrams / tables

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Thyroidectomy

Relationship to other structures

Pyramidal lobe

Development of inverted U shaped thyroid gland

Anatomical variations

Blood supply

Clinical features

Anatomical relationships

Thyroid gland is enveloped by the middle layer of deep cervical fascia (false capsule), which forms a suspensory ligament (ligament of Berry) on the posterior surface; this ligament fixes the gland to the trachea and facilitates movement of thyroid during swallowing
Anterior surface of thyroid lobes and isthmus is covered by sternothyroid muscle
Medial surface is adjacent to superior trachea and larynx with thyroid cartilage
Lateral surface of both lobes is covered by sternothyroid muscle
Recurrent laryngeal nerves run in groove between trachea and esophagus behind the medial aspects of the lateral lobes
Common carotid artery, internal jugular vein and vagus, encased within the carotid sheath, course along the posterolateral aspects of the lateral lobes
Parathyroid glands are usually adjacent to posterior surface
Surgically important anatomical relations of thyroid are recurrent laryngeal nerve, parathyroid glands and external branch of laryngeal nerve and accidental injury of these structures during thyroid surgery may result in lifelong clinical consequences (Clin Anat 2012;25:19)

Variations

Mild thyroid developmental anomalies include pyramidal lobe, thyroglossal duct cysts and thyroid hemiagenesis (Pediatr Endocrinol Rev 2016;13:612)
Pyramidal lobe (lobe of Lalouette) is a vestige of the inferior portion of thyroglossal duct
- Narrow conical shaped projection of thyroid tissue extending upward from isthmus to hyoid bone and lying on the surface of thyroid cartilage (Surg Radiol Anat 2007;29:21)
- Present in approximately half of all thyroid glands, reported range 30% - 75% (Surg Radiol Anat 2007;29:21)
- Mean length 24 mm, with half of pyramidal lobes exceeding 20 mm (Rom J Morphol Embryol 2013;54:285)
- More frequently attached to the left side of the isthmus and even to the left lobe itself
- Usually appears as fibrous tract, but in pathologic conditions becomes prominent or cystic
- Thyroid tissue in pyramidal lobe is usually not active, hence is not visible on scintigraphy (Rom J Morphol Embryol 2013;54:285)
- Pyramidal lobe can be a source of recurrent disease if it is left behind during thyroid surgery
Rare structural abnormalities
- Small accessory thyroids derived from thyroglossal duct remnants can be found close to the normally located gland
- Absence of the isthmus with two independent lateral lobes has been reported in 5% - 30% (J Anat Physiol 1895;29:234, Singapore Med J 2008;49:831)
- Infrequent anatomic variants:
  - Posterior part is split into two distinct globes of thyroid tissue (5% of population, Netter: Endocrine System and Selected Metabolic Diseases, Vol 4, 1965)
  - Absence of a significant portion of a lateral lobe (< 1% of healthy individuals), frequently the lower half of the left lobe (De Groot: Endocrinology Adult and Pediatric: The Thyroid Gland, 6th edition, 2013)
  - Inverted U shaped thyroid (Indian J Otolaryngol Head Neck Surg 2014;66:224)
  - W shaped thyroid (J Clin Diagn Res 2014;8:AD03)
Levator muscle of thyroid gland (levator glandulae thyroideae of Soemmerring)
- Fibrous or fibromuscular band that stretches from pyramidal lobe or upper border of isthmus, usually on the left side, to the body of hyoid bone
- Origin is related to thyroglossal duct (can be considered as caudal extension/part of pyramidal lobe), may contain thyroid follicles
Tubercle of Zuckerkandl
- Posterior extension of the lateral edge of thyroid lobe that stems from the fusion of the lateral and median thyroid anlages (Clin Anat 2012;25:19)
- Appears as focal enlargement from a slight thickening to 1 cm or larger nodular structure
- Can be found on either side or bilaterally in 60% - 95% of thyroidectomies (World J Endoc Surg 2014;6:110)
- Helpful surgical landmark for identification of recurrent laryngeal nerve, which runs medially, sometimes in a cleft between the tubercle and lateral lobe
- Superior parathyroid gland is commonly found just cephalad to the tubercle

Blood supply

Thyroid is extremely vascular
Arterial supply is derived from the right and left superior thyroid arteries and the right and left inferior thyroid arteries
- Inferior thyroid artery (originates from thyrocervical trunk of the subclavian artery) approaches base of the gland and divides into superior and inferior branches to supply inferior and posterior surfaces of thyroid gland
- Smaller superior thyroid artery (arises from the external carotid) enters upper pole of the gland and divides into anterior and posterior branches to supply anterior, lateral and medial surfaces
- Arteria thyroidea ima is inconsistent (3% - 10%) and variable in terms of origin (from brachiocephalic trunk or aortic arch), size and area of supply
- Branches of arteries anastomose frequently on surface and within the gland
Venous drainage is through the superior, middle and inferior thyroid veins (form venous plexus in the thyroid capsule), which open into the internal jugular and brachiocephalic veins

Lymphatic drainage

Thyroid lymphatics originate from interfollicular spaces and form rich intraglandular (lying in the interlobular connective tissue) and subcapsular networks
Larger subcapsular collecting trunks leave the gland in close proximity to the veins and drain into the regional lymph nodes
- Pericapsular (perithyroidal) nodes
- Internal jugular chain nodes (e.g. subdigastric) draining superior portion of thyroid lobes and isthmus
- Pretracheal, paratracheal and prelaryngeal (including midline located Delphian node), draining inferior portion of the gland
- Recurrent laryngeal nerve chain nodes
- Retropharyngeal and retroesophageal lymph nodes
Bypass routes
- Anterosuperior mediastinal lymph nodes are secondary to the recurrent laryngeal nerve chain and pretracheal groups, but thyroid isthmus portion can be also drained directly into them (Ann Surg 1957;145:317)
- Thyroid lymphatics may empty directly with no intervening node into thoracic duct
Grouping of the thyroid draining lymph nodes according to the cervical lymph node levels (ordered by proximity)
- Level VI: pericapsular, paralaryngeal, paratracheal, prelaryngeal and recurrent laryngeal chain
- Levels III - IV: internal jugular (also known as deep cervical)
- Level VII: superior mediastinal
- Level I: submandibular and submental
Anatomy of thyroid lymphatics explains patterns of spread of thyroid cancer
- Abundant network of intraglandular lymphatics freely anastomosing between lateral lobes through the isthmus is responsible for the intrathyroidal spread common in papillary carcinoma
- Plexus of pericapsular lymph nodes and vessels permits the transfer of cancer cells from the surface of one part of the gland to another (Cancer 1963;16:1425)
- First extraglandular metastasis of papillary carcinoma occurs in paratracheal nodes, regardless of the location of the primary tumor
- In the early cancer stages, metastases are more frequent in the lower part of the neck, and in later stages, when lymphatic obstruction has occurred, metastases appear in upper (up to submandibular) nodes (Cancer 1970;26:1053)

Innervation

Thyroid gland receives only a few nerve fibers compared to other visceral organs
Innervated from superior, middle and inferior cervical sympathetic ganglia
- Adrenergic nerve fibers may influence thyroid secretion indirectly via vasomotor effects (J Endocrinol Invest 1978;1:175)
- Presence of adrenergic receptors in follicular cells and a network of adrenergic nerve terminals near follicular basement membrane suggest direct sympathetic regulation of thyroid secretion (Endocrinology 1975;97:1123)
Cholinergic nerve fibers derived from vagus are also found, suggesting a role of parasympathetic nervous system in the regulation of thyroid activity (e.g. C cells in chicken are surrounded by rich cholinergic network, Am J Anat 1988;182:353)
Overall impact of nervous system on thyroid secretion is negligible compared to hypothalamic-pituitary axis (via TSH)
Small paraganglia are normally present close to thyroid and occasionally found beneath thyroid capsule, which explains origin of peri- and intrathyroidal paragangliomas

Clinical images

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On surgery

In situ

Inverted U shaped thyroid

W shaped thyroid

Zuckerkandl tubercle

Gross description

Weight
- Normal adult weight in non-endemic area is 15 - 20 g (M > F), increase over 50 g is likely abnormal (Health Phys 1985;49:1097, Ann ICRP 2002;32:5)
- Depends on gender (heavier in women during secretory phase of menstrual cycle), body weight and iodine intake (iodine deficiency is a main cause of goiter)
- Increases in childhood and adolescence (weight doubles from 5 to 10 years and from 10 to 20 years), also during pregnancy; shrinks in elderly (Health Phys 1963;9:1299, Ann ICRP 2002;32:5)
- Children
  - Normal weight in newborn is 1 - 3 g, 5 g is borderline for goiter (Acta Obstet Gynecol Scand 1948;28:1, Virchows Arch Pathol Anat Physiol Klin Med 1964;338:30)
  - Tables with a weight of fetal thyroid in relation to gestational age and body weight are available (Anat Rec 1964;148:123, Anat Rec 1971;171:227, Pediatr Dev Pathol 2002;5:559)
Size
- Each lateral lobe is 4 - 6 cm long, 2 - 3 cm wide and 1.5 - 2 cm deep (anteroposterior)
- Isthmus is about 1.25 cm in greatest transverse and vertical dimensions and 0.5 cm thick
- Right lobe is usually larger than the left one (up to twice), isthmus may be exceptionally wide (De Groot: Endocrinology Adult and Pediatric: The Thyroid Gland, 6th Edition, 2013)
- Easily estimated by sonography along with thyroid volume (10 - 15 ml)
- Most thyroid diseases have significant alterations in these measurements
Thyroid parenchyma is reddish brown in color
- Coal black stain due to pigment accumulation can be noted in elderly individuals (Mills: Histology for Pathologists, 4th Edition, 2012)
Homogenous firm consistency
- 10% of endocrinologically normal adults have asymptomatic grossly identified thyroid nodules (J Clin Pathol 1986;39:475)
Thin fibrous capsule is firmly attached to the surface and produces septa, which incompletely divide parenchyma into lobules (thyromeres)

Gross images

Images hosted on other servers:

Surgical specimen

Levator glandulae thyroideae

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Pyramidal lobe

Videos

Thyroid anatomy

Additional references

Websites

Books

Presentation

Clinical anatomy of the thyroid and adrenal glands by Lawrence M. Witmer, PhD (Ohio University)

Anatomy & histology-parathyroid

Table of Contents

Definition / general

Endocrine organs composed of 4 glands, located in close relationship to the posterior aspects of the thyroid lobes
- Superior glands are usually located at the cricothyroid junction, derived from the fourth branchial pouches, together with thyroid
- Inferior glands are close to the point where the inferior parathyroid artery crosses the recurrent laryngeal nerve, derived from fourth branchial pouches, together with the ultimobranchial bodies (Kierszenbaum: Histology and Cell Biology - An Introduction to Pathology, 4th Edition, 2016)
Number varies from 2 to 12, including ectopic (39.3%) and supernumerary (6.5%) glands (World J Surg 2011;35:1260)
Ectopic parathyroid glands may be found anywhere along pathway of descent of branchial pouches: thymus (30%), anterior mediastinum (20%), thyroid (20%) or thyrothymic ligament (15%) (Exp Clin Endocrinol Diabetes 2012;120:604, Am J Surg 2006;191:418)
Discovered in 1880 by Ivar Sandström, a Swedish medical student (Am J Surg Pathol 1996;20:1123)

Essential features

4 tiny glands located on the posterior surface of the thyroid
Histologically composed of a parenchyma of chief cells, oxyphils and transitional cells, and stromal fat
Regulate calcium homeostasis through synthesis and secretion of parathyroid hormone (PTH)

Terminology

Glandulae parathyroidae (by Ivar Sandström, 1880), Epithelkörperchen (by Kohn, 1895)

Physiology

Genes involved in differentiation and growth of parathyroid glands
- Transcription factors: Hoxa3, Pax9, Pax1, Tbx1, Gcm2, Eya1, GATA3, SOX3, AIRE1
- Growth factors and their signaling pathways (Fgf8, BMPs, Chordin, TGFβ, Shh, Tbce) regulate migration of the pharyngeal pouch endoderm, its interaction with the mesenchyme and the balance between proliferation and apoptosis (Dev Biol 1998;195:1, Genes Dev 1998;12:2735, Endocrinol Metab Clin North Am 2018;47:733)
Synthesis and secretion of parathyroid hormone (PTH), an 84 amino acid peptide derived from a large precursor of 115 amino acids (preproPTH); only the 34 N terminal amino acids have biologic activity (J Endocrinol 2005;187:311)
Main function of PTH is regulation of serum calcium which mediated by the calcium sensing receptor (CaSR); hypocalcemia activates CaSR, inducing increased PTH synthesis and secretion (Biochem Biophys Res Commun 1995;214:524, Proc Natl Acad Sci USA 1995;92:131)
PTH acts by increasing calcium resorption into blood from bone, kidney and the gut
- Acting on the PTH receptor (PTHR1) that stimulates renal tubular reabsorption of calcium
- Enhances calcitriol formation in kidney by stimulating 1α vitamin D hydroxylase to convert 25(OH) vitamin D to 1α25(OH)2 vitamin D, resulting in increased gut absorption of calcium
- Prolong life and increase activity of osteoblast, while osteoblast signaling activates osteoclasts, indirectly causing bone resorption; PTH activates osteocytes, causing lysis of perilacunar bone (Mills: Histology for Pathologists, 5th Edition, 2020)

Diagrams / tables

Images hosted on other servers:

Embryological pathway of parathyroid migration

Anatomy

Laboratory

Serum intact PTH concentration is 23 (15 - 31.6) pg/mL (Horm Res Paediatr 2015;84:124)

Gross description

Small, smooth, soft, flattened ovoid or bean shaped structures (4 - 6 mm long, 3 - 4 mm wide, 1 - 2 mm thick), yellow-tan
Each gland weighs ~30 - 40 mg but can also extremely variable; inferior glands are slightly larger
- 60 mg is the upper limit of normal weight for a parathyroid gland, although weight > 40 mg can be considered abnormal (J Am Coll Surg 2006;203:758)
Parenchyma is yellow to orange-tan depending on the amount of stromal fat, percent of oncocytic cells and vascularity
Reference: Lindberg: Diagnostic Pathology - Normal Histology, 3rd Edition, 2022

Gross images

Contributed by Truong Phan Xuan Nguyen, M.D.

Normal parathyroid gland

Frozen section description

Parathyroids often sent for intraoperative consultation: 1) identification of parathyroid tissue to preserve the glands in situ or for autotransplantation to avoid postoperative hypoparathyroidism and 2) evaluation during surgery for primary hyperparathyroidism to verify abnormal glands
Parathyroid to be differentiated from fat, lymph nodes, thymus, thyroid and other tissue (Arch Pathol Lab Med 2005;129:1575)
Parathyroid consists of a mixture of parenchymal cells (chief, oxyphil) and fat
Near infrared fluorescence imaging with indocyanine green imaging is a useful tool for intraoperative detection of parathyroid by surgeon (In Vivo 2020;34:23)

Microscopic (histologic) description

Thinly encapsulated with fibrous septa extending into parenchyma dividing gland into vague lobules
Parenchyma has 3 cell types: chief cells, oxyphils and transitional cells; these are all variants of the chief cells that have differing degrees of oncocytic change
- Parenchymal cells arranged in nests and cords
Chief cells
- Functional cells, responsible for the synthesis and secretion of PTH
- 8 - 12 μm in diameter, round to polygonal with centrally located nuclei, coarse chromatin and small nucleoli
- Cytoplasm varies from clear to amphophilic or faintly eosinophilic
  - Clear vacuolated appearance is due to accumulation of glycogen or lipid
- Arranged in small nests and thin cords and separated by stromal adipose tissue
Oxyphil cells
- Typically appear at puberty and increase in number with age
- Larger than chief cells, measuring 12 - 20 μm in diameter
- Singly, in small clusters or as large nodules and sheets
- Abundant granular eosinophilic cytoplasm due to the accumulation of numerous mitochondria
Transitional cells
- Intermediate forms that have features of chief cells and partial oncocytic change
Water clear cell
- Found in the fetal gland but are not present in normal adult glands
- Found usually only in pathologic states (hyperplasia and adenoma)
- Very large, measuring 15 - 20 μm and up to 40 μm
- Represent chief cells with excessive cytoplasmic glycogen
May have cysts and follicles filled with proteinaceous material that resembles colloid of the thyroid gland
- Positive with periodic acid-Schiff (PAS)
- Do not contain birefringent calcium oxalate crystals (polarized light)
Stroma comprised of stromal fat cells and fibroconnective tissue with rich vascular supply
- Amount of stromal fat tends to be higher in women (Mills: Histology for Pathologists, 5th Edition, 2020)
Age related changes: increased stromal fat cells, accumulation of fibroconnective tissue, more oxyphils
Reference: Lindberg: Diagnostic Pathology - Normal Histology, 3rd Edition, 2022

Microscopic (histologic) images

Contributed by Truong Phan Xuan Nguyen, M.D.

Normal parathyroid gland

Chief cells

Oxyphil cells

Transitional cells

Water clear cells

Colloid type material, without oxalate crystals

Virtual slides

Images hosted on other servers:

Parathyroid gland

Frozen section

Positive stains

Histochemistry
- PAS (chief cells contain abundant glycogen, colloid-like material in cysts and follicles)
- Oil red O (chief cells contain intracytoplasmic lipid droplets - frozen section)
Immunohistochemistry
- Neuroendocrine lineage: synaptophysin (cytoplasmic), chromogranin A (cytoplasmic)
- GATA3 (nuclear), GCM2 (nuclear), PTH (cytoplasmic) (distinguish parathyroid cells from other neuroendocrine cells) (Endocr Pathol 2018;29:113)
- Polyclonal PAX8 (nuclear), CK AE1 / AE3, CK7, CK8/18, CK19 (cytoplasmic)

Negative stains

Thyroid specific markers: TTF1, thyroglobulin (Endocr Pathol 2018;29:113)
Calcitonin and calcitonin gene related peptide (usually) (Endocr Patho 2019;30:168)
Monoclonal PAX8, PGP9.5, neurofilaments

Electron microscopy description

Chief cells: contain relatively few secretory granules
Oxyphil cells: the cytoplasm is filled with numerous mitochondria
Transitional cells: have fewer mitochondria than fully developed oncocytic cells but more than chief cells
Reference: Mills: Histology for Pathologists, 5th Edition, 2020

Electron microscopy images

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Parathyroid gland

Videos

Histology of parathyroid

Board review style question #1

Which cell type of parathyroid glands is round to polygonal with centrally located nuclei, coarse chromatin, small nucleoli and cytoplasm that ranges from clear to amphophilic or faintly eosinophilic?

Chief cell
Oxyphil cell
Transitional cell
Water clear cell

Board review style answer #1

A. Chief cell. These features are suitable for the chief cell's function of producing and releasing PTH hormone. Answer B is incorrect because oxyphil cells have granular eosinophilic cytoplasm. Answer C is incorrect because transitional cells have partial features of chief cells and oxyphil cells. Answer D is incorrect because water clear cell has foamy cytoplasm.

Comment Here

Reference: Anatomy & histology - parathyroid

Board review style question #2

In which type of parathyroid glands are water clear cells found?

Ectopic glands
Fetal glands
Normal adult glands
Supernumerary glands

Board review style answer #2

B. Fetal glands. Water clear cells are usually found in fetal parathyroid glands with excessive cytoplasmic glycogen. Answers A, C and D are incorrect because they only comprise 3 cell types (chief cells, oxyphil cells and transitional cells) of normal adult parathyroid glands.

Comment Here

Reference: Anatomy & histology - parathyroid

Angiosarcoma

Table of Contents

Definition / general

Seen in elderly in Alpine regions of Europe, where tumor may comprise 16% of thyroid malignancies, due to high prevalence of iodine deficient goiter
Non-Alpine tumors are rare

Clinical features

Thyroid mass
Compression symptoms
Symptoms related to distant metastasis

Prognostic factors

Often poor prognosis due to persistent local disease and distant metastases (Am J Clin Pathol 1994;102:322)
May have favorable prognosis if confined to thyroid at surgery (Virchows Arch 1996;429:131)

Case reports

38 year old woman with juxtathyroidal neck soft tissue angiosarcoma (Thyroid 2002;12:427)
64 year old man with coexistent angiosarcoma and follicular carcinoma of the thyroid (J Korean Med Sci 2003;18:908)
73 year old woman from an non-Alpine area with epithelioid angiosarcoma of thyroid (Endocr Pathol 2015;26:152)
74 and 86 year old men with epithelioid angiosarcoma involving the thyroid (Arch Pathol Lab Med 2003;127:E70)
Two cases of epithelioid angiosarcoma of the thyroid gland (Arch Pathol Lab Med 1994;118:642)
Metastatic angiosarcoma to the thyroid (Rev Laryngol Otol Rhinol (Bord) 2005;126:111)

Gross description

Single nodule commonly filled with bloody fluid, compressing thyroid

Gross images

AFIP images

Necrotic and hemorrhagic tumor

Microscopic (histologic) description

Pleomorphic tumor, usually poorly differentiated, with irregular slit vascular spaces with anastomosing channels or discrete cytoplasmic vacuoles
Epithelioid variant has poorly circumscribed growth in sheets / cords, intracytoplasmic lumina filled with RBCs; composed of polygonal epithelioid cells with abundant eosinophilic cytoplasm, vesicular nuclei, prominent amphophilic-basophilic nucleoli

Microscopic (histologic) images

AFIP images

Solid and cellular areas

Abortive vascular lumina

Keratin+ tumor cells

Vimentin+

Plump endothelial, Factor VIII+

Ulex europaeus I lectin+

Type IV collagen stains basal lamina

Cytology description

Cellular smear with single cells and small clusters of oval and round tumor cells
Cell borders are indistinct and cytoplasm is vacuolated
Nuclei are eccentric with coarse chromatin, irregular membranes and a single, prominent nucleoli
Also features suggestive of intracytoplasmic lumens (Acta Cytol 2002;46:767)

Positive stains

Vimentin, factor VIII, CD31, CD34, variable cytokeratin (Am J Surg Pathol 1990;14:737) and Ulex europaeus agglutinin I

Negative stains

Thyroglobulin, calcitonin, SMA

Differential diagnosis

Anaplastic carcinoma or other carcinoma with angiosarcomatous foci: negative for endothelial markers (Am J Surg Pathol 1990;14:69, Am J Clin Pathol 1986;86:674, Diagn Cytopathol 2007;35:424)
Metastatic angiosarcoma
Reactive endothelial hyperplasia (Masson Tumor)

Aplasia / hypoplasia

Table of Contents

Definition / general

Total or partial absence of thyroid gland
Most common cause of congenital hypothyroidism
First well documented cases of absent thyroid as a cause of cretinism were presented by Curling in 1850 (Med Chir Trans 1850;33:303); thyroid hemiagenesis and hypoplasia were first described by Jones in 1852 (The Cyclopaedia of Anatomy and Physiology, Vol 4)
400+ cases of thyroid hemiagenesis have been reported to date

Terminology

Thyroid aplasia is the total absence of thyroid gland in orthotopic (normal place) and ectopic locations
- Synonyms: athyreosis / athyrosis, thyroid agenesis
  - Outdated: athyreotic cretinism, cryptothyroidism
- True athyreosis is diagnosed only if serum thyroglobulin is undetectable
- Term "apparent athyrosis" describes patients with no functional thyroid tissue on thyroid scans, but demonstration of a thyroid gland remnant (ectopia or severe hypoplasia) by ultrasound or serum thyroglobulin
Hemiagenesis is a failure in the formation of one lobe of the thyroid (i.e. hemiaplasia)
- Thyroid hemiagenesis is included in the group of mild thyroid developmental anomalies along with thyroglossal duct cysts and pyramidal lobe (Pediatr Endocrinol Rev 2016;13:612)
Hypoplasia is incomplete development of orthotopic thyroid
Thyroid dysgenesis (dysthyroidosis, thyroid dysgenetic disorder) is a collective term for various anomalies in the anatomic development of the thyroid, including thyroid gland proper abnormalities (agenesis, hemiagenesis and hypoplasia) and ectopic thyroid tissue

Epidemiology

Congenital anomalies of the thyroid are uncommon, with a prevalence of 1.4 cases per 1000 (J Pathol 1989;159:135)
Relative frequency of ectopic thyroid tissue is slightly more common than anatomic abnormalities of eutopic thyroid gland; however it is often subclinical
Athyreosis : Thyroid hypoplasia : Thyroid hemiagenesis = 15:5:1, with collective prevalence 1 per 3 to 4,000 live births (Braverman, Cooper: Werner & Ingbar's The Thyroid, 10th Edition, 2012, N Engl J Med 1981;304:702)
Thyroid dysgenesis accounts for 80% - 85% of cases of primary (i.e. due to thyroid gland disorder) congenital hypothyroidism (OMIM, #218700):
- Congenital hypothyroidism is the most common congenital endocrine / metabolic disorder with estimated prevalence 1 per 1,600 to 3,500 newborn infants (depends on TSH cutoff); incidence is increasing (Nat Rev Endocrinol 2011;8:104)
- Another major cause of congenital hypothyroidism is thyroid dyshormonogenesis, caused by defects in thyroid hormone biosynthesis and manifested as goiter
Dysgenesis is more common in females than in males (3:1), Asians > Hispanics > Whites > Blacks (Stocker, Dehner, Husain: Stocker and Dehner's Pediatric Pathology, 3rd Edition, 2010, Thyroid 2011;21:13)
Thyroid dysgenesis is mainly sporadic, but up to 2% can be familial (N Engl J Med 2000;343:441)
Thyroid hypoplasia, absence of isthmus and lobe were reported in DiGeorge syndrome

Sites

Most cases of hemiagenesis show absence of the left lobe with a left:right ratio of 4:1 (J Clin Endocrinol Metab 1981;52:247)
Thyroid hemiagenesis has several variations: absent lobe, absent lobe and isthmus, absent isthmus, absent both lateral lobes with remaining isthmus

Pathophysiology

The absence of thyroid tissue may reflect failure of thyroid follicular cell precursors to survive due to defective expression of main thyroid transcription factors (TTF1, TTF2, PAX8), which results in inability to initiate formation of the medial anlage or maintain it during growth and migration (Endocrinol Metab Clin North Am 2016;45:243)
Genes associated with thyroid gland dysgenesis include those causing nonsyndromic congenital hypothyroidism (mutations of TSHR are the most common genetic cause of dysgenesis and hypothyroidism) and those causing syndromic / multiorgan congenital hypothyroidism (NKX2.1, FOXE1, PAX8, NKX2.5) (J Med Genet 2005;42:379)
Most cases of thyroid dysgenesis are explained by non Mendelian mechanisms, such as epigenetic modifications, somatic mutations occurring early in embryogenesis in the thyroid bud, or stochastic developmental events (Best Pract Res Clin Endocrinol Metab 2014;28:133)
A two hit model combining germline and somatic (epi)genetic variation has been proposed (Endocr Dev 2007;10:29)
Familial cases are caused by germline mutations in genes involved in thyroid development (NKX2.1, FOXE1, PAX8, GLIS3) and growth (TSH receptor):
- Bamforth-Lazarus syndrome, characterized by thyroid agenesis, spiky hair and choanal atresia, is associated with mutation of FOXE1 gene encoding TTF2 (Nat Genet 1998;19:399)
- No specific gene defect has clearly emerged yet as the cause of familial cases of thyroid hemiagenesis (Pediatr Res 2005;57:908)
- Defects of any gene which controls thyroid development and function can result in hypoplasia
- Familial cases show dominant inheritance with variable penetrance (N Engl J Med 2000;343:441)
Hypothyroid state develops gradually from the "in utero" period, when it is partially compensated by transplacental transfer of maternal thyroid hormones, to the postnatal period, when infants are completely dependent on their own thyroid function (Best Pract Res Clin Endocrinol Metab 2014;28:133)
The risk of congenital hypothyroidism is 0.5% to 1% for subsequent siblings and for the offspring of the affected child (Braverman, Cooper: Werner & Ingbar's The Thyroid, 10th Edition, 2012)

Diagrams / tables

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PAX8 mutation in thyroid hypoplasia

Clinical features

Athyreosis and severe hypoplasia manifest as congenital hypothyroidism:
- Jaundice, lethargy, macroglossia
- Signs are often subtle and not present at birth (> 90% infants)
- Growth and developmental delay are usually apparent by 4 - 6 months
The biochemical severity of the hypothyroidism tends to be greater in infants with true athyreosis than in those with thyroid hypoplasia or ectopy
Hemiagenesis rarely causes hypothyroidism and is usually detected incidentally:
- Most individuals are euthyroid (Thyroid 2008;18:637)
- Patients with thyroid hemiagenesis have increased risk of concomitant thyroid disease, e.g. nodular and autoimmune (Eur J Endocrinol 2010;162:153)

Diagnosis

Use thyroid function tests, scintigraphy and ultrasound
Screening for neonatal hypothyroidism was established on a worldwide basis in 1970s, now it is acclaimed as the most successful pediatric screening test
Serum TSH and free T4 should be measured in all newborns with abnormal screening results or suspected clinically to have hypothyroidism
Scintigraphy in pediatric practice is more sensitive than ultrasound, but both imaging techniques are recommended to complement each other (Eur J Endocrinol 2012;166:43)
If thyroid gland is not found on pediatric autopsy, serial sectioning along thyroglossal duct (especially in the posterior lingual-sublingual region) is warranted to identify ectopic thyroid tissue (Khong, Malcomson: Keeling's Fetal and Neonatal Pathology, 5th Edition, 2015)

Laboratory

Hypothyroidism: elevated TSH (> 50 mU/L), low T4, T3
Traces of serum thyroglobulin found in infants with radiologically undetectable thyroid help to differentiate ectopic or severely hypoplastic thyroid from true athyreosis (Clin Biochem 2004;37:818)

Radiology description

Thyroid scintigraphy is performed to distinguish different types of thyroid dysgenesis; it shows the isotope uptake, position and rough anatomic structure of the thyroid gland, although it is less helpful in assessing thyroid size and morphology (Eur J Endocrinol 2012;166:43)
In infants, scintigraphy with 99m Tc pertechnetate is favored over 123I (Pediatrics 2004;114:e683)
Thyroid sonography is noninvasive and no radioactivity is given, but it is less sensitive than scintigraphy in identifying small amounts of ectopic thyroid tissue; ultimobranchial remnants constitute a diagnostic trap, being often reported as small thyroid lobes (Pediatr Radiol 2010;40:725)
The onset of hypothyroidism can be estimated from an anteroposterior Xray of the knee; the absence of both the femoral and tibial epiphyseal centers in a term newborn suggests hypothyroidism of prenatal onset (Braverman, Cooper: Werner & Ingbar's The Thyroid, 10th Edition, 2012)

Prognostic factors

Early diagnosis and treatment (not later than 3 months of age) of hypothyroidism are critical to prevent neurological damage
Untreated congenital hypothyroidism inevitably progresses to severe neurodevelopmental impairment and infertility

Case reports

Athyreosis:

Two male siblings with thyroid agenesis, cleft palate and choanal atresia caused by mutation in FOXE1 / TTF2 gene (Nat Genet 1998;19:399)
Two male siblings with thyroid agenesis and cleft palate caused by mutation in FOXE1 / TTF2 gene (Hum Mol Genet 2002;11:2051)
Male infant with athyreosis associated with CHARGE syndrome (J Med Genet 1991;28:207)
Male infant with thyroid aplasia born from a mother treated with propylthiouracil during pregnancy (Endocr Regul 2012;46:27)
Infant with bilobar thyroid agenesis associated with accidental maternal I131 administration (Ann Endocrinol (Paris) 2013;74:62)
3 month old male infant with thyroid agenesis and phalangeal anomaly (J Pediatr Endocrinol Metab 2000;13:99)
2 year old girl with complete athyreosis (Clin Infect Dis 2000;31:196)
6 year old girl with athyreosis and prominent skeletal changes (Arch Dis Child 1962;37:543)

Hypoplasia

Female infant with Down syndrome and thyroid hypoplasia caused by mutation in PAX8 gene (Thyroid 2014;24:939)
Twin infants with thyroid hypoplasia as a cause of congenital hypothyroidism (J Clin Res Pediatr Endocrinol 2011;3:32)
Infants with familial congenital hypothyroidism due to TSH receptor mutation causing profound hypoplasia of the thyroid gland (J Clin Invest 1997;99:3018)
Familial case of thyroid hypoplasia caused by mutation of the TSH receptor gene (Thyroid 2001;11:977)
53 year old man with unsuspected congenital hypothyroidism due to thyroid hypoplasia (Medicina (B Aires) 2013;73:145)

Hemiagenesis

23 year old woman with thyroid hemiagenesis associated with Hashimoto thyroiditis (Case Rep Endocrinol 2013;2013:414506)
26 year old woman with thyroid hemiagenesis and ectopic lingual thyroid presenting as a goiter (J Laryngol Otol 2008;122:e17)
27 year old woman with thyroid hemiagenesis and severe hyperparathyroidism due to ipsilateral parathyroid adenoma (J Pak Med Assoc 2015;65:1022)
28 year old woman with thyroid hemiagenesis and postpartum silent thyroiditis (Intern Med 2004;43:306)
36 year old man with thyroid hemiagenesis, Graves disease and papillary thyroid cancer (Hormones (Athens) 2015;14:451)
37 year old man with thyroid hemiagenesis and ipsilateral fourth branchial cleft cyst (ANZ J Surg 2016 May 19 [Epub ahead of print])
40 year woman with thyroid hemiagenesis complicated by multinodular goiter (Acta Radiol Short Rep 2014;3:2047981614530286)
44 year woman with thyroid hemiagenesis accompanied by Graves disease and having a daughter with thyroid agenesis (Horm Res 2003;59:47)
49 year old woman with bilobar thyroid agenesis, hypertrophied isthmus and parathyroid adenoma (Surg Today 2015;45:787)
55 year old woman with an absent left thyroid lobe (Indian J Otolaryngol Head Neck Surg 2011;63:198)
Two cases of thyroid hemiagenesis associated with papillary and medullary thyroid cancer (Head Neck 2014;36:E106)

Treatment

Lifelong thyroid hormone replacement therapy for correction of hypothyroidism - the treatment of choice is T4
Treatment of presumed congenital hypothyroidism should be started immediately, regardless of imaging or confirmatory lab results, because every day of delay may result in loss of IQ (J Pediatr 2000;136:273)
If replacement therapy is commenced within the first 2 weeks of life, intellectual disability can be prevented in > 90% of children with congenital hypothyroidism (Nat Rev Endocrinol 2011;8:104)

Clinical images

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Phenotype of congenital hypothyroidism

Hemiagenesis on CT

Hemiagenesis on scintiscan

Hemiagenesis on sonography

Gross description

Agenesis: absence of thyroid gland in proper place or at any ectopic location
Hemiagenesis:
- Absence of single lobe, absence of lobe + isthmus or bilobar agenesis with hypertrophied isthmus
- Remaining lobe is often hypertrophied
Hypoplasia: reduced size and weight of one or both thyroid lobes

Microscopic (histologic) description

Hemiagenesis:
- Remaining thyroid parenchyma in adults is often hyperplastic or pathologically changed
- Mild C cell hyperplasia (Folia Histochem Cytobiol 2011;49:299)
- Missing thyroid lobe may be replaced by mucinous glands and crypts set in a fibrous stroma (Gilbert-Barness, Kapur, Oligny, Siebert (Eds): Potter's Pathology of the Fetus, Infant and Child, 2nd Edition, 2007)
Abundant fetal-like follicles may suggest thyroid dysgenesis (J Clin Endocrinol Metab 2011;96:E2039)

Microscopic (histologic) images

Images hosted on other servers:

Hashimoto thyroiditis in
thyroid hemiagenesis

Cytology description

Benign smear with follicular cells and colloid in hemiagenesis (Eur J Endocrinol 2010;162:153)

Molecular / cytogenetics description

Currently molecular genetic analyses are only performed on a research basis and could probably be restricted to patients with positive family history or suggestive associations (Braverman, Cooper: Werner & Ingbar's The Thyroid, 10th Edition, 2012)
Typical suggestive associations (Endocrinol Metab Clin North Am 2016;45:243):
- Isolated thyroid hypoplasia or apparent athyreosis with a family history and recessive inheritance suggests TSH receptor mutation
- Thyroid dysgenesis combined with kidney anomalies, or isolated thyroid hypoplasia / apparent athyreosis with a family history and dominant inheritance points to PAX8 mutation
- Associated cleft palate and spiky hair should prompt the search for FOXE1 mutations
- Anomalies of lungs (unexplained respiratory distress) and brain (hypotonia, choreoathetosis) suggest NKX2.1 mutation; these mutations are heterozygous and generally sporadic
- Neonatal diabetes, polycystic kidneys, glaucoma, hepatic fibrosis and exocrine pancreatic deficiency should lead to GLIS3 analysis; transmission is autosomal recessive

Videos

Screening for congenital hypothyroidism (2014)

Differential diagnosis

True athyreosis should be differentiated from severe hypoplasia and ectopic thyroid either clinically (by scintiscan) or postmortem
Thyroid dysgenesis is often being a part of complex syndrome with extrathyroid comorbidities, which needs further diagnostic workup to establish full phenotype

Additional references

Thyroid Disease Manager, Szinnai, Mullis (Eds): Paediatric Thyroidology (Endocrine Development, Vol 26), 1st Edition, 2014

AUS

Table of Contents

Definition / general

The Bethesda category III, Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance (AUS / FLUS) is used for cases with a minor degree of atypia, primarily cytologic or architectural in nature, insufficient to qualify for either of the suspicious categories (category IV and higher)

Essential features

AUS / FLUS include cases with few cells that have distinct but mild nuclear atypia or with more extensive but very mild nuclear atypia
Frequency 8%, resection rate 43.0 - 64.7%, risk of malignancy 10 - 30% of all nodules (6 - 18% after noninvasive follicular thyroid neoplasm with papillary-like nuclear features exclusion) and up to 40% of resected nodules
The most common histopathological diagnosis of AUS nodules is nodular hyperplasia and follicular adenoma, followed by papillary thyroid carcinoma (PTC)
Repeat fine needle aspiration (FNA) results in a more definitive cytologic interpretation (70 - 90%)

Terminology

AUS: preferred term
FLUS: acceptable alternative for the cases with the atypia of follicular cell origin
Laboratory should choose the one preferable term and use it exclusively for this category
AUS can be subdivided into AUS with cytologic (AUS-C) and architectural (AUS-A) atypia, which have different risk of malignancy (AUS-C > AUS-A)
AUS-C: mostly benign appearing with mild cytologic / nuclear atypia (also called AUS-N)
AUS-A: cannot be denied a possibility of follicular neoplasm (applicable to FLUS), see Explanatory notes below

Clinical features

Frequency: 8% in meta analysis (Expert Rev Endocrinol Metab 2014;9:97)
- AUS / FLUS is considered as the last resort after excluding all the rest of the Bethesda categories
- Goal is to have 7 - 10% (Cancer Cytopathol 2015;123:713) and ideally AUS / malignant ratio should not exceed 3:1 (Cancer Cytopathol 2012;120:111) – used as quality control criteria
Resection rate: 43.0 - 64.7% (Thyroid 2014;24:832, Arch Pathol Lab Med 2013;137:1664)
Risk of malignancy (ROM): 10 - 30% (Ali: The Bethesda System for Reporting Thyroid Cytopathology - Definitions, Criteria, and Explanatory Notes, 2nd Edition, 2018, Cancer Cytopathol 2012;120:111)
- Cytologic (nuclear) atypia > architectural atypia (Acta Cytol 2011;55:518)
- Hürthle cell type AUS / FLUS Acta Cytol 2011;55:518)
- 6 - 18% when noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is implicated (Ali: The Bethesda System for Reporting Thyroid Cytopathology - Definitions, Criteria, and Explanatory Notes, 2nd Edition, 2018, Cancer Cytopathol 2012;120:111)

Diagnosis

Aspirates containing cells (follicular, lymphoid or other) with architectural or nuclear atypia that is not sufficient to be classified as suspicious for a follicular neoplasm, suspicious for malignancy or malignant (Ali: The Bethesda System for Reporting Thyroid Cytopathology - Definitions, Criteria, and Explanatory Notes, 2nd Edition, 2018)
Atypia is more marked than can be ascribed confidently to benign changes

Case reports

36 year old woman with primary sclerosing paraganglioma of the thyroid (Ann Otol Rhinol Laryngol 2012;121:510)
47 year old woman with IgG4-related disease of the thyroid (Head Neck Pathol 2018 May 31 [Epub ahead of print])
60 year old woman with aggressive PTC (Thyroid 2015;25:1375)
74 year old man with metastatic clear cell renal cell carcinoma to the thyroid (Diagn Cytopathol 2017;45:161)

Cytology description

Cytologic atypia
Can be focal or can show most cells with mild cytologic atypia
Most of the aspirate appears benign but rare cells have:
- Nuclear enlargement
- Pale chromatin
- Irregular nuclear contours
- No nuclear pseudoinclusions

Cytology images

Contributed by Ayana Suzuki, C.T.

Cytologic atypia

Architectural atypia

Hürthle cell atypia

Atypical lymphocytes

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Cytologic atypia

Atypical cyst lining cells

Architectural atypia

Atypical lymphocytes

Explanatory notes

AUS / FLUS is an interpretation of last resort and should be used judiciously
Specimen preparation artifacts may potentially raise concern for AUS / FLUS
AUS with cytologic atypia is associated with PTC (28 - 56%) (Am J Clin Pathol 2011;136:572, Diagn Cytopathol 2012;40:410)
- Rare cells (Well defined, intranuclear pseudoinclusions or psammomatous calcifications (more suspicious) (Acta Cytol 2008;52:320)

Management

2015 American Thyroid Association Management Guidelines recommend either repeat FNA or molecular testing (Thyroid 2016;26:1)
About half of AUS / FLUS cases have a negative Afirma gene expression classifier (GEC) result (architectural atypia > cytologic atypia)
- Hürthle cell pattern of AUS / FLUS has a lower rate of GEC benign results despite its very low risk of malignancy (Thyroid 2015;25:789)
- Surgery versus continued observation is based on a synthesis of cytologic, molecular, clinical and radiologic findings as well as clinical risk factors and patient preference
- Noninvasive follicular thyroid neoplasm with papillary-like nuclear features will diminish the overall risk of malignancy for AUS / FLUS (Thyroid 2015;25:987, Cancer Cytopathol 2016;124:181)

Sample pathology report

Dx/Category: Atypia of undetermined significance (AUS), a possibility of follicular neoplasm. Sparsely cellular aspirate comprised of follicular cells with microfollicular pattern colloid is absent.
- Note: A repeat FNA or molecular testing may be helpful if clinically indicated.
Dx/Category: Atypia of undetermined significance (AUS), a possibility of papillary thyroid carcinoma. Follicular cells with mild nuclear irregularity.
- Note: A repeat FNA or molecular testing may be helpful if clinically indicated.
Dx/Category: Atypia of undetermined significance (AUS), a possibility of papillary thyroid carcinoma. Follicular cells, predominantly benign appearing, with focal cytologic atypia.
- Note: A repeat FNA or molecular testing may be helpful if clinically indicated.
Dx/Category: Atypia of undetermined significance (AUS), a possibility of lymphoma. Numerous relatively monomorphic lymphoid cells.
- Note: An additional aspiration, with apportioning of needle wash out fluid for flow cytometry, may be helpful if clinically indicated.

Videos

Atypical thyroid FNA

Head and tail of the Bethesda system for thyroid

Thyroid cytology - Bethesda classification

Differential diagnosis

Extensive but mild cytologic atypia

Many if not most cells have mildly enlarged nuclei with:
- Slightly pale chromatin
- Only limited nuclear contour irregularity
- No nuclear pseudoinclusions

Atypical cyst lining cells

Cyst lining cells may appear atypical (rare cases) such as:
- Nuclear grooves
- Prominent nucleoli
- Elongated nuclei and cytoplasm
- Rare intranuclear pseudoinclusions
Associated with hemosiderin laden macrophages
Reactive follicular or mesenchymal cells associated with cystic degeneration of thyroid nodules
Most cases are benign (Cancer 2005;105:71)

Histiocytoid cells

Compared with histiocytes:
- Larger
- Rounder nuclei
- Higher nuclear to cytoplasmic ratio
- Harder (glassier) cytoplasm
- Larger, discrete vacuoles without the hemosiderin or microvacuolization of histiocytes
Characteristic of cystic PTC (Cancer 2002;96:240)
Immunostaining: keratins (PTC cells), CD68 (histiocytes)

Architectural atypia

Rare clusters with microfollicles or crowded three dimensional groups with scant colloid
- Low risk
- Follicular neoplasm / suspicious for a follicular neoplasm (FN / SFN) diagnosis if the specimen were more cellular

Focally prominent microfollicles with minimal nuclear atypia

A more prominent than usual population of microfollicles but not sufficient for a diagnosis of FN / SFN
Should not be confused with an overall mixed but predominantly macrofollicular, aspirate (benign)

Cytologic and architectural atypia

The presence of both mild cytologic and architectural atypia may be more common with noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Hürthle cell aspirates

A sparsely cellular aspirate comprised of Hürthle cells with minimal colloid
- Very low risk
- Follicular neoplasm, Hürthle cell type / suspicious for a follicular neoplasm, Hürthle cell type diagnosis if the specimen were highly cellular

Markedly cellular sample composed of Hürthle cells with sparse colloid, yet the clinical setting suggests benign

Clinically suggesting lymphocytic thyroiditis or a multinodular goiter
More highly predictive of a hyperplastic Hürthle cell nodule than usual (Am J Clin Pathol 2011;135:139)
Hürthle cells are all in cohesive flat sheets without nuclear atypia and there is abundant colloid → benign (in the absence of high risk clinical or radiologic findings)
To follow a patient rather than perform a lobectomy will often be based on clinical and sonographic correlation

Atypia, not otherwise specified (NOS)

A minor population of follicular cells with nuclear enlargement and prominent nucleoli
- Does not raise concern for PTC and best classified as NOS
- Specimens from patients with a history of radioactive iodine, carbimazole or other pharmaceutical agents can usually be diagnosed as benign

Psammomatous calcifications in the absence of nuclear features of PTC

Psammoma bodies raise concern for PTC and should prompt careful scrutiny of PTC cells
Lamellar bodies of inspissated colloid may be indistinguishable from true psammomatous calcifications

Atypical lymphoid cells, rule out lymphoma

There is an atypical lymphoid infiltrate but the degree of atypia is insufficient for suspicious for malignancy
Repeat aspirate for flow cytometry is desirable

Parathyroid lesion

Crowded three dimensional clusters or trabecular arrangements, abundant granular cytoplasm, salt and pepper chromatin (Head Neck 2002;24:157, Acta Cytol 2004;48:133)
25 - 30% of parathyroid lesions can be recognized
Immunohistochemistry (GATA3, PTH, chromogranin A) and ancillary studies (parathyroid hormone assays, molecular studies) can confirm the diagnosis

Descriptive language may occasionally influence management

Scant or poorly preserved → Repeat aspirate
Follow up of a cellular, well preserved aspirate with diffuse mild atypia → Molecular testing

Subclassify according to the most likely diagnosis

Board review style question #1

A sparsely cellular aspirate comprised of Hürthle cells with minimal colloid
Atypical lymphoid cells
Focally prominent microfollicles with minimal nuclear atypia
Most of the aspirate appears benign but rare cells have irregular nuclear contours
Psammomatous calcifications in the absence of nuclear features of PTC

Board review style answer #1

C. Focally prominent microfollicles with minimal nuclear atypia. Microfollicles are architectural atypia suggesting follicular neoplasm.

Comment Here

Reference: Atypia of undetermined significance / follicular lesion of undetermined significance

Board review style question #2

PAX8
Calcitonin
GATA3
Thyroglobulin
TTF1

Board review style answer #2

C. GATA3. This is intrathyroidal parathyroid adenoma.

Comment Here

Reference: Atypia of undetermined significance / follicular lesion of undetermined significance

Autoimmune thyroiditis

Table of Contents

Definition / general | Epidemiology | Clinical features

Definition / general

Nonneoplastic thyroid disorders with antithyroid antibodies and associated with specific HLA haplotypes
#1 cause of hypothyroidism in iodine sufficient areas
Includes Graves' disease, Hashimoto's thyroiditis and most forms of thyroiditis in this section except infectious
Rosai differentiates based on follicular epithelium: lymphocytic thyroiditis if relatively normal follicles, Hashimoto's thyroiditis if oncocytic change, Graves' disease if diffusely hyperplastic follicles

Epidemiology

Children often present with asymptomatic goiter of short duration (J Pediatr Endocrinol Metab 2007;20:961, Arch Dis Child 2009;94:33)
Associated with female children of bipolar parents (Eur Neuropsychopharmacol 2007;17:394), radioactive iodine (Epidemiology 2006;17:604, but see JAMA 2006;295:1011), iodine supplementation (Hormones (Athens) 2007;6:25), history of pregnancy (Autoimmunity 2008;41:174)

Clinical features

May be due to disturbance in suppressor T cells

Benign

Table of Contents

Definition / general

Designation "benign follicular nodule" applies to a cytologic sample that is adequate for evaluation and consists of colloid and benign appearing follicular cells in varying proportions (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2017)
Most common fine needle aspiration (FNA) interpretation (60 - 70% of all cases) (Clin Lab Med 1993;13:699, Cancer 2007;111:508)
Primary benefit of thyroid FNA is ability to reliably make a benign diagnosis, which spares many patients with nodular thyroid disease unnecessary surgery (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2017)
Approximately 10 - 20% of patients with benign cytology require surgery due to clinical indications (large goiter, suspicious sonogram, rapid growth, coexistent nodule, etc.) and cosmetic reasons (Diagn Cytopathol 2000;23:233)
Nodular goiter (colloid, hyperplastic, adenomatous) is the most common lesion, followed by chronic thyroiditis

Essential features

Cytologic sample that is adequate for evaluation and consists of colloid and benign appearing follicular cells
60 - 70% of all thyroid FNA, resection rate 10 - 20%, risk of malignancy (ROM) 0 - 3%
Role of benign diagnosis is to avoid unnecessary surgery

Terminology

Equal to negative for malignancy and nonneoplastic
Term "benign" preferred over negative for malignancy and nonneoplastic
Category II in the Bethesda system

Radiology description

Adenomatoid nodules: multinodular goiter on ultrasound
Chronic lymphocytic (Hashimoto) thyroiditis: heterogeneous appearance on ultrasound

Radiology images

Contributed by Ayana Suzuki, C.T.

Isoechoic nodule

Hypoechoic nodule

Large cyst

Large multilocular cyst

Case reports

35 year old woman with IgG4 related thyroiditis (Korean J Intern Med 2016;31:399)
35 year old woman with microfilaria in aspirated thyroid nodule (Ci Ji Yi Xue Za Zhi 2016;28:27)
46 year old woman with Hashimoto thyroiditis associated with Hürthle cell adenoma (Rom J Morphol Embryol 2017;58:241)
48 year old woman with subacute thyroiditis mimicking malignacy (Diagn Cytopathol 2016;44:682)
69 year old man with acute exacerbation of Hashimoto thyroiditis mimicking anaplastic carcinoma (Ear Nose Throat J 2014;93:E18)
80 year old woman with acute suppurative thyroiditis (Clin Case Rep 2017;5:1238)

Prognostic factors

0 - 3% of cytologically proven benign thyroid nodules have a malignancy on resection; usually these nodules are clinically suspicious (Endocr Pract 2001;7:237, JAMA 2015;313:926, Thyroid 2007;17:1061)

Treatment

American Thyroid Association (ATA) recommends that followup should be determined by risk stratification based on ultrasound pattern (Thyroid 2016;26:1)
- High suspicion: repeat ultrasound and FNA within 12 months
- Low to intermediate suspicion: repeat ultrasound 12 - 24 months → growth or development of new suspicious ultrasound features → repeat FNA
- Very low suspicion: ultrasound surveillance is not necessary; if ultrasound is repeated, it should be done after 24 months
Repeat FNA or surgery is considered only for a selected subset including those that are large, symptomatic or have worrisome clinical or sonographic characteristics (Thyroid 2016;26:1)

Cytology description

Benign follicular nodule
- Adequate, consists of colloid and benign appearing follicular cells
- Classified histologically as nodular hyperplasia in nodular goiter, hyperplastic (adenomatoid) nodules, colloid nodules and nodules in Graves disease
- Cytology: cellularity: sparse to moderate
  - Colloid: viscous, shiny, light yellow or gold (gross), dark blue-violet-magenta (Romanowsky stain), green or orange-pink (Pap stain)
  - Watery colloid: cellophane coating, film with frequent folds (crazy pavement, chicken wire or mosaic appearance)
  - Thick (dense, hard) colloid: a hyaline quality, cracks
- Macrophages: common, containing hemosiderin pigment
- Follicular cells
  - Appearance: monolayered sheets, spaces (honeycomb-like) within the sheets, intact 3D variably sized balls
  - Cytoplasm: scant or moderate, stripped (may be misinterpreted as lymphocytes), paravacuolar granules (Cancer 2003;99:217)
  - Nuclei: variable in size, low N/C ratio, round to oval, anisonucleosis, uniformly granular chromatin pattern
  - In abundant colloid: shrunken, spindled, degenerated
  - In cystic lesion: focal reparative changes (cyst lining cells with enlarged nuclei, finely granular chromatin, squamoid or spindle shaped appearance)
  - Minor components: oncocytes, microfollicles, papillary hyperplasia (Cancer 2003;99:217, Cancer Cytopathol 2014;122:666)
  - Liquid based cytology preparations (LBC): decrease in the amount of colloid, superior nuclear details
Graves disease
- Features similar to non-Graves benign follicular nodules (Acta Med Scand;205:263)
Lymphocytic thyroiditis (Hashimoto thyroiditis)
- Many polymorphic lymphoid cells associated with benign thyroid follicular cells or oncocytes (Acta Cytol 1987;31:687)
- Oncocytes: flat sheets or isolated, abundant granular cytoplasm, large nuclei, prominent nucleoli, anisonucleosis, mild nuclear atypia (Acta Cytol 1999;43:400)
- Lymphocytes: background or infiltrating epithelial cell groups, polymorphic (small mature lymphocytes, larger reactive lymphoid cells, occasional plasma cells), variable chromatin pattern (rich and granular heterochromatin in small lymphocytes, diminished and fine in large lymphocytes)
- Monomorphic lymphoid population should prompt additional samples for flow cytometry if lymphoma suspected
- LBC: decrease in lymphocytes, oncocytes with irregular nuclei (Acta Cytol 2018;62:93, Diagn Cytopathol 2012;40:404)
Granulomatous (de Quervain) thyroiditis (Acta Cytol 1997;41:238)
- Cellularity: variable (depends on the stage of disease)
- Granulomas: clusters of epithelioid histiocytes, numerous multinucleated giant cells
- Early stage: many neutrophils and eosinophils, similar to acute thyroiditis
- Later stage: hypocellular, giant cells surrounding and engulfing colloid, epithelioid cells, lymphocytes, macrophages, scant degenerated follicular cells
- Involutional stage: absent giant cells and inflammatory cells
Acute thyroiditis (Exp Ther Med;9:860)
- Numerous neutrophils associated with necrosis, fibrin, macrophages, blood
- Scant reactive follicular cells and limited to absent colloid
- Bacterial or fungal organisms (immunocompromised patients)
Riedel thyroiditis (Diagn Cytopathol 2004;30:193)
- Cellularity: acellular
- Collagen strands and bland spindle cells
- Rare chronic inflammatory cells, absence colloid and follicular cells
Black thyroid (Diagn Cytopathol 1991;7:640, Diagn Cytopathol 2006;34:106)
- Follicular cells with abundant dark brown cytoplasmic pigment (darker than hemosiderin, similar to melanin)
Amyloid goiter
- Abundant purple to pink-orange amorphous material (Cytopathology 2006;17:262)

Cytology images

Contributed by Ayana Suzuki, C.T.

Colloid nodule

Adenomatous nodules

Hashimoto thyroiditis

Granulomatous thyroiditis

Thyroglossal duct cyst

Videos

Thyroid cytology: colloid nodule

Essential thyroid cytopathology

Differential diagnosis

Differential with benign follicular nodule (Kini: Color Atlas of Differential Diagnosis in Exfoliative and Aspiration Cytopathology, 2nd Edition, 2011)
- Follicular neoplasm
  - Background: clean, sometimes hyaline colloid
  - Follicular pattern: small, uniform
  - Cytoplasm and nuclei: uniform, high N/C ratio, enlarged nuclei
- Follicular neoplasm, Hürthle cell type
  - Background: clean, sometimes cystic
  - Presentation: isolated, in loosely cohesive groups, sheets, syncytial tissue fragments
  - Cytoplasm and nuclei: uniform, high N/C ratio, enlarged nuclei, binucleation to multinucleation
- Papillary thyroid carcinoma
  - Nuclear psedoinclusions (Orphan Annie nuclei)
Differential with lymphocytic thyroiditis
- Papillary thyroid carcinoma
  - Nuclear psedoinclusions (Orphan Annie nuclei)
- Follicular neoplasm, Hürthle cell type
  - Background: clean, sometimes cystic
- MALT lymphoma
  - Lymphoglandular bodies in the background (Acta Cytol 2018;62:93)
  - Similar chromatin pattern of lymphoid cells regardless of the difference in size
  - Absence of oncocytic cells (Acta Cytol 2018;62:93)
Differential with granulomatous thyroiditis
- Papillary thyroid carcinoma
  - Nuclear psedoinclusions (Orphan Annie nuclei) can mimic macrophages with enlarged nuclei, nuclear irregularity
- Lymphocytic thyroiditis
  - Absence of epithelioid histiocytes
Differential with acute thyroiditis
- Anaplastic carcinoma
  - Carefully observe whether large atypical cells are present or absent
Differential with thyroid cyst (nonthyroid lesions)
- Thyroglossal duct cyst (Thyroid Res & Prac 2013;10:104)
  - Differential diagnosis of thyroid cystic lesions
  - Cytology: proteinaceous material, inflammatory cells, rare degenerated squamous or ciliated columnar cells
  - Appropriate clinical presentation (anterior midline neck cyst, above the thyroid isthmus, below the hyoid bone)
- Parathyroid cyst (Case Rep Surg 2015;2015:243527)
  - Cyst fluid: characteristic watery, clear gross appearance
  - Cytology: acellular or hypocellular
  - Preoperative Dx: elevated parathormone levels in the cyst fluid

Board review style question #1

What risk of malignancy is associated with benign thyroid cytology?

0 - 3%
5 - 10%
12 - 15%
20 - 30%
40 - 50%

Board review style answer #1

A. 0 - 3% Most published studies reported that a benign FNA diagnosis is associated with a very low false negative rate, estimated to be in the range of 0 - 3%. It should be noted that the precise risk of malignancy for cytologically benign nodules is difficult to assess because only a minority of these patients undergo surgery.

Comment Here

Reference: Benign

Bethesda system diagnostic categories

Table of Contents

Definition / general

The Bethesda System for Reporting Thyroid Cytopathology (TBS) is an international reporting system for thyroid cytology (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2017)
Uniform terminology aimed to standardize the reporting of thyroid fine needle aspiration (FNA) cytology
- Understandable by various specialists in different countries
- In conjunction with the International Academy of Cytology, endorsed by the American Thyroid Association and other leading professional communities (Thyroid 2016;26:1)
- Currently widely adopted worldwide
- Similar to reporting systems in other organs (Adv Anat Pathol 2016;23:193, Cancer Cytopathol 2020;128:348)
FNA is gold standard for the preoperative evaluation of thyroid nodules
- Clinical decision making usually relies on combination of FNA findings, thyroid ultrasound and laboratory / clinical investigation
Developed and maintained by an international panel of experts, including cytopathologists, thyroid pathologists and clinicians
- Conceived in 2008 at state of the science conference (Diagn Cytopathol 2008;36:425)
- First edition in 2009 (Thyroid 2009;19:1159)
- Second edition in 2017 (Thyroid 2017;27:1341, Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2017)
- Next edition is due in 2023
Structure
- 6 categories with different propensity to malignancy, from benign to malignant (from < 5% to > 99%), each assigned management approach
- Indeterminate categories constitute categories III - V and may require molecular testing to tailor clinical decision, i.e. surgery versus conservative (Molecular testing in FNA)
Other national systems exist, including modern British, Japanese, Italian and outdated Papanicolaou, which could be translated into TBS terminology (Cancer Cytopathol 2016;124:457)

Essential features

TBS is an international standard for reporting thyroid FNA
Divided into 6 categories that are linked to malignancy risk and recommended clinical management
Clinically significant statistical metrics of each category are frequency, resection rate and risk of malignancy

Diagrams / tables

Contributed by Andrey Bychkov, M.D., Ph.D.

TBS 2017

TBS metrics

Metrics

TBS metrics / outputs include several statistical indicators:
- Frequency: number of nodules in a given category out of all aspirated nodules
- Resection rate (RR): ratio of operated / resected nodules out of all aspirated nodules in a category
- Malignancy risk, also known as risk of malignancy (ROM): number of malignant nodules on surgery out of all resected in a given category
- Indicators not currently included in TBS:
  - Overall risk of malignancy (oROM): calculated out of all aspirated nodules, including resected and unresected (Thyroid 2021 May 14 [Epub ahead of print])
  - Risk of neoplasia (RON): number of neoplastic nodules (benign plus malignant) on surgery out of all resected in a given category (Cancer Cytopathol 2020;128:232)
Utility:
- Defines management of thyroid nodules: high ROM suggests surgical resection while low ROM implies conservative strategy, e.g. follow up
- Quality control in lab / hospital:
  - High nondiagnostic rate (> 15%) requires revision of FNA sampling procedure and lab workflow, e.g. implementation of rapid onsite evaluation or ultrasound guided sampling
  - Abnormal measures, such as high rate of indeterminate diagnoses, low ROM in malignant nodules or high ROM in benign nodules may be due to limited expertise of FNA readers
Variation in TBS outputs depends on different factors:
- Institutions: reference center versus primary care; expertise of operator and reader
- Geography: North America versus Asia, due to different practice patterns (Cancer Cytopathol 2020;128:238)
- Population: adults versus children (Thyroid 2021;31:1203)
- Classification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) either as benign or malignant tumor (Endocr Pract 2019;25:49)
- All of the above explain differences between the model outputs implied by TBS and real world data reported in meta analysis studies
Ideally, local institutional metrics (especially ROM) should be calculated to adjust clinical decisions in a given hospital (Cancer Cytopathol 2020;128:917)

Bethesda categories

TBS I: nondiagnostic / unsatisfactory
- Includes inadequate by cellularity, unsatisfactory by quality and cyst fluid only specimens
  - TBS criteria for adequacy of thyroid FNA specimens is ≥ 6 groups of well visualized follicular cells (≥ 10 per cluster)
- Frequency 10 - 15%, resection rate 10 - 15%, ROM up to 20% of all nodules and up to 30% of resected nodules
- Management: reaspiration, except for pure cyst
TBS II: benign
- Cytology sample that is adequate for evaluation and consists of colloid and benign appearing follicular cells
- Frequency 60 - 70%, resection rate 10 - 15%, ROM < 10% (oROM < 1%)
  - Usually nodular hyperplasia on resection
- Management: follow up based on ultrasound pattern
TBS III: atypia of undermined significance / follicular lesion of undetermined significance (AUS / FLUS)
- Aspirates with few cells that have distinct but mild nuclear atypia or with more extensive but very mild nuclear atypia
- Frequency < 10%, resection rate 30 - 40%, ROM 25 - 40% (NIFTP = malignant) or 6 - 18% (NIFTP ≠ malignant) and up to 40% of resected TBS III nodules
  - On resection / histopathology diagnosed as nodular hyperplasia, follicular adenoma and papillary thyroid carcinoma (PTC)
- Management: reaspiration or molecular testing (Thyroid 2016;26:1)
TBS IV: follicular neoplasm / suspicious for a follicular neoplasm (FN / SFN)
- Cases with most of the follicular cells arranged in cell crowding or microfollicle formation
- Frequency 6%, resection rate 60%, ROM 25 - 30% (NIFTP = malignant) or 10 - 40% (NIFTP ≠ malignant)
  - Histopathology: follicular adenoma, adenomatous nodule, follicular variant of papillary thyroid carcinoma and follicular carcinoma
- Management: diagnostic thyroid lobectomy or molecular testing
TBS IV: follicular neoplasm, Hürthle cell type / suspicious for a follicular neoplasm, Hürthle cell type (FN-H / SFN-H)
- Cases with most of the follicular cells showing abundant fine granular cytoplasm (Hürthle cells)
- Frequency 1.2 - 9%, resection rate 30%, ROM 10 - 40%
  - Histopathology: oncocytic (Hürthle cell) adenoma and carcinoma
- Management: diagnostic thyroid lobectomy, molecular testing is not helpful
TBS V: suspicious for malignancy
- Used when cytology strongly suggests malignancy but is not sufficient for a conclusive diagnosis
- Frequency < 5%, resection rate 70%, ROM 80% (NIFTP = malignant) or 45 - 60% (NIFTP ≠ malignant)
  - Histopathology: usually papillary thyroid carcinoma
- Management: surgery (usually)
TBS VI: malignant
- Used when cytology strongly suggests malignancy
- Frequency 5 - 10%, resection rate 65 - 80%, ROM 99% (NIFTP = malignant) or 94 - 96% (NIFTP ≠ malignant)
  - Histopathology: wide spectrum of thyroid malignancies, from papillary thyroid carcinoma (most common) to medullary thyroid carcinoma, anaplastic thyroid carcinoma, lymphoma, etc.
- Management: surgery (usually)

Major updates in TBS 2017

The 2017 revision was influenced by (Thyroid 2017;27:1341):
- Accumulation of knowledge and meta analysis studies of TBS
- American Thyroid Association 2015 guidelines for the management of patients with thyroid nodules
- Introduction of molecular testing as an adjunct to cytopathologic examination
- Introduction of NIFTP to replace noninvasive encapsulated follicular variant of papillary thyroid carcinoma
Adjustments to the ROM based on the post 2010 data
NIFTP impact:
- Incorporate criteria to recognize NIFTP to avoid the malignant category for these lesions
- 2 types of ROM, i.e. when NIFTP = malignant and NIFTP ≠ malignant
- NIFTP note for follicular neoplasm / suspicious for a follicular neoplasm, suspicious for malignancy and malignant; papillary thyroid carcinoma
Updated management recommendations, including molecular testing for AUS / FLUS and FN / SFN
Subclassified AUS / FLUS
Diagnostic criteria for papillary thyroid carcinoma subset of the malignant category limited to cases with classical features of papillary thyroid carcinoma

Cytology images

Contributed by Ayana Suzuki, C.T.

Unsatisfactory:

Hemorrhagic background

Muscle

Respiratory epithelium

Air dried smear

Cyst fluid only

Benign:

Watery colloid

Cracking colloid

Follicular clusters

3D structures

Atypia of undermined significance /
follicular lesion of undetermined significance:

FLUS - cellular

FLUS - architectural

FLUS - Hürthle

Atypical lymphocytes

Follicular neoplasm /
suspicious for a follicular neoplasm:

Microfollicles

FN - Hürthle

Suspicious for malignancy:

Suspicious for papillary thyroid carcinoma

Suspicious for lymphoma

Hyalinizing trabecular tumor

Malignant:

Papillary carcinoma

Medullary carcinoma

Insular carcinoma

Anaplastic carcinoma

Lymphoma

Videos

Algorithmic approach to thyroid FNA

Head & tail of the Bethesda system

Thyroid cytology: approach

Thyroid cytology: cases

Thyroid cytology: ND/UNS, benign and FN/SFN

Thyroid cytology: malignant, SUS and AUS/FLUS

Thyroid cytopathology

Additional references

Papanicolau Society of Cytopathology: Image Atlas [Accessed 2 September 2021]

Board review style question #1

What is most likely The Bethesda System for Reporting Thyroid Cytopathology category of this thyroid aspirate?

Atypia of undermined significance / follicular lesion of undetermined significance
Benign
Follicular neoplasm / suspicious for a follicular neoplasm
Malignant
Nondiagnostic / unsatisfactory

Board review style answer #1

E. Nondiagnostic / unsatisfactory. When the aspirated material contains only foamy histiocytes and no follicular epithelium or colloid it is qualified as nondiagnostic. However, in some local reporting systems (e.g. Japanese), these cases are reported as adequate, cyst fluid only, because their malignancy risk is almost the same as that of the benign category and lower than that in the nondiagnostic category.

Comment Here

Reference: Overview / diagnostic categories

Board review style question #2

Which is the most recommended management for the benign category of The Bethesda System for Reporting Thyroid Cytopathology?

Follow up
Molecular testing
Reaspiration
Thyroid lobectomy
Total thyroidectomy

Board review style answer #2

A. Follow up. The American Thyroid Association recommends follow up based on the ultrasound pattern for a benign lesion.

Comment Here

Reference: Overview / diagnostic categories

Black / pigmented thyroid

Table of Contents

Definition / general

Rare side effect of minocycline therapy, ~ 100 cases reported
Pigment deposition in thyroid gland in patients on minocycline (often prescribed for chronic acne) or related tetracyclines
Pigment also deposited in bone, teeth, skin, nails and oral mucosa (Diagn Cytopathol 1991;7:640)
Pigment may be lipofuscin, melanin / neuromelanin or an oxidation product of minocycline; however, lipofuscin is a predominant fraction (Diagn Cytopathol 2006;34:106)
Thyroid discoloration (dark red tissue) may also be due to psychotropic drugs such as doxepin, lithium carbonate or tricyclic antidepressants (Arch Pathol Lab Med 1994;118:79)

Terminology

Black thyroid "syndrome" is a controversial term (Thyroid 2007;17:905)

Pathophysiology

Proposed mechanisms include (Otolaryngol Head Neck Surg 1999;121:293):
- Degradation products of drug combined with lipofuscin and melanin-type pigments; minocycline accelerates and accentuates the normal process of lipofuscin accumulation (Biochem Pharmacol 1978;27:1103)
- Oxidative degradation of the drug itself (Isr J Med Sci 1988;24:51)
- Drug interaction and alteration of tyrosine metabolism
- Lysosomal dysfunction resulting in concentration of drug metabolites rather than their elimination (Am J Clin Pathol 1983;79:738)
Thyroid pigmentation by psychotropic medications is a result of lysosomal accumulation of the drugs (Arch Pathol Lab Med 1994;118:79)

Clinical features

Typically does not affect thyroid function; only a few cases reported of minocycline induced hyperthyroidism (Thyroid 2008;18:795)
Although several reports claim high rate (30 - 65%) of thyroid cancer in black thyroid, no casual relationship has been established (ORL J Otorhinolaryngol Relat Spec 2015;77:33)

Diagnosis

Incidental discovery at neck surgery or autopsy
Hypopigmented foci in gross specimens that are otherwise pigmented should be thoroughly examined to rule out papillary carcinoma (Mod Pathol 1999;12:1181, Arch Pathol Lab Med 2004;128:355)

Case reports

18 year old man with cystic fibrosis and Burkholderia dolosa infection (Case of the Week #98)
18 year old man with tumor in pigmented thyroid gland (Arch Pathol Lab Med 2004;128:355)
21 year old man with black thyroid (Postgrad Med J 1989;65:34)
35 year old woman with papillary thyroid carcinoma (Neth J Med 2007;65:185)
42 year old woman with black thyroid associated with hyalinizing trabecular tumor (Endocr J 2008;55:1109)
69 year old man and 72 year old woman (Br Med J 1976;2:1109, Intern Med 2010;49:1835)
Black thyroid resulting from short term doxycycline use (Head Neck 2006;28:373)
Follicular carcinoma associated with minocycline induced black thyroid (Endocr Pathol 1996;7:345)
Trabecular adenoma of the thyroid with black pigmentation (Thyroid 2007;17:593)

Gross description

Normal size, uniformly dark brown to jet black on surface and on cut section
Coexisting tumor tissue, if present, is frequently hypopigmented compared to rest of the gland, due to altered function of thyroid peroxidase in neoplastic cells

Gross images

Case #98

Thyroid gland with black pigment

Images hosted on other servers:

Black thyroid and follicular adenoma

Cut surface

Coal black coloration

Microscopic (histologic) description

Dark brown, granular, dust-like cytoplasmic pigment abundant in apical portion of follicular cells, colloid and stromal macrophages (Am J Pathol 1984;117:98)
Pigment is nonfluorescent and nonbirefringent (Arch Pathol Lab Med 2004;128:355)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and Mark R. Wick M.D.

Perinuclear brown pigment

Minocycline induced pigmentation

Images hosted on other servers:

Pigmented cells and colloid

Fontana-Masson

Cytology description

Dark brown, finely granular intracytoplasmic pigment in follicular cells and macrophages on Papanicolaou stain
Small round granules are darker and more regular in size and shape than hemosiderin
On Diff-Quik stain, granules are dark blue (Diagn Cytopathol 2010;38:579)
Often no specific findings when FNA is done for a thyroid nodule - neoplasms likely do not contain pigment (Diagn Cytopathol 2007;35:135)

Positive stains

Fontana-Masson and Schmorl for melanin component
PAS and Ziehl-Neelsen for lipofuscin component

Negative stains

Iron

Electron microscopy description

Numerous electron dense granular structures in lysosomes, with leakage into cytoplasm and exocytosis into follicular lumina

Electron microscopy images

Images hosted on other servers:

Pigment granules in cytoplasm and colloid space

Pigment deposits and Xray spectrogram

Experimental black thyroid, dog

Experimental black thyroid, monkey

Differential diagnosis

Cystic fibrosis
Hemochromatosis
Ochronosis
Pigmented / melanotic medullary thyroid carcinoma (Diagn Pathol 2008;3:2)

Branchial pouch / cleft anomalies

Table of Contents

Definition / general

Congenital lesions due to incomplete obliteration of the branchial apparatus
May be cyst, sinus, fistula or cartilage in anterolateral neck
Cysts derived from branchial cleft have squamous epithelium; cysts derived from branchial pouch have respiratory epithelium, although repeated infections may cause squamous metaplasia (Ann R Coll Surg Engl 2007;89:W12)

Terminology

A sinus is a blind ending tract
"Branchial cleft sinus" connects to the skin, but a "branchial pouch sinus" connects to the pharynx; neither arises from the mesenchyme of the branchial arch (J Laryngol Otol 2004;118:19)
A "true fistula" is a communication between two epithelialized surfaces; a "congenital branchial fistula" should be present at birth and should communicate between a persistent pouch and a cleft
Most of the branchial fistulas are pseudofistulas, formed between a pouch remnant and a skin opening produced following an infection or a surgical incision or are just sinuses (AJNR Am J Neuroradiol 2010;31:755)

Epidemiology

20 - 40 years old, M = F
20% of cervical masses in children (Int J Pediatr Otorhinolaryngol 2011;75:1020)
Cysts: fistulas = 10:1 (Eur J Inflamm 2012;10:39)
2% - 3% are bilateral (Ear Nose Throat J 2008;87:291)

Sites

Sites of cysts:
- First branchial cleft: preauricular area (type I cyst) or below the angle of mandible (type II), may be connected to external auditory canal; cysts are rarely malignant (Diagn Cytopathol 2008;36:876); 5% - 8%
- Second branchial cleft: anterior to sternocleidomastoid muscle in midneck, may communicate with pharynx; 95% (Singapore Med J 2015;56:203)
- Third / fourth branchial cleft (Pyriform sinus fistula): 2% - 5%
  - May be misdiagnosed as bronchogenic cyst
  - Usually left sided and associated with neck infection, treatment is ipsilateral thyroidectomy as lesions pass through thyroid

Pathophysiology / etiology

Branchial theory suggests that incomplete obliteration of branchial cleft mucosa, which remains dormant until stimulated to grow later in life, results in cyst formation (Ascherson, 1832) (Am J Pathol 1967;50:533)
More theories: persistence of vestiges of the precervical sinus, thymopharyngeal duct origin and cystic lymph node origin (J Am Dent Assoc 2003;134:81)

Diagrams / tables

Images hosted on other servers:

Branchial apparatus

Branchial cleft anomalies location

Anatomical relations

Clinical features

Slow growing movable mass in the lateral neck, often asymptomatic
Manifested as inflammatory neck mass or fistula
Rarely associated with squamous cell carcinoma (J Laryngol Otol 1994;108:1068), but cystic neck masses should be considered to be nodal metastases until proven otherwise (common sites of small primary occult tumors are tonsil, posterior tonsillar pillar, retromolar tongue, nasopharynx)
Clinical branchial cysts may rarely:
- Arise within thyroid gland (Korean J Radiol 2006;7:149)
- Actually be cystic remnants of ultimobranchial body
- Actually be papillary thyroid carcinoma (Kaohsiung J Med Sci 2007;23:634)
- Arise within ectopic thyroid tissue that transforms to papillary carcinoma (Ear Nose Throat J 2006;85:675, World J Surg Oncol 2006;4:24)
- 33% of patients with congenital third branchial arch anomalies and 45% with fourth branchial arch abnormalities present with acute infectious thyroiditis (Otolaryngol Head Neck Surg 2010;142:21, J Pediatr Surg 2009;44:1432)

Diagnosis

Imaging and fluoroscopic fustulography to visualize cyst / fistula and anatomic tract
Pyriform sinus examination via direct laryngoscopy to detect third / fourth branchial cleft anomaly

Radiology description

Ultrasound: low echogenic lesion with lack of internal septation
CT scan and MRI require sedation in children

Radiology images

Images hosted on other servers:

Cystic lesion in left parotid gland

CT fistulogram

Infrahyoid cyst

Prognostic factors

Recurrence rate depends on completeness of resection, mean 5% (Dentomaxillofac Radiol 2012;41:696)

Case reports

18 month old child with third branchial pouch cyst presenting as stridor (Ann R Coll Surg Engl 2007;89:W12)
9 year old boy and 42 year old man with fourth branchial complex anomaly (Case Rep Otolaryngol 2011;2011:958652)
10 year old girl with branchial cleft cyst at an unusual location (Dentomaxillofac Radiol 2012;41:696)
12 year old girl with type II first branchial cleft anomaly presenting as a post auricular salivary fistula (Ann Med Health Sci Res 2014;4:136)
22 year old woman with type I first branchial cleft cyst masquerading as a parotid tumor (Natl J Maxillofac Surg 2014;5:84)
32 year old woman with intrathyroidal branchial cleft cyst (Korean J Radiol 2006;7:149)
50 year old woman with branchial cleft cyst (J Oral Maxillofac Pathol 2014;18:150)
Multiple branchial cleft-like cysts in Hashimoto thyroiditis (Am J Surg Pathol 1989;13:45)

Treatment

Complete surgical excision of cyst and associated tract after clearing infection
Endoscopic cauterization via pyriform sinus for fourth branchial cleft cysts

Clinical images

Images hosted on other servers:

Fistula opening (1st branchial cleft anomaly)

First branchial cleft fistula opening

Bilateral fistula opening

Saliva coming out, third branchial fistula

Fistula opening above sternocleidomastoid muscle

Sinus originating from pyriform sinus

With cervical abscess

Fistulous tract in right pyriform sinus

Gross description

A smooth walled cyst with mucoid or watery contents, 2 - 6 cm in diameter (up to 10 cm in greatest dimension)
Infected / ruptured cyst may be obscured or obliterated by the fibroinflammatory reaction; the surrounding soft tissues may be densely fibrotic

Gross images

Images hosted on other servers:

Fistula tract

Fistula tract ending in parotid gland

Collaural fistula

Third branchial fistula

Fistula tract exiting pharynx

Fourth branchial fistula

Microscopic (histologic) description

Stratified squamous or ciliated columnar epithelium lining (Am J Pathol 1967;50:765, APMIS 1997;105:623)
Fibrotic wall with lymphoid follicles resembling lymph node or tonsil
May be secondarily infected
Cysts may have sebaceous or mucinous glands
Occasionally found in thyroid tissue as heterotopic cartilage, thymus or solid cell nests representing ultimobranchial body remnants
Parathyroid glands, thymic tissue, tiny masses of cartilage and tiny glands lined by ciliated cells may be seen in normal thyroid glands, presumably related to anomalies of the development of the branchial pouches (J Anat 1976;122:77)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

PTC: cystic node mimics branchial cyst

Hashimoto thyroiditis with lymphoepithelial cyst

Images hosted on other servers:

Cyst lined by stratified squamous epithelium

Sinus tract in parotid gland

Cyst wall with chronic inflammation

Fibrotic wall of a cyst

Lymphoid aggregates in cyst wall

Ciliated pseudostratified columnar epithelium

Virtual slides

Images hosted on other servers:

Case 10, right neck node

Cytology description

Squamous epithelial cells of variable maturity, abundant lymphocytes, macrophages, background of amorphous debris - these features are nonspecific (Acta Dermatovenerol Alp Pannonica Adriat 2006;15:85, Eurocytology)
May be interpreted as suspicious for carcinoma (Cytopathology 2007;18:184)

Cytology images

Images hosted on other servers:

Squamous cells, keratin debris

High power

Pap stain

Inflammation

Cholesterol crystals

Videos

Pharyngeal pouches

Differential diagnosis

First branchial cleft cyst: epidermoid cyst, dermoid cyst, cystic sebaceous lymphadenoma
Second branchial cleft cyst: lateral thyroglossal duct cyst
Third branchial cleft cyst: papillary carcinoma with cystic change (positive for TTF1, thyroglobulin)
Fourth branchial cleft cyst: thymic cyst

Additional references

C cell hyperplasia

Table of Contents

Definition / general

Variously defined as at least 50 immunostained C cells per low power of x100 (Endocr Pathol 2001;12:365) and more than 50 calcitonin positive cells in three low power fields of x100 (Mod Pathol 2003;16:756)
Neoplastic CCH is diagnosed as a separate form of CCH, when intrafollicular or nodular C cells with nuclear pleomorphism are seen on H&E, and are morphologically distinct from follicular cells
Estimated on at least 2 sections taken from the junction of the middle and upper thirds of the thyroid lobes which can be grossly recognized by the presence of prominent vessels

Essential features

Neoplastic CCH can be diagnosed by routine H&E stains, but reactive CCH requires calcitonin staining
Calcitonin levels may be elevated in both reactive and neoplastic CCH

ICD coding

E07.0

Epidemiology

Reactive CCH commonly occurs in adults (at autopsy, 41% of men and 15% of women, J Clin Endocrinol Metab 1997;82:42)
Women with elevated basal calcitonin and CCH have almost 100% risk of developing medullary thyroid carcinoma versus 31% of men, who may have C cell hyperplasia only (Mod Pathol 2003;16:756, Endocr Relat Cancer 2009;16:243)

Sites

Upper 2/3 of both thyroid lobes

Clinical features

C Cell hyperplasia is classified as:
- Reactive or physiologic CCH
  - May be seen in neonates and elderly subjects
  - Twice as common in men as in women
  - Associated with prolonged hypercalcemia, hyperparathyroidism, hypergastrinemia, Hashimoto thyroiditis, follicular thyroid neoplasm and nodular or diffuse hyperplastic goiter
- Neoplastic C cell hyperplasia or carcinoma in situ / intraepithelial neoplasia
  - Has genetic and kinetic characteristics consistent with a malignant C cell lesion, including a family history of thyroid cancer or MEN 2A or 2B (J Clin Endocrinol Metab 2001;86:3948)
  - Precursor lesion of sporadic and familial medullary carcinoma
  - Caused by mutation of RET oncogene
  - Bilateral and multifocal tiny nodules in thyroid visualized by ultrasound
  - Mildly increased calcitonin levels

Diagnosis

Suspected in cases of elevated calcitonin levels and fine needle aspiration cytology; diagnosis on histology from thyroidectomy for definitive diagnosis

Laboratory

Mildly elevated calcitonin levels: routine screening of serum calcitonin in patients with nodular goiter demonstrated abnormal values in 4.5% and all of the abnormal cases had MTC or CCH (Am J Surg Pathol 1998;22:722)

Radiology description

Neoplastic CCH: tiny nodules in upper 2/3 of both lobes of thyroid

Prognostic factors

Reactive CCH: good prognosis since it has no premalignant potential or RET mutation
Neoplastic CCH: premalignant and progresses to medullary thyroid cancer over time

Case reports

58 year old man with bilateral C cell hyperplasia and chronic lymphocytic thyroiditis (Am J Surg Pathol 1991;15:599)

Treatment

Total thyroidectomy, particularly if familial history or RET mutation positive
Isthmus preserving total bilobectomy: rationale for this procedure is that C cells derived from the ultimobranchial body migrating into the thyroid do not reach isthmus region and are distributed along the vertical axes of the thyroid lobes
Remnant of isthmus can, over time, compensate for loss of thyroid, especially in children (World J Surg 2006;30:860)

Gross description

Neoplastic CCH may have 1 - 2 mm nodules in upper 2/3 of thyroid lobes
Reactive CCH does not have distinct gross lesion apart from that associated with the underlying pathology

Microscopic (histologic) description

Increased C cells
3 architectural patterns: (Cancer 1996;77:750)
- Focal (segmental proliferation of C cells within thyroid follicles)
- Diffuse (circumferential intrafollicular collars pushing the follicular cells into the lumen)
- Nodular (clusters of C cells completely replacing the follicle)
C cells are pale staining, polygonal or spindle shaped, with abundant clear to fine granular cytoplasm and round / oval vesicular nuclei; they are located within the follicular basement membrane, do not extend through defects in follicular basal lamina, do not infiltrate thyroid interstitium
Unlike reactive CCH, neoplastic CCH is associated with cytologic atypia and hence recognizable on H & E

Reactive CCH criteria:
Not evident on routine H & E staining
Cytologically bland C cells are similar to follicular cells and histiocytes
Need immunohistochemical staining for calcitonin to identify C cells

Neoplastic CCH criteria:
Often bilateral
Can be readily identified by routine H & E staining and does not require calcitonin staining
Cells with mild to moderate atypia and nuclear pleomorphism resembling medullary thyroid carcinoma cells
Progresses from focal to diffuse and nodular hyperplasia to medullary thyroid carcinoma in situ
Can use PAS or anticollagen IV antibodies to highlight follicular basement membrane and distinguish cells within follicles (noninvasive) from those outside follicles (invasive)

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Various images

AFIP images

Calcitonin staining:

C cells highlighted

Nodular CCH

C cells adjacent to follicular carcinoma

MEN2A patients:

Circumferential proliferation

Focal proliferation of C cells

Eccentric intrafollicular proliferation

MEN2A patients with early medullary carcinoma:

Group of C cells extends into interstitium

Images hosted on other servers:

Calcitonin staining, C cells form ring around follicle

Associated with nodular goiter

MEN2A patient

High power

Cytology description

Scant bimodal cell population of benign follicular cells and larger calcitonin positive cells (Acta Cytol 1998;42:963)

Positive stains

Calcitonin
Also calcitonin gene related peptide, CEA, chromogranin, synaptophysin and neuron specific enolase (NSE), NCAM/CD56 (NCAM/CD56) (neoplastic cases)
Also ER-beta (neoplastic cases, Virchows Arch 2007;450:433)

Negative stains

Thyroglobulin, neural cell adhesion molecular (reactive cases), galectin3 (Clin Endocrinol (Oxf) 2002;57:813)

Electron microscopy description

Proliferation of C cells within follicular basement membrane adjacent to luminal colloid; two main types of secretory granules (containing calcitonin)
Prominent rough endoplasmic reticulum

Molecular / cytogenetics description

RET mutation in neoplastic (Ann Endocrinol (Paris) 2006;67:190) but not in reactive CCH (J Mol Diagn 2007;9:214)

Differential diagnosis

Nodular CCH versus microinvasive medullary carcinoma:
- PAS or anti collagen IV antibodies to highlight follicular basement membrane and distinguish neoplastic CCH cells within follicles (noninvasive) from those outside follicles (invasive / microinvasive medullary thyroid carcinoma)
- Stromal sclerosis in microcarcinoma
- Ongoing debate of lower limit for microinvasive medullary carcinoma and upper limit of nodular CCH
Solid cell nests including squamous metaplasia (associated with thyroiditis), parathyroid nests, thymic remnants, nests of thyroid follicular cells with tangential sectioning (cytoplasm not clear)

Additional references

Oncol Res Treat 2015;38:249, N Engl J Med 1973;289:437, Rom J Morphol Embryol 1999;45:53

Board review style question #1

C cells are found along the entire longitudinal axis of the thyroid lobe
Neoplastic C cell hyperplasia can be detected in H&E stains
Patients with a thyroid mass and hypercalcinemia may have something other than MTC
Reactive and neoplastic C cell hyperplasia are biologically and morphologically distinct
RET mutation distinguishes neoplastic from reactive C cell hyperplasia

Board review style answer #1

A. C cells are not found along the entire longitudinal axis of the thyroid lobe, since only the upper two thirds of the thyroid lobes are populated by C cells.

Comment Here

Reference: C cell hyperplasia

Calcification

Table of Contents

Definition / general

Deposition of calcium salts in thyroid gland
More important to radiologists than pathologists

Epidemiology

Prevalence in thyroidectomy specimens is 15% (Head Neck 2002;24:651)
Found by ultrasound in 8% of benign (multinodular goiter) and 26% of malignant nodules (Head Neck 2002;24:651)
Increases with advancing age

Sites

Retrosternal thyroid / goiter tends to be calcified more heavily

Pathophysiology

Dystrophic calcification of thyroid results from degenerative changes (calcified colloid and degenerated epithelium, psammoma bodies, old hemorrhage, vessel wall, etc.)
Metastatic calcification is caused by elevated blood calcium / phosphate
Stromal calcification may progress to bone formation (Mod Pathol 2009;22:887)

Diagnosis

Core needle biopsy is superior to FNA for thyroid nodules with macrocalcification (Thyroid 2015;25:657)

Laboratory

Hypercalcemia due to hyperparathyroidism, in rare cases of metastatic calcification

Radiology description

Microcalcifications (< 2 mm and without acoustic shadow by ultrasound) in thyroid nodules are usually psammoma bodies
Macrocalcifications (≥ 2 mm and with acoustic shadow) are secondary to tumor necrosis and can be seen in both benign and malignant nodules
Peripheral (eggshell) calcifications surrounding the nodule are secondary to chronic degenerative changes
Various patterns of calcification may be observed on Xray: nodular, flat, curvilinear, cloudy and a mixed type (Clin Radiol 1981;32:571)

Prognostic factors

Microcalcification due to psammoma bodies is a strong predictor of thyroid carcinoma (Head Neck 2002;24:651, J Int Med Res 2012;40:350), but the association of macrocalcifications with malignancy is controversial (Thyroid 2013;23:1106)

Case reports

41, 49 and 72 year old women with osseous metaplasia and mature bone formation (Oncol Lett 2013;6:977)
49 year old woman with long standing goiter (Minerva Endocrinol 2000;25:81)
67 year old man with eggshell calcification (Cases J 2008;1:11)
74 year old man with metastatic calcification (J Nucl Med 1986;27:373)
Unusual calcification in mixed papillary and follicular carcinoma (Radiology 1976;119:554)
Association with hypothyroidism (Clin Radiol 1992;45:209)

Clinical images

Images hosted on other servers:

Eggshell calcified retrosternal thyroid

Gross images

Images hosted on other servers:

Muddy appearance

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Calcium oxalate crystals (abundant)

Calcium oxalate crystals

Papillary thyroid carcinoma

PTC follicular variant with ossification

Concentric layers of calcium deposition in tumor stroma

Psammoma bodies, laminated calcifications

Evolution in psammoma body in PTC

Psammoma bodies in benign appearing thyroid

Images hosted on other servers:

Extensive dystrophic calcification

Osseous metaplasia with fatty marrow

Calcification induced artifact

Positive stains

Alizarin red / von Kossa

Differential diagnosis

Psammoma bodies are highly specific for papillary thyroid carcinoma, but should be differentiated from dystrophic stromal calcifications and inspissated colloid, both of which lack concentric laminations
Thyroid calcium oxalate crystals

Children

Table of Contents

Definition / general

Papillary (80%), follicular (10 - 20%), some cases historically may have been follicular variant of papillary carcinoma or Hürthle cell neoplasms (Am J Clin Pathol 2000;114:681), medullary (5%), anaplastic (rare)

Epidemiology

Increased risk for thyroid cancer in those < 1 year old who were exposed to Chernobyl fallout (J Pediatr Endocrinol Metab 2001;14 Suppl 5:1289, Best Pract Res Clin Endocrinol Metab 2008;22:1061)
Family history is also a risk factor

Clinical features

Regional nodal metastases occur in 60 - 80%, distant metastases in 10 - 20% at diagnosis, often lung

Prognostic factors

Usually more advanced disease than adults (cervical nodal metastases, distant metastases) but excellent prognosis (Hormones (Athens) 2007;6:200)
Overall survival 100% and progression free survival is 77%, after median followup of 16 years (Am J Surg Pathol 2006;30:1420, Eur J Cancer 2006;42:2150)
Tall cell morphology has no prognostic significance, in comparison with adults

Case reports

12 year old girl with extensive lung metastases (J Med Case Rep 2007;1:29)

Molecular / cytogenetics description

RET rearrangements more common than adults, BRAF activation less common (20% versus 77% in adults, Mod Pathol 2005;18:898)

Videos

Pediatric thyroid nodules by A. Wassner and A. Bauer (2020)

Additional references

eMedicine: Pediatric Thyroid Cancer [Accessed 28 August 2019]

Clear cell

Table of Contents

Definition / general

Unusual morphologic subtype of papillary thyroid carcinoma (PTC) with retained papillary nuclear features and clear cytoplasm
Clear cell features are likely due to the mitochondrial expansion, abundant glycogen, lipid or thyroglobulin in the tumor cells (Am J Surg Pathol 1985;9:705)

Essential features

Rare papillary thyroid carcinoma subtype which comprises < 2% of all papillary thyroid carcinomas (Thyroid 2017;27:819)
Not associated with a worse prognosis
Needs to be distinguished from clear cell metastatic tumors to the thyroid

Terminology

Papillary thyroid carcinoma, clear cell variant

Epidemiology

Clear cell features are seen in < 2% of papillary thyroid carcinoma subtypes (Thyroid 2017;27:819)
M = F

Sites

Thyroid

Etiology

May be related to thyroid stimulating hormone (TSH) overstimulation (Thyroid 2017;27:819)

Clinical features

Neck mass
May have obstructive symptoms

Diagnosis

Neck ultrasound
Fine needle aspiration
Hemithyroidectomy versus complete thyroidectomy

Prognostic factors

Similar to conventional / classic papillary thyroid carcinoma
Angiolymphatic invasion, extrathyroidal extension and lymph node metastasis are associated with a worse outcome (Thyroid 2017;27:819)
Rare case associated with anaplastic thyroid carcinoma (Int J Surg Pathol 2019;27:658)

Case reports

49 year old woman with euthyroid status after total thyroidectomy due to functioning lung metastases from a clear cell variant of papillary thyroid carcinoma (Thyroid 2012;22:1084)
64 year old woman diagnosed with clear cell variant of papillary thyroid carcinoma (J Med Cases 2019;10:113)
79 year old woman with clear cell variant of papillary thyroid carcinoma with associated anaplastic thyroid carcinoma (Int J Surg Pathol 2019;27:658)

Treatment

Similar to conventional / classic papillary thyroid carcinoma (Thyroid 2017;27:819)
Surgical resection
Lymph node dissection may be indicated
Radioactive iodine may be used on case to case basis

Gross description

Solitary or multifocal masses with average size of 1.9 cm (range: 0.2 - 5.5 cm) (Thyroid 2017;27:819)
Solid in consistency
Ranges from pale to white in color
Contour may be well defined to infiltrative

Microscopic (histologic) description

Architecture may be follicular, solid or papillary
Tumor cell cytoplasm may be entirely clear to somewhat granular
Nuclear size and shape range from largely round to irregular
Classic nuclear features of papillary thyroid carcinoma: enlarged overlapped nuclei, chromatin clearing, irregular contours, grooves and intranuclear cytoplasmic pseudoinclusions are frequently observed throughout the tumor
Tumor proportion with clear cell features may vary and can be only focal
Psammoma bodies may be seen
Necrosis, increased mitotic activity and cytological pleomorphism are worrisome features of dedifferentiation (Int J Surg Pathol 2019;27:658)

Microscopic (histologic) images

Contributed by Julie Guilmette, M.D.

Predominantly follicular architecture

Clear cell features

Nuclear characteristics

HBME1 stain

Cytology description

Cells show cytoplasmic clearing (Clin Nucl Med 2015;40:885)
Range from watery clear to granular in appearance
Cells are cuboidal to columnar in shape
Typical nuclear features of papillary thyroid carcinoma are present but may only be focal

Positive stains

Negative stains

Electron microscopy description

Reveals dilated empty mitochondria, which can explain the clear cell feature
Characteristic findings of conventional papillary thyroid carcinoma were observed as well (Am J Surg Pathol 1980;4:501)
- Microvilli
- Infolded nuclei
- Nuclear bodies

Molecular / cytogenetics description

Few described molecular alterations (Thyroid 2017;27:819):
- RAS mutation
- PAX8::PPARy translocation
- EML4::ALK translocation
- TFG::MET translocation

Sample pathology report

Thyroid, total thyroidectomy:
- Papillary thyroid carcinoma, clear cell subtype, 1.5 cm, isthmus (see synoptic report)
- Negative for lymphatic invasion and extrathyroidal extension; resection margin negative

Differential diagnosis

Follicular thyroid carcinoma with clear cell features:
- Does not have papillary thyroid carcinoma nuclear features
- Usually HBME1 negative
Clear cell medullary carcinoma of the thyroid:
- Has C cell differentiation
  - Positive for calcitonin, synaptophysin and chromogranin but negative for HBME1
- Stroma may have amyloid deposits
Intrathyroidal parathyroid tumors (Surg Pathol Clin 2019;12:1007):
- Most are composed of round, finely granular chief cells and occasionally oxyphilic / oncocytic cells
- Has PTH immunoreactivity
- Does not express TTF1 and thyroglobulin
Metastatic clear cell renal cell carcinoma:
- Does not have papillary thyroid carcinoma nuclear features
- CD10, CAIX and RCC positive

Board review style question #1

Which of the following papillary thyroid carcinoma (PTC) subtypes shares a similar prognosis with classic / conventional papillary thyroid carcinoma?

Clear cell papillary thyroid carcinoma
Columnar papillary thyroid carcinoma
Hobnail papillary thyroid carcinoma
Solid papillary thyroid carcinoma
Tall cell papillary thyroid carcinoma

Board review style answer #1

A. Clear cell papillary thyroid carcinoma

Comment Here

Reference: Clear cell papillary thyroid carcinoma

Clear cell change

Table of Contents

Definition / general

Nonspecific finding in benign and malignant thyroid tumors; also seen in Hashimoto thyroiditis and dyshormonogenetic goiter
Follicular adenoma and carcinoma: due to empty vacuoles associated with dilated endoplasmic reticulum and Golgi (Ultrastruct Pathol 2001;25:361, Am J Surg Pathol 1988;12:240) or intracellular lipid and mucin (Acta Cytol 2002;46:757)
Follicular carcinoma with McCune-Albright syndrome: due to uncontrolled fatty acid synthesis (Mod Pathol 1999;12:969)
Lipid-rich cell adenoma: due to neutral fat
Medullary carcinoma: may be thyroglobulin negative (Hum Pathol 1985;16:844)
Papillary carcinoma: due to glycogen
Signet ring or lipoblast type tumors: vacuoles may contain thyroglobulin (Am J Surg Pathol 1985;9:705)
Undifferentiated carcinoma: due to glycogen

Case reports

29 year old woman with clear cell follicular adenoma arising in ectopic thyroid tissue (Endocr Pathol 1998;9:339)
37 year old woman with follicular carcinoma with FNA showing clear cells that were negative for thyroglobulin (Diagn Cytopathol 2000;23:222)

Gross images

AFIP images

Nodular hyperplasia with clear cell change

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

Papillary thyroid carcinoma metastatic to cervical lymph node

Hashimoto thyroiditis with clear cells

Nodular hyperplasia

Papillary carcinoma

Clear cell change

Clear cell change
(follicular variant)

Follicular neoplasms

Follicular carcinoma

Follicular neoplasm with clear cell change

Signet ring follicular adenoma

Oncocytic neoplasms

Sharp demarcation between clear and oncocytic cells

Gradual transition from oncocytic to clear cells

Both patterns exist in same cell

Renal cell carcinoma metastases

Clear cell type

Adenoma is thyroglobulin+

Cytology description

Follicular carcinoma:
- Clearing due to intracellular lipid and mucin
- Cohesive sheets of round / oval cells with abundant pale staining cytoplasm, tumor cells often cluster around branching capillaries, also frequent fat cells with discrete cell borders, cytoplasm distended by fat globules and eccentric nuclei (Acta Cytol 2002;46:757)

Positive stains

Thyroid tumors are generally thyroglobulin+ (Am J Surg Pathol 1984;8:187), but may be weak / negative

Electron microscopy images

AFIP images

Signet ring follicular adenoma

Marked dilation of cisternae

Differential diagnosis

Parathyroid carcinoma: metastatic or from parathyroid tissue in thyroid gland
Renal cell carcinoma

Columnar cell

Table of Contents

Definition / general

Rare aggressive variant of papillary thyroid carcinoma
Columnar cells with nuclear pseudostratification, scant cytoplasm and absent / minimal nuclear features of papillary thyroid carcinoma

Essential features

Aggressive variant of papillary thyroid carcinoma with papillary structures lined by columnar cells showing prominent nuclear stratification and lacking nuclear features of papillary thyroid carcinoma
Needs to be differentiated from metastatic colon and endometrial adenocarcinoma

Terminology

Papillary carcinoma, columnar cell variant

ICD coding

ICD-O: 8344/3 - Papillary carcinoma, columnar cell
ICD-10: C73 - Malignant neoplasm of thyroid gland

Epidemiology

0.15 - 0.4% of all papillary carcinomas (Pathol Int 2018;68:641)
Age: 32 - 90 years; usually older than patients with classic papillary thyroid carcinoma (Cancer Cytopathol 2017;125:389, Thyroid 2013;23:714, Turk Patoloji Derg 2015;31:34)
40 - 72% women (Mod Pathol 2011;24:739, Cancer Cytopathol 2017;125:389, Am J Transl Res 2019;11:6262)

Sites

Lateral lobes or isthmus of thyroid gland

Clinical features

Painless neck mass or symptomatic thyroid mass with compression symptoms or enlarged cervical lymph node (Mod Pathol 2011;24:739)
Associated with aggressive behavior and poor prognosis when unencapsulated (Am J Transl Res 2019;11:6262, Cancer Manag Res 2018;10:465)
- Extrathyroidal extension and nodal metastases in up to 55%
- Distant metastases in up to 5%
- Local recurrence
- Advanced clinical stage (AJCC stage III or IV) at presentation
- Poorer cancer specific survival in comparison with classic papillary thyroid carcinoma

Diagnosis

Workup is similar to any thyroid mass / nodule
- Ultrasound with fine needle aspiration cytology
- CT scan may be useful to evaluate extrathyroidal extension and lymph node metastases
Diagnosis is made via histological examination of a resection specimen, supplemented by immunohistochemistry
- Fine needle aspiration cytology can raise a suspicion of columnar cell variant and influence surgical decision making
- Need to differentiate from adenocarcinoma metastatic to the thyroid gland

Radiology description

Sonography: solid and hypoechoic nodules with microcalcifications; smooth margins in indolent tumors; microlobulated margins in invasive cases (Ultrasonography 2017;36:103, Korean J Radiol 2018;19:1000)
Heterogeneously enhancing nodule on contrast enhanced computed tomographic scanning (Diagn Cytopathol 2016;44:816)

Radiology images

Images hosted on other servers:

Ultrasound

Prognostic factors

Poorer prognosis than classic papillary thyroid carcinoma (Am J Transl Res 2019;11:6262, Cancer Manag Res 2018;10:465, Thyroid 2016;26:1)
Studies have reported better outcome for asymptomatic patients, young patients, smaller / lower stage and circumscribed / encapsulated tumors (Korean J Radiol 2018;19:1000, Mod Pathol 2011;24:739, Cancer Manag Res 2018;10:465)
Risk stratification as per ATA (American Thyroid Association) 2015 (Thyroid 2016;26:1)

Case reports

18 year old woman with mixed columnar cell and tall cell variant of papillary carcinoma (Diagn Cytopathol 2012;40:E4)
42 year old woman with thyroid mass (Cytopathology 2017;28:338)
50 year old man with colon carcinoma and 18FDG avid nodules in thyroid and neck lymph nodes (Endocr Pathol 2015;26:187)
58 year old woman with history of progressively increasing neck swelling (Cytojournal 2014;11:27)
64 year old woman with pathologic fracture of the femur neck (Pathol Res Pract 1998;194:861)
86 year old man with composite mucoepidermoid carcinoma and columnar cell variant of papillary thyroid carcinoma (Int J Surg Pathol 2016;24:336)
87 year old woman with brain metastasis (Virchows Arch 2013;462:473)

Treatment

Based on ATA (American Thyroid Association) 2015 and NCCN guidelines, usually surgical excision (Thyroid 2016;26:1, J Natl Compr Canc Netw 2018;16:1429)

Gross description

Solid nodule, 0.6 - 10 cm (Cancer Cytopathol 2017;125:389, Mod Pathol 2011;24:739)
Invasive, rarely encapsulated
Variable calcification

Gross images

Images hosted on other servers:

Circumscribed and infiltrative

Microscopic (histologic) description

Patterns
- Papillary is the most common (Cancer Cytopathol 2017;125:389)
- Others include trabecular, follicular, solid and cribriform (Histopathology 2018;72:40, Turk Patoloji Derg 2015;31:34, Mod Pathol 2011;24:739)
- Rare squamous morule formation or rosette-like structures (Mod Pathol 2011;24:739, Cytojournal 2014;11:27)
Columnar cells
- Clear to pale eosinophilic cytoplasm (Mod Pathol 2011;24:739)
- Supranuclear or subnuclear cytoplasmic vacuoles resembling secretory endometrium (Histopathology 2018;72:40, Adv Anat Pathol 2018;25:172, Cancer Cytopathol 2017;125:389)
Nuclear features
- Prominent pseudostratification (Cancer Cytopathol 2017;125:389)
- Elongated, hyperchromatic nuclei with coarse chromatin (Histopathology 2018;72:40, Adv Anat Pathol 2018;25:172, Head Neck 2011;33:1052)
- Rare or absent chromatin clearing, nuclear grooves and intranuclear inclusions
- Nuclear grooves may be prominent (Cancer Cytopathol 2017;125:389, Cytojournal 2014;11:27)
- Inconspicuous nucleoli
Mitotic activity can be increased (Adv Anat Pathol 2018;25:172, Mod Pathol 2011;24:739)
Variable necrosis (Mod Pathol 2011;24:739)
Usually lacks psammoma bodies (Adv Anat Pathol 2018;25:172, Cancer Cytopathol 2017;125:389)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Papillary pattern

Pseudostratification

Tightly packed

Invasive

High Ki67

Cytology description

Cellular aspirate with absent or scant colloid
Patterns
- Papillary fragments with fibrovascular cores (Cancer Cytopathol 2017;125:389)
- Variable interspersed singly distributed cells
- Less common syncytial, honeycomb, microfollicular or cribriform
- Rare rosette-like structures (Cytojournal 2014;11:27, J Cytol 2017;34:183)
Tumor cells
- Columnar and spindle shaped
- Variably vacuolated or wispy cytoplasm (Diagn Cytopathol 2012;40:E4, Cytojournal 2014;11:27)
- Elongated, hyperchromatic oval / elongated / pleomorphic nuclei
- Nuclear pseudostratification
- Rare or absent nuclear features of papillary thyroid carcinoma
- Rare cases with frequent nuclear grooves (Cancer Cytopathol 2017;125:389, Cytojournal 2014;11:27)
- Inconspicuous nucleoli
- Sometimes mitotic figures
Most correspond to the Bethesda VI category (Cancer Cytopathol 2017;125:389)

Cytology images

Contributed by Ayana Suzuki, C.T.

Papillary fragments

Nuclear features

Positive stains

Thyroid specific: TTF1, PAX8, thyroglobulin
Cytokeratins: AE1 / AE3, CK7
CDX2 expression is diagnostic, reported in 10 - 66% (Thyroid 2013;23:1498, Thyroid 2013;23:714, Am J Clin Pathol 2012;137:722)
ER in 67 - 70%, PR in 50 - 55% (Thyroid 2013;23:714, Mod Pathol 2011;24:739)
Variable Ki67 proliferative index, up to 50% (Thyroid 2013;23:714, Mod Pathol 2011;24:739)
Increased nuclear expression of cyclin D1

Negative stains

CK20, calcitonin, vimentin

Molecular / cytogenetics description

BRAF V600E mutation in 17 - 33% based on limited evidence (Thyroid 2013;23:1498, Thyroid 2013;23:714, Mod Pathol 2011;24:739)

Sample pathology report

Thyroid, total thyroidectomy:
- Papillary thyroid carcinoma, columnar cell variant, right lobe, 5.5 cm (see synoptic report)

Differential diagnosis

Tall cell variant of papillary thyroid carcinoma:
- Height of cells 2 - 3 times the cell width
- Oncocytic cytoplasm
- Well developed nuclear features of papillary thyroid carcinoma
- Prominent intranuclear inclusions
Metastatic intestinal adenocarcinoma:
- Clinical history or endoscopic and radiology findings
- CK20 positive
- CK7 negative
- TTF1 / PAX8 / thyroglobulin negative
- CDX2 is not helpful because expressed by both colorectal carcinoma and columnar cell variant of papillary thyroid carcinoma
Metastatic endometrial adenocarcinoma:
- Clinical history or radiology findings
- Vimentin positive
- TTF1 / PAX8 / thyroglobulin negative
- CDX2 negative
Metastatic pulmonary adenocarcinoma:
- Clinical history or radiology findings
- PAX8 / thyroglobulin negative
Medullary thyroid carcinoma (rare on cytology):
- Thyroglobulin negative
- Calcitonin positive

Board review style question #1

Which of the following is the most likely immunohistochemical profile of this thyroid tumor?

TTF1+, PAX8+, CDX2+
TTF1+, PAX8+, CDX2-
TTF1+, PAX8-, CDX2+
TTF1-, PAX8+, CDX2-
TTF1-, PAX8-, CDX2-

Board review style answer #1

A. TTF1+, PAX8+, CDX2+. Cells of columnar cell variant of papillary thyroid carcinoma are positive for thyroid specific markers (TTF1 / PAX8), as well as the intestinal epithelial marker CDX2.

Comment Here

Reference: Columnar cell variant

Board review style question #2

Which of the following is true about columnar cell variant of papillary thyroid carcinoma?

An indolent clinical course
Abundant oncocytic cytoplasm
Multiple intranuclear pseudoinclusions
One of the most common variants of papillary thyroid carcinoma
Morphology mimics metastatic adenocarcinoma

Board review style answer #2

E. Morphology mimics metastatic adenocarcinoma. Columnar cell variant is rare and an aggressive papillary thyroid carcinoma type, characterized by scant clear or eosinophilic cytoplasm and lack of well developed nuclear features of papillary thyroid carcinoma. Due to absence of typical nuclear features of papillary thyroid carcinoma, metastatic adenocarcinoma needs to be ruled out.

Comment Here

Reference: Columnar cell variant

Congenital hypothyroidism

Table of Contents

Definition / general

Also called cretinism
Congenital hypothyroidism (CH) is a clinical condition characterized by absence of thyroid hormone secondary to abnormal thyroid gland developmental or biosynthesis disorders (J Coll Physicians Surg Pak 2013;23:214)
This topic also contains links to its two causes, Aplasia / hypoplasia and Dyshormonogenetic goiter
Congenital hypothyroidism is now treatable due to newborn testing, iodine supplementation and hormone replacement therapy (Pediatrics 2006;117:2290)
The consequence of untreated CH is a constellation of physical and mental conditions, called cretinism
The incidence of congenital hypothyroidism has been increasing in the U.S. since mandated screening began (Mol Genet Metab 2007;91:268)

Essential features

Congenital hypothyroidism (CH) is a preventable cause of intellectual disability (formerly mental retardation), usually caused by thyroid gland dysgenesis or agenesis
Rarely, CH may result from a pituitary or hypothalamic abnormality (Pediatrics 2006;117:2290)
Occasionally newborn thyroid abnormalities, including CH, are due to transplacental passage of medication, blocking antibodies or iodine excess / deficiency from the mother; in these cases, the abnormality is often transient (Pediatrics 2006;117:2290)
National screening programs allow early diagnosis and treatment (Iran J Pediatr 2014;24:665)
Clinically, signs and symptoms related to CH arise in early infancy and include impaired skeletal development, dwarfism, intellectual disability and GU congenital malformation (J Pediatr 2009;154:263)
Histological examination reveals variably size nodules with microfollicular, solid predominant and macrofollicular patterns
Follicular cytological atypia may be observed (Diagn Cytopathol 2013;41:720, Ann Transl Med 2013;1:21)

Epidemiology

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
2 million children are affected globally every year (Pediatrics 2015;135:594)
Affects one per 2,000 - 4,000 newborns (Best Pract Res Clin Endocrinol Metab 2008;22:57)

Pathophysiology

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
Maternal hypothyroidism may cause severe mental retardation, because maternal T3 / T4 crosses the placenta and is critical to support fetal brain development before the fetal thyroid gland develops
Two types of congenital hypothyroidism are described (Endocr Dev 2014;26:60):
- Thyroid dysgenesis (TD) results in a thyroid organogenesis defect
  - Mutations identified in these genes: TSHR, PAX8, NKX2-1, FOXE1 and NKX2-5
- Thyroid dyshormonogenesis affects overall thyroid hormone synthesis
  - Mutations cause iodine organification defects (TPO, DUOX2, DUOXA2, SLC26A4), iodine transport defect (SLC5A5), thyroglobulin (TG) synthesis or transport defect or iodotyrosine deiodinase (IYD / DEHAL1) deficiency

Etiology

Usually due to thyroid dysgenesis / agenesis, rarely due to inborn errors of metabolism
2% of patients with CH have a positive family history
This disorder is usually considered to be sporadic (J Clin Endocrinol Metab 2001;86:2009)

Clinical features

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
95% of CH neonates are asymptomatic at birth (J Coll Physicians Surg Pak 2013;23:214)
Unexpected death often occurs in untreated CH due to bronchoaspiration, heart failure or other organ dysfunction with serious infections (Gac Med Mex 1995;131:141)
Signs / symptoms include impaired development of skeletal system (short, coarse facial features and protruding tongue), severe intellectual disability, GU abnormalities and congenital malformation of the lungs, forebrain and palate (J Pediatr 2009;154:263)
Rare presenting signs are bradycardia at birth (J Coll Physicians Surg Pak 2013;23:214) or menorrhagia in adulthood (J Assoc Physicians India 2013;61:660)
Death may occur despite therapy (Am J Dis Child 1979;133:165)

Diagnosis

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
Screening programs for congenital hypothyroidism have been developed in Canada, the United States, parts of Mexico, Western Europe, Japan, Australia and New Zealand and they are under development in parts of many countries in Eastern Europe, Asia, South America and Africa (Iran J Pediatr 2014;24:665, Arq Bras Endocrinol Metabol 2013;57:184, Pediatrics 2006;117:2290)

Laboratory

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
TSH value cut-offs in blood samples vary based on national screening guidelines (Arch Dis Child Educ Pract Ed 2015;100:260, Clin Pediatr Endocrinol 2015;24:107, Klin Padiatr 2015;227:199)

Radiology description

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
Early thyroid ultrasound examination assesses gland volume, athyreosis ("empty thyroid area"), ectopic tissue and thyroid hypoplasia (Radiol Bras 2015;48:220)

Case reports

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
15 year old girl with congenital dyshormonogenetic hypothyroidism who presents with papillary thyroid carcinoma (Vojnosanit Pregl 2014;71:1078)
22 year old man with hypothyroidism and an enlarging thyroid nodule (Arq Bras Endocrinol Metabol 2014;58:958)
40 year old woman whose two children had congenital hypothyroidism (J Clin Endocrinol Metab 2011;96:E2039)
43 year old Indian man with congenital hypothyroidism treated for an unusual giant pituitary pseudotumor (BMJ Case Rep 2015 Jan 9;2015)

Treatment

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
CH patients die without treatment or despite treatment
Immediate hormone replacement (Horm Res 2007;68 Suppl 5:107)
Newborn screening and thyroid therapy started within two weeks of age can normalize cognitive development (Iran J Pediatr 2014;24:665)
Nationwide salt iodization programs (J Endocrinol Invest 2015;38:185, Pediatrics 2015;135:594)

Gross description

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
Enlarged multinodular thyroid gland may occur (Arq Bras Endocrinol Metabol 2014;58:958)
Nodules of varying size, fibrosis and occasionally hemorrhagic / cystic degenerative changes in a case of dyshormonogenetic goiter in a patient with CH and on thyroid hormone replacement therapy since early childhood (Ann Transl Med 2013;1:21)

Microscopic (histologic) description

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
CH patients treated with hormone replacement therapy:
- Prominent bridging fibrosis surrounding thyroid nodules
- Multiple thyroid nodules with different architectures, including a hypercellular microfollicular arrangement with scant colloid, hypercellular solid / trabecular nodules and macrofollicles containing colloid (Diagn Cytopathol 2013;41:720, Ann Transl Med 2013;1:21)
- Some follicular cells may contain vacuolated cytoplasm (Phlebologie 1990;43:319)
- Follicular cells may have bizarre, markedly enlarged hyperchromatic nuclei (Ann Transl Med 2013;1:21)

Cytology description

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
Large syncytial aggregates of follicular cells intermixed with smaller microfollicles, some with slightly enlarged hyperchromatic nuclei
No intranuclear grooves or pseudoinclusions (Diagn Cytopathol 2013;41:720)

Differential diagnosis

See also sections in these topics: Aplasia / hypoplasia and Dyshormonogenetic goiter
On cytology, CH can mimic follicular neoplasms of the thyroid gland (Diagn Cytopathol 2013;41:720)

Additional references

Wikipedia #1, #2, eMedicine

Cribriform-morular thyroid carcinoma

Table of Contents

Definition / general

Uncommon thyroid carcinoma of uncertain histogenesis characterized by a complex architecture, primarily cribriform with squamoid morules and absent / scant colloid formation
Cribriform-morular thyroid carcinoma (CMTC) was traditionally considered as a variant of papillary thyroid carcinoma (PTC); recent studies, however, showed that CMTC constitutes a clinicopathologically distinct category of thyroid carcinoma driven by Wnt / beta catenin pathway activation (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Relat Cancer 2017;24:R109)

Essential features

Histologic features include areas of cribriform, papillary, trabecular and solid growth with squamoid morules and absent / scant colloid formation
Classical nuclear features of papillary thyroid carcinoma (nuclear enlargement, elongation, overlapping, grooves, membrane irregularity, pseudoinclusions, clearing, chromatic marginalization) are often rare or absent (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168)
Almost all cases have genetic alterations in the Wnt / beta catenin pathway with APC mutations being the most common and found in both the familial and sporadic setting (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Pathol 2022;33:27)
Germline APC gene mutation in cases of familial adenomatous polyposis (FAP)
Diffuse nuclear and cytoplasmic positivity for beta catenin is the hallmark of CMTC in both FAP associated or non-FAP associated cases (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Pathol 2022;33:27)
Diagnosis of CMTC should alert the pathologist and clinician for a possible diagnosis of FAP and initiation of genetic screening (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168)

Terminology

Previously known as cribriform-morular variant of papillary thyroid carcinoma (not recommended) (Endocr Pathol 2022;33:27)

ICD coding

ICD-O: 8201/3 - cribriform carcinoma, NOS
ICD-11: 2D10.Y & XH1YZ3 - other specified malignant neoplasms of thyroid gland & cribriform carcinoma, NOS

Epidemiology

Almost exclusively in women; mean age is 26 - 33 years (range of 8 - 61; median is 24 - 30) (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Relat Cancer 2017;24:R109)
Frequently associated (up to 53%) with FAP or Gardner syndrome (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Relat Cancer 2017;24:R109)

Sites

Thyroid

Pathophysiology

Germline mutation in APC gene is seen in cases of FAP with thyroid tumors
Somatic mutations that result in activation of the Wnt / beta catenin signaling pathway can also lead to CMTC (Endocr Pathol 2022;33:27)
APC protein is a tumor suppressor that normally promotes degradation of beta catenin; in cases of APC protein mutation, the Wnt / beta catenin signaling pathway is constitutively activated, thus leading to uncontrolled proliferation and loss of cellular differentiation (see Diagrams)
Due to distinct clinicopathological, immunohistochemical profile and genetics, CMTC is no longer considered as a subtype of papillary thyroid carcinoma in the 2022 WHO classification of thyroid tumors (Endocr Pathol 2022;33:27)
- Complete lack of colloid in CMTC; absent PAX8 and thyroglobulin immunoreactivity suggest it is not a follicular cell derived tumor but rather a tumor of uncertain histogenesis (Endocr Pathol 2021;32:327)
- Squamoid morules typically coexpress CK5 and CD5, which suggests a thymic / ultimobranchial pouch related differentiation (Endocr Pathol 2021;32:327)

Etiology

Genetic alterations in the Wnt / beta catenin pathway
APC mutations are the most common genetic alteration and can be found in both familial and sporadic forms
Some cases may develop after external radiotherapy to the neck (J Clin Lab Anal 2023;37:e24819)

Diagrams / tables

Images hosted on other servers:

Molecular alterations associated with pathogenesis

Clinical features

Generally euthyroid
Thyroid enlargement or mass noted during physical examination
Incidental discovery during ultrasonography (Endocr Pathol 2014;25:302)
CMTC often precedes by several years the development of polyposis coli
Generally, FAP associated CMTC occurs in younger patients and is multifocal, whereas sporadic CMTC presents as a solitary thyroid nodule (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Pathol 2022;33:27)

Diagnosis

Diagnosis may be done or suggested either preoperatively using thyroid FNA or (more commonly) postoperatively with histologic evaluation and immunohistochemical confirmation

Laboratory

Serum thyroglobulin are normal or slightly elevated (J Med Ultrason (2001) 2015;42:83)
Because CMTC frequently does not express thyroglobulin, the use of serum thyroglobulin as a tumor marker in the follow up of patients may be unreliable (Endocr Pathol 2017;28:49)

Radiology description

Sonography findings are similar to follicular tumor or nodular goiter, rather than papillary thyroid carcinoma (J Med Ultrason (2001) 2015;42:83)
- Sonographic findings include smooth or focal jagged margin, hypoechoic nodule, lateral shadow, posterior acoustic enhancement, poor marginal and internal vascularity and no microcalcification (J Med Ultrason (2001) 2015;42:83)
- Most cases do not have features of malignancy on sonography (Thyroid 2013;23:45)

Radiology images

Images hosted on other servers:

Heterogeneous, hypoechoic mass without calcifications

Prognostic factors

Generally indolent clinical course with good prognosis but some aggressive cases have been reported
Lymph node metastases at presentation: 5 - 12% of cases (Endocr Relat Cancer 2017;24:R109, Mod Pathol 2018;31:1168)
Distant metastases: 3 - 6% of cases (Endocr Relat Cancer 2017;24:R109, Mod Pathol 2018;31:1168)
Overall mortality: 2% (Endocr Relat Cancer 2017;24:R109)
High proliferative index, poorly differentiated features, TERT promoter mutations suggest aggressive features with poor outcome (Int J Surg Pathol 2013;21:379, Endocr Pathol 2017;28:49)
CMTC can show a high Ki67 labeling index, despite its excellent prognosis (Ki67 labeling index ranges from 4.8 to 36.4% [mean of 15.2%]) (Pathobiology 2019;86:248)

Case reports

15 year old girl who underwent external radiotherapy to the neck for Hodgkin disease and developed CMTC 5 years after radiotherapy (J Clin Lab Anal 2023;37:e24819)
19 year old woman, with a 3.7 cm thyroid mass (Case #528)
19 year old woman with right sided neck swelling (Case #470)
20 year old woman with thyroid carcinoma (Acta Biomed 2021;92:e2021153)
22 year old woman with an incidental neck lump (Endocr Pathol 2014;25:302)
22 year old woman with no history of FAP (Fam Cancer 2020;19:15)
28 year old woman with FAP and lung lesions (Pathol Int 2018;68:700)
42 year old man with FAP and lung and brain lesions (Am J Clin Pathol 2009;131:134)

Treatment

Lobectomy is recommended for non-FAP associated CMTC and total thyroidectomy for FAP associated CMTC (Endocr J 2011;58:685, Pathol Res Pract 2015;211:712)
Extensive lymph node dissection is not necessary because nodal metastases are rare (Endocr J 2011;58:685, Pathol Res Pract 2015;211:712)
Lack of follicular cell differentiation raises the possibility that these tumors may not benefit from radioactive iodine (RAI) related adjuvant therapies
Cases with recurrences or distant metastases may respond to lenvatinib (Thyroid 2019;29:1511)
Clinicians should be alerted to exclude FAP since this diagnosis is the first indicator of FAP syndrome in 25% of cases

Gross description

Multifocal lesions throughout the entire thyroid in syndromic patients (Arch Pathol Lab Med 2019;143:1382)
Well circumscribed, solid with cystic areas and white lesions (Arch Pathol Lab Med 2019;143:1382)

Gross images

Images hosted on other servers:

Multifocal tumors throughout the entire thyroid

Microscopic (histologic) description

Lesion is well circumscribed and encapsulated
Fibrous septa separating the tumor into multiple lobules
Common growth patterns: cribriform, follicular, papillary, trabecular and solid
Tubular follicles without colloid
Papillary or pseudopapillary structures lined with tall or pseudostratified columnar cells
Cribriform architecture with anastomosing bars and arches without intervening fibrous stroma
Hyperchromatic nuclei with occasional papillary thyroid carcinoma nuclear features, such as nuclear overlap, grooves, pseudoinclusions and clearing
Distinctive squamoid morules composed of whorls of spindle to ovoid cells with nuclear clearing and lacking keratinization
These morules may be rare and difficult to find in some cases
Psammoma bodies are rare (Endocr Relat Cancer 2017;24:R109)
Capsular invasion (30%), angioinvasion (40%) and extrathyroidal extension in a subset of cases (Mod Pathol 2018;31:1168)
Aggressive features include neuroendocrine differentiation, necrosis and high mitotic activity (Mod Pathol 2018;31:1168, Am J Clin Pathol 2009;131:134, Pathol Int 2018;68:700)

Microscopic (histologic) images

Contributed by Jonathan K. Lai, M.D., Drs. Safa Alshaikh and Aalaa Mohammed (Case #470) and Dr. Bin Xu (Case #528)

Encapsulated thyroid nodule

Complex architecture

Cribriform-morular architecture

Trabecular pattern

Sieve-like spaces and morules

Squamoid morules

Hallmark feature

19 year old woman with right sided neck swelling

Papillary and cribriform architecture

Scattered squamous morules

Scattered mitotic figures

Multifocal tumor necrosis

CK5/6

TTF1

PAX8

Thyroglobulin

Beta catenin

Estrogen receptor

CD10

CDX2

Virtual slides

Images hosted on other servers:

Cribriform-morular thyroid carcinoma

Cytology description

Smears are hypercellular (Diagn Cytopathol 2010;38:890)
Colloid is absent (Diagn Cytopathol 2010;38:890)
Tall, columnar neoplastic cells with a papillary-like arrangement (Diagn Cytopathol 2010;38:890)
Round to oval slit-like empty spaces formed by spindle to ovoid cells within cell clusters are present (cribriform pattern) (Acta Cytol 2013;57:127)
Cell clusters with eddy formation (morules) are present (Acta Cytol 2013;57:127, Diagn Cytopathol 2010;38:890)
- Spindle shaped tumor cells are present in the background (Diagn Cytopathol 2010;38:890)
- Pale staining nuclei with thickened nuclear membranes is present focally (Diagn Cytopathol 2010;38:890)
- Nuclear grooves are present but intranuclear pseudoinclusions are less common than in the conventional papillary thyroid carcinoma (Diagn Cytopathol 2010;38:890)
- Cell block, if available, is extremely valuable to perform confirmatory immunostains including beta catenin (see below)

Cytology images

Contributed by Drs. Safa Alshaikh and Aalaa Mohammed (Case #470)

May-Grünwald-Giemsa

Pap stain

Images hosted on other servers:

Hypercellular, morular or papillary fragments

Positive stains

Cribriform component: beta catenin (nuclear and cytoplasmic), LEF1, TTF1, CK, EMA, estrogen, progesterone (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168)
Morular component: CDX2, CD10, CD5, CK5, BCL2, cyclin D1, Galectin3, CA 19-9 (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168)

Negative stains

Cribriform component: CK20, calcitonin, WT1, thyroglobulin, PAX8, HBME1 (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168)
Morular component: 34 beta E12, CK7, CK20, p63, p40, thyroglobulin, TTF1, PAX8, CEA, estrogen, progesterone (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168)

Electron microscopy description

Numerous microfilaments ~100 nm long at the nuclear clearing area of the morular regions (Ultrastruct Pathol 2004;28:97)

Molecular / cytogenetics description

Almost all cases have genetic alterations in the Wnt / beta catenin pathway with APC mutations being the most common and found in both the familial and sporadic setting (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Pathol 2022;33:27)
Mutations in other genes involved in the Wnt / beta catenin pathway such as CTNNB1 have also been detected (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Pathol 2022;33:27)
BRAF mutations are absent (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Endocr Pathol 2022;33:27)
Other uncommon associated molecular alterations include RET / PTC rearrangements, mutations in PIK3CA or RAS genes
TERT mutation may be associated with poor outcome (Endocr Pathol 2021;32:327, Mod Pathol 2018;31:1168, Thyroid 2014;24:1184)

Sample pathology report

Left thyroid lobe, resection:
- Cribriform-morular thyroid carcinoma, pathologic stage: pT2, N0 (see comment)
  - Tumor size: 2.0 cm
  - Microscopic extrathyroidal extension: not identified
  - Margins: Lymphovascular invasion: identified
  - Perineural invasion: not identified
  - Ancillary studies: BRAF V600E immunostain is negative; beta catenin immunostain is positive (cytoplasmic and nuclear)
  - Lymph nodes:
    - Number identified: 1
    - Number involved: 0
  - Intrathyroidal parathyroid identified
- Comment: Cribriform-morular thyroid carcinoma is frequently associated (up to 53%) with FAP or Gardner syndrome. Genetic testing is recommended.

Differential diagnosis

Papillary thyroid carcinoma subtypes:
- Columnar cell:
  - CMTC has darker nuclear chromatin, solid areas, tall cells with marked pseudostratification
  - Columnar cell papillary thyroid carcinoma displays supranuclear and subnuclear cytoplasmic vacuoles
  - Thyroglobulin, TTF1 and PAX8 positive
  - CDX2 positive in up to 50% of cases (note: CMTC is also CDX2 positive in the morular component)
- Tall cell:
  - Basal nuclei
  - Positive for thyroglobulin, TTF1, PAX8, HBME1 and BRAF V600E (90% of cases)
- Conventional:
  - Prominent papillary thyroid carcinoma nuclear features and colloid
  - Positive for thyroglobulin, TTF1, PAX8, HBME1 and BRAF V600E (40 - 60% of cases)
Poorly differentiated thyroid carcinoma:
- CMTC displays CD10 positive morulae, lower mitotic activity and is negative for thyroglobulin and PAX8
Hyalinizing trabecular tumor:
- CMTC can have areas of trabecular growth
- Positive for thyroglobulin, TTF1 and PAX8
- Positive for Ki67 with a membranous pattern of staining (using MIB1 antibody at room temperature)
Metastatic breast carcinoma:
- GATA3 positive, TTF1 negative
- CMTC is also ER and PR positive
Metastatic colon cancer:
- CMTC may have pseudoglandular component
- CDX2 positive (note: morular component of CMTC is also CDX2 positive)
- TTF1 negative

Board review style question #1

A 26 year old woman presented with multiple thyroid lesions. After a thyroidectomy, the histological features were consistent with the diagnosis of cribriform-morular thyroid carcinoma. Further clinical surveillance includes monitoring for which of the following associated neoplasms?

Cardiac myxoma
Colorectal carcinoma
Pheochromocytoma
Pleuropulmonary blastoma
Trichilemmomas

Board review style answer #1

B. Colorectal carcinoma. Familial adenomatous polyposis (FAP) is a related to germline mutation of APC tumor suppressor gene, which strongly predisposes to colorectal carcinoma. Cribriform-morular thyroid carcinoma is associated with FAP as well. Other syndromes associated with thyroid pathologies include DICER1 syndrome (pleuropulmonary blastoma and multinodular goiter), Carney complex (cardiac myxoma and thyroid follicular adenoma / carcinoma), Cowden disease (trichilemmomas and follicular adenoma / carcinoma), MEN 2A / B (pheochromocytoma and C cell hyperplasia / medullary thyroid carcinoma).

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Reference: Cribriform-morular thyroid carcinoma

Board review style question #2

What is the beta catenin immunohistochemical staining pattern in cribriform-morular thyroid carcinoma (CMTC)?

Diffuse cytoplasmic and nuclear positivity
Loss of nuclear staining
Membranous, cytoplasmic and Golgi staining
Stippled nuclear staining
Strong membranous staining

Board review style answer #2

A. Diffuse cytoplasmic and nuclear positivity. CMTC is associated with FAP and driven by Wnt / beta catenin pathway activation. The hallmark immunoreactivity of CMTC is diffuse nuclear and cytoplasmic positivity for beta catenin due to decreased proteasomal degradation of beta catenin following mutation of the APC tumor suppressor gene.

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Reference: Cribriform-morular thyroid carcinoma

Board review style question #3

Which of the following statements about cribriform-morular thyroid carcinoma is true?

It does not occur in a familial setting
It is a subtype (variant) of papillary thyroid carcinoma
It typically is negative for thyroglobulin and PAX8
No distinct mutations are commonly identified

Board review style answer #3

C. It typically is negative for thyroglobulin and PAX8. Answer A is incorrect because they may be familial. Answer B is incorrect because the tumors are no longer considered a variant of papillary thyroid carcinoma. Answer D is incorrect because up to 53% of cases occur in the setting of germline APC mutation (familial adenomatous polyposis) and sporadic cases often harbor molecular alterations of the WNT / beta catenin pathway.

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Reference: Cribriform-morular thyroid carcinoma

Crystals

Table of Contents

Definition / general

Calcium oxalate crystals are frequently found in colloid, especially in inactive follicles of aged individuals (Am J Surg Pathol 1993;17:698)
Useful in differentiating thyroid tissue from parathyroid tissue (no crystals) on frozen section (Am J Surg Pathol 2002;26:813, Am J Surg Pathol 2014;38:1212)
Patients with chronic renal failure on long term dialysis have increased frequency of intracolloidal crystals due to systemic oxalate deposition; also noted in kidney, myocardium and other sites (Arch Pathol Lab Med 1979;103:58)
First described by Zeiss in 1877, who mentioned octahedral crystals of calcium oxalate in the thyroid gland (Am J Pathol 1954;30:545)
Accumulation of cystine crystals is found in cystinosis and leads to destruction and atrophy of follicular cells (J Pediatr 1977;91:204)

Essential features

Colloid often contains calcium oxalate crystals, particularly in nodular goiter but also in aged or hypoactive benign thyroid and rarely in tumors
Appear as intracolloidal birefringent crystals of various shape incidentally found in histologic sections or fine needle aspirates
Calcium oxalate crystals are useful in differentiating thyroid tissue from parathyroid tissue (no crystals) at frozen section

Epidemiology

Present in 79% of normal appearing thyroids at autopsy (Am J Clin Pathol 1987;87:443)
More prevalent in older individuals, with the highest prevalence (85%) in over 70 year olds, while no crystals were seen in those under 10 years old (Virchows Arch A Pathol Anat Histopathol 1993;422:301)
Heavy deposits of calcium crystals seen almost exclusively in benign conditions (Am J Surg Pathol 1993;17:698)
- Found in 70% of benign nodules (goiter, adenoma) vs. 8% of malignant nodules (FTC > PTC) (Am J Surg Pathol 1993;17:698)

Pathophysiology

Occurrence of calcium crystals in normal human thyroid is associated with a low functional state of the thyroid follicles (Virchows Arch A Pathol Anat Histopathol 1993;422:301)
Finding intracolloidal crystals may be a function of increasing age or disease state (Wenig: Atlas of Head and Neck Pathology, Third Edition, 2015)
Progressive accumulation may advance to dystrophic calcification

Diagnosis

Incidental microscopic finding (Nose: Diagnostic Pathology - Endocrine, First Edition, 2012)

Laboratory

No association with abnormal laboratory findings of thyroid function
Patients with renal failure on dialysis may have disseminated oxalate deposition in visceral organs including thyroid

Prognostic factors

No prognostic implications

Case reports

77 year old woman with multinodular goiter (Diagn Cytopathol 2016;44:814)

Microscopic (histologic) description

Anisotropic crystals appear as small transparent pale or colorless refractile foci variable in size and shape (polygonal, sand-like, needle shaped, rhomboid or irregular)
Large round or oval vacuoles within the colloid may contain calcium oxalate crystals
Crystals are strongly birefringent under polarized light microscopy
Intrathyroidal crystals are exclusively found within colloid and do not appear within cytoplasm of the follicular epithelial cells or in stroma (Wenig: Atlas of Head and Neck Pathology, Third Edition, 2015)
Background thyroid (Am J Surg Pathol 1993;17:698):
- There is no association with any specific thyroid condition
- Highest prevalence of crystals was found in nodular goiters and follicular adenomas (up to 80%)
- Rarely associated with malignant tumors, 33% prevalence in follicular carcinoma and 5% in papillary carcinoma
- One study found low prevalence in Graves' disease and Hashimoto thyroiditis but a large amount of crystals in subacute thyroiditis, which were also located in granulomas (Mills: Histology for Pathologists, Fourth Edition, 2012)
Crystals found at autopsy tend to disappear within hours after death (Virchows Arch A Pathol Anat Histopathol 1993;422:301)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

Abundant calcium oxalate crystals

Follicular adenoma: calcium oxalate crystals

Calcium oxalate crystals in the colloid

Calcium oxalate crystals

Cytology description

Variably sized and shaped crystals in the background of colloid (Diagn Cytopathol 2016;44:814)
In one series, total incidence of birefringent crystals was 45%, including 68% in benign lesions and 21% in malignant tumors (Acta Cytol 1999;43:575)
Benign diseases show a more scattered distribution of birefringent crystals, compared to the typical focal distribution in cancer
Occurrence of crystals in thyroid FNAC is lower than that in histologic specimens

Immunohistochemistry & special stains

Crystals are associated with weak or negatively thyroglobulin stained colloid and are not common in strongly Tg positive colloid (Virchows Arch A Pathol Anat Histopathol 1993;422:301)

Electron microscopy images

Images hosted on other servers:

Calcium oxalate crystallite

Spherical apatite crystallites

Differential diagnosis

Intracolloidal vacuoles (empty spaces) and dense particulated colloid (basophilic clumps) do not show birefringence under polarized light

Additional references

Thyroid gland: calcification

Board review style question #1

How are calcium oxalate crystals useful in frozen sections from thyroid and parathyroid?

Differentiate cancer from benign tissue
Distinguishing thyroid from parathyroid tissue
Helps to locate psammoma bodies
Identify age of patient
No practical utility

Board review style answer #1

B. Distinguishing thyroid from parathyroid tissue. Calcium oxalate crystals are useful in differentiating thyroid tissue (scattered to abundant crystals) from parathyroid tissue (no crystals) at frozen section.

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Reference: Crystals

Differentiated high grade thyroid carcinoma / high grade differentiated thyroid carcinoma (HGDTC)

Table of Contents

Definition / general

Malignant follicular cell derived thyroid neoplasm that retains the distinctive architectural and cytomorphological features of differentiated thyroid carcinoma (DTC) (including papillary thyroid carcinoma [PTC], follicular thyroid carcinoma [FTC] and oncocytic thyroid carcinoma [OTC]) except for the presence of ≥ 5 mitoses/2 mm² or tumor necrosis
Biologic features and prognoses are
- Intermediate between the favorable outcome of DTC and the very poor outcome of anaplastic thyroid carcinoma (ATC)
- Similar to poorly differentiated thyroid carcinoma (PDTC) (classified as per Turin criteria)

Essential features

Differentiated high grade thyroid carcinoma (DHGTC) is a new diagnostic entity most recently defined in the 2022 WHO Classification of Endocrine and Neuroendocrine Tumors (Endocr Pathol 2022;33:27)
DHGTC follows the definition of poorly differentiated thyroid carcinoma (PDTC) proposed by the Memorial Sloan Kettering Cancer Center (MSKCC) in 2006, which differs from the diagnostic criteria of PDTC proposed by the Turin consensus and restricts PDTC to mitotically active or necrotic tumor with solid / trabecular / insular growth pattern that lacks nuclear features of papillary thyroid carcinoma (Cancer 2006;106:1286)
Diagnostic concept of DHGTC captures a subset of aggressive thyroid carcinoma that was previously classified as regular papillary thyroid carcinoma, follicular thyroid carcinoma or oncocytic thyroid carcinoma that otherwise do not meet the Turin criteria for PDTC and fall short of meeting criteria for anaplastic thyroid carcinoma

Terminology

High grade differentiated thyroid carcinoma, papillary thyroid carcinoma (PTC) with high grade features, high grade PTC, high grade follicular carcinoma, follicular carcinoma with high grade features, PDTC on the basis of MSKCC criteria

ICD coding

ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

Uncommon and underrecognized tumor representing < 3% of all thyroid cancers (Hum Pathol 2024;144:53, Endocr Pathol 2023;34:34)
However, incidence may vary around the world, perhaps due to geographic or environmental influences
Most common in the sixth to eighth decades of life (mean age: 63.3; range: 3 - 90) (Hum Pathol 2024;144:53)
Typically occurs a decade later than differentiated thyroid carcinoma
Slightly more common in women; F:M = 1.1 - 2.1:1 (Hum Pathol 2024;144:53)

Sites

Usually thyroid gland
May rarely develop from ectopic thyroid tissue (e.g., mediastinum, thyroglossal duct cysts, ovary, etc.)
Progression to DHGTC may occur in lymph node metastases or at other metastatic sites

Pathophysiology

Arises following synchronous or metachronous progression of differentiated thyroid carcinoma (mainly papillary thyroid carcinoma), of which it retains the driving molecular signatures (mainly BRAF V600E mutation) and typically gains additional mutations, such as TERT promoter, TP53 and PI3K (Hum Pathol 2024;144:53, Endocr Pathol 2023;34:34, Adv Anat Pathol 2023;30:3)

Etiology

Not well characterized

Diagrams / tables

Images hosted on other servers:

PDTC versus DHGTC

Suggested diagnostic algorithm

Genetic evolution

Clinical features

Typically presents as a large solitary mass that has grown over several months
May develop as rapidly growing masses in the background of multinodular goiter
At presentation, often (but not always) associated with locally advanced disease, including gross extrathyroidal extension
Distant metastasis identified in up to 25% of patients at presentation but with time, there is increased incidence (40 - 70%) of distant metastasis, the most common sites being lung, bone and brain (Histopathology 2022;80:322, Cureus 2022;14:e32177)
Accounts for half of radioactive iodine (RAI) refractory FDG avid thyroid carcinoma cases

Diagnosis

Workup is similar to any thyroid mass / nodule
- Ultrasound with fine needle aspiration cytology
- CT scan may be useful to evaluate extrathyroidal extension and lymph node metastases
Because of the lack of criteria with high specificity and sensitivity, the preoperative diagnosis of DHGTC is hardly ever made or suggested on cytology
Variable cytologic appearance and categorization according to the Bethesda system are expected depending on the underlying well differentiated thyroid carcinoma (papillary thyroid carcinoma, follicular thyroid carcinoma, oncocytic follicular thyroid carcinoma [OFTC]); most cases are classified as Bethesda VI or Bethesda V, since most cases are high grade papillary thyroid carcinoma
Molecular testing of cytologic aspirates may assist in preoperative diagnosis
Definitive diagnosis is made via histological examination of a resection specimen, supplemented by immunohistochemistry
References: Cureus 2022;14:e32177, Hum Pathol 2024;144:53

Laboratory

Patients are euthyroid

Radiology description

Ultrasonography
- Usually described as solid, heterogeneous and hypoechoic with irregular and indistinct borders
- Most common Thyroid Imaging Reporting and Data System (TIRADS) scores are 4 and 5 (Hum Pathol 2024;144:53)
18F fluorodeoxyglucose positron tomography (PET / CT 18F FDG) may show an hypermetabolic mass (Diagnostics (Basel) 2020;11:4, Indian J Nucl Med 2011;26:196)

Radiology images

Images hosted on other servers:

5 cm nodule on ultrasound

Prognostic factors

Established adverse prognostic factors include larger tumor size, age over 45, extrathyroidal extension and distant metastasis
On multivariate analysis, independent adverse prognostic factors for disease specific survival may be older age, extensive necrosis and lack of encapsulation (Histopathology 2022;80:322)
Independent adverse factors for distant metastasis free survival include older age, male sex and vascular invasion (Histopathology 2022;80:322)
Independent adverse factors for locoregional recurrence free survival are older age, extensive necrosis, high N stage and positive margins (Histopathology 2022;80:322)
Disease specific survival of DHGTC may be worse compared with those with PDTC (Histopathology 2022;80:322)
In a recent study of cases meeting PDTC or DHGTC criteria, long term survival was poor, with 3 year, 5 year, 10 year and 20 year overall survival rates of 88%, 75%, 54% and 28% respectively and disease specific survival rates of 89%, 76%, 60% and 35%, respectively (Histopathology 2022;80:322)
TP53, PTEN and TERT promoter mutations are associated with adverse prognosis in DHGTC (Histopathology 2022;80:322)
Noninvasive DHGTC
- Rare but recognized occurrence
- Characterized by a tumor fulfilling all criteria for DHGTC but without evidence of invasive growth (after evaluation of the whole capsule / tumor interface)
- Usually has indolent biologic behavior, although some metastatic cases and fatal cases have been reported (Histopathology 2022;80:322, Mod Pathol 2000;13:861, Int J Surg Pathol 2014;22:749)

Case reports

43 year old woman with DHGTC and NRAS mutation, presenting with metastatic follicular component to the bone and papillary component to lymph nodes (Cureus 2022;14:e32177)
62 year old man with distant metastases to the left sixth rib, iliac crest and vertebrae ( J Clin Images Med Case Rep 2023;4:2730)

Treatment

Standardized management strategies are not well defined
Standard clinical management includes total thyroidectomy with consideration of lateral neck dissection (in the setting of clinically or radiographically abnormal nodes) (Endocr Pathol 2023;34:34)
Adjuvant therapy and external beam radiation can be considered for advanced or refractory disease on a case by case basis (Endocr Pathol 2023;34:34)
Targeted therapeutics should be considered since many cases of DHGTC (at least 50%) have targetable driver mutations, including BRAF V600E mutation or RET or NTRK rearrangements (Endocr Pathol 2023;34:34)
Tyrosine kinase inhibitors lenvatinib and sorafenib have been used in patients with radioiodine resistant / refractory carcinoma; dabrafenib and trametinib in BRAF V600E mutant tumors; selpercatinib and pralsetinib in RET rearranged tumors; and larotrectinib and entrectinib in NTRK rearranged tumors
Postoperative radioactive iodine (RAI): DHGTC is enriched with RAI refractory FDG avid thyroid carcinoma (~50% of cases); therefore, management and surveillance with fluorodeoxyglucose positron emission tomography (FDG PET) is recommended by the American Thyroid Association (Endocr Pathol 2023;34:34)
Similarly, as this lesion may produce less thyroglobulin given its relatively diminished maturation, serum thyroglobulin measurements may be an inaccurate method of surveilling these patients for disease recurrence (Histopathology 2022;80:322, Endocr Pathol 2023;34:34)

Gross description

Typically, overtly infiltrative with extrathyroidal extension but may rarely appear partially or even totally encapsulated (Hum Pathol 2024;144:53, Endocr Pathol 2023;34:34)
Varies in size between 2 and 13 cm but most are large tumors > 4 cm (average: 5 cm) (Hum Pathol 2024;144:53, Endocr Pathol 2023;34:34)
Foci of hemorrhage and tumor necrosis may be seen macroscopically (Hum Pathol 2024;144:53, Endocr Pathol 2023;34:34)
~30 - 50% are associated with easily identifiable lymph node metastases

Gross images

Images hosted on other servers:

Large with solid, fleshy areas

Thyroid mass, 6.2 cm

Frozen section description

Usually not performed

Microscopic (histologic) description

Overall cytomorphology and growth patterns depend on the underlying differentiated thyroid carcinoma and should be subclassified according to the dominant subtype, as follows
High grade papillary thyroid carcinoma (PTC)
- Most common histology of DHGTC (> 80%) (Histopathology 2022;80:322)
- Commonly associated with aggressive PTCs, including tall cell, columnar cell and hobnail subtypes
- Can also be seen in classical PTC and follicular variant of PTC (infiltrative or encapsulated)
- High grade PTC can show transition to PDTC (based on the Turin criteria) or to anaplastic thyroid carcinoma
- If the tumor shows dominant solid / trabecular / insular growth patterns but retains diagnostic nuclear features of PTC, the tumor is still classified as high grade PTC
High grade follicular thyroid carcinoma (FTC) (< 10% of DHGTC)
- Usually widely invasive FTC or tumors with extensive angioinvasion (> 4 vessels)
- High grade FTC can show transition to PDTC (based on the Turin criteria) or to anaplastic thyroid carcinoma
- If the tumor shows dominant solid / trabecular / insular growth patterns, the tumor is better classified as PDTC
High grade oncocytic thyroid carcinoma (OTC) (< 10% of DHGTC)
- Uncommon and restricted to OTC that shows follicular architecture
- OTC tends to have dominant solid, trabecular and insular growth patterns; in such cases, the tumor is better classified as PDTC
Mitotic activity
- Increased mitotic activity (≥ 5 per 2 mm²) is one of the hallmark of DHGTC
- Atypical mitoses may be found
- Mitotic count to be performed in the hotspot with the highest mitotic activity
- If there are areas of increased mitotic activity but they fall short of ≥ 5 per 2 mm², additional sampling is recommended
Tumor necrosis
- Tumor necrosis is the other hallmark of DHGTC
- Represents coagulative type necrosis characterized by karyorrhectic nuclear debris or ghost contours of dead tumor cells
- May be focal or extensive, sometimes comedo-like (Histopathology 2022;80:322)
- Must be distinguished from infarct type necrosis secondary to FNAB, which is often accompanied by fibrosis, granulation tissue, histiocytes, hemosiderin, calcification or cholesterol clefts or regressive changes in oncocytic tumors (Hum Pathol 2024;144:53, Endocr Pathol 2023;34:34)

Microscopic (histologic) images

Contributed by Marc Pusztaszeri, M.D. (source: World Tumor Registry)

Comedonecrosis

Tall cell PTC with necrosis

Widely invasive

Tumor necrosis in FTC subtype

Increased mitotic activity

Mitotic activity in PTC subtype

NRAS Q61R in FTC subtype

BRAF V600E

Increased Ki67

Virtual slides

Images hosted on other servers:

FTC subtype

PTC subtype

PTC subtype with lung metastases

PTC subtype with lymph node and lung metastases

Cytology description

Due to its rarity, reports on the cytological features of DHGTC are limited
Because of the lack of criteria with high specificity and sensitivity, the preoperative diagnosis of DHGTC is hardly ever made or suggested on cytology
Variable cytologic appearance and categorization according to the Bethesda system are expected depending on the underlying well differentiated thyroid carcinoma (papillary thyroid carcinoma, follicular thyroid carcinoma, oncocytic thyroid carcinoma)
Since most cases are high grade papillary thyroid carcinoma, most cases were classified as Bethesda VI or Bethesda V (Hum Pathol 2024;144:53)
However, ~30 - 35% are classified as Bethesda IV (Hum Pathol 2024;144:53)
Necrosis and mitotic figures may or may not be identified

Cytology images

Images hosted on other servers:

Bethesda V, suspicious for PTC

Positive stains

Thyroglobulin (tends to be weak and focal with dot-like reactivity), TTF1, PAX8, CK7
BRAF V600E (VE1): positive in up to 80 - 90% of cases (high grade papillary thyroid carcinoma)
Ki67: ranges from 1 to 30% (Hum Pathol 2024;144:53)

Negative stains

PTH, GATA3, calcitonin, synaptophysin, chromogranin and INSM1 (Endocr Pathol 2023;34:34)

Molecular / cytogenetics description

Molecularly heterogeneous group of tumors
Molecular profile of DHGTC follows the BRAF::RAS mutation driver dichotomy of differentiated thyroid carcinoma
In contrast to PDTC, DHGTC is enriched with BRAF V600E mutations (81%), given the high frequency of high grade papillary thyroid carcinoma in this group (Endocr Pathol 2023;34:34, Histopathology 2022;80:322)
~25% of high grade papillary thyroid carcinoma cases harbor oncogenic fusions, including ETV6::NTRK3, AGK::BRAF, CCDC30::ROS1 (Endocr Pathol 2023;34:34, Histopathology 2022;80:322)
RAS mutations, in particular NRAS mutations, are the second most common mutations in DHGTC and correlate with a high grade follicular thyroid carcinoma phenotype (Endocr Pathol 2023;34:34, Histopathology 2022;80:322)
DHGTC has an increasing frequency of additional molecular alterations, including TERT promoter mutations (39 - 44%), TP53 (8 - 43%), E1F1AX (6 - 11%) (Endocr Pathol 2023;34:34. Histopathology 2022;80:322)
PIK3CA (2 - 6%) and PTEN mutations (3%) can coexist with RAS mutation and correlate with a high grade follicular thyroid carcinoma phenotype (Endocr Pathol 2023;34:34, Histopathology 2022;80:322)

Molecular / cytogenetics images

See Diagrams

Videos

Special types of thyroid cancer with Dr. Virginia LiVolsi

Poorly differentiated carcinoma of the thyroid with Dr. Margaret Brandwein

What is new in the WHO 2022 in thyroid pathology

Sample pathology report

Thyroid, total thyroidectomy:
- Differentiated high grade thyroid carcinoma, papillary subtype, 5.5 cm in the left lobe (see synoptic report)
Thyroid, left hemithyroidectomy:
- Differentiated high grade thyroid carcinoma, follicular subtype, 5 cm (see synoptic report)
Thyroid, right hemithyroidectomy:
- Differentiated high grade thyroid carcinoma, oncocytic subtype, 6 cm (see synoptic report)

Differential diagnosis

Classic papillary thyroid carcinoma (PTC) and PTC subtypes:
- No high grade features (i.e., mitotic activity [≥ 5 per 2 mm²]) or presence of tumor necrosis
Follicular thyroid carcinoma:
- No high grade features (i.e., mitotic activity [≥ 5 per 2 mm²]) or presence of tumor necrosis
Poorly differentiated thyroid (insular) carcinoma:
- Shares increased mitotic activity (≥ 5 per 2 mm²) or presence of tumor necrosis
- Solid / trabecular / insular growth patterns
- No nuclear features of PTC but may have convoluted nuclei (Am J Surg Pathol 2007;31:1256)
Anaplastic thyroid carcinoma (ATC):
- Small percentage of DHGTC cases may progress to ATC at primary site, recurrence or metastasis
- ATC shows loss of follicular cell differentiation by histology and immunohistochemistry, such as loss of thyroglobulin and TTF1 expression
Medullary thyroid carcinoma:
- Absence of colloid
- No nuclear features of PTC; salt and pepper chromatin
- Immunoreactivity for calcitonin, CEA, synaptophysin, chromogranin and INSM1
- Absence of immunoreactivity for thyroglobulin and PAX8
Parathyroid carcinoma:
- Clinicoradiological context
- Immunoreactivity for PTH, GATA3, synaptophysin, chromogranin and INSM1
- Absence of immunoreactivity for thyroglobulin, TTF1 and PAX8
Metastases to the thyroid gland:
- Clinicoradiological context
- Absence of immunoreactivity for thyroglobulin
- Absence of immunoreactivity for TTF1 (except lung) and PAX8 (except renal and upper Müllerian origin tumors)
NUT carcinoma:
- Positive for NUT by immunohistochemistry or for NUTM1 fusion
- Can be positive for TTF1 and PAX8 in about 33% to > 50% of cases (Am J Surg Pathol 2022;46:1706, Histopathology 2024 May 6 [Epub ahead of print])

Additional references

Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015, Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012, Nosé: Diagnostic Pathology - Endocrine, 3rd Edition, 2022, Kakudo: Thyroid FNA Cytology - Differential Diagnoses and Pitfalls, 3rd Edition, 2023

Board review style question #1

What is the main difference between poorly differentiated thyroid carcinoma (PDTC) and differentiated high grade thyroid carcinoma (DHGTC)?

Increased mitotic activity
Presence of necrosis
Presence of RAS mutations
Presence of solid / trabecular / insular architecture and absence of nuclear features of papillary thyroid carcinoma
Presence of TERT promoter mutations

Board review style answer #1

D. Presence of solid / trabecular / insular architecture and absence of nuclear features of papillary thyroid carcinoma (PTC). Although PDTC may have convoluted nuclei, nuclear features of PTC is a rule out criterion for the diagnosis of PDTC according to the Turin criteria. In contrast, any nuclear features (including follicular neoplasm-like or papillary-like) and any growth pattern are allowed in DHGTC. Answers A, B, C and E are incorrect because PDTC and DHGTC can both have tumor necrosis or increased mitotic activity, RAS mutations and TERT promoter mutations; however, in contrast to PDTC, DHGTC is enriched with BRAF V600E mutations (81%), given the high frequency of high grade PTC in this group.

Comment Here

Reference: Differentiated high grade thyroid carcinoma / high grade differentiated thyroid carcinoma (HGDTC)

Board review style question #2

Which of the following statements about differentiated high grade thyroid carcinoma (DHGTC) is correct?

DHGTC is typically classified as Bethesda IV (follicular neoplasm) on cytology
Most common subtype of DHGTC is high grade papillary carcinoma
Most cases of DHGTC respond well to postoperative radioactive iodine (RAI)
Prognosis of DHGTC is better than poorly differentiated thyroid carcinoma (PDTC)

Board review style answer #2

B. Most common subtype of DHGTC is high grade papillary carcinoma. The most common subtype of DHGTC is high grade papillary thyroid carcinoma (PTC) (> 80%). Oncocytic thyroid carcinoma (OTC) and follicular thyroid carcinoma (FTC) are both uncommon. Answer A is incorrect because most cases of DHGTC are high grade PTC (especially aggressive subtypes), so the majority of them can be classified as Bethesda V or VI on cytology. About 30 - 35% are classified as Bethesda IV, corresponding mainly to high grade FTC and high grade OTC. Necrosis and mitotic figures may or may not be present on cytology. Answer C is incorrect because DHGTC is enriched with RAI refractory FDG avid thyroid carcinoma (~50% of cases). Answer D is incorrect because DHGTC is enriched with RAI refractory FDG avid thyroid carcinoma (~50% of cases). Answer D is incorrect because the prognosis of DHGTC is similar or even worse than poorly differentiated thyroid carcinoma (PDTC).

Comment Here

Reference: Differentiated high grade thyroid carcinoma / high grade differentiated thyroid carcinoma (HGDTC)

Diffuse follicular

Table of Contents

Definition / general | Terminology | Microscopic (histologic) description | Microscopic (histologic) images | Differential diagnosis

Definition / general

Tumor involvement of most of a lobe or both lobes by follicular variant of papillary carcinoma
Uncommon (1 - 2% of papillary thyroid carcinomas at most)
Younger patients than those with classic papillary carcinoma
Aggressive with more extrathyroidal extension, nodal metastases and vascular invasion than classic (encapsulated) follicular variant of papillary thyroid carcinoma (Virchows Arch 2002;440:418, Cancer 2006;107:1255)

Terminology

Also called nonencapsulated / infiltrative

Microscopic (histologic) description

Diffuse or micronodular pattern of growth
More intratumoral fibrosis than classic variant

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Infiltrative growth

Images hosted on other servers:

53 year old man with metastatic carcinoma

Differential diagnosis

Macrofollicular adenoma at frozen section
Multinodular goiter

Diffuse sclerosing

Table of Contents

Definition / general

Papillary thyroid carcinoma (PTC) variant characterized by diffuse involvement of one or both thyroid lobes with dense sclerosis, abundant psammoma bodies, solid foci with associated squamous metaplasia, chronic lymphocytic thyroiditis background and extensive lymphatic invasion
First described in 1985 by Vickery et al. (Semin Diagn Pathol 1985;2:90)

Essential features

Diffuse sclerosing variant of PTC (DSV PTC) is an uncommon variant of PTC highly prevalent in female pediatric / young patients and in patients with history of radiation exposure
Characterized by diffuse involvement of thyroid lobes, extensive lymphatic invasion, sclerosis, abundant psammoma bodies, squamous metaplasia and background thyroiditis
Has distinct clinical, pathological and molecular profiles when compared with conventional PTC
Aggressive subtype of PTC associated with frequent extrathyroidal extension, cervical lymph node metastasis, greater incidence of distant metastasis (5 - 15%) and more frequent recurrence than conventional PTC, however, mortality rates are similar to classic PTC

ICD coding

ICD-O: 8260/3 - papillary carcinoma of thyroid
ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

Rare: 0.7 - 2% of all PTC (World J Surg 2009;33:958, Endocr Pathol 2005;16:323, Ann Surg Oncol 2006;13:176, Crit Rev Oncol Hematol 2015;94:64)
F > M (4 - 5:1) (Ann Surg Oncol 2006;13:176, World J Surg 2009;33:958, J Surg Oncol 2004;86:44)
Presents more frequently in the second or third decade of life with a mean age of 30 at presentation, which is 10 - 15 years earlier than conventional PTC (Ann Surg Oncol 2006;13:176, J Clin Endocrinol Metab 2016;101:4603, Endocr Pathol 2005;16:331, Crit Rev Oncol Hematol 2015;94:64)

Sites

Thyroid, usually diffusely involving both lobes
Sometimes can present as a single nodule (Am J Surg Pathol 1989;13:1041)

Pathophysiology

Clonal neoplastic proliferation of thyroid follicular cells, usually with a specific driver mutation, mainly RET / PTC rearrangements resulting in the activation of the RAS / RAF / MAPK pathway (see Molecular / cytogenetics description below)

Etiology

Sporadic in most cases
Can occur in patients with a history of radiation exposure (Thyroid 2012;22:1016, Crit Rev Oncol Hematol 2015;94:64)

Clinical features

Diffuse involvement of one or both thyroid lobes, usually without forming a dominant mass (Crit Rev Oncol Hematol 2015;94:64)
Hard ("woody") thyroid gland, which may mimic Riedel thyroiditis (Case Rep Endocrinol 2015;2015:686085)
May be associated with hyperthyroidism or hypothyroidism (Endocr Pathol 2005;16:331)
Possible local compression symptoms such as dysphagia, hoarseness and dysphonia (Crit Rev Oncol Hematol 2015;94:64, Endocr Pathol 2005;16:331)
Frequently enlarged cervical lymph nodes, including lateral

Diagnosis

Workup is similar to any thyroid mass / nodule
- Ultrasound with fine needle aspiration cytology
- CT scan may be useful to evaluate extrathyroidal extension and lymph node metastases
Diagnosis is made via histological examination of a resection specimen
- Fine needle aspiration cytology can raise a suspicion of DSV PTC and influence surgical decision making

Laboratory

Commonly elevated antithyroglobulin, antimicrosomal and antithyroid peroxidase antibodies, perhaps due to destruction of normal thyroid follicles by tumor and exposure of cryptic antigens
May mimic Hashimoto thyroiditis clinically, which is also a frequent association (30 - 75%) (World J Surg 2009;33:958, Cytopathology 2014;25:199, World J Surg 2015;39:1728)

Radiology description

Most cases show diffuse, scattered microcalcifications ("snowstorm appearance") with or without associated suspicious masses and underlying heterogeneous hypoechogenicity (Clin Radiol 2007;62:382)
Ultrasound features correlate with numerous psammoma bodies and lymphocytic infiltration on histology (Korean J Radiol 2010;11:579)
Cervical lymphadenopathy is frequently present at the time of the ultrasound examination (Korean J Radiol 2010;11:579)

Radiology images

Images hosted on other servers:

Ultrasonographic features

Prognostic factors

Associated with higher rates of extrathyroidal extension (40 - 77%), lymph node metastases (68 - 86%) and distant metastases (11.6%, usually in lungs) at presentation compared with conventional PTC (J Surg Oncol 2004;86:44, Thyroid 2016;26:1285, J Clin Endocrinol Metab 2016;101:4603, Eur J Endocrinol 2017;176:433
Associated with a shorter disease free survival; however, the overall mortality rate is similar to that of conventional PTC with disease specific survival of 95% and 93% at 5 and 10 years, respectively (possibly due to younger patient age and aggressive initial treatment) (Ann Surg Oncol 2006;13:176, Endocr Pathol 2005;16:331, World J Surg 2009;33:958, World J Surg 2015;39:1728)
Risk stratification as per ATA (American Thyroid Association) 2015 (Thyroid 2016;26:1)

Case reports

11 year old girl with thyroid enlargement, hyperthyroidism and antibodies to thyroglobulin and thyroid peroxidase (Arch Pathol Lab Med 2005;129:e159)
18 year old woman with goiter (Ulster Med J 2007;76:113)
22 year old woman with diffuse thyroid calcifications (Medicine (Baltimore) 2016;95:e3141)
44 year old woman with a neck mass, sore throat, hoarseness and intermittent dysphagia (Case Rep Endocrinol 2015;2015:686085)
53 year old man with multiple brain metastases (Endocr Pathol 2000;11:97)
58 year old woman with hypertension and rheumatoid arthritis (Case #439)

Treatment

This diagnosis should trigger aggressive therapeutic management in an effort to achieve a possibly excellent long term clinical outcome (Endocr Pathol 2005;16:331)
Common treatment strategies are initial total thyroidectomy with neck dissection followed by radioiodine treatment, TSH suppression and a long term follow up (World J Surg 2009;33:958, J Surg Oncol 2004;86:44, J Clin Endocrinol Metab 2016;101:4603)

Gross description

Diffuse enlargement of one or both thyroid lobes (Crit Rev Oncol Hematol 2015;94:64)
Usually without a discrete tumor mass or alternatively with one or multiple ill defined masses recognizable on gross examination (Crit Rev Oncol Hematol 2015;94:64)
The cut surface shows a patchy, reticulated white-gray appearance with a gritty consistency due to presence of innumerable psammoma bodies (Crit Rev Oncol Hematol 2015;94:64)

Gross images

AFIP images

Diffuse growth and fibrosis

Images hosted on other servers:

Fibrotic cut surface

Frozen section description

Frozen section is usually not indicated
Standard of care is to perform preoperative fine needle aspiration to establish the diagnosis of PTC and to determine the most appropriate surgical procedure

Microscopic (histologic) description

Infiltrative growth with diffuse involvement of one or both lobes (papillary, solid or follicular pattern) (Endocr Pathol 2005;16:331, Crit Rev Oncol Hematol 2015;94:64)
- Tumor foci within large distended lymphatics throughout
- Numerous psammoma bodies frequently arranged in large clusters (Endocr Pathol 2005;16:331, Crit Rev Oncol Hematol 2015;94:64)
Dense fibrosis
Extensive lymphocytic infiltration and a background of chronic lymphocytic thyroiditis
Foci of squamous metaplasia in solid patterned areas (squamous morules) (Endocr Pathol 2005;16:331, Crit Rev Oncol Hematol 2015;94:64)
- Diagnostic nuclear features of PTC can be identified in nonsquamous areas
Extrathyroidal extension is common (Endocr Pathol 2005;16:331, Crit Rev Oncol Hematol 2015;94:64)
Lymph node metastases in ~ 80%, often affecting several levels of lymph nodes bilaterally (Endocr Pathol 2005;16:331)

Microscopic (histologic) images

Contributed by Livia Florianova, M.D., M.Sc. and Marc Pusztaszeri, M.D.

Lymphocytic infiltrate

Papillary pattern

Dense fibrosis

Dense sclerosing fibrosis

Infiltrative growth

Nuclear features

Psammoma bodies and sclerosis

Solid pattern

Squamous morule

Lymphovascular invasion

Lymph node metastasis

Contributed by Andrey Bychkov, M.D., Ph.D.

Multiple tumor nodules

Fibrosis and lymphocytic infiltration

Large psammoma bodies

Prominent sclerosis

Thick fibrous bands

Extensive squamous metaplasia

Virtual slides

Images hosted on other servers:

Papillary thyroid carcinoma, diffuse sclerosing type

PTC, diffuse sclerosing type

Cytology description

Moderately to highly cellular with scant or absent colloid
Neoplastic cells are often arranged in 3 dimensional ball-like clusters from which protruding hobnail cells can be frequently observed (Cytopathology 2014;25:199)
In contrast to conventional PTC, there is less chromatin pallor (slightly coarser chromatin) and fewer nuclear grooves and nuclear pseudoinclusions (Cytopathology 2014;25:199)
Squamous metaplastic changes: flat, polygonal shaped cells with sharply demarcated cell membranes, fitting together like jigsaw pieces (without overt keratinization) (Cytopathology 2014;25:199)
Numerous lymphocytes and psammoma bodies present in the background (Cytopathology 2014;25:199)
Cytological differential diagnosis includes chronic lymphocytic thyroiditis, PTC Warthin-like variant and lymphoma

Cytology images

Contributed by Livia Florianova, M.D., M.Sc., Marc Pusztaszeri, M.D. and Manon Auger, M.D.C.M.

3D ball-like clusters

Protruding hobnail cells

Squamous metaplasia

Cytological atypia

3D ball-like clusters

Psammoma body

Cytological and architectural atypia

Cytological atypia

Cytological and architectural atypia

Psammoma bodies and lymphocytes

Nuclear features

Psammoma bodies and lymphocytes

Positive stains

CK19, thyroglobulin and TTF1 expression in both papillary carcinoma and squamous metaplasia cells (Endocr Pathol 2005;16:331)
p63 reactivity in squamous metaplastic cells (Crit Rev Oncol Hematol 2015;94:64)
May be Napsin A positive and PAX8 negative (potential pitfalls) (Auris Nasus Larynx 2019 [Epub ahead of print], Endocr Pathol 2020;31:39)

Negative stains

Calcitonin, chromogranin, synaptophysin

Molecular / cytogenetics description

RET / PTC rearrangements are common (~ 60%), including RET / PTC1 (28 - 46%) and RET / PTC3 (14 - 16%) (Eur J Endocrinol 2017;176:433, Mod Pathol 2007;20:779, Histopathology 2016;69:45)
- RET / PTC3 rearrangement is associated with advanced stage at diagnosis and poor clinical outcome (Histopathology 2016;69:45)
Overall, BRAF mutations are uncommon (0 - 24%) (Mod Pathol 2007;20:779, Am J Surg Pathol 2012;36:844, Histopathology 2016;69:45)
- In contrast, the prevalence of BRAF mutation is higher in Korea (50 - 61%) (Pathology 2006;38:201, Thyroid 2013;23:1423)
RAS mutations have not been found (Br J Cancer 2000;82:315)
ALK translocations may be more common in DSV PTC (13%) compared with other PTC variants (2%) (Am J Surg Pathol 2015;39:652, Eur J Endocrinol 2017;176:433)

Sample pathology report

Thyroid, left lobe, fine needle aspiration:
- Satisfactory for evaluation
- Malignant (Bethesda Diagnostic Category VI)
- Papillary thyroid carcinoma, favor diffuse sclerosing variant
Thyroid, total thyroidectomy:
- Papillary thyroid carcinoma, diffuse sclerosing variant (see synoptic report)

Differential diagnosis

Chronic lymphocytic thyroiditis (with squamous metaplasia)
- No psammoma bodies
- Reactive atypia; no well developed nuclear features of PTC
- No solid clusters
- No lymphovascular invasion or metastasis, unless it is associated with PTC
PTC Warthin-like variant
- Usually one tumor mass instead of multiple tumor foci diffusely involving one or both thyroid lobes
- Oncocytic tumor cells
- Usually no solid clusters, psammoma bodies or squamous metaplasia

Board review style question #1

Which of the following statements is true about the diffuse sclerosing variant of papillary thyroid carcinoma (PTC)?

Extrathyroidal extension and lymph node metastasis are usually not detected
Not considered an aggressive type of papillary thyroid carcinoma
Patients are usually older than those with classical papillary thyroid carcinoma
Presents as a solitary thyroid nodule in which calcifications are infrequent
Shows a high 10 year disease specific survival

Board review style answer #1

E. Shows a high 10 year disease specific survival. Despite being an aggressive variant of PTC with some adverse prognostic features, mortality rates are similar to those of classical PTC with 93% disease specific survival at 10 years.

Comment Here

Reference: Papillary thyroid carcinoma, diffuse sclerosing variant

Board review style question #2

What is the most common molecular alteration found in the diffuse sclerosing variant of papillary thyroid carcinoma?

ALK translocation
BRAF V600E mutation
ETV6 / NTRK rearrangement
RAS mutation
RET / PTC rearrangement

Board review style answer #2

E. RET / PTC rearrangement. RET / PTC rearrangements are common (~ 60%), including RET / PTC1 (28 - 46%) and RET / PTC3 (14 - 16%). Overall, BRAF V600E is uncommon (0 - 24%), except in Korea (50 - 61%). ALK translocation is also uncommon (13%). RAS mutation and ETV6 / NTRK rearrangement have not been reported in diffuse sclerosing variant of papillary thyroid carcinoma.

Comment Here

Reference: Papillary thyroid carcinoma, diffuse sclerosing variant

DiGeorge syndrome

Table of Contents

Definition / general

DiGeorge syndrome is a chromosomal disorder due to 22q11.2 deletion, characterized by failure of development of the third to fourth pharyngeal pouches and fourth branchial arch, which leads to a combination of congenital heart disease, parathyroid abnormalities (hypocalcemia) and thymic abnormalities (immunodeficiency)
In 1965 DiGeorge described a group of infants with congenital absence of the thymus and parathyroid glands (J Pediatr 1965;67:907); however a constellation of clinical signs was known at least since 1829 (London Medical Gazette 1829;3:314)
See also Thymic dysplasia

Terminology

There are numerous synonyms, which were used historically to describe various manifestations of chromosome 22q11.2 deletion (OMIM #188400)
Most common synonyms: DiGeorge syndrome / anomaly, velocardiofacial syndrome (Shprintzen syndrome), conotruncal anomaly face syndrome (Takao syndrome)
Other synonyms: hypoplasia of thymus and parathyroids, III - IV pharyngeal pouch syndrome, Opitz G / BBB syndrome, CATCH 22 syndrome, Sedlackova syndrome, Cayler cardiofacial syndrome, Strong syndrome, congenital thymic aplasia
It is now recommended that patients with the classic chromosome 22q11.2 deletion be described according to the genetic nomenclature, i.e. "22q11.2 deletion syndrome", and patients with a clinical phenotype but a distinct cause or no known cause be described using syndromic nomenclature, i.e. "DiGeorge syndrome" (Medicine (Baltimore) 2011;90:1)

Epidemiology

Estimated prevalence is 1:4,000 births, range 1:3,000 - 1:6,000 (Lancet 2007;370:1443)
M = F
Spontaneous : familial = 10:1 (Genet Med 2001;3:23)
22q11.2 deletion syndrome is one of the most common genetic abnormalities (slightly less frequent than Down syndrome), and the most common chromosomal deletion syndrome in humans
5% of congenital cardiac defects and 2% - 3% of childhood onset schizophrenia are due to 22q11.2 deletion (J Med Genet 1993;30:852)
Infant mortality in 22q11 deletion syndrome is now relatively low (4%) due to adequate cardiac care, however the overall mortality rate compared to general population is elevated, especially in adults (J Pediatr 2011;159:332)

Sites

The syndrome crosses all organ systems, and is classically defined as polytopic developmental field defect (Am J Med Genet Suppl 1986;2:113)
Major targets are the organs derived from branchial apparatus; see details in Clinical Features
Thyroid is one of the organs involved, however clinical impact in the thyroid is low compared to other manifestations

Pathophysiology / etiology

Due to the hemizygous (only one of the chromosome pair) 22q11.2 deletion
The occurrence of 22q11.2 deletions is related to the genomic architecture of the chromosome 22q11.2 region with several common rearrangement breakpoints (J Pediatr 2011;159:332)
The characteristic deletion of chromosome 22q11.2 is at least 10 times more common than the next most frequent human deletion syndrome, suggesting that this region is inherently unstable (Dev Disabil Res Rev 2008;14:11)
The deletion typically arises via unequal meiotic crossover / exchange, facilitated by asynchronous replication at the site of the deletion (J Med Genet 2004;41:413)
Alternative mechanism is 22q11.2 microduplication (Eur J Med Genet 2009;52:88)
Approximately 85% - 90% of individuals with the syndrome have 3 Mb deletion, 8% - 10% have 1.5 Mb deletion with mild phenotype, and individuals with atypical deletions (so called central and distal) have also been reported (Cytogenet Genome Res 2015;146:89)
There are approximately 40 genes within the commonly deleted region of chromosome 22q11.2
- TBX1 is the main gene responsible for DiGeorge phenotype
- TBX1 is a transcription factor normally expressed in the pharyngeal pouches, which give rise to the face, neck (parathyroids and thymus) and upper thorax (Medicine (Baltimore) 2011;90:1)
- TBX1 is involved in retinoic acid signaling (Circ Res 2010;106:630)
- TBX1 is not expressed in the thyroid primordium, but in surrounding mesoderm, and determines thyroid size and positioning (Hum Mol Genet 2007;16:276)
- Other candidate genes are CRKL, COMT, DCGR8 (Cytogenet Genome Res 2015;146:89)
Over 90% of the deletions occur de novo, while 6% - 10% of new cases are inherited from an affected parent (Hum Mol Genet 2004;13:417)
Risk of recurrence in the offspring is up to 50% in each pregnancy

Diagrams / tables

Images hosted on other servers:

Pathophysiology

Mode of inheritance

Pedigree

Chromosome 22 abnormalities

Genetic mapping

Clinical features

Classic phenotype is a triad of heart defects (usually involving the aorta and the part of the heart from which the aorta develops), thymus gland abnormalities with related immunodeficiency / autoimmunity, and parathyroid gland abnormalities with hypocalcemia
However, it is widely acclaimed today that DiGeorge / 22q11.2 deletion syndrome has many more manifestations beyond the classical triad
Phenotypic features grouped by frequency and clinical significance (Medicine (Baltimore) 2011;90:1)
- Major:
  - Cardiac anomalies mainly involving outflow tract, i.e. conotruncal (80%): tetralogy of Fallot, pulmonary atresia, truncus arteriosus, interrupted aortic arch, ventricular septal defect
  - Immune deficiency (> 75%): thymic hypoplasia, rarely aplasia, with T cell lymphopenia
  - Palatal anomalies (70%): velopharyngeal insufficiency and cleft palate, both contributing to poor feeding and speech
  - Developmental delay with low IQ (50%)
- Intermediate: hypocalcemia, various structural anomalies (renal, GI, CNS, etc.), and psychiatric illnesses
- Minor: facial dysmorphism (bulbous nasal tip, hypertelorism, hooded eyelid, micrognathia, low set ears)
Depending on whether thymic hypoplasia or aplasia is present (in addition to heart defects and hypoparathyroidism), DiGeorge syndrome can be classified as partial or complete (Eur J Pediatr 1989;149:96):
- Complete phenotype (< 1%) is used to describe patients who are athymic and have no circulating T cells
- Patients with partial or incomplete phenotype have thymic hypoplasia with circulating T cells
Thyroid issues:
- Up to 10% of patients have overt thyroid disease, with hypo- or hyperthyroidism (4:1, Am J Med Genet A 2015;167:1560)
- Subclinical thyroid dysfunction often converts to apparent disease
- Recommended to monitor TSH and thyroxine levels in all 22q11.2 deletion syndrome patients (J Pediatr 2011;159:332)
- Rarely presents with Graves disease (16× risk compared to general population, Hormones (Athens) 2005;4:200)
- Structural defects are detailed in Gross Description

Diagnosis

Most patients are identified shortly after birth due to the presence of cardiac anomaly, hypocalcemia or recurrent infections
Genetic testing (see Molecular / Cytogenetics Descriptions / Images):
- May be warranted if affected parent/sibling or suspicious prenatal US findings;
- Advised in children with certain combinations: cardiac anomaly + any major / intermediate phenotypic feature; speech delay + any major / intermediate phenotypic feature; hypocalcemia alone or with any major / intermediate phenotypic feature (J Allergy Clin Immunol Pract 2013;1:589)
DiGeorge syndrome needs to be considered for some pediatric autopsies; for example, thymus and parathyroid should be located in cases of congenital heart disease, and in turn, absent parathyroids / thymus should prompt a detailed heart examination (J Pediatr 1979;94:883)

Radiology description

US and CT are useful to evaluate precise thyroid anatomy (Clin Endocrinol (Oxf) 2010;72:839, Laryngoscope 2009;119:1495)

Radiology images

Images hosted on other servers:

Absent thymus on CT

Subglottic stenosis on CT

Basal ganglia and periventricular calcification

Case reports

Male newborn with thyroid hemiagenesis (Horm Res Paediatr 2013;79:243)
1 month old girl with congenital hypothyroidism (J Pediatr Endocrinol Metab 1998;11:273)
3 month old girl with hypoplastic thyroid (J Postgrad Med 1989;35:114)
3 year old boy and 18 year old woman with Graves disease in DiGeorge syndrome (J Pediatr Endocrinol Metab 2004;17:1575, Endocr J 2000;47:91)
34 year old man with follicular adenomata and a nodular goiter (Case Rep Med 2013;2013:923129)

Treatment

Varies by age and phenotype
May include cardiac and palatal surgery, thymus transplantation, calcium supplementation, etc.

Clinical images

Images hosted on other servers:

Facial dysmorphism

Gross description

Unremarkable thyroid in half of the cases
Reported anomalies include (J Pediatr 1979;94:883, Pediatr Pathol 1993;13:463):
- Thyroid hypoplasia, with a left lobe predilection (Clin Endocrinol (Oxf) 2010;72:839)
- Absence of the isthmus of thyroid
- Agenesis of lobe of thyroid
- Retrocarotid or retroesophageal extension (Laryngoscope 2009;119:1495)
Hypoplasia and persistent fetal shape of thyroid cartilage (Pediatr Pathol 1986;6:209)

Microscopic (histologic) description

Consistent with normal thyroid histology (most specimens come from pediatric autopsies)
Rarely, pathological changes has been described:
- Predominant fetal follicles
- Hyperplasia
- Follicular adenoma and nodular goiter (Case Rep Med 2013;2013:923129)
- Thyroid carcinoma (Am J Med Genet A 2006;140:906)
C cells can be absent or significantly reduced in number, consistently with their pharyngeal pouch origin (Hum Pathol 1987;18:355, Am J Med Genet 1993;46:641, Pediatr Pathol 1993;13:463)

Microscopic (histologic) images

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Hypoplastic thyroid in mice

Various malformations in mice

Molecular / cytogenetics description

FISH is usually performed with a chromosome 22 specific probe that identifies the chromosome and a second probe that hybridizes to the commonly deleted region; if the second probe is absent on a "tagged" chromosome, then the diagnosis is established (Medicine (Baltimore) 2011;90:1)
- Turnaround time is 3 - 14 days
- Cost of the commercial test is $750
Alternative genetic tests
- Multiplex PCR (MLPA): rapid and cost effective
- CGH array: identifies atypical deletions and duplications not recognized by FISH

Molecular / cytogenetics images

Images hosted on other servers:

Deletion of 22q11.2 on FISH

Karyotype

Various techniques

Videos

DiGeorge syndrome

Pharyngeal apparatus

Differential diagnosis

Some genetic syndromes have overlapping features with 22q11 deletion syndrome (resolved by genetic testing):
- CHARGE syndrome: coloboma, heart, atresia, retarded growth / development (or both), genital, ear (Wikipedia)
- Smith-Lemli-Opitz syndrome (Genetics Home Reference)
- Kabuki syndrome (Genetics Home Reference)
- Goldenhar syndrome (Wikipedia)

Additional references

GeneReviews, Immune Deficiency Foundation (IDF), eMedicine, Wikipedia, Patient, MaxAppeal

Dyshormonogenetic goiter

Table of Contents

Definition / general

Thyroid enlargement due to various inherited defects in thyroid hormone synthesis
Lack of circulating thyroid hormone activates TSH secretion, which causes overstimulation and hyperplasia of defective thyroid gland
Important cause of congenital hypothyroidism often found during neonatal screening or otherwise manifested around puberty
Sporadic goitrous cretinism was known before 20th century (for example, documented by Pendred and Osler), however biochemical defects and causative mutations of different entities began to be identified only after 1950 and 1990, respectively (Thyroid 2003;13:771)
Less than 200 cases with detailed morphology have been reported (series and case reports), including around 30 cases with cancer

Essential features

Genetic autosomal recessive enzymatic defects in one of the steps of thyroid hormone synthesis, which causes congenital hypothyroidism (decreased to absent T3 / T4 and high TSH)
Deficiency of thyroid peroxidase (TPO) is the most common cause worldwide
Diffuse asymmetric enlargement of thyroid gland with prominent nodularity
Histologic hallmarks are markedly hypercellular nodules with papillary hyperplasia, absence of colloid, frequent internodular bizarre cells and bridging fibrosis

Terminology

Dyshormonogenetic goiter = thyroid dyshormonogenesis
Also known as inherited congenital / familial goiter and congenital / sporadic goitrous cretinism (more vague terms)

ICD coding

E07.1

Epidemiology

Rare inherited disorder with incidence of 1 per 30 - 50K live births in Europe and North America
- Higher rates in consanguineous communities (Clin Endocrinol (Oxf) 2013;79:275)
Second most common cause of congenital hypothyroidism (accounts for 10% - 15%) after thyroid dysgenesis
F > M (2:1)
Mean age at surgery is 16 years (range varies from neonates to sixth decade), with 80% cases occur before 25 years
No racial or ethnic predilection (Thyroid 2011;21:13)

Sites

Diffuse involvement of both lobes

Pathophysiology / etiology

Mutations in genes encoding enzymes, which participate in thyroid hormone synthesis
- There are 7 genes involved in thyroid hormonogenesis and all related steps may be impaired: thyroglobulin synthesis (TG), iodide transport via basal (NIS/SLC5A5) and apical (PDS/SLC26A4) membranes of follicular cell, generation of H₂O₂ (DUOX2, DUOXA2), iodide organification (TPO), coupling of mono- and diiodotyrosine (TPO), proteolytic breakdown of thyroglobulin and iodide recycling (IYD/DEHAL1)
- TPO (OMIM 274500) and TG (OMIM 274700) are the most frequent responsible genes (Thyroid Res 2015;8:5)
- Mostly due to single gene mutation, multiple mutations is more uncommon
- The earlier the enzyme abnormality occurs in pathway of hormone synthesis, the more severe the clinical presentation (Endocr Rev 1983;4:213)
Mode of inheritance of all forms of thyroid dyshormonogenesis is autosomal recessive, with the exception of DUOX2 mutations, which may be autosomal dominant (Endocr Dev 2014;26:60)
Mechanism: impaired T3 / T4 synthesis → deficient circulating thyroid hormone → loss of negative feedback loop → normal physiologic response to increased thyrotropin releasing hormone production in hypothalamus → increased TSH secretion in anterior pituitary → chronic TSH stimulation → hyperplasia of thyroid gland

Diagrams / tables

Images hosted on other servers:

Thyroid hormone synthesis

Mechanism of
dyshormonogenesis

Congenital hypothyroidism

Genetic causes of
dyshormonogenesis

Thyroid imaging in congenital hypothyroidism

Scintigraphic classification of dyshormonogenesis

Pedigrees

Clinical features

Various degrees of hypothyroidism and goiter are seen
Clinical presentation depends on severity of the metabolic error (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)
- Early presentation in neonatal period with evident goiter and congenital hypothyroidism complicated by growth and intellectual disability (cretinism) suggests severe defect
- Presentation in puberty or adult life with goiter and minimal evidence of thyroid dysfunction (euthyroidism, subclinical hypothyroidism) implies mild defect
- Some metabolic defects may be masked by a high dietary iodine intake, evident from Japanese series (Endocr Dev 2014;26:60)
Familial recurrence of congenital hypothyroidism due to dyshormonogenesis is 25% (J Clin Endocrinol Metab 2014 Feb;99:363)
Most cases manifest before third decade
Very rarely a diagnosis is made only at autopsy
Pendred syndrome (Pendred Syndrome/DFNB4, J Med Genet 1996 Dec;33:1037)
- Familial association of congenital goiter with deaf mutism (most patients presents with severe deafness rather than with hypothyroidism)
- Caused by mutations (150+ variants) in PDS / SLC26A4 gene encoding pendrin (OMIM 274600)
- Occurs in 7.5 to 20 per 100,000 individuals
- Accounts for 10% of patients with hereditary deafness
- With sufficient dietary iodide, 90% are clinically and biochemically euthyroid (Curr Opin Pediatr 2011 Aug;23:421)
No associated malformations are present in dyshormonogenetic goiter except Pendred syndrome (J Clin Endocrinol Metab 2014 Feb;99:363)
Tumors may develop in dyshormonogenetic goiter (see Case Reports)
- Most common are follicular carcinoma and incidental papillary microcarcinoma
- Also papillary carcinoma and rarely follicular adenoma
- Dyshormonogenesis may predispose to follicular carcinoma or follicular variant PTC by increasing chance of mutation in dividing follicular cells under chronic TSH stimulation (Clin Endocrinol Metab 1979;8:193) but additional genetic hits may be needed, such as p53 mutation (Endocr Pathol 2016;27:70)

Diagnosis

History of congenital or familial goiter in a young individual (often diagnosed due to routine screening of newborns for congenital hypothyroidism)
Radiologic evaluation includes thyroid ultrasound and scintiscan
Correlation of clinical signs with laboratory and ancillary tests
Laboratory workup is complex - goal is identifying impaired step of thyroid hormone synthesis
Prenatal diagnosis can be made in utero by sonography and measurement of TSH in amniotic fluid (J Obstet Gynaecol Res 2013;39:720)

Laboratory

Hypothyroidism (if present): elevated TSH, low serum T4, T3 and thyroglobulin
Additional tests (J Med Genet 2005;42:379): thyroxine binding globulin, thyrotropin releasing hormone (to evaluate hypothalamic-pituitary axis), thyroglobulin antibodies (to rule out autoimmune thyroiditis), urinary mono and diiodotyrosine, oral radioiodine test (to measure iodide trapping via saliva to plasma ratio)

Radiology description

Ultrasound reveals enlarged, orthotropic thyroid (Korean J Radiol 2015;16:419)
- Solid hypoechoic nodules
- Lobes develop a convex appearance laterally, and isthmus is readily visualized, in contrast to a normal gland
- Thyroid gland size in children varies with age and should be correlated with height, weight and body surface area
- Ultrasound scans at 20 to 22 weeks gestation are able to detect fetal thyroid hypertrophy (J Clin Endocrinol Metab 2014;99:363)
Scintigraphy (Endocr Dev 2014;26:60, Pediatr Radiol 2013;43:1244)
- In iodide trapping defect (NIS), patients show no or very low radioiodine uptake in the thyroid; further, in contrast to athyreosis, salivary glands and the gastric mucosa lack uptake ("white scintigraphy")
- In iodide organification defect (TPO, DUOX2, PDS), radioiodine uptake is normal, but perchlorate discharge test is positive - most radioisotope is washed out into the bloodstream instead of accumulating in thyroid
- Patients with TG and DEHAL1 defects show normal radioiodine uptake and normal perchlorate test

Radiology images

Images hosted on other servers:

Ultrasound of fetal goiter

Ultrasound of 26 year old man

Various defects
on scintigraphy
(NIS, TPO and PDS)

Scintigraphy

Case reports

Boy with thyroid peroxidase gene defect (Clin Endocrinol (Oxf) 2006;64:514)
5 and 10 year old brothers with congenital goiter due to TPO mutation (J Pediatr Endocrinol Metab 2016;29:627)
7 year old girl with DUOXA2 mutation (J Clin Endocrinol Metab 2008;93:605)
22 year old woman with Pendred syndrome (J Pediatr Endocrinol Metab 2008;21:1179)
35 year old man with Pendred syndrome and retrosternal goiter (Indian J Surg 2013;75:329)
38 year old man with iodide transport defect (Endocr Pathol 1998;9:225)
Case with thyroglobulin synthesis defect (Thyroid 1996;6:11)
Two families with TPO mutations (Exp Clin Endocrinol Diabetes 2013;121:343)
Dyshormonogenetic goiter with clear cell change resembling parathyroid adenoma (Indian J Pathol Microbiol 1998;41:469)

Cancers in dyshormonogenetic goiter

Female infant with metastatic follicular thyroid carcinoma arising from congenital goiter due to TPO mutation (J Clin Endocrinol Metab 1998;83:4162)
6 year old girl with papillary carcinoma and congenital dyshormonogenetic hypothyroidism (Diagn Cytopathol 2009;37:707)
14 year old boy with follicular adenoma and papillary carcinoma arising in dyshormonogenetic goiter (Univ Pittsburgh Case #425)
17 year old girl with metastatic papillary carcinoma arising from dyshormonogenetic goiter (Case Rep Med 2013:813167)
26 year old woman with follicular thyroid carcinoma and dyshormonogenetic goiter due to TPO gene mutation (Thyroid 2012;22:542)
31 year old woman with metastatic papillary thyroid carcinoma in goiter caused by TG mutation (J Clin Endocrinol Metab 2010;95:1000)
35 year old man with papillary thyroid carcinoma arising from dyshormonogenetic goiter (Endocrinol Jpn 1987;34:955)
37 year old man with rare and particular form of goiter (Ann Transl Med 2013;1:21)
53 year old woman with Pendred syndrome and metastatic follicular thyroid carcinoma with anaplastic transformation (Thyroid 2001;11:981)
65 year old woman with Pendred syndrome associated thyroid carcinoma (Endocr Pathol 2016;27:70)
66 year old woman with hyperfunctioning metastatic follicular thyroid carcinoma in Pendred syndrome (Cancer 1991;67:2191)
Two siblings with congenital goiter and metastatic follicular carcinoma (J Clin Endocrinol Metab 1981;52:294)

Treatment

T4 replacement therapy until the serum TSH becomes normalized
Some disorders can be treated with iodine supplementation, e.g. all SLC26A4, DUOX2, DUOXA2 and IYD defects and partial defects in SLC5A5 (Curr Opin Pediatr 2011;23:421)
Surgery is considered in patients with very large goiters (compressive or cosmetic reasons) or when malignancy is suspected
Fetal goiter detected by ultrasound with confirmed hypothyroidism (high amniotic TSH) can be treated by intra-amniotic injections of thyroxine (J Obstet Gynaecol Res 2013;39:720)

Clinical images

Images hosted on other servers:

Pendred syndrome

Gross description

Asymmetrically enlarged thyroid gland with multiple nodules, grossly indistinguishable from multinodular goiter
Adult weight is 50 to 250 g, with exceptional cases over 2000 g (Endocr Pathol 1997;8:283, J Pathol 1969;99:251)
Cut surface is firm and tan with pale nodules of varying size (1 to 6 cm), which may be encapsulated (J Pathol 1969;99:251)
Internodular tissue is scant, delicately lobular and medullary to myxomatous, totally lacking the "beefy" texture of normal thyroid gland (Am J Pathol 1955;31:997)
Secondary changes include old and fresh hemorrhage, fibrosis, cyst formation, rarely calcification (Endocrine Pathology 1994;5:49)

Gross images

AFIP images

Marked nodular hyperplastic changes

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Enlarged multinodular thyroid

Excision

Follicular adenoma in a goiter

Microscopic (histologic) description

Diffuse process with prominent nodularity and no normal appearing thyroid tissue (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)
Nodules and internodular thyroid parenchyma are markedly cellular/hyperplastic (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012)
- Predominant pattern of nodules is solid or microfollicular, also trabecular, insular and macrofollicular / microcystic
- Papillary hyperplasia prominent within the nodules; papillae are mainly simple (without fibrovascular cores and branching) and broad
- Marked nuclear atypia with bizarre nuclei (enlarged, irregularly shaped, hyperchromatic), more evident in internodular tissue than in the nodules; also random vesicular nuclei, occasional mitotic figures
- No / minimal colloid ("empty follicles") within the entire gland; when present, it is usually pale, filamentous and found in apparent nodules
- "Kaleidoscopic" pattern of nodules is remarkable: different nodules show different degrees of cellularity and architecture (Am J Pathol 1955;31:997), and any one nodule is not uniform in structure (J Pathol 1969;99:251)
- Internodular background is uniform in structure
Associated changes
- Extensive bridging fibrosis of internodular tissue; sometimes may circumscribe nodules and cause irregularities at the border simulating capsular invasion
- Cytoplasmic oxyphilia (sign of functional exhaustion) and focal clear cell metaplasia (sign of hormone overproduction) (Int J Surg Pathol 1999;7:3)
- Myxoid change
- Absent or rare focal mild thyroiditis
Important considerations
- Histologic features of the background thyroid are as important as the appearance of the nodules (Int J Surg Pathol 1999;7:3 )
- Histologic changes in newborns are not as prominent as in older patients, who develop variation of patterns and secondary changes over the course of disease (J Pathol 1969;99:251)
- Severity of microscopic appearance depends on degree and duration of TSH stimulation and is modulated by therapy (hormone replacement or iodine supplementation)
- Dyshormonogenetic goiter should be suspected in a child or young adult with diffuse follicular hyperplasia, nodularity, scant colloid and nuclear atypia
- Several studies (J Pathol 1969;99:251, Endocrine Pathology 1994;5:49) found that structural changes in the gland may correlate with particular defects (e.g. microcystic / alveolar pattern in cases with formation of abnormal iodoprotein, or severe atypia and solid pattern in organification defects), however most modern authors believe that morphology is independent of the biochemical abnormality (Mills: Sternberg's Diagnostic Surgical Pathology, 6th Edition, 2015, Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)
Cancer in dyshormonogenetic goiter
- Nuclear and architectural features typical for dyshormonogenesis often mimic malignancy
- In one study almost every fifth case was considered as follicular, papillary, medullary, or undifferentiated carcinoma (Endocr Pathol 1997;8:283)
- Some previously reported cases of congenital thyroid carcinoma were actually examples of thyroid dyshormonogenesis (Clin Endocrinol Metab 1981;10:317)
- Only strict criteria for diagnosing malignancy should be applied, e.g. true capsular or vascular invasion in case of follicular carcinoma

Microscopic (histologic) images

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Contributed by Mark R. Wick, M.D. and AFIP

Various images

Resembles nodular hyperplasia

Hyperplastic nodules showing solid growth pattern

Marked fibrosis causes apparent increased lobularity

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Multinodularity

Fibrosis

Hypercellular nodule

Papillarity

Hyperplastic nodule

Scant colloid

Atypia

IHC in Pendred syndrome

Follicular adenoma in dyshormonogenetic goiter

Papillary microcarcinoma in dyshormonogenetic goiter

Papillary carcinoma in goiter

Cytology description

Highly cellular aspirate with syncytial fragments arranged in predominantly microfollicular pattern (Indian J Pathol Microbiol 2001;44:169, Diagn Cytopathol 2013;41:720)
- Follicular cells with round to oval nuclei, sometimes atypical or vesicular, but without grooves / inclusions
- No / scant colloid
- Fragments of fibrocollagenous tissue
Marked hyperplastic changes closely resemble follicular lesion and follicular neoplasm (Diagn Cytopathol 2005;33:252)
- Cytology alone is not able to differentiate dyshormonogenesis from tumor
- Fine needle biopsy is not recommended for dyshormonogenetic goiter (Kini: Thyroid Cytopathology: An Atlas and Text, 2nd Edition, 2015)
Rarely presents as benign cyst (Arq Bras Endocrinol Metabol 2014;58:958)

Positive stains

Thyroglobulin and TTF1, but thyroglobulin may show a marked decrease in follicular lumina in dyshormonogenesis due to TG mutations (J Clin Invest 1996;98:2838, J Clin Endocrinol Metab 2010;95:1000)
Weak staining with antibodies against corresponding targets of dyshormonogenesis
- Faint TPO immunostaining in cases with TPO defects (Rev Hosp Clin Fac Med Sao Paulo 1998;53:86)
- Weak staining with pendrin in Pendred syndrome (J Clin Endocrinol Metab 2008;93:267)
Increased proliferation rate by Ki67 in solid nodules (Indian J Pathol Microbiol 2001 Apr;44:169)
PAS can detect traces of colloid, if not evident on H&E (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)

Negative stains

No diffuse positivity for calcitonin and neuroendocrine markers (e.g., chromogranin, synaptophysin), however C cells are present within the gland (Endocrine Pathology 1994;5:49)

Electron microscopy description

Tall follicular cells with long and numerous microvilli reflecting high metabolic activity (Endocr Pathol 1997;8:283)
Cytoplasm with numerous mitochondria and abundant rough endoplasmic reticulum with vesicular dilated cisternae (J Clin Invest 1996;98:2838)

Molecular / cytogenetics description

Early genetic screening is justified even without complete clinical workup, because a precise molecular diagnosis allows genetic counseling and the identification of asymptomatic mutation carriers at risk of recurrent hypothyroidism, and provides a rationale for treatment (Curr Opin Pediatr 2011;23:421, J Clin Endocrinol Metab 2014;99:363)

Molecular / cytogenetics images

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Structure of TPO mutations

DUOXA2 mutation

Differential diagnosis

Multinodular endemic goiter (Endocrine Pathology 1994;5:49)
- Similar: identical gross appearance, extensive hyperplasia
- Difference: abundant colloid, hyperplasia confined by nodules (not throughout the entire gland), normal thyroid tissue present between nodules, frequent secondary degenerative changes (hemorrhage, foamy and hemosiderin laden macrophages, dystrophic calcification, fibrosis and cyst formation)
- Ancillary studies: euthyroidism, rarely toxic goiter
Radiation thyroiditis: diffuse cytologic atypia through gland, history of thyroid radiation
Iatrogenic goiter caused by antithyroid drugs: similar histology, history of thionamides treatment of patient or mother (in case of fetal goiter)
Graves disease (especially untreated): diffuse hyperplasia without nodularity, no solid or related patterns, columnar epithelium present without nuclear atypia, hyperthyroidism clinically
Follicular adenoma: unilocular lesion
Follicular thyroid carcinoma with capsular invasion
- Localized lesion with otherwise uninvolved thyroid parenchyma
- Clear cut capsular or vascular invasion must be present; capsule is often vascularized
- In widely invasive carcinoma, multiple satellite nodules display similar morphology
- Laboratory tests show absence of hypothyroidism
- It is proposed that dyshormonogenetic goiter be excluded in every case of follicular carcinoma diagnosed in a patient < 20 years (Int J Surg Pathol July 1999;7:125)
Multifocal papillary thyroid carcinoma: cytologic, architectural (true papillae) and other (extrathyroidal extension, cervical or distant metastasis) features of cancer (Int J Surg Pathol July 1999;7:125)
Poorly differentiated (insular) carcinoma: mitotic activity, necrosis, invasive growth
Medullary thyroid carcinoma may resemble goiter with prominent myxomatosis and hyalinosis, but is calcitonin+

Additional references

Related pages: Thyroid histology
Websites: Thyroid Disease Manager
Books: Szinnai (ed): Paediatric Thyroidology, 1st Edition, 2014, Medeiros-Neto, Stanbury: Inherited Disorders of the Thyroid System, 1st Edition, 1994

Board review style question #1

Dyshormonogenetic goiter is characterized by all of the following except:

Decreased T3, T4 and increased TSH
Family history of hypothyroidism or goiter in 20% cases
Highly atypical pleomorphic and hyperchromatic nuclei in internodular areas
Increased T3, T4 and decreased TSH
Markedly cellular nodules showing a variety of architectural patterns with minimal to absent pale colloid

Board review style answer #1

D. Increased T3, T4 and decreased TSH. Dyshormonogenetic goiter is characterized by thyroid enlargement due to various hereditary defects in thyroid hormone synthesis. It is the second most common cause of congenital hypothyroidism after thyroid agenesis / dysgenesis. Family history of hypothyroidism or goiter is present in 20% of cases. Lack of circulating thyroid hormone activates TSH secretion, which causes overstimulation and hyperplasia of defective thyroid gland. There is diffuse asymmetric enlargement of thyroid gland with multinodular cut surface with absent to minimal pale colloid. Nodular and internodular thyroid parenchyma is markedly hypercellular. Nodular follicular cells are without atypia whereas internodular areas show fibrosis with single highly pleomorphic and hyperchromatic nuclei.

Comment Here

Reference: Dyshormonogenetic goiter

Board review style question #2

Which microscopic feature of dyshormonogenetic goiter mimics thyroid malignancy?

Capsular invasion of the nodules
Highly atypical pleomorphic and hyperchromatic (bizarre) nuclei
Large areas of necrosis
Orphan Annie nuclei
Scattered psammoma bodies

Board review style answer #2

B. Highly atypical pleomorphic and hyperchromatic (bizarre) nuclei. Dyshormonogenetic goiter is a benign thyroid hyperplasia due to hereditary defects in thyroid hormone synthesis. It lacks malignant features common for papillary (Orphan Annie nuclei, psammoma bodies), follicular (capsular invasion) or high grade (necrosis) thyroid cancer. However, internodular tissue in dyshormonogenetic goiter often displays marked nuclear atypia with bizarre nuclei (enlarged, irregularly shaped, pleomorphic, hyperchromatic) similar to those found in radiation thyroiditis and anaplastic carcinoma.

Comment Here

Reference: Dyshormonogenetic goiter

Ectopic parathyroid tissue

Table of Contents

Definition / general | Sites | Case reports | Microscopic (histologic) images

Definition / general

Estimated incidence of 35%; due to aberrant migration during early stages of development
Common etiology of persistent or recurrent hyperparathyroidism when missed at initial diagnosis (Exp Clin Endocrinol Diabetes 2012;120:604)
Often symptomatic due to hyperplasia associated with secondary hyperparathyroidism
Often symmetrical from side to side, even when ectopic, making localization somewhat easier (eMedicine: Embryology of the Thyroid and Parathyroids [Accessed 24 July 2017])
Can undergo adenomatous change and cause primary hyperparathyroidism, hypercalcemia and acute pancreatitis (World J Surg Oncol 2004;2:41)
Inability to identify may lead to failure of parathyroid surgery

Sites

Axilla (Int Surg 2004;89:6)
Mediastinum (Ann Thorac Surg 1997;64:238)
Pyriform sinus (Arch Otolaryngol Head Neck Surg 2002;128:71)
Thyroid gland (Nihon Rinsho 1995;53:920)
Vagus nerves of children (Arch Pathol Lab Med 1988;112:304)
Ectopic inferior parathyroids are most frequently found in anterior mediastinum, in association with thymus or thyroid gland; ectopic superior parathyroids are usually at tracheoesophageal groove or retroesophageal region (Exp Clin Endocrinol Diabetes 2012;120:604)

Case reports

86 year old woman with neck pain and difficulty swallowing (Case #108)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and Case #108

Aberrant parathyroid

Various images

Cytokeratin cocktail

Chromogranin

Synaptophysin

Parathyroid hormone

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Thymic tissue contains a mass of parathyroid cells

Ectopic thyroid tissue

Table of Contents

Definition / general

Developmental abnormality characterized by the presence of thyroid tissue in any location other than its normal anatomic position
First well documented case was reported by Hickman in 1869 (AMA Arch Otolaryngol 1953;57:60)

Terminology

Synonyms:
- Heterotopic thyroid, accessory thyroid, aberrant thyroid rests, choristoma
- Wolfler gland (cervical accessory thyroid), struma cordis (cardiac thyroid)
Types:
- Sole / total ectopia vs. accessory thyroid (partial, associated with orthotopic thyroid)
- Single or multiple (dual, triple, etc.)
- Gross vs. microscopic
- True vs. mimickers (metastasis, parasitic nodule, see Differential Diagnosis)

Epidemiology

The most frequent form of thyroid dysgenesis, accounting for ~50% of cases (Endocr Rev 2004;25:722)
Several hundred cases of ectopic thyroid have been reported
Prevalence in general population is 1 per 100,000 to 300,000 people
Prevalence in population with thyroid disease is 1 per 4,000 to 8,000 (Thyroid 2007;17:1117); however intense imaging screening yields up to 2% of ectopic thyroid in patients with thyroid disease (Arch Endocrinol Metab 2015;60:231)
Autopsy studies suggest that 7 - 10% of adults may have remnants of thyroid tissue along the path of thyroid descent (J Pathol 1970;102:239)
F:M = 3 - 4:1
May occur at any age, from 5 months to eighth decade but is most common at younger ages (Hormones (Athens) 2011;10:261)

Sites

The target area for thyroid heterotopia lies along the track of medial anlage descent between the base of tongue and the normal thyroid location; a wider region can be defined as the Wolfler area, spanning from the edges of the mandible through the neck to the aortic arch (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012)
Sites in descending order of frequency:
- Lingual thyroid is the most common type, accounting for up to 90% of the cases
- Often found within thyroglossal duct cysts (25 - 65%, more sections yield higher percentage)
- Neck midline organs (larynx and trachea) and superior mediastinum
- Benign thyroid follicles occur in perithyroid soft tissue and muscles (often around isthmus), which are silent and harmless (Hum Pathol 1988;19:689)
- Nonmidline sites, including salivary glands, retropharyngeal space, cervical lymph nodes and branchial cleft cysts
Distant sites are rare (categorized in Case reports)
Thyroid tissue in ovary (struma ovarii) represents a component of teratoma, sometimes in the absence of other tissues (monodermal teratoma)

Diagrams / tables

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Thyroid descent

Locations

Pathophysiology / etiology

Thyroid anlages may descend too slow or fast and develop ectopia above or below normal thyroid position
Heart, large vessels and thymus originate very close to the primordial thyroid and attachment of thyroid tissue may occur before their caudal migration
Developmental anomalies of the foregut may explain ectopia in the thorax and upper gastrointestinal tract (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012)
Aberrant thyroid tissue in the submandibular and lateral neck regions could originate from a defective lateral thyroid component that cannot migrate and fuse with the median thyroid anlage (Endocr Rev 2004;25:722)
Heterotopic differentiation (heteroplasia, transdifferentiation) of uncommitted endodermal cells may hypothetically explain the presence of ectopic thyroid tissues in distant locations (Thyroid 2003;13:503)
Mutation in the genes of thyroid specific transcription factors TTF1, TTF2 (FOXE1) and PAX8 may be involved in abnormal migration of the thyroid, as shown in animals (Nat Genet 1998;19:395)
- However, no mutation in known genes has so far been associated with the human ectopic thyroid
Rarely, familial thyroid heterotopia occurs (Thyroid 1992;2:325)

Clinical features

Most cases are asymptomatic, and detected incidentally
Symptoms are usually related to size / location of heterotopia and associated thyroid dysfunction
Ectopic thyroid is commonly detected during puberty and pregnancy, when increased levels of thyrotropin stimulates enlargement of the ectopic thyroid tissue (Hormones (Athens) 2011;10:261)
- This enlargement may manifest with compression (airway obstruction) or swelling (neck mass) symptoms
Heterotopia due to aberrant migration has inadequate blood supply and is not able to release sufficient amount of hormones (Development 2006;133:3797)
Presentation with features of hypothyroidism occurs often in children (Laryngoscope 2008;118:1174)
Hyperthyroidism arising from ectopic thyroid tissue is rare (Thyroid 2000;10:363)
Ectopic thyroid tissue may be the only functioning thyroid tissue in ~50% of cases, particularly with lingual and cervical heterotopia (Eur J Endocrinol 2011;165:375)
Heterotopic thyroid may have the same diseases as eutopic thyroid gland, including:
- Nodular goiter (Hormones (Athens) 2009;8:150) but most mediastinal goiters are actually parasitic nodules and not ectopic thyroid tissue
- Inflammatory diseases, e.g. Hashimoto thyroiditis (Otolaryngol Head Neck Surg 2001;125:274) and Graves disease (Endocr J 1999;46:731)
- Neoplasms, both benign (AJR Am J Roentgenol 2008;190:W161) and malignant (J Clin Endocrinol Metab 2011;96:2684), with a frequency comparable to orthotopic thyroid tumors (Thyroid 2015;25:1050)

Diagnosis

Thyroid cancer metastases should always be considered and excluded before accepting the diagnosis of ectopic thyroid
Imaging:
- Radionuclide imaging with technetium-99m pertechnetate, iodine-131 or iodine-123
- CT and MRI
- Ultrasonography with color Doppler
FNA

Laboratory

Hypothyroidism (low T3 and T4, high TSH) occurs frequently
The inability to image the normal gland combined with a normal serum thyroglobulin may suggest an ectopic thyroid

Radiology description

Scintigraphy: radioisotope tracer uptake in the area other than normal thyroid location (background from salivary glands should be considered)
Ectopic thyroid tissue has a characteristic uniform high attenuation on non contrast CT, while on MRI it shows an elevated signal on T1 and T2 weighted images compared with the surrounding musculature (Int J Surg 2014;12:S3)
Sonography: echotexture of thyroid tissue; usually isoechogenic, with regular margins, rare cystic degeneration, and without calcification (Arch Endocrinol Metab 2015;60:231)

Radiology images

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Neck ultrasound

Neck CT

Radionuclide scan

Abdominal MRI

Head MRI

Chest CT

Intracardiac thyroid

Prognostic factors

Prognosis is good: there is a very low chance of recurrence after surgical excision

Case reports

Lingual
Neck:
- 32 year old man with supraclavicular thyroid tissue (Internet J Surg 2007;13(1))
- 32 year old woman with parotid gland tissue (Singapore Med J 2004;45:437)
- 33 year old pregnant woman with intratracheal ectopic thyroid tissue with adenomatous hyperplasia (AJR Am J Roentgenol 2008;190:W161)
- 35 year old woman with cutaneous thyroid tissue (J Cutan Pathol 2004;31:195)
- 36 year old woman with thyroid papillary carcinoma arising in ectopic thyroid tissue within a neck branchial cyst (World J Surg Oncol 2006;4:24)
- 40 year old man with intratracheal ectopic thyroid tissue (Ear Nose Throat J 2007;86:406)
- 59 year old woman with intralaryngeal thyroid (Otolaryngol Pol 2014;68:46)
- 61 year old woman with ectopic thyroid gland in the mandible (J Oral Maxillofac Surg 2012;70:363)
- 64 year old woman with ectopic thyroid tissue surrounding laryngeal nerve (Int J Clin Exp Pathol 2014;7:5313)
- 65 year old woman with thyroid tissue in submandibular and infrahyoid region (Eurasian J Med 2014;46:216)
Mediastinum and thorax:
- 33 year old woman with intracardiac ectopic thyroid adenoma (Interact Cardiovasc Thorac Surg 2009;8:587)
- 42 year old woman with ectopic thyroid gland on the ascending aorta (Surg Today 2007;37:486)
- 46 year old woman with intracardiac ectopic thyroid mass (Interact Cardiovasc Thorac Surg 2013;17:903)
- 51 year old man with intrapericardial ectopic thyroid (Int J Cardiol 2012;158:e55)
- 61 year old woman with ectopic thyroid mass in the heart (Lancet 2012;379:1762)
- 65 year old man with mediastinal ectopic thyroid (Korean J Intern Med 2013;28:361)
- 66 year old woman with ectopic thyroid tissue in the lateral chest wall (Acta Cytol 2009;53:313)
- 74 year old man with ectopic thyroid tissue in posterior mediastinum (Cases J 2008;1:53)
- 74 year old woman with intracardiac ectopic thyroid mass (Eur J Echocardiogr 2009;10:704)
- 77 year old man with ectopic thyroid of the lung (Pathologica 2010;102:102)
- Two cases in anterior mediastinum (J Bras Pneumol 2009;35:383)
Subdiaphragmatic:
- Fetus with heterotopic thyroid tissue at the porta hepatis (Virchows Arch 2000;436:498)
- 16 year old girl with gastric heterotopia containing thyroid tissue (J Pediatr Gastroenterol Nutr 2007;45:484)
- 29 year old woman with ectopic thyroid tissue in gallbladder (Endocr Pathol 2010;21:263)
- 32 year old woman and 51 year old woman with ectopic thyroid tissue in the adrenal gland (Int J Surg Pathol 2015;23:170, Endocr Pathol 2014;25:353)
- 45 year old woman with ectopic thyroid tissue in the uterus (Acta Obstet Gynecol Scand 2005;84:201)
- 50 year old woman with ectopic thyroid tissue in the pancreas (Surg Today 1999;29:472)
- 54 year old woman with adrenal mass (BMC Urol 2006;6:18)
- 63 year old man with thyroid follicles in the submucosa of the duodenum (Virchows Arch A Pathol Anat Histopathol 1991;418:547)
- 71 year old woman with liver mass (Clin Gastroenterol Hepatol 2012;10:xxx)
- Female with thyroid and parathyroid glands in the vaginal wall (Am J Clin Pathol 1973;59:503)
- Two cases in adrenal gland (Hum Pathol 1999;30:105)
Other unique sites:
- 15 year old boy with ectopic thyroid tissue in the iris (Arch Ophthalmol 2006;124:1497)
- 19 year old woman with thyroid nodule of the breast (Breast J 2016;22:240)
- 43 year old woman with thyroid tissue in the axilla (Thyroid 2005;15:1095)
- Two cases of thyroid tissue in pituitary (Chin Med J (Engl) 2015;128:3389)
Multiple sites:
- 5 year old girl with dual ectopic thyroid (Iran J Radiol 2011;8:29)
- 10 year old girl with triple ectopic thyroid (Thyroid Disorders Ther 2013;2:126)
- 16 year old girl with triple ectopic thyroid (Med J Armed Forces India 2012;68:173)
- 17 year old girl with dual ectopic thyroid (J Thyroid Res 2011;2011:159703)
- 37 year old woman with adenomatous hyperplasia arising from dual ectopic thyroid (Clin Exp Otorhinolaryngol 2009;2:155)
- 42 year old woman with triple ectopic thyroid (Indian J Endocrinol Metab 2014;18:238)

Treatment

Asymptomatic euthyroid patients do not usually require therapy but are kept under observation
Mild hypothyroidism is corrected by thyroid hormones
Radioiodine ablation is indicated for patients who are symptomatic or unresponsive to medical treatment (BMJ Case Rep 2015 Aug 3; 2015)
Surgical excision is indicated for severe obstructive symptoms, bleeding, ulceration, cystic degeneration or malignancy (Thyroid 2007;17:1117)
It is important to determine the presence of an orthotopic thyroid gland before removing ectopic tissue to avoid hypothyroidism, because the ectopic gland may be the only functional thyroid (Hormones (Athens) 2011;10:261)
Autotransplantation may help retain some degree of thyroid function

Clinical images

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Neck mass

Gross description

Average size of manifested lesion is 2 - 4 cm, range is 0.2 - 7.3 cm (Int J Clin Exp Pathol 2014;7:5313, J Thorac Dis 2014;6:E39)
Often encapsulated, can be cystic
Cut surface resembles normal thyroid parenchyma (brownish red)

Gross images

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Submental mass

Ectopic thyroid, lateral neck

Intratracheal thyroid tissue, hyperplasia

Mediastinal mass

Cystic mass, adrenal gland

Microscopic (histologic) description

The same histological appearance as the orthotopic thyroid tissue, composed of colloid filled follicles
Signs of hyperplasia or thyroiditis in relevant clinical situations
Ectopic thyroid tissue showing cytologic or histologic features of thyroid carcinoma should be considered as metastases until proven otherwise, although there are several reports of tumors arising de novo in ectopic thyroid (Thyroid 2007;17:603):
- Follicular adenoma (J Med Case Rep 2014;8:270)
- Follicular carcinoma (Am J Clin Pathol 1987;87:776)
- Classic variant of papillary thyroid carcinoma (BMJ Case Rep. 2012 Jul 9;2012)
- Follicular variant of papillary thyroid carcinoma (Ear Nose Throat J 2009;88:E7)
- Hurthle cell carcinoma (Acta Cytol 1983;27:188)
- Medullary thyroid carcinoma (Singapore Med J 2008;49:251)
- Poorly differentiated thyroid carcinoma (Endocr Pathol 2002;13:353)
- Anaplastic carcinoma (BMJ Case Rep 2010 Aug 31; 2010)
- Teratoma (Anal Quant Cytol Histol 2009;31:233)
- B cell lymphoma (Acta Chir Belg 2009;109:802)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Perithyroid thyroid follicles

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Benign conditions

Ectopic vs. orthotopic thyroid

Posterior mediastinal mass

Adrenal mass

Adrenal mass, IHC

Adenoma, ectopic thyroid

PTC arising in ectopic thyroid

Anaplastic carcinoma

Cytology description

Microfollicular aggregates and colloid (IRCMJ 2009;11:100)
Additional findings may reflect pathological conditions of thyroid tissue, e.g. abundant lymphocytes (thyroiditis) or atypical cells with nuclear grooves and inclusions (papillary carcinoma)

Cytology images

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Follicular cells

Positive stains

Immunophenotype of thyroid tissue: thyroglobulin, TTF1 in follicular cells, and calcitonin in C cells (J Clin Endocrinol Metab 2012;97:951)

Molecular / cytogenetics description

Absence of thyroid cancer related molecular alterations (BRAFV600E, N-RAS, H-RAS, K-RAS) in benign appearing ectopic thyroid tissue (Int J Surg Pathol 2015;23:170)

Differential diagnosis

If any morphologic signs of malignancy are identified, then diagnosis is metastatic papillary thyroid carcinoma until proven otherwise
- Clues to malignancy: classic architectural and cytomorphologic features of papillary carcinoma, with fibrotic response (desmoplasia) of surrounding tissue
- Features against malignancy: separate blood supply of the ectopic gland from extracervical vessels, no personal history of malignancy, and normal or absent orthotopic thyroid with no history of surgery (Ann Thorac Cardiovasc Surg 2007;13:122)
- Metastasis from ectopic thyroid carcinoma may also be considered
Benign mimickers of thyroid ectopia:
- Cystically dilated nonthyroid glands with flattened epithelium and inspissated secretions
- Parasitic nodule
- Mechanical implantation outside gland due to surgery or trauma: history of neck surgery
- Retrosternal goiter
- Teratoma with thyroid component
Differential diagnosis in rare sites depends on the location
Accidental finding of thyroid follicles in unusual site may pose a concern about specimen contamination by tissue from an unrelated case ("floater"), which can be resolved by genetic fingerprinting (Hum Pathol 2007;38:378)

Embryology

Table of Contents

Definition / general

Thyroid originates from a medial anlage and two lateral anlagen, which fuse during development
- Medial anlage gives rise to the major portion of each lateral lobe, isthmus and thyroglossal duct with pyramidal lobe; it is a source of follicular cells
- Lateral anlagen (ultimobranchial bodies) give rise to C cells, solid cell nests and portions of the lateral thyroids
- Recent articles suggest that both medial and lateral anlagen are of endodermal origin and the earlier theory of a neural crest origin of thyroid C cells is dubious (Development 2015;142:3519, Eur Thyroid J 2016;5:79)
Thyroid development starts from the late 3rd to early 4th weeks of gestation, then the fetal thyroid gland develops rapidly until the 4th month of intrauterine growth
Thyroid development is complete with the onset of thyroid hormone synthesis
Thyroid is the first endocrine organ to develop in embryo, which points to its importance

Diagrams / tables

Summary table:

Event	Week	Day
Specification of the thyroid domain in the ventral endoderm	week 3	E20 - 22
Thyroid bud (medial anlage) formation	weeks 3 - 4	E20 - 24
Thyroid bud begins migration	week 4	E24 - 28
Formation of the lateral anlagen (ultimobranchial bodies)	weeks 4 - 7
Migration of lateral anlagen	weeks 5 - 7
Thyroglossal duct disappears	weeks 5 - 6	E30 - 40
Thyroid migration is complete	weeks 7 - 8	E45 - 50
Fusion with ultimobranchial bodies	weeks 7 - 9	E44 - 60
Onset of folliculogenesis	week 10	E70
Release of thyroid hormone	weeks 10 - 12	E80

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Embryonic development of thyroid gland

Branchial arches

Thyroglossal duct

Relation to vessels

Interplay of transcription factors

Organogenesis

Medial thyroid anlage originates from endoderm in the ﬂoor of primordial pharynx (ventral endoderm of the foregut) (Carlson: Human Embryology and Developmental Biology, Fifth Edition, 2013)
- Local mesodermal inductive signals render specification of a small number of endodermal cells (as few as 60 in mouse) to be destined to a thyroid fate
- Endodermal thickening (placode) begins to extend into the surrounding mesodermal mesenchyme forming thyroid bud
- Thyroid primordium soon elongates to form a prominent downgrowth (outpouching) called the thyroid diverticulum
- This area lies caudad to the first pharyngeal pouches (between the first and second branchial arches) and the developing tuberculum impar of tongue, which corresponds to the apex of the foramen cecum on the developing tongue
- Thyroid bud formation takes place during days 20 - 24 post conception
Thyroid diverticulum migrates deep into the neck
- Descent of thyroid bud is due to elongated cephalad embryonic growth rather than active descent (Stocker and Dehner: Stocker and Dehner's Pediatric Pathology, Third Edition, 2010)
- Initial descent of thyroid primordium follows the primitive heart and occurs anterior to the pharyngeal gut
- The route of migration passes ventral (or anterior) to the developing hyoid bone and laryngeal cartilages
- The pathway of caudal extension of thyroid diverticulum is determined by the pattern of arteries in the neck and further modified during pharyngeal development (Carlson: Human Embryology and Developmental Biology, Fifth Edition, 2013)
- Descent is during weeks 5 to 7 of gestation
During the migration, medial thyroid anlage remains attached to the base of tongue by a narrow tube, the thyroglossal duct
- Position of thyroglossal duct is modified by development of the hyoid bone (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
- Thyroglossal duct loses its lumen and degenerates by weeks 8 - 10, when thyroid reaches its normal position
- Proximal opening of thyroglossal duct persists as a small pit in the dorsum (posterosuperior surface) of the tongue known as foramen cecum
- Distal portion of thyroglossal duct may persist as the pyramidal lobe of thyroid, which is found in almost half the population
Shaping and landing
- Shortly after starting descent, thyroid diverticulum appears as a hollow vesicular structure
- During further migration, it solidifies and the tip of thyroid diverticulum bifurcates into right and left lobes (evident early in week 5) connected by the isthmus (visible during week 6)
- By the end of week 7 of gestation thyroid gets its definitive shape and final position in the neck anterior to the trachea between 2nd and 5th tracheal ring
Paired lateral thyroid anlagen arise from anterior endoderm that form transient embryonic structures called the ultimobranchial bodies (UBB)
- Ultimopharyngeal or ultimobranchial body is a small gland found in vertebrates, which participates in calcium homeostasis in addition to parathyroid
- The early human UBB develops from the pharyngeal endoderm
  - It was long believed that UBB was invaded by neural crest cells, which further differentiate into C cells
  - Neural crest is a transient tissue initially found at the junction of the neural groove and ectoderm and forming an intermediate zone between the surface ectoderm and neural tube after fusion of neural groove into the tube
  - The most recent concept suggests that UBBs are of endodermal but not of neural crest origin (Development 2015;142:3519, Eur Thyroid J 2016;5:79)
- Geographically UBBs originate from the ventral elongated part of the IV - Vth branchial pouch complex and develop during weeks 5 to 7 of fetal life (Mills: Histology for Pathologists, Fourth Edition, 2012)
  - In vertebrates, UBB typically arises from the Vth pharyngeal pouch, which corresponds to the ventral portion of the IVth pharyngeal pouch in humans; whether Vth pharyngeal pouches actually exist in humans is debatable, hence a term "IV - Vth branchial pouch complex" is used instead
- While still connected to the pharynx, paired UBBs start migration downward and at weeks 7 to 8, they separate from the pharynx and the parathyroid
- At weeks 8 to 9, lumens of UBBs become obliterated by proliferating cells and they appear as solid masses
- Fusion of the medial and both lateral anlagen occurs in the upper dorsolateral aspect of thyroid, which produces thickenings of the gland known as the tubercles of Zuckerkandl (Terris: Thyroid and Parathyroid Diseases: Medical and Surgical Management, Second Edition, 2016)
- UBB cells disseminate within the thyroid, mainly giving rise to C cells but also contributing to follicular cells (thyroid weight increases 30% after fusion)
- Site of fusion of the median and lateral anlagen (upper dorsolateral thyroid) determines restriction of C cells and solid cell nests to area within the middle to upper third of the lateral lobes, while the upper and lower poles and the isthmus are largely devoid of C cells
Differentiation and functional maturation continues during weeks 8 to 12 (see Histogenesis below)
Weight dynamics
- Weight of thyroid gland increases in a nearly linear manner from about 5 to 20 mg to 250 to 500 mg between weeks 10 and 20 (Histol Histopathol 1997;12:79)
- During the second trimester, the gland weight increases 7 to 8 fold, from approximately 100 to 125 mg to 700 to 800 mg
- Tables with a weight of fetal thyroid in relation to gestational age and body weight are available (Anat Rec 1964;148:123, Anat Rec 1971;171:227, Pediatr Dev Pathol 2002;5:559)

Histogenesis

Primordium
- Thyroid primordium consists of a solid mass of proliferating endodermal cells
- This cellular aggregation breaks up into a network of epithelial cords and clusters as it is invaded by the surrounding vascular mesenchyme (by week 9)
Maturation (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
- Precolloid stage with a pattern of cords and tubular structures and well defined mesodermal septa but there is no colloid (at about 10 weeks)
- Primitive follicles with forming lumen are first seen by weeks 10 - 11
- Colloid stage with colloid collection (by week 12) and well developed follicles (by week 14)
  - Follicular cells appear morphologically well developed at ultrastructural level after week 13, earlier changes are also well documented by electron microscopic study (Cell Tissue Res 1983;233:693)
- Colloid secretion proceeds and by week 16 noniodinated thyroglobulin is present in many of the widely dispersed follicular spaces
- The gland rapidly grows between weeks 16 and 18 with appearance of increasing number of colloid filled follicles and establishment of a rich capillary network
UBB derived structures (Mills: Histology for Pathologists, Fourth Edition, 2012)
- After fusion with medial thyroid at week 9, UBB enters into a dissolution phase and divides into a central, thick walled, stratified epithelial cyst and peripheral component
- Peripheral component scatters among the follicles to provide parafollicular cells (C cells)
  - Histologically C cells have more ovoid nuclei and pale cytoplasm, they locate subfollicular or interstitially with close relation to capillaries
  - C cells may be identified tentatively by light microscopy around week 12 but the characteristic neurosecretory granules are found around week 16 at the earliest (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
  - The cells can be identified confidently as C cells by about 20 weeks, using immunohistochemical techniques
  - The neonatal gland contains 10x more C cells than the adult thyroid, as the number of C cells diminishes with age (Stocker and Dehner: Stocker and Dehner's Pediatric Pathology, Third Edition, 2010)
- In postnatal life, the central epithelial cyst derived from UBB largely disappears, its occasional remnants are found in thyroid interstitium in the form of solid cell nests
Histology of perinatal thyroid (Khong: Keeling's Fetal and Neonatal Pathology, Fifth Edition, 2015)
- Small uniform follicles lined by cuboidal to low columnar epithelium with round nuclei and containing a variable amount of colloid
- Follicular size and colloid content vary from lobe to lobe and even within each lobule and may reflect fluctuations in the activity of each follicle
- C cells appear as relatively polygonal, paler stained cells usually lying within the walls of follicles between basement membrane and follicular epithelium
- Stroma is more abundant than in adult thyroid
- Perinatal thyroid gland may have areas with more solid appearance due to colloid depletion and collapse of the glandular parenchyma probably resulted from stress of labor and delivery

Functional development

Thyroid gland begins to function at weeks 10 - 12
- By week 10 of gestation, follicles containing some colloid material are evident and a few weeks later, the gland begins to synthesize noniodinated thyroglobulin
- Actual synthesis of thyroglobulin detected with sensitive techniques begins when thyroid is still a solid mass at the base of tongue, which is long before follicle formation and morphologically identifiable colloid secretion (J Clin Endocrinol Metab 1969;29:849)
Hypothalamic - pituitary - thyroid axis
- Early growth and development is independent of TSH (Best Pract Res Clin Endocrinol Metab 2008;22:57)
- Hypothalamic thyrotropin releasing hormone (TRH) is present by about weeks 8 - 10 of gestation
- Pituitary begins releasing TSH at about the same time
- Full regulatory interactions within hypothalamic - pituitary - thyroid axis are established between weeks 12 and 18, after that thyroid gland may be considered to be under autonomous fetal control
- Under normal circumstances, maternal thyroid stimulating factors do not have an effect on fetal thyroid function
Blood levels of hormones
- T3 is present by late in the 4th month and T4 by the end of the 5th month; overall significant fetal hormone secretion is present after week 20 (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, Second Edition, 2007)
- TSH levels grow sharply around weeks 16 - 18, the rise is slowing to plateau at about week 28 and finally reaching adult levels by week 35
- Iodine uptake and T3 / T4 levels reflect the above TSH fluctuations
- Until midgestation fetus depends on maternal supply of thyroid hormone, which is reduced to 30% later in the pregnancy; T3 / T4 synthesis also depends on maternal iodine supply via placenta (Khong: Keeling's Fetal and Neonatal Pathology, Fifth Edition, 2015)

Regulation

Specification of thyroid primordium begins under inﬂuence of FGF signaling pathways
Morphogenetic process during early embryologic stages (bud formation) is regulated by coordinated action of four major transcription factors: NKX2-1 (TTF1), FOXE1 (TTF2), PAX8 and HHEX
- Mutations in these genes cause thyroid dysgenesis, often as a part of syndrome with multiple organ involvement
Contributing effect of mesoderm derived mechanisms, e.g. mediated by TBX1 and FGF family
TSHR gene along with Thyroglobulin (Tg), Thyroid peroxidase (TPO), NIS, HOXA3, FGFR2 and NKX2 family genes are expressed during late stages of fetal development (after migration of medial anlage is completed)
Murine models suggest that transcription factors NKX2-1 and MASH1 influence development of C cells (Dev Dyn 2006;235:1300, Dev Dyn 2007;236:262)

IHC phenotype

Medial anlage: TTF1+, TTF2+ (FOXE1), PAX8+
Lateral anlagen: TTF1+, PAX8+
Fetal thyroid: Tg+, calcitonin / mCEA and the above
More markers (Mills: Histology for Pathologists, Fourth Edition, 2012):
- Transient expression of ghrelin
- Gal1 but not Gal3 in fetal stroma
- Ki67 proliferation index is highest (~15%) between weeks 10 and 20, then diminishes through the latter half of gestation, dropping to < 0.5% at birth (J Clin Endocrinol Metab 2006;91:2672)

Developmental abnormalities

Manifested as congenital hypothyroidism
- Failure of thyroid development (dysgenesis), including aplasia and hypoplasia
- Dyshormonogenetic goiter due to inherited defects in thyroid hormone synthesis
Manifested as neck mass
- Persistence of thyroglossal duct with cyst formation
- Branchial cleft cysts
Other remnants and ectopias
- Lingual thyroid
- Cervical and extracervical ectopic thyroid tissue due to failure of normal migration
- Presence of pyramidal lobe is considered as mild thyroid developmental anomaly
Other syndromes
- 22q11.2 deletion syndrome (DiGeorge syndrome)

Microscopic (histologic) images

AFIP images

Human embryo 14 weeks

Images hosted on other servers:

Stages 13 and 22

Mouse model

TTF1 expression

Videos

Thyroid development

Development of pharyngeal area

Additional references

Board review style question #1

Which of the following are the main genes involved in regulation of thyroid development?

BRAF, TP53, TERT
HRas, NRAS, KRAS
NKX2-1, FOXE1, PAX8, HHEX
PAX6, ASPM, KATNB1, TUBB5
RET, PPARg, NTRK

Board review style answer #1

C. NKX2-1, FOXE1, PAX8, HHEX

Comment Here

Reference: Embryology

Board review style question #2

Thyroid gland is derived from which of the following embryonal structures?

1 lateral and 2 medial anlagen
1 medial, 1 lateral and 2 intermediate anlagen
1 medial and 1 lateral anlagen
1 medial and 2 lateral anlagen
2 lateral anlagen only

Board review style answer #2

D. 1 medial and 2 lateral anlagen

Comment Here

Reference: Embryology

Encapsulated

Table of Contents

Definition / general

Papillary carcinoma totally surrounded by a capsule
8 - 13% of papillary carcinomas

Prognostic factors

Excellent prognosis (Eur J Surg 1996;162:177, Cancer 1984;54:90)
May have nodal metastases, but only rarely angiolymphatic invasion or distant metastases

Case reports

22 year old woman with encapsulated macrofollicular variant (Indian J Pathol Microbiol 2006;49:24)

Gross description

Thick capsule, resembles follicular adenoma

Gross images

AFIP images

Tumor surrounded by fibrous capsule

Microscopic (histologic) description

Nuclear changes of papillary carcinoma and psammoma bodies

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

Papillary carcinoma encapsulated variant

Transcapsular invasion

Thickened capsule is violated by tumor growth

Typical papillary appearance

Cytology description

Scattered clusters of follicular cells with focal Hürthle cell changes and prominent nuclear pleomorphism, mixed with colloid and normal appearing follicular cells
May not show classic papillary nuclear features (Acta Cytol 2002;46:555)

Differential diagnosis

Hyperplastic nodule with central cystic degeneration: papillary formations face lumen of cystically dilated cavity, "hot" on scan, pale and vacuolated colloid, no papillary nuclear features, negative for high molecular weight keratin

Encapsulated follicular

Table of Contents

Definition / general

Encapsulated follicular neoplasm with features of encapsulated and follicular variant of papillary carcinoma
Commonly sent for consultation

Diagnosis

Recommended to use strict criteria for diagnosis, and to classify questionable cases as well differentiated thyroid neoplasm of uncertain malignant potential (Am J Clin Pathol 2002;117:16)

Prognostic factors

Excellent prognosis, better than nonencapsulated follicular variant (Cancer 2006;107:1255)
May have late bone metastases with follicular pattern but without papillary nuclear features (Mod Pathol 2000;13:861)

Microscopic (histologic) description

Capsular and vascular invasion may be present; if no capsular or vascular invasion present, should have widespread nuclear features of papillary carcinoma PLUS some additional features of papillary carcinoma (papillae, fibrous bands, dense eosinophilic colloid), otherwise diagnose as follicular adenoma or well differentiated thyroid neoplasm of uncertain malignant potential

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Enlarged vesicular nuclei with irregular membranes

Evident major and minor diagnostic features

Minor diagnostic features

Free floating of small tumor fragment in vascular lumen

Small piece of tumor floats in vascular lumen

Images hosted on other servers:

Encapsulated follicular
lesion with nuclear
features of papillary
carcinoma (inset)

Capsular invasion

3 cm tumor in 51 year old man (fig. 1)

Cytology description

Ultrafast Papanicolaou stained smears makes clear nuclei more conspicuous (Cancer 2006;108:174)

Cytology images

Images hosted on other servers:

Ultrafast Pap stain

Diff-Quik versus
Ultrafast Pap staining of
follicular adenoma and
follicular variant

Endemic goiter

Table of Contents

Definition / general

Defined as thyroid enlargement due to iodine deficiency, primarily dietary deficiency
Endemic goiter term is used when the local prevalence is greater than 5 - 10%
Common in mountainous and iodine deficient areas of the world where the diet contains insufficient amount of iodine
Iodine supplementation reduces frequency of goiter but may increase prevalence of autoimmunity (Hormones (Athens) 2007;6:25) and follicular neoplasm
May be exacerbated by goitrogens, such as cassava and cruciferous vegetables or sewage contamination of water
May also be due to high iodine intake (Am J Public Health 2000;90:1633)
Cretinism: severely stunted physical and mental growth due to untreated congenital deficiency of thyroid hormone secondary to maternal hypothyroidism; may be due to iodine deficiency in pregnancy or selenium deficiency

Essential features

Diffuse goiter is followed by nodular goiter and autonomous nodule formation upon iodine supplementation
Generally due to dietary deficiency of iodine due to low content of iodine in soil or water
Other factors include exposure to goitrogens

Terminology

Iodine deficiency related thyroid goiter

ICD coding

E01.2

Epidemiology

Over 1/3 of world population live in iodine deficient area; 1.6 billion are at risk of iodine deficiency; 655 million have goiter
Prevalence of endemic goiter can be artificially increased if the normal upper limit of thyroid volume is decreased
Still present in mountainous districts of Alps, Andes or Himalayas, Bulgaria (Biol Trace Elem Res 2007;116:273), India (Indian J Med Res 2008;128:601), Russia (Georgian Med News 2005;126:67), Spain (An Pediatr (Barc) 2006;65:234), Turkey (Exp Clin Endocrinol Diabetes 2009;117:64), Egypt (Case Rep Med 2011;2011:620480)

Sites

Global involvement of thyroid gland

Pathophysiology

Iodine is required for thyroid hormone synthesis
- When there is nutritional deficiency of iodine, there is decreased capacity of the thyroid gland to produce thyroid hormones
- Due to the negative feedback, there is increased secretion of TSH by hypothalamus
- Increased TSH results in diffuse hypertrophy of thyroid glandular tissue which manifests grossly as a goiter
Euthyroidism is maintained with iodine intake levels of 150 - 200 ug/day and 250 ug/day during pregnancy and puberty
Not everyone in endemic area will have a goiter, due to variation in utilization of iodine, renal clearance of iodide or ratio of T3 (more metabolically potent) to T4

Etiology

Dietary deficiency of iodine
May be exacerbated by goitrogens, such as cassava and cruciferous vegetables or sewage contamination of water

Clinical features

Thyroid enlargement (goiter)
Hypothyroidism due to decreased production of T3 & T4 hormones
Hyperthyroidism
Compression of trachea and esophagus

Diagnosis

Clinical examination by palpation to assess thyroid enlargement
Ultrasonography
Serum T3, T4 and TSH
Urinary iodine levels

Laboratory

Increased TSH and decreased T3 & T4
Urine iodine level decreased (mild: 50 - 99 ug/l, moderate 20 - 49 ug/l and severe: < 20 ug/l)

Radiology description

Ultrasound: estimation of thyroid volume, isoechoeic nodules with cystic changes, hemorrhage or calcification
For adults, upper limit of volume is 25 ml (men), 18 ml (women), 16 ml (children aged 5 yrs) and 5 ml for children aged 6 yrs

Treatment

Supplemental iodine in the form of tablets, iodinated salt / oil / water / bread is effective in prevention
Treatment for established goiter is thyroxine; , iodine is contraindicated
Surgery only for pressure symptoms or autonomous nodules

Clinical images

Images hosted on other servers:

Endemic multinodular goiter

Gross description

Diffuse enlargement initially, progresses to multiple nodules, degenerative cystic changes, fibrosis, old and new hemorrhage (similar to multinodular goiter)

Gross images

Images hosted on other servers:

Endemic multinodular goiter

Microscopic (histologic) description

Follicles of varying size, flat / effaced follicular cells, cysts, hemorrhage or calcification
Follicular adenoma
Lymphocytic infiltrate

Cytology description

Follicular cells arranged in monolayered, honeycomb-like sheets, with delicate cytoplasm and indistinct cytoplasmic borders
Round to oval monomorphic nuclei and finely granular chromatin and absent nucleoli
Rare microfollicles
Abundant colloid

Cytology images

Contributed by Ayana Suzuki, C.T.

Watery colloid

Cracking colloid

Follicular clusters

3D structures

Paravacuolar granules

Additional references

Eur J Endocrinol 2002;146:19, UpToDate: Iodine Deficiency Disorders [Accessed 27 July 2018]

Board review style question #1

Which statement regarding endemic goiter is false?

Increases risk for follicular neoplasm
Increases risk for papillary neoplasm
May cause tracheal compression
Most common cause is dietary deficiency of iodine

Board review style answer #1

B. Endemic goiter increases the risk of follicular neoplasm and anaplastic carcinoma. On the contrary, papillary neoplasms occur more in iodine sufficient areas.

Comment Here

Reference: Endemic goiter

Features to report

Table of Contents

Definition / general

Protocols for histopathology reporting of thyroid cancer are issued by U.S. College of American Pathologists / CAP (CAP: Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland [Accessed 31 October 2018]), U.K. Royal College of Pathologists / RCPath (rcpath.org: Dataset for thyroid cancer histopathology reports [Accessed 31 October 2018]), The Royal College of Pathologists of Australasia / RCPA (CAP: Thyroid cancer structured reporting protocol 1st Edition 2011 [Accessed 31 October 2018]) and other expert societies
CAP provides the most comprehensive and regularly updated protocol for the examination of specimens from patients with carcinomas of the thyroid gland
Synoptic reporting considers a use of structured checklists to produce more complete and standardized medical reports
Reporting protocol is aimed to supply clinicians with information required for cancer staging (AJCC / TNM), initial risk stratification (American Thyroid Association / ATA) and treatment decisions, e.g. necessity of additional surgery (completion thyroidectomy) and radioactive iodine / RAI ablation (see Diagrams / tables below)

Essential features

Mandatory features to report (by CAP): procedure, tumor focality, tumor site, tumor size, histologic type, margins, angioinvasion, lymphatic invasion, extrathyroidal extension; number of lymph nodes examined and involved, size of the largest metastatic deposit, extranodal extension; pTNM
Important for cancer staging (AJCC / TNM), initial risk stratification (ATA) and treatment decision

Key features to report for Thyroid Cancer

Procedure
- Lobectomy
- Hemithyroidectomy: lobe with isthmus
- Subtotal thyroidectomy: small portion of uninvolved thyroid gland is left to preserve endocrine function
- Total thyroidectomy: entire gland, including posterior capsule, is removed
- Completion thyroidectomy
Tumor focality
- Unifocal
- Multifocal
- CAP note:
  - In multifocal cancers the protocol is applicable to the dominant excised tumor, which is defined as the most aggressive tumor - often but not necessarily the largest tumor
  - If the second tumor is clinically relevant (e.g. medullary carcinoma in case of papillary carcinoma), a second report can be generated
- Comment:
  - Multiple foci, whether minute or large, ipsi- or contralateral, can be either independent tumors or may result from intrathyroid spread of index tumor, which is difficult to distinguish (Endocr Pathol 2012;23:101)
Tumor site (laterality)
- Right lobe
- Left lobe
- Isthmus
- Pyramidal lobe
Tumor size
- Greatest dimension, in centimeters
- CAP note: additional dimensions are optional
- Comment:
  - Papillary cancers ≤ 1 cm and > 4 cm are associated with excellent and worse prognosis, respectively
  - Follicular cancer ≥ 3.5 cm has adverse prognosis
  - Average tumor size in Western practice is 2.5 cm, number of subcentimeter cancers is growing (from 20 - 30% in the USA to 80% in Korea) (J Endocrinol Invest 2017;40:683)
Histologic type (see topic: Thyroid gland - WHO classification - Major Updates)
- Papillary carcinoma, specify variant
- Follicular carcinoma, specify type
- Poorly differentiated carcinoma
- Anaplastic carcinoma, including just focal component
- Medullary carcinoma
- Comment:
  - Papillary microcarcinomas (≤ 1 cm), whether incidental / occult or nonincidental, are reported
  - Hürthle cell (oncocytic) tumors have been reintroduced as a separate entity in the new WHO classification
  - Poorly differentiated and anaplastic carcinomas are often seen with pre-existent well differentiated carcinoma
  - Minor component with high grade (insular, anaplastic) and "aggressive" histology (tall cell, solid, hobnail) can be of significance and is worth reporting as an additional feature
  - Papillary carcinoma is the most common type (up to 85 - 90% of all thyroid cancers) in daily practice, mainly represented by classic variant, follicular variant and microcarcinomas (Annu Rev Pathol 2017 Oct 30 [Epub ahead of print])
Margins
- Positive
- Negative
- Cannot be assessed
- CAP note: site of invasion and distance, from the closest margin in millimeters, are optional
- Comment:
  - According to Amin: AJCC Cancer Staging Manual, 8th ed, 2017, there is no difference in outcome between tumors with microscopically negative margins (R0) versus those with microscopically positive margins (R1); only grossly positive margins (R2) carry higher risks of recurrence and disease specific mortality (CA Cancer J Clin 2017 Nov 1 [Epub ahead of print])
  - Reported frequency of microscopically positive margin is 6 - 14% (Histopathology 2018;72:32)
  - Microscopic positive posterior but not anterior margin is a predictor for recurrence (J Surg Oncol 2016;113:635)
Angioinvasion (vascular invasion)
- Present
- Absent
- Cannot be determined
- CAP note: extent of invasion can be optionally reported as focal (Comment:
  - Only extensive vascular invasion predicts adverse outcome (recurrence, distant metastasis and cancer related death) (Histopathology 2018;72:32)
  - Angioinvasion is mainly seen in encapsulated (follicular carcinoma, follicular variant of papillary carcinoma) or ex-encapsulated (poorly differentiated carcinoma) thyroid cancers
  - In nonencapsulated cancers, e.g. papillary carcinomas, it sometimes can be seen in the extraglandular component of the tumor associated with extrathyroidal extension
  - Vascular invasion is applicable to vessels of the tumor capsule or vessels beyond tumor interface
  - Areas of angioinvasion that are closely adjacent to one another are counted as separate foci (Hum Pathol 2015;46:1789)
  - Clinical significance - association with distant metastasis (bones / spine, lungs)
  - Extensive angioinvasion is a rare event, found in less than 10% of encapsulated well differentiated cancers (Hum Pathol 2015;46:1789)
Lymphatic invasion
- Present
- Absent
- Cannot be determined
- Comment:
  - Extremely common in papillary cancers, can be identified by peritumoral foci / seeds, psammoma bodies or (indirectly) by presence of nodal metastasis
  - Clinical significance - association with lymph node metastasis and multifocality
Extrathyroidal extension (ETE)
- Present
- Absent
- Cannot be determined
- Comment:
  - If present, specify extent as gross ETE (usually involving larynx / trachea, large vessels / nerves) or only microscopic / minimal ETE (perithyroid fat, strap muscles)
  - Gross ETE is identified by clinician on imaging and during surgery or by pathologist on grossing
  - Minimal ETE requires a tumor to extend beyond the contour of the gland with a desmoplastic response, invasion of strap muscles (reliable ETE) or at least perithyroidal fat (Thyroid 2016;26:512)
  - Clinical significance - association with recurrence
  - According to Amin: AJCC Cancer Staging Manual, 8th ed, 2017, minor extrathyroidal extension identified only on histologic examination is no longer a variable in determining the T category - only gross extrathyroidal extension (invasion of strap muscle, at least) has prognostic significance (CA Cancer J Clin 2017 Nov 1 [Epub ahead of print])
  - ETE is detected in 1/4 of thyroid cancers (Thyroid 2017;27:1490)
Additional histologic features of the tumor are optional
- Mitotic rate in 10 consecutive HPFs at 400x in the hot spots
  - Comment: check carefully in the solid and trabecular patterned areas
- Perineural invasion
  - Comment: search in tumors with extensive ETE
- Grading system is not established for thyroid cancer

Additional pathologic findings in nonneoplastic part are optional
- Nodular lesions: follicular adenoma, hyperplastic nodule(s)
- Diffuse disease: thyroiditis, Graves
- Presence of parathyroid gland
Results of ancillary studies are optional
- Immunohistochemistry:
  - Tumor type specific markers, e.g. calcitonin for medullary carcinoma or beta catenin for cribriform morular papillary carcinoma
  - Markers to differentiate benign vs. malignant follicular-derived tumors (CK19, Galectin-3, HBME1)
  - Markers of high grade progression (Tg loss, Ki67 >10%, p53)
  - Mutation specific antibodies: VE1, SP174
- Molecular testing: not common on surgical samples

Key features to report for lymph nodes

Number of lymph nodes examined and involved
- Nodal levels should be specified, e.g. levels VI-VII (central compartment) or II-V (lateral)
- Number of nodes depends on type of neck dissection (selective, modified radical or radical)
- CAP note:
  - Adverse prognostic influence of lymph node metastasis in patients with differentiated carcinomas is observed only in the older age group
  - Less prognostic significance in papillary than in medullary cancer
- Comment:
  - Extremely common in papillary cancers (up to 50 - 80%, depending on the extent of neck dissection and sampling)
  - According to Amin: AJCC Cancer Staging Manual, 8th ed, 2017, identification of a psammoma body in a cervical lymph node, even in the absence of associated malignant cells, meets the definition of pathologic N1 disease (CA Cancer J Clin 2017 Nov 1 [Epub ahead of print])
  - To rule out occult nodal disease with 90% confidence, 6, 9 and 18 nodes would need to be examined for patients with T1b, T2 and T3 disease, respectively (J Clin Oncol 2016;34:3434)
Size of the largest metastatic deposit, in centimeters
- Comment: micrometastases (
- Extranodal extension
  - Comment:
    - Involvement of perinodal adipose tissue is the most consistent diagnostic criteria (Thyroid 2016;26:816)
    - Reported in up to 12% of papillary thyroid carcinoma / PTC overall and 33% of nodal metastatic PTC
- The protocol described in this topic is not applicable to these thyroid tumors:
  - Noninvasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP): reporting of NIFTP is optional and only size, laterality and margin status are reported
  - Thyroid carcinoma arising from struma ovarii
  - Thyroid carcinoma arising in thyroglossal duct cysts
  - Lymphoma: consider the Hodgkin (CAP Cancer Protocal Templates: Protocol for the Examination of Specimens From Patients With Hodgkin Lymphoma* [Accessed 31 October 2018]) or non-Hodgkin lymphoma protocols (CAP Cancer Protocal Templates: Protocol for the Examination of Specimens From Patients With Non-Hodgkin Lymphoma/Lymphoid Neoplasms [Accessed 31 October 2018])
  - Sarcoma: consider the soft tissue protocol (CAP Cancer Protocal Templates: Protocol for the Examination of Specimens From Patients With Soft Tissue Tumors [Accessed 31 October 2018])

Diagrams / tables

Contributed by Andrey Bychkov, M.D., Ph.D.

AJCC / TNM charts

ATA initial stratification

WHO classification

Images hosted on other servers:

Levels of the cervical lymph nodes

Pattern of nodal metasatasis

Extranodal

Microscopic (histologic) images

Contributed by Chan Kwon Jung, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.

Papillary thyroid carcinoma - lymphatic invasion

Vascular invasion

Psammoma bodies

Microscopically positive margin

Extrathyroidal extension

Extranodal extension

Videos

Extrathyroidal extension by J. Hernandez-Prera (2020)

Sample of case summary

Papillary thyroid carcinoma of the right lobe, tall cell variant (4.7 x 2.5 x 2.5 cm)
Lymphatic invasion positive
No angioinvasion
Minimal extrathyroidal extension (perithyroidal fat)
Microscopically involved superior resection margin, all other margins negative
Lymph node metastasis, 2/2 nodes (perithyroid), 0.5 cm in largest diameter, no extranodal extension
Hashimoto thyroiditis of nonneoplastic thyroid
pT3a (size > 4 cm), pN1a (positive perithyroidal nodes)

Additional references

Expert guides
Local experience
- Thyroid 2012;22:604
- Endocr Pathol 2012;23:215
Clinical guidelines

Board review style question #1

Extranodal extension
Histologic type
Lymphatic invasion
Perineural invasion
Tumor focality

Board review style answer #1

D. Perineural invasion is an optional feature to report, because its clinical significance is not well defined.

Comment Here

Reference: Features to report

Fibromatosis / fasciitis-like

Table of Contents

Definition / general

Rare histological variant of papillary thyroid carcinoma (PTC)
Characterized by an abundant stroma resembling nodular fasciitis / fibromatosis / other myofibroblastic proliferative processes
First described by Ostrowski as PTC with fibromatosis-like stroma and by Chan et al. as PTC with nodular fasciitis-like stroma (Am J Clin Pathol 1991;95:309)

Essential features

Prominent myofibroblastic proliferation histomorphologically similar to fibromatosis or nodular fasciitis of soft tissue
Varying proportion of PTC component
CTNNB1 (beta catenin) mutation frequent in mesenchymal component

Terminology

PTC with fibromatosis / fasciitis-like stroma
PTC with desmoid type fibromatosis (Mod Pathol 2017;30:236)

ICD coding

ICD-O: 8260/3 - Papillary carcinoma of thyroid
ICD-10: C73 - Malignant neoplasm of thyroid gland

Epidemiology

Exceedingly rare, with less than 50 well documented cases reported (Mod Pathol 2017;30:236)
- Estimated 0.04 - 0.5% of all PTC cases (Mod Pathol 2017;30:236, Am J Clin Pathol 1991;95:309)
20 - 82 years (mean: 44.5 years); F:M = 3:1 (J Laryngol Otol 2006;120:338)

Sites

Either lobe or isthmus of thyroid gland

Pathophysiology

Stromal proliferation mechanism:
- Activated Wnt / APC / beta catenin signaling pathway (Mod Pathol 2017;30:236)
- Downstream signaling induced by BRAF mutation (Virchows Arch 2019;475:519)
- Reactive, remains to be proved (Am J Clin Pathol 1991;95:309, Histopathology 1992;21:577)

Clinical features

Asymptomatic / palpable firm neck mass (Endocr J 2017;64:1017)
May manifest with cervical nodal metastasis or obstructive symptoms

Diagnosis

Diagnostic workup is similar to any thyroid mass / nodule
- Ultrasound with fine needle aspiration cytology (FNAC)
- CT scan may be useful to evaluate extrathyroidal extension and lymph node metastases
Final diagnosis is rendered on histopathological examination of resected tumor
- Accurate diagnosis of PTC with fibromatosis / fasciitis-like stroma is usually not possible on FNAC; however, preoperative recognition of this variant among other PTC variants does not influence treatment decisions (Endocr J 2017;64:1017)

Radiology description

Sonography:
- Similar to classical PTC (Ultrasound Int Open 2018;4:E39)
- Classified as intermediate or high suspicion nodule
- Irregular shape
- Heterogeneous echogenicity
- Taller than wide sign (85%)
- Usually lacks microcalcification (76.9%), macrocalcification (> 2 mm) in 31%
- Mesenchymal component: heterogeneous (62.5%), more hypoechoic (71.4%) than PTC areas; lacks microcalcification
Doppler ultrasound:
- No or mild flow signal (75.0%)
Ultrasound elastography:
- Mesenchymal component: not stiff; more elastic than PTC areas

Radiology images

Images hosted on other servers:

Ultrasound

Ultrasound elastography

Color doppler ultrasound

Prognostic factors

Prognosis similar to classic PTC of similar size and stage (J Laryngol Otol 2006;120:338)
Risk stratification as per American Thyroid Association 2015 (Thyroid 2016;26:1)

Case reports

20 year old man with desmoid type fibromatosis postthyroidectomy (Int J Surg Case Rep 2019;63:5)
38 year old woman with left side neck swelling (Indian J Pathol Microbiol 2017;60:390)
44 year old woman with neck swelling (Int J Surg Pathol 2015;23:305)
48 year old woman with desmoid type fibromatosis postthyroidectomy (Int J Clin Exp Pathol 2018;11:2879)
58 year old patient with SOX11 expression in a case of PTC with fibromatosis / fasciitis-like stroma containing BRAF c.1799_1801delTGA and CTNNB1 c.133T>C mutations (Virchows Arch 2019;475:519)

Treatment

Based on American Thyroid Association and NCCN guidelines, usually surgical excision (Thyroid 2016;26:1, J Natl Compr Canc Netw 2018;16:1429)
Response of radioactive iodine on the mesenchymal component not proven (Mod Pathol 2017;30:236)

Gross description

Size: 1.6 - 9 cm (J Laryngol Otol 2006;120:338, Ultrasound Int Open 2018;4:E39)
Usually well circumscribed but not encapsulated, firm, homogeneous, whitish nodule (Endocr J 2017;64:1017)
Mesenchymal area: translucent, rubbery elastic, tan in color (Endocr J 2017;64:1017)

Gross images

Images hosted on other servers:

Well demarcated, solid

Fibrotic nodule

Frozen section description

May not be diagnostic if demonstrates only mesenchymal component (Indian J Pathol Microbiol 2017;60:390)

Microscopic (histologic) description

Mixed epithelial-mesenchymal tumor
Epithelial component:
- PTC (usually classical PTC; follicular variant of PTC also documented) (Mod Pathol 2020;33:1702)
Mesenchymal component:
- 20 - 95% of tumor area (Endocr J 2017;64:1017, Ultrasound Int Open 2018;4:E39)
- Myofibroblastic proliferation similar to fibromatosis / nodular fasciitis / other myofibroblastic proliferative processes
- Fibromatosis type stroma: dense hypocellular collagenous connective tissue
- Nodular fasciitis-like stroma: edematous, extravasated red blood cells, inflammatory cells; reminiscent of granulation tissue
- May infiltrate surrounding neck structures
- May metastasize to lymph nodes along with the epithelial cell component (Endocr J 2017;64:1017)

Microscopic (histologic) images

Contributed by Ayana Suzuki, C.T.

Mixed epithelial-mesenchymal tumor

Fibromatosis type stroma

Beta catenin

Virtual slides

Images hosted on other servers:

PTC with fibromatosis type stroma

Cytology description

Usually Bethesda V (suspicious for PTC) or VI (diagnostic of PTC) (Endocr J 2017;64:1017)
Aspirate may show stromal fragments containing spindle cells in a myxoid background
- May be misdiagnosed as nonneoplastic or benign / malignant spindle cell neoplasm or anaplastic thyroid carcinoma
Aspirate may be biphasic
- Admixed epithelial and stromal fragments
May be hypocellular / unsatisfactory (Mod Pathol 2020;33:1702)

Cytology images

Images hosted on other servers:

Stromal fragment

Positive stains

PTC component:
- Cytokeratins: AE1 / AE3, CK7, CK19
- Thyroid specific markers: TTF1, thyroglobulin, PAX8
- Galectin3, HBME
- Membranous beta catenin staining
Mesenchymal component:
- Nuclear and cytoplasmic staining for beta catenin in cases with fibromatosis-like stroma (Mod Pathol 2020;33:1702, Pathobiology 2018;85:300)
- Focal cytoplasmic beta catenin staining in nodular fasciitis-like variant
- Vimentin, alpha smooth muscle actin, desmin
- MIB1 < 5%

Negative stains

CK20, calcitonin, S100, p53

Electron microscopy description

Collagen fibers in proximity of mesenchymal cells (Mod Pathol 2017;30:236)
Abundant rough endoplasmic reticulum

Molecular / cytogenetics description

PTC: BRAF V600E mutation most common, rarely NRAS mutation (Mod Pathol 2020;33:1702)
Mesenchymal component: CTNNB1 (beta catenin) mutations
Absent USP6 gene rearrangement (limited evidence)

Differential diagnosis

Hashimoto thyroiditis, fibrous variant:
- Absent PTC component
- No extrathyroidal extension / metastases
- Dense lymphocytic infiltrate, oncocytic metaplasia
- No beta catenin expression (nuclear or cytoplasmic) in stroma
Riedel thyroiditis:
- Absent PTC component
- No lymph node metastases
- Lymphoplasmacytic infiltrate
- No beta catenin expression (nuclear or cytoplasmic) in fibroblasts
Postoperative spindle cell nodules:
- Previous history of surgery
- Absent PTC component
- No metastases
- No beta catenin expression (nuclear or cytoplasmic) in fibroblasts
Diffuse sclerosing variant of PTC:
- Diffuse involvement of one lobe or entire gland
- Stroma rich in lymphocytic infiltrate
- Numerous psammoma bodies
- Squamous metaplasia, squamous morules
- Rare fibroblastic proliferation
- No beta catenin expression (nuclear or cytoplasmic) in fibroblasts
Anaplastic thyroid carcinoma:
- Marked atypia of spindle cells
- No beta catenin expression (nuclear or cytoplasmic) in fibroblasts
- May be positive for cytokeratin, PAX8 and p53
Medullary thyroid carcinoma:
- Amyloid
- Stippled chromatin
- Calcitonin and pancytokeratin immunopositivity
- No beta catenin expression (nuclear or cytoplasmic) in fibroblasts
Mesenchymal spindle cell neoplasms like solitary fibrous tumor, sarcoma:
- Specific immunoprofile
- Absent PTC component

Board review style question #1

How is the variant of papillary thyroid carcinoma shown in the image distinct from other variants?

BRAF V600E mutation in epithelial component
EWSR1 fusions
CTNNB1 (beta catenin) mutation in mesenchymal component
HRAS mutation in epithelial component
CTNNB1 (beta catenin) mutation in epithelial component

Board review style answer #1

C. CTNNB1 (beta catenin) mutation in mesenchymal component

CTNNB1 (beta catenin) mutations have been documented in the mesenchymal component of papillary thyroid carcinoma (PTC) with fibromatosis / fasciitis-like stroma. The PTC (epithelial) component of this tumor lacks CTNNB1 mutation; it instead usually harbors BRAF V600E mutation and less commonly HRAS mutation. BRAF and HRAS mutations are, however, not specific for PTC with fibromatosis / fasciitis-like stroma. CTNNB1 mutations are seen in cancer cells of cribriform-morular variant of PTC. EWSR1 gene fusions are a hallmark of Ewing sarcoma.

Comment Here

Reference: Fibromatosis / fasciitis-like

Board review style question #2

Which of the following is true about papillary thyroid carcinoma with fibromatosis / fasciitis-like stroma?

Aggressive clinical course
Fibromatosis may recur postthyroidectomy
Only the epithelial component can metastasize
Membranous expression of beta catenin in both epithelial and mesenchymal elements
Stroma always mimics desmoid type fibromatosis

Board review style answer #2

B. Fibromatosis may recur postthyroidectomy

Clinical course of papillary thyroid carcinoma (PTC) with fibromatosis / fasciitis-like stroma is usually similar to classical PTC. The tumor is characterized by a prominent myofibroblastic proliferation reminiscent of fibromatosis or nodular fasciitis, hence the name. Stromal component of tumors with fibromatosis-like stroma commonly harbors CTNNB1 (beta catenin) mutation, which on immunohistochemistry is depicted by nuclear positivity and loss of membranous staining. The PTC component retains normal membranous beta catenin immunoreactivity. The tumor is also unique in that the patients can develop recurrence of fibromatosis postthyroidectomy. Metastases can show both mesenchymal and epithelial components similar to the primary tumor.

Comment Here

Reference: Fibromatosis / fasciitis-like

FNA-general

Table of Contents

Definition / general

Minimally invasive technique to obtain cytologic specimens of thyroid nodules
Recommended procedure when evaluating thyroid nodules for malignancy, to triage patients for possible surgery (Thyroid 2016;26:1)
Can be performed using palpation guidance or ultrasound guidance
Operators of thyroid fine needle aspiration (FNA) differ among countries and institutions: from clinicians (endocrinologist, head and neck surgeon) to radiologists and cytopathologists (J Pathol Transl Med 2017;51:571)
Results are recommended to be reported in standardized format using the Bethesda System for Reporting Thyroid Cytopathology (see Bethesda categories)
Sensitivity and specificity of FNA have been reported as high as 100% and 94%, respectively, if specimen is adequate; larger nodules have been reported to have higher false negative rate (PLoS One 2017;12:e0186242, BMC Res Notes 2008;1:12)
Thyroid FNA was introduced in 1930 by Martin and Ellis, who used an 18 gauge needle aspiration technique; however, it became a mainstream approach much later, after introducing a so called small needle aspiration biopsy (now referred to as FNA) (Ann Surg 1930;92:169)

Essential features

Superficial thyroid nodules may be targeted by palpation (if palpable) or with ultrasound guidance (nonpalpable or complex) with minimal complication
Rapid on site evaluation (ROSE) may be performed to assess specimen adequacy
Thyroid FNA is a highly accurate diagnostic procedure with few complications
The Bethesda System for Reporting Thyroid Cytopathology is the recommended system to report results

Terminology

Fine needle aspiration, thin needle aspiration, ultrasound guided fine needle aspiration (USG FNA) or palpation guided fine needle aspiration
Fine needle aspiration cytology (FNAC), fine needle aspiration biopsy (FNAB)

CPT coding

10021 - fine needle aspiration
10022 - fine needle aspiration using imaging guidance
88112 - cytopathology, selective cellular enhancement technique with interpretation (e.g., liquid based slide preparation method), except cervical or vaginal (ThinPrep / SurePath technique)
88172 - cytohistologic evaluation of fine needle aspirate to determine adequacy for diagnosis
88173 - cytopathology, evaluation of fine needle aspirate; interpretation and report
88177 - cytohistologic evaluation of fine needle aspirate to determine adequacy for diagnosis (additional passes)

Epidemiology

Thyroid nodules are common and are increasingly found incidentally
Ultrasound identifies nodules in 19 - 68% of individuals selected at random (Thyroid 2016;26:1)
More commonly found in women and the elderly
Majority of thyroid nodules are benign (Thyroid 2016;26:1)

Sites

In addition to presenting in the thyroid parenchyma, thyroid nodules may present as lymph nodes or other neck masses, as there can be ectopic thyroid or accessory thyroid nodules in thyroiditis
Nodule location within thyroid gland should be confirmed by ultrasound to avoid unintentional biopsy of adjacent tissues (Diagn Cytopathol 2008;36:390)

Diagrams / tables

Contributed by Rachel Jug, M.B.B.Ch.

Ultrasound FNA techniques

Images hosted on other servers:

Risk based on appearance and nodule characteristics

Technique

Short, rapid strokes
with only slight
changes in direction

Clinical features

Indications (stratified by approach)

Palpation guided	Ultrasound guided
Incidentally or radiographically identified predominantly solid (> 75%) thyroid nodule > 1 cm diameter confirmed by ultrasound	Complex and cystic nodules (> 25% cystic component); ultrasound helps target specific areas, such as solid areas (Diagn Cytopathol 2008;36:390)
Thyroid nodule of interest is discrete and palpable	Nonpalpable or difficult to palpate nodules (e.g., posteriorly located) (Diagn Cytopathol 2008;36:390)
When access to ultrasound guided FNA is limited, palpation guided FNA may be considered (Diagn Cytopathol 2008;36:390)	To aid skilled operator in ascertaining sample of specific nodule of interest and to avoid adjacent critical structures (Diagn Cytopathol 2008;36:390)
	For repeat FNA, when a prior palpation guided FNA sample was insufficient (Diagn Cytopathol 2008;36:390)
	Follow up for patients, post partial or total thyroidectomy for malignancy, such as to sample thyroid bed (J Ultrasound Med 2013;32:1319)

2015 American Thyroid Association (ATA) Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer (Thyroid 2016;26:1):
- Strongly recommends ultrasonic examination of thyroid nodules and cervical lymph nodes
- Recommended sampling if > 1 cm in greatest dimension and high suspicion sonographic pattern (estimates a 70 - 90% risk of malignancy), including solid hypoechoic nodule or nodule that is partially solid and hypoechoic and partially cystic with 1 or more of the following features:
  - Irregular margins (infiltrative, microlobulated)
  - Microcalcifications
  - Oval (taller than wide) shape
  - Rim calcifications with an extrusive soft tissue component
  - Evidence of extrathyroidal extension

Contraindications

Relative contraindications:
- Unable to lie recumbent
- Unable to control their rate and depth of respiration adequacy
- Severe anxiety (reassure variable anxiolytics)
- Young children (may require sedation)
- On heparin, warfarin, clopidogrel, high dose aspirin and other anticoagulants (Baskin: Thyroid Ultrasound and Ultrasound-Guided FNA, 2nd Edition, 2008)
- Variant anatomy due to previous illness or surgery
- Nodule of interest is hot on radionuclide thyroid scan
- Goiter (diffuse or asymmetric) precluding localization of nodule of interest (Diagn Cytopathol 2008;36:390)
Absolute contraindication: severe coagulopathy disorder

Diagnosis

Comparison of procedural ultrasound is made with diagnostic ultrasound to corroborate lesion of interest; findings on diagnostic ultrasound contribute to risk stratification of thyroid lesions in accordance with the 2015 ATA Management Guidelines (see Thyroid gland - Ultrasound) (Thyroid 2016;26:1)
Diagnostic categories are assigned based on the Bethesda system for reporting thyroid cytopathology (Thyroid 2016;26:256)

Radiology description

See Thyroid gland - Ultrasound

Radiology images

See Thyroid gland - Ultrasound

Case reports

29 and 42 year old women with pneumothorax after thyroid FNA (Case Rep Otolaryngol 2021;2021:8944119)
30 year old woman with acute thyroid swelling after thyroid FNA (BMC Surg 2021;21:175)
56 year old man with acute thyroid swelling after thyroid FNA ( Diagn Cytopathol 2022;50:E193)
78 year old woman with a fatal hemorrhage after thyroid FNA (Am J Forensic Med Pathol 2022;43:291)
80 year old man with a massive hemorrhage after thyroid FNA (BMC Surg 2021;21:220)

Treatment

Following the FNA procedure, ultrasound may be utilized to scan the neck for potential complications before they become apparent and prior to the patient leaving the clinic / hospital (AJSP 2018;23:165)
Patient should be reminded of aftercare:
- Acetaminophen and icing may be used to relieve pain and swelling in accordance with medication directions on the packaging, if they do not have contraindications
If bleeding is profuse or massive swelling occurs, patients should present to urgent care or emergency department for further evaluation

Benefits of ultrasound guided FNA compared to conventional FNA alone

Ultrasound guided has higher adequacy and fewer false negative rates than palpation guided (J Clin Ultrasound 1994;22:535, Thyroid 1998;8:15, Thyroid 1998;8:283)
Potentially lowers risk of damage to surrounding structures, which can be visualized
Varying reports on cost effectiveness (BMC Endocr Disord 2009;9:14, Thyroid 2006;16:555)
Efficacy of ultrasound guided FNA is improved by the presence of a cytopathologist on site, decreasing the overall inadequacy rate from 9.3% to 6% and improving adequacy rate and concordance with final diagnoses (Br J Radiol 2014;87:20130571, Cancer Cytopathol 2017;125:161)
For additional details on thyroid ultrasound features and performance, see Thyroid gland - Ultrasound

Core biopsies

Core biopsies are not the preferred initial procedure of choice in evaluation of a concerning thyroid nodule, as per ATA 2015 guidelines (Thyroid 2016;26:1)
Core biopsies may be useful for fibrotic nodules that yield inadequate samples on repeat FNA or for collecting additional material for ancillary testing (Endocrinol Metab (Seoul) 2017;32:407)
Korean Thyroid Association 2019 practice guidelines for thyroid core needle biopsy (J Pathol Transl Med 2020;54:64)

Set up

Position patient supine with neck extended and pillow under shoulders
- Seated or semi-seated position used in some hospitals
Examine the thyroid lobes and neck for thyroid masses and lymphadenopathy
Assess the size of suspicious nodules identified; this is to help select FNA needle size and length to obtain an appropriate sample (Baskin: Thyroid Ultrasound and Ultrasound-Guided FNA, 2nd Edition, 2008)

Needle based sample collection techniques

Determine how you want to hold the needle during the procedure; options include the French technique (open ended needle without suction with or without syringe attached without plunger), syringe pistol / gun, pencil grip syringe holder, vibrating holder (experimental) (Niger Postgrad Med J 2013;20:116, Diagn Cytopathol 1999;20:99, Laryngoscope 2021;131:E1393)
Prior to aspiration with needle, use nondominant hand to stabilize the nodule and pull the skin taught between stabilizing fingers; clean the site with alcohol and let it dry prior to needle entry to prevent stinging
Approach the skin at 45 degree angle with needle
Local anesthetic with buffered lidocaine may be used but is not necessary (and adds an extra needle stick that may compromise cytology) since the majority of patients do not report pain after the procedure (J Emerg Med 1992;10:411, J Pain Res 2017;11:61)
With aspiration / suction:
- 27 or 25G needle attached to a 10 cc syringe (with or without extension tubing), withdrawn so that 1 - 2 cc of negative pressure induces aspiration
Without aspiration / nonsuction:
- 27 or 25G needle (with or without stylet, may attach open syringe) is introduced into nodule and capillary action causes uptake of cellular material into the needle
- Systematic review and meta analysis concluded superiority of thyroid FNA with smaller needle gauges (24 - 27G) and without aspiration (Thyroid 2018;28:857)
- May opt to use larger needle (22G) in severely calcified nodules to prevent bending of smaller needles within the lesion (Endocr J 2019;66:143)
- Use of a bare needle without a syringe or negative suction is termed the Zajdela technique, which capitalizes on the capillary action induced by forward motion of the needle in contrast to the application of suction (by syringe with or without a syringe holder)
Regardless of the method, immobilization of the target while completing multiple rapid passes through the lesion in a fanning motion is required to adequately sample the lesion (Diagn Cytopathol 2008;36:407)

Sample preparation

Sample preparation depends on the institution's preferred method
Preparation methods include smears (air dried and alcohol fixed), liquid based preparations (ThinPrep, SurePath, etc.) and cell block
For air dried slides, the Romanowsky staining method (using a stain such as Diff-Quik) is commonly used and alcohol fixed smears prevent drying artifacts and may be stained with the Papanicolaou stain
For cases with rapid on site evaluation for adequacy, air dried slides can be used to evaluate material
- If the initial smear is of poor quality or insufficient to make a diagnosis, create another set of smears; otherwise, put the remainder of the sample into an ethanol based solution for ThinPrep processing (Papsociety.org: FNA Techniques [Accessed 8 June 2022])
If a pathologist is not present to perform the FNA or to provide rapid on site evaluation, the institution may prefer to prepare exclusively Papanicolaou stained or ThinPrep slides
- Telecytology can be used for remote ROSE
Additional material for ancillary tests, including biochemical (thyroglobulin washout, calcitonin, parathyroid hormone, etc.) and molecular testing (see Molecular testing in FNA) may be collected; for the latter, aspirated material is placed into nucleic acid preservative solution at the time of all initial thyroid biopsies or at the time of repeat sampling of an indeterminate nodule
Tips:
- If samples are very bloody, consider placing excess blood / clot into a liquid based sample vial or making cell block, rather than making multiple bloody smears
- Follicular epithelium may get stuck in needle hubs; needle shield devices may be used to help flick excess material out of needle hub safely

Complications

Hemorrhage (including local puncture site bleeding, ecchymosis, hematoma formation)
Puncture site infection (Baskin: Thyroid Ultrasound and Ultrasound-Guided FNA, 2nd Edition, 2008)
Damage to surrounding structures (e.g., potentially leading to dysphonia)
Pain at puncture site (Nuklearmedizin 2018;57:211)
Serious complications of FNA procedure are very rare (Clin Endocrinol (Oxf) 2009;71:157)

Microscopic (histologic) description

Histopathological changes in thyroid after FNA procedure include acute and chronic:
- Acute changes are hemorrhage, granulation tissue, giant cells, hemosiderin laden macrophages, cholesterol clefts, necrosis, rarely infarction (Diagn Cytopathol 1996;15:211)
- Chronic changes are infarction, oncocytes, squamous or spindle metaplasia, fibrosis, calcification, vascular thrombosis; rarely tumor implantation along needle tract, rarely papillary endothelial hyperplasia (World J Surg 2020;44:378, Pathol Res Pract 2007;203:641, Arch Pathol Lab Med 1992;116:1040, Arch Pathol Lab Med 1991;115:240)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

FNA induced alterations in thyroid nodule

Pseudo angiosarcomatous pattern

Fine needle
induced changes
in follicular
adenoma

Molecular / cytogenetics description

See Molecular testing in FNA

Molecular / cytogenetics images

See Molecular testing in FNA

Videos

FNA biopsy techniques

Thyroid FNA and smearing techniques

Superficial FNA technique

Additional references

AJSP 2018;23:176, Baskin: Thyroid Ultrasound and Ultrasound-Guided FNA, 3rd Edition, 2013, Milas: Advanced Thyroid and Parathyroid Ultrasound, 1st Edition, 2017, Bardales: The Invasive Cytopathologist - Ultrasound Guided Fine-Needle Aspiration of Superficial Masses, 2014, Yang: Thyroid Fine Needle Aspiration, 1st Edition, 2013

Board review style question #1

What type of sample is evaluated during a rapid on site evaluation of a thyroid fine needle aspiration?

Air dried stained slide
Cell block material
Core biopsy slide
SurePath slide
ThinPrep slide

Board review style answer #1

A. Air dried stained slide. Air dried slides are ideal for rapid on site evaluation.

Comment Here

Reference: FNA-general

Board review style question #2

Which of the following fine needle aspiration indications would favor using ultrasound guided rather than palpation guided fine needle aspiration?

First biopsy of the specific lesion in question
Patient referred specifically for fine needle aspiration with rapid on site evaluation
Predominantly solid nodule
Superficial thyroid nodule > 1 cm
Thyroid nodule of interest in background of a multinodular goiter

Board review style answer #2

E. Thyroid nodule of interest in background of a multinodular goiter. Ultrasound guidance will assist in localizing fine needle aspiration to nodule of interest as opposed to off target nodules with benign radiographic features. Ultrasound guided fine needle aspiration allows for real time correlation to diagnostic ultrasound images.

Comment Here

Reference: FNA-general

Focal lymphocytic thyroiditis

Table of Contents

Definition / general

Focal lymphocytes in thyroid gland
Usually an incidental finding

Epidemiology

5 - 20% of adult autopsies, more common in elderly women (Endocr J 2000;47:575)

Clinical features

Associated with low levels of antithyroid antibodies, lack of clinical symptoms
May be early or mild form of autoimmune thyroiditis (J Clin Pathol 1969;22:326)

Treatment

None

Gross description

No findings

Microscopic (histologic) description

Focal aggregates of lymphocytes in inter- or intralobular fibrous tissue
No oxyphilic metaplasia, no follicular atrophy, no follicular disruption
May be associated with other thyroid disease

Microscopic (histologic) images

Images hosted on other servers:

Patchy lymphocytic inflammation

Small and large lymphocytes,
occasional plasma cells

Electron microscopy description

Extra- and intrafollicular lymphocytes (Immunobiology 1994;190:290)

Electron microscopy images

Images hosted on other servers:

Coarsely
condensed
chromatin at
nuclear periphery

Follicular adenoma

Table of Contents

Definition / general

Benign, encapsulated tumor that exhibits thyroid follicular cell differentiation
Lacks capsular and vascular invasion
Absent nuclear features of papillary thyroid carcinoma

Essential features

Benign thyroid tumor, lacking infiltrative properties and usually exhibiting follicular architecture
Needs to be differentiated from adenomatoid thyroid nodule and other follicular patterned thyroid neoplasms

ICD coding

ICD-O: 8330/0 - follicular adenoma

Epidemiology

Incidence: 3 - 5%
Adults, wide age range; usually in fifth to sixth decades (Clin Endocrinol (Oxf) 2018;88:936)
Female preponderance

Sites

Either thyroid lobe, isthmus, ectopic thyroid tissue

Etiology

Usually sporadic
Radiation exposure (Cancer 2003;97:2397)
Iodine deficiency (Cancer 1987;60:3096)
Familial tumor syndromes
- PTEN (phosphatase and tensin homolog deleted on chromosome ten): younger age of presentation; multiple and bilateral (Ann Diagn Pathol 1999;3:331)
- Carney complex (Diagn Histopathol 2017;23:366)
- MEN1 syndrome (Wermer syndrome)
- McCune-Albright syndrome
- Familial multinodular goiter (FMNG) syndrome

Diagrams / tables

Images hosted on other servers:

Diagnostic capsular invasions

Incomplete / questionable capsular invasions

Clinical features

Painless solitary thyroid nodule
May be detected incidentally (during palpation or neck ultrasound)
Rarely compression symptoms, if large
Hyperthyroidism in case of hyperfunctioning adenomas (Plummer adenoma)
Reference: Surg Clin North Am 2014;94:499

Diagnosis

Diagnostic workup is similar to any thyroid nodule
- Ultrasound with fine needle aspiration cytology (FNAC)

Laboratory

Thyroid function test; usually euthyroid
Can be hyperthyroid in case of hyperfunctioning adenoma

Radiology description

Sonography: solid / solid cystic nodule, smooth and well defined margins, homogeneous or heterogeneous echotexture, isoechoic or hypoechoic, occasionally peripheral hypoechoic halo (Asian J Surg 2020;43:339, J Ultrasound Med 2014;33:221, AJR Am J Roentgenol 2010;194:44)
Doppler ultrasound: absent or low blood flow
Radionuclide scan: cold nodule; hot nodule if hyperfunctioning

Radiology images

Images hosted on other servers:

Ultrasound

Color Doppler sonogram

Prognostic factors

Benign tumor

Case reports

3 year old girl with adenochondroma of the thyroid gland (Ear Nose Throat J 2021;100:412S)
12 year old boy with follicular adenoma harboring BRAF K601E mutation (Int J Surg Pathol 2017;25:348)
29 year old woman with clear cell follicular adenoma of ectopic thyroid (Endocr Pathol 1998;9:339)
39 year old woman with follicular adenoma having intracytoplasmic lumina (Cytopathology 2016;27:495)
45 year old woman with follicular adenoma with papillary architecture (Cytopathology 2015;26:256)
48 year old woman with renal cell carcinoma metastatic to follicular adenoma of thyroid gland (Acta Cytol 2004;48:64)
58 year old woman with Plummer adenoma following percutaneous thyroid ethanol injection in thyroid gland (Case Rep Endocrinol 2017;2017:1026139)
59 year old woman with metastasis of colonic adenocarcinoma to thyroid follicular adenoma (Pathol Int 2005;55:574)
61 year old man with clear cell follicular adenoma of thyroid (Exp Clin Endocrinol Diabetes 2010;118:19)
61 year old man with follicular adenoma showing spindle cell metaplasia (Am J Surg Pathol 2019;24:84)
63 year old woman with follicular adenoma showing osseous metaplasia (Int J Surg Case Rep 2017;37:83)
72 year old man with follicular adenoma showing chondroid metaplasia (Histopathology 1991;18:278)
75 year old woman with follicular adenoma showing cellular atypia and mimicking anaplastic thyroid carcinoma on cytology (Diagn Cytopathol 2017;45:928)

Treatment

Lobectomy
Hyperfunctioning follicular adenomas: lobectomy preferred over radioiodine (Oncologist 2011;16:585)

Gross description

Solitary, encapsulated nodule; multiple if familial
Variable size (1 - 10 cm)
Solid, gray-white, tan to light brown
Secondary changes: hemorrhage, cystic change, fibrosis, calcification, infarction; may develop post-fine needle aspiration cytology
Rarely black; especially seen with minocycline therapy

Gross images

Contributed by Andrey Bychkov, M.D., Ph.D., Mark R. Wick, M.D. and AFIP

Encapsulated thyroid nodule

Circumscribed thyroid nodule

Encapsulated, homogeneous tan cut surface

Bisected adenoma has fresh hemorrhage

Marked necrosis, hemorrhage and cystic change

Marked cystic degeneration

Images hosted on other servers:

Well circumscribed tumor

Well encapsulated

Central scar

Cystic and partially necrotic tumor

Microscopic (histologic) description

Architecturally and cytologically different from surrounding gland
Compression signs in surrounding thyroid tissue
Encapsulated; thin or moderately thick capsule
Architectural patterns (can be seen in any combination)
- Normofollicular (simple): size similar to normal thyroid follicles
- Microfollicular (fetal): smaller follicles, small amount of intraluminal colloid
- Macrofollicular (colloid): large follicles, flattened epithelium, abundant colloid
- Solid / trabecular (embryonal): minimal or no colloid
Focal papillary pattern, occasionally; especially in hyperfunctioning adenoma and follicular adenoma with papillary hyperplasia
Cuboidal to low columnar cells
Small round nuclei, smooth nuclear boundary, uniformly hyperchromatic or euchromatic, dense chromatin, absent nuclear features of papillary thyroid carcinoma, nuclear score 0 or 1 (JAMA Oncol 2016;2:1023)
Inconspicuous nucleoli
Rarely, lipid filled vacuoles in cytoplasm
Mitoses are uncommon
Scant stroma
Secondary changes: fibrosis, hyalinization, hemorrhage, hemosiderin deposition, edema, cystic degeneration, calcification, osseous or cartilaginous metaplasia
Variants
- Hyperfunctioning adenoma (Plummer adenoma): tall columnar epithelium, papillary infoldings, vacuolated cytoplasm, watery colloid showing scalloping
- Follicular adenoma with papillary hyperplasia: cystically dilated follicles, intraluminal papillae
- Lipoadenoma: adipocytic metaplasia of the follicular adenoma
- Follicular adenoma with bizarre nuclei: may be seen after radiation exposure and in hyperfunctioning adenoma
- Signet ring cell follicular adenoma: signet ring cell change
- Clear cell follicular adenoma: follicular adenoma with clear cell change
- Spindle cell follicular adenoma: spindle cell metaplasia
- Black follicular adenoma (black pigment in tumor cell cytoplasm; in patients on minocycline therapy)
No capsular or vascular invasion after thorough sampling (at least 10 blocks)

Microscopic (histologic) images

Contributed by Shipra Agarwal, M.D., Andrey Bychkov, M.D., Ph.D., Mark R. Wick, M.D., Asmaa Gaber Abdou, M.D. and AFIP

Capsule & compressed thyroid

Mixed micro and normofollicular pattern

Hyperchromatic, small round nuclei

Abundant crystals of calcium oxalate

Calcium oxalate crystals

Processing artifact with distorted nuclei

Distorted nuclei due to technical / processing artifact

Tissue degeneration

Circumscribed thyroid nodule

Cellular follicular adenoma

Trabecular type

Thin and uniform fibrous capsule

Marked fibrosis and stromal hyalinization

Marked hyaline thickening of vessel walls

Marked fibrosis, hyalinization and calcium deposition

Marked vascularization

Capsular vessel with smooth muscle cells

Bizarre nuclei

Large, extremely irregular nuclei

With papillary hyperplasia

With papillary hyperplasia and adipose metaplasia

Cartilaginous metaplasia (adenochondroma)

Prominent, clear cell change

Squamous metaplasia

Mucin production

Thyroglobulin+

Alcian blue+

Patterns:

Solid, trabecular, microfollicular, macrofollicular patterns

Left: macrofollicular, right: solid pattern

Signet ring

Atypical adenomas:

Markedly cellular with irregular growth

Well formed follicles merge with solid pattern

Spindle cells mix with round cells

Not invasion:

Fine needle
induced changes
resemble invasion

Cytology description

Cellular aspirate (Korean J Pathol 2013;47:61, J Pathol Transl Med 2018;52:110)
Cellular crowding
Variable number of singly dispersed cells
Microfollicular and solid / trabecular variants: numerous microfollicles, may have scant luminal colloid; absent or minimal background colloid
Normofollicular and macrofollicular variants: monolayer sheets of follicular cells, abundant colloid; may mimic benign follicular nodule
Hyperfunctioning follicular adenoma and follicular adenoma with papillary hyperplasia: monolayer sheets of polygonal cells with abundant cytoplasm, flame cells and occasionally, papillary fragments
Uniform small round to ovoid nuclei, smooth nuclear margin, fine nuclear chromatin
Absent nuclear features of papillary thyroid carcinoma
The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) IV (follicular neoplasm / suspicious for a follicular neoplasm [FN / SFN]), III (atypia of undetermined significance [AUS A]) or II (benign) (Thyroid 2017;27:1341, Clin Endocrinol (Oxf) 2018;88:936)
Cannot rule out follicular thyroid carcinoma based on cytologic findings

Cytology images

Contributed by Shipra Agarwal, M.D. and Ayana Suzuki, C.T.

Cellular aspirate

Microfollicles and small round nuclei

Microfollicles

Images hosted on other servers:

Microfollicular

FNA

Round hyperchromatic nuclei

FNAC

Thyroid neoplasms

Positive stains

Thyroid lineage specific markers
- Thyroglobulin
- TTF1
PAX8
Low molecular weight cytokeratin
CD56
Low proliferative index (Ki67 proliferative index PPARG: rare; correlates with PAX8::PPARG translocation (Am J Surg Pathol 2002;26:1016)

Negative stains

CK19: usually negative, may be weak and focal (Acta Endocrinol (Buchar) 2016;12:387)
Chromogranin
Synaptophysin
Calcitonin
CK20
Rarely galectin3, HBME-1 and CITED1; up to 1 of these can be positive when used as a panel
- Can rarely be positive

Electron microscopy description

Similar to normal thyroid gland and hyperplastic nodules
Hyperfunctioning follicular adenomas: organelle rich cytoplasm, especially rough endoplasmic reticulum; numerous, long microvilli on surface (Am J Clin Pathol 1982;78:299)
Clear cell follicular adenomas: cytoplasmic vesicles of variable size; these may be dilated cisternae of the rough endoplasmic reticulum or mitochondria, lysosomes or endocytic vesicles (Virchows Arch A Pathol Anat Histol 1978;380:205)

Electron microscopy images

AFIP images

Abundant dilated endoplasmic reticulum

Microvilli project into well developed lumina

Signet ring follicular adenoma

Molecular / cytogenetics description

Clonal tumor
RAS gene mutations (20 - 30%), most commonly codon 61 of NRAS, followed by codon 61 of HRAS and least frequently KRAS mutations (Oncotarget 2016;7:69638, PLoS Genet 2016;12:e1006239)
EIF1AX alterations (10 - 15%) (Endocr Relat Cancer 2016;23:295, PLoS Genet 2016;12:e1006239)
- 13% (Diagn Pathol 2019;14:39)
Microsatellite instability (MSI) (Mol Diagn Ther 2019;23:369)
PTEN (5 - 20%) (Cancer Res 1997;57:4710)
DICER1 (10%)
- 8% (PLoS Genet 2016;12:e1006239)
BRAF K601E ( PIK3CA
SPOP (Oncotarget 2016;7:69638)
KMT2C
KDM5C
NF1
TSHR mutations in 50 - 80% hyperfunctioning adenomas (J Clin Invest 2016;126:3383, J Mol Med (Berl) 2001;78:684)
GNAS mutations in ~5% of hyperfunctioning adenomas
EZH1 mutations in 20 - 30% of hyperfunctioning adenomas, usually in combination with TSHR or GNAS mutations
THADA fusion (Thyroid 2021;31:1212)
PAX8::PPARG fusion (~10%) (Cancer Genet Cytogenet 2010;196:7)
Clonal cytogenetic abnormalities and copy number variations (~50%) (Cancer Genet Cytogenet 1998;101:42, PLoS Genet 2016;12:e1006239)
Gene expression profile partially overlaps with minimally invasive follicular thyroid carcinoma and encapsulated follicular variant of papillary thyroid carcinoma; limited evidence (PLoS Genet 2016;12:e1006239, Oncotarget 2017;9:10343)
Differential gene expression can help in differential diagnosis between follicular adenoma and follicular thyroid carcinoma (Int J Mol Sci 2017;18:1184, Endocr Connect 2018;7:124)
Differential expression of miRNAs (miR-146-5p, miR-221-5p, miR-222-3p, miR-30e-3p, miR-152-3p, miR-185-5p, miR-1915-3p, miR-199b-5p, 199a-5p, miR-574-3p, miR-4516 and miR-148b-3p) in follicular adenoma in comparison to noninvasive follicular thyroid neoplasm with papillary-like nuclear features and infiltrative follicular variant of papillary thyroid carcinoma (Mod Pathol 2017;30:39)

Molecular / cytogenetics images

Images hosted on other servers:

Gene expression analysis

CNV landscape of thyroid tumors

Driver mutations in thyroid tumors

Driver mutations and pathway analyses

Microarray and qRT PCR

Expression ratios of CRABP1, FABP4 and HMGA2

Clinicopathological features and mutation spectrum

Hierarchical clustering

Videos

Solitary thyroid nodule

Thyroid: compare and contrast

Histopathology thyroid: follicular adenoma (microfollicular)

Sample pathology report

Thyroid, right lobectomy:
- Follicular adenoma, right lobe, 3.2 cm

Differential diagnosis

Nodular hyperplasia with dominant nodule:
- Hyperplastic changes elsewhere in gland
- Often not encapsulated or incomplete capsule of variable thickness
- Variable architectural patterns
- May be multiple; lack of compression signs in adjacent thyroid gland
Minimally invasive follicular thyroid carcinoma:
- Thick capsule
- Vascular or capsular invasion
- May show increased mitotic activity; may have foci of necrosis
- Immunoreactivity for > 1 of the following markers: galectin3, HBME-1, CITED1 and PPARG
- Presence of PAX8::PPARG or THADA fusions (Diagn Pathol 2010;5:9, Clin Chem 2010;56:391)
Follicular variant of papillary carcinoma:
- Nuclear features of papillary thyroid carcinoma
- Invasive features, vascular or capsular invasion
- Immunopositive for multiple markers, namely CK19, galectin3, HBME-1, CITED1 and RET; immunonegative for CD56 (Acta Endocrinol (Buchar) 2016;12:387, Diagn Pathol 2010;5:9, Pathol Res Pract 2009;205:303)
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP):
- Nuclear features of papillary thyroid carcinoma with a nuclear score of 2 or 3 (JAMA Oncol 2016;2:1023)
Well differentiated tumor of uncertain malignant potential (WDT-UMP):
- Encapsulated tumor
- Equivocal nuclear features of papillary thyroid carcinoma
- Questionable blood vessel or capsular invasion
Follicular tumor of uncertain malignant potential (FT-UMP):
- Encapsulated tumor
- Questionable vascular or capsular invasion
- Lacks nuclear features of papillary thyroid carcinoma
Papillary thyroid carcinoma, encapsulated variant:
- Among differential diagnosis of follicular adenoma with papillary hyperplasia
- Nuclear features of papillary thyroid carcinoma
Papillary thyroid carcinoma, tall cell variant:
- May mimic hyperfunctioning follicular adenoma
- Papillae with prominent vascular cores
- Tall cells with oncocytic cytoplasm, nuclear features of papillary thyroid carcinoma
- Immunopositive for CK19, galectin3, HBME-1
- BRAF V600E mutation frequent
Intrathyroidal parathyroid adenoma / hyperplasia:
- Can mimic follicular adenoma of microfollicular, clear cell type
- Positive for PTH, GATA3, chromogranin, synaptophysin
- Negative for thyroglobulin, TTF1
Encapsulated medullary thyroid carcinoma of solid or trabecular pattern or with spindle or clear cells:
- Invasive features
- Amyloid deposition
- Salt and pepper chromatin
- Calcitonin positive, thyroglobulin negative

Additional references

Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017

Board review style question #1

Which of the following best describes this thyroid tumor?

Benign, completely encapsulated, lacks nuclear features of papillary thyroid carcinoma, absent capsular and vascular invasion
Benign, partially encapsulated, lacks nuclear features of papillary thyroid carcinoma, absent capsular and vascular invasion
Malignant, encapsulated, lacks nuclear features of papillary thyroid carcinoma, capsular invasion present
Uncertain malignant potential, completely encapsulated, lacks nuclear features of papillary thyroid carcinoma, questionable capsular invasion
Uncertain malignant potential, completely encapsulated, nuclear score 2, lacks capsular and vascular invasion

Board review style answer #1

A. Benign, completely encapsulated, lacks nuclear features of papillary thyroid carcinoma, absent capsular and vascular invasion. Follicular adenoma is a benign encapsulated tumor, which lacks capsular and vascular invasion as well as nuclear features of papillary thyroid carcinoma. Answer B is incorrect because follicular adenoma is completely encapsulated, unlike a case of nodular hyperplasia with a dominant nodule that can be unencapsulated or partially encapsulated. Answer C is incorrect because follicular adenoma lacks capsular invasion and is benign, unlike a case of follicular thyroid carcinoma. Answer D is incorrect because follicular adenoma is completely encapsulated, lacks even doubtful foci of invasion and is benign. This will be a case of a follicular tumor of uncertain malignant potential. Answer E is incorrect because follicular adenoma has a nuclear score of 0 or 1 and is benign. A tumor with a nuclear score of 2 and lacking capsular and vascular invasion will be noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

Comment Here

Reference: Follicular adenoma

Board review style question #2

Which of the following immunohistochemical / molecular profiles best fits with the diagnosis of follicular adenoma?

Galectin3+, HBME-1+, CITED1+
PAX8-, calcitonin+, chromogranin+
TTF1+, CD56+, PAX8+
TTF1+, CK19+, HBME-1+
TTF1-, synaptophysin+, GATA3+

Board review style answer #2

C. TTF1+, CD56+, PAX8+. Follicular adenoma is immunopositive for TTF1, thyroglobulin, PAX8, CK7 and CD56. Answer A is incorrect because follicular adenoma shows immunoreactivity for no more than 1 of the following markers: galectin3, HBME-1 and CITED1. Answer D is incorrect because CK19 is commonly positive in papillary thyroid carcinoma. Answers B and E are incorrect because calcitonin and GATA3 label medullary thyroid carcinoma and parathyroid tissue, respectively.

Comment Here

Reference: Follicular adenoma

Follicular adenoma with papillary architecture (pending)

[Pending]

Follicular neoplasm

Table of Contents

Definition / general

Bethesda category IV, "follicular neoplasm / suspicious for a follicular neoplasm (FN / SFN)" is used for cases with a cellular aspirate comprised of follicular cells showing cell crowding or microfollicle formation (Thyroid 2017;27:1341)
Cases cytologically suspected for follicular adenoma and follicular carcinoma are included
- Final diagnosis is based on tissue histology because capsular or vascular invasion are essential criteria
- Follicular patterned lesions (nodular goiter, follicular adenoma, follicular variant of papillary carcinoma, follicular carcinoma and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)) have overlapping cytomorphologic features and cannot be accurately distinguished by fine needle aspiration alone
Some definitions and criteria for this category were slightly modified in the latest edition of the Bethesda system to accommodate a new entity: noninvasive follicular thyroid neoplasm with papillary-like nuclear features (Cancer 2007;111:306)
- Criteria: cases with mild nuclear atypia (papillary carcinoma-like changes) were included in follicular neoplasm / suspicious for a follicular neoplasm
- Reporting: recommended to mention the possibility of noninvasive follicular thyroid neoplasm with papillary-like nuclear features in the note (to avoid overtreatment)

Essential features

Includes cases with most of the follicular cells are arranged in cell crowding or microfollicle formation
Frequency 2.3 - 2.9%, resection rate 41.8 - 45.0%, risk of malignancy 25 - 40%
Most common histopathological diagnosis is follicular adenoma, followed by adenomatous nodule, follicular variant of papillary carcinoma and follicular carcinoma (Diagn Cytopathol 2018;46:148)
Impossible to distinguish follicular adenoma from follicular carcinoma by fine needle aspiration cytology

Terminology

Laboratory should choose one preferable term and use it exclusively for this category
Term "suspicious for a follicular neoplasm" may be more convenient than "follicular neoplasm" because some nodular goiter cases are included in this category

Clinical features

Frequency: 2.3 - 2.9% (Cytojournal 2018;15:4)
Resection rate: 41.8 - 45.0% (Arch Pathol Lab Med 2013;137:1664)
Rate of neoplastic lesion after resection: 65 - 85%
Risk of malignancy: 25 - 40% (Ali: The Bethesda System for Reporting Thyroid Cytopathology - Definitions, Criteria, and Explanatory Notes, 2nd Edition, 2018, BMJ 1993;306:469)
- 27 - 68%: interpreted histologically as papillary carcinoma, usually follicular variant
- Risk of malignancy decreased to 10 - 40% when noninvasive follicular thyroid neoplasm with papillary-like nuclear features is implicated (Thyroid 2017;27:1341)

Diagnosis

Cellular aspirate comprised of follicular cells; most are arranged in an altered architectural pattern characterized by significant cell crowding or microfollicle formation
Sparsely cellular aspirates are excluded from this category and could be interpreted as atypia of undetermined significance or follicular lesion of undetermined significance (AUS / FLUS)
Cases that demonstrate suspicious or definitive nuclear features for papillary carcinoma are excluded from this category and should be classified as suspicious for malignancy or malignant, respectively
Follicular patterned aspirates with mild nuclear changes (swelling, contour irregularity or chromatin clearing) can be classified as follicular neoplasm / suspicious for a follicular neoplasm if true papillae and intranuclear cytoplasmic inclusions are absent
Invasive follicular variant of papillary carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features can be represented in this category (Cancer Cytopathol 2016;124:767, Hum Pathol 2016;54:134)

Case reports

21 year old man with multifocal follicular thyroid carcinoma following radiotherapy for Hodgkin disease (Postgrad Med J 1982;58:180)
30 year old woman with mucin producing microfollicular adenoma of the thyroid (J Clin Pathol 1985;38:277)
39 year old woman with follicular thyroid adenoma showing numerous intracytoplasmic lumina mimicking yellow bodies (Cytopathology 2016;27:495)
45 year old man with follicular thyroid carcinoma and clinical hyperthyroidism showing due to functioning metastases (Can Med Assoc J 1975;112:724)
75 year old woman with follicular carcinoma of the thyroid metastasizing to the breast (J Natl Med Assoc 1980;72:1101)

Treatment

Diagnostic thyroid lobectomy (Thyroid 2016;26:1)
Molecular testing may guide treatment

Cytology description

Moderate or marked cellularity
Atypical follicular cell architecture (cell crowding, microfollicles, trabecular and dispersed isolated cells)
- Microfollicle is a flat group of < 15 follicular cells arranged in a circle that is at least two thirds complete (Am J Clin Pathol 2008;130:736)
Follicular cells are normal sized or enlarged and relatively uniform, with scant or moderate amount of cytoplasm
Nuclei are usually round and slightly hyperchromatic, with inconspicuous nucleoli
Some nuclear atypia may be seen, either enlarged, variably sized nuclei and prominent nucleoli or enlarged nuclei with nuclear contour irregularity and mild or focal chromatin clearing
Colloid is scant or absent but a small amount of inspissated colloid may be present within the microfollicle
Foamy histiocytes are not common unless the neoplasm is large
Hürthle cell predominant cases should be classified as follicular neoplasm, Hürthle cell type or suspicious for a follicular neoplasm, Hürthle cell type

Cytology images

Contributed by Ayana Suzuki, C.T. and Mark R. Wick, M.D.

Microfollicle

Images hosted on other servers:

Microfollicle

Follicular crowding

Trabecular pattern

Videos

Head and tail of the Bethesda system for thyroid

Thyroid cancer: fine needle aspiration, malignant or indeterminate results

Sample cytology report

Dx / category: follicular neoplasm
- Cellular aspirate of follicular cells with a predominantly microfollicular architecture, scattered isolated cells and scant colloid.
Dx / category: suspicious for a follicular neoplasm
- Although the architectural features suggest a follicular neoplasm, some nuclear features raise the possibility of an invasive follicular variant of papillary carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features; distinction between these entities is not cytologically possible.
Dx / category: suspicious for a follicular neoplasm
- Cellular aspirate composed predominantly of crowded uniform cells without colloid. Features suggest a follicular neoplasm but the possibility of a parathyroid lesion cannot be excluded. Correlation with clinical, serologic and radiologic findings should be considered.

Differential diagnosis

Invasive follicular variant of papillary carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features:
- Microfollicles but nuclear irregularity (grooves, chromatin clearing, pseudoinclusions) are present
Parathyroid adenoma:
- Trabecular or microfollicular pattern but nuclei showing salt and pepper chromatin
- When located within the thyroid parenchyma and aspirated as a thyroid nodule, fine needle aspiration may be misdiagnosed as follicular neoplasm (Diagn Cytopathol 2009;37:407)

Board review style question #1

Which lesion is not included in follicular neoplasm / suspicious for a follicular neoplasm category?

Conventional papillary carcinoma
Follicular carcinoma
Invasive follicular variant of papillary carcinoma
Nodular goiter
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features

Board review style answer #1

A. Conventional papillary carcinoma. Lesions included in this category are follicular patterned lesions. Conventional papillary carcinoma is a papillary lesion with remarkable nuclear morphology.

Comment Here

Reference: Follicular neoplasm

Board review style question #2

Which histological diagnosis is most likely to correspond with this cytologic aspirate?

Conventional papillary carcinoma
Follicular adenoma or follicular carcinoma
Invasive follicular variant of papillary carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features
Nodular goiter
Parathyroid adenoma

Board review style answer #2

C. Invasive follicular variant of papillary carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Although the architectural features suggest a follicular neoplasm, the nuclei show grooves and powdery chromatin indicating papillary carcinoma

Comment Here

Reference: Follicular neoplasm

Follicular thyroid carcinoma

Table of Contents

Definition / general

Thyroid carcinoma with follicular differentiation but no papillary nuclear features (Hürthle cell (oncocytic) carcinoma is discussed separately)
Comprises 6 - 10% of thyroid carcinomas
Insufficient dietary iodine is a risk factor
Usually solitary "cold" nodule on radionuclide scan
Extensive sampling of capsule is recommended (Am J Surg Pathol 1992;16:392)
Three types (Lloyd: WHO Classification of Tumours of Endocrine Organs, 2017):
- Minimally invasive follicular carcinoma
  - With capsular invasion only
- Encapsulated angioinvasive:
  - Tumors with limited vascular invasion (< 4) have a better prognosis than those with extensive vascular invasion
- Widely invasive:
  - Extensive invasion of thyroid and extrathyroidal soft tissue
Two types (ARP: Tumors of the Thyroid and Parathyroid Glands, 2016):
- Minimally invasive follicular carcinoma
  - With capsular invasion (not obvious, need to search)
  - With limited (fewer than 4 vessels) vascular invasion
  - With extensive (4+ vessels) vascular
- Widely invasive

Essential features

Follicular lesion with capsular or vascular invasion but without papillary nuclear features

Epidemiology

75% women
Older age than papillary carcinoma, peak age: 40 - 60
Rarely in children

Diagrams / tables

Images hosted on other servers:

Schematic drawing for capsular invasion

Schematic drawing for vascular invasion

Etiology

Iodine deficiency and irradiation exposure, older age

Clinical features

Usually "cold" on radionuclide scan
May arise from preexisting adenoma
Does not metastasize through lymphatics but does spread to lungs, liver, bone, brain via blood vessels
Less than 5% with ipsilateral lymphadenopathy
Up to 69% distant metastasis: lung and bone (common in widely invasive carcinoma)

Radiology description

Ultrasound: solid hypoechoic nodule with a peripheral halo (fibrous capsule); irregular or poorly defined margins may be suggestive of carcinoma

Prognostic factors

Minimally invasive follicular carcinoma: very low long term mortality (Cancer 2001;91:505)
Widely invasive: 50% long term mortality
Poor prognostic factors: tumor size greater than 4 cm, distant metastases, age greater than 45 years, large size, extensive vascular invasion, extrathyroidal extension (World J Surg 2007;31:1417)

Case reports

33 year old pregnant woman with lung and bone metastases (Hormones (Athens) 2006;5:295)
61 year old woman with tumor dissemination along fine needle aspiration track (Surg Today 2007;37:34)
76 year old woman with multiple giant scalp metastases (World J Surg Oncol 2008;6:82)

Treatment

T3 / T4 to suppress endogenous TSH, thyroidectomy and radioactive iodine
No nodal dissection is needed

Gross description

Tan to brown solid cut surface, can have cystic changes and hemorrhage
Minimally invasive: usually single encapsulated nodule, with thickened and irregular capsule
Widely invasive: extensive permeation of capsule or no capsule
All capsule with adjacent tissue needs to be submitted for histological evaluation

Gross images

Contributed by Andrey Bychkov, M.D., Ph.D., Wafaey Fahmy Badawy Mohamed, M.D., Mark R. Wick, M.D. and AFIP

Minimal capsular invasion

Focal invasion

47 year old woman with follicular thyroid carcinoma and multinodular goiter

Various images

Minimally invasive follicular carcinoma

Indistinguishable from adenoma

Images hosted on other servers:

Apparently encapsulated

Widely invasive

Fig A: multiple white tan
nodules in thyroid tumor
Fig B: scalp metastases
show erosion through skull

Microscopic (histologic) description

Trabecular or solid pattern of follicles (small, normal sized or large - microfollicular, normofollicular or macrofollicular respectively)
No nuclear features of papillary thyroid carcinoma
Invasion of adjacent thyroid parenchyma, capsule (complete penetration) or blood vessels (in or beyond the capsule)
Capsular invasion: capsule is typically thickened and irregular, needs penetration through the capsule (full thickness), may have reactive pseudocapsule around the invasion edge, exclude FNA site
Vascular invasion: vessel within or beyond capsule, tumor covered with endothelium, attached to the wall or with thrombus
May have nuclear atypia, focal spindled areas, mitotic figures (< 3/10HPF)
No necrosis
Usually no squamous metaplasia, no psammoma bodies, no / rare lymphatic invasion
Metastatic follicular carcinoma can mimic normal thyroid tissue

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D., Mark R. Wick, M.D. and AFIP

False angioinvasion

Capsular vessel with tumor

Vascular invasion

Tumor in vascular space

Transcapsular penetration

Invasion through tumor capsule

Propagation of tumor embolus

Extensive necrosis

Tumor necrosis

Unusual brisk mitotic activity

TTF1: bone metastasis

Moderate pleomorphism

Mucin production

Capsular invasion

Metastases to iliac bone

Thick, irregular capsule

Images hosted on other servers:

Tumor, normal parenchyma

Insular type

Foci of tumor
beyond the border

Van Gieson stain

Penetration of former capsule

Not capsular invasion

Cytology description

Microfollicules (6 - 12 nuclei) with nuclear enlargement, overlapping and crowding
No or scant colloid
Nuclear atypia is not specific for malignancy
Cannot distinguish between follicular adenoma and carcinoma by fine needle aspiration since there needs to be evidence of capsular invasion, vascular invasion or invasion of adjacent parenchyma

Cytology images

Contributed by Ayana Suzuki, C.T., Xiaoyin "Sara" Jiang, M.D. and Jose Mellado, M.D.

Microfollicles

Follicular carcinoma

Follicular carcinoma, microfollicules with nuclear enlargement

Positive stains

Thyroglobulin, TTF1

Electron microscopy images

AFIP images

Follicular cells converge toward central lumen

Molecular / cytogenetics description

Activated PI3K / AKT or RAS of the receptor tyrosine kinase signaling pathway
NRAS and HRAS mutations in 49%, PAX8 and PPAR gamma rearrangements in 36% (J Clin Endocrinol Metab 2003;88:2318)
PI3CA and PTEN mutations in 5 - 10%
Tumors with rearrangement tend to be overtly invasive versus minimally invasive without this rearrangement (Am J Surg Pathol 2002;26:1016)
Widely invasive carcinomas have higher frequency of allelic loss than minimally invasive carcinomas (Hum Pathol 2003;34:375)

Molecular / cytogenetics images

Contributed by LeicaBiosystems, Amsterdam

PPARG (3p25)

Videos

Thyroid carcinoma: gross and micro

Histopathology thyroid: follicular carcinoma

Differential diagnosis

Metastatic clear cell renal cell carcinoma vs. clear cell follicular carcinoma: the latter is TTF1+ and thyroglobulin+
Parathyroid carcinoma: PTH+
Poorly differentiated thyroid carcinoma: solid, trabecular and insular growth patterns, necrosis, mitotic figure ≥ 3/10 HPF, convoluted nuclei (many previously diagnosed widely invasive follicular carcinoma could be this category)
Well differentiated thyroid carcinoma, NOS: encapsulated follicular derived neoplasm with tumor capsular or vascular invasion and questionable nuclear features of papillary carcinoma

Additional references

eMedicine: Follicular Thyroid Carcinoma [Accessed 2 November 2017]

Board review style question #1

Cannot have necrosis or increased mitotic figures (≥ 3/10 HPF)
Commonly metastases to bone, lung, not lymph node
Detecting RAS mutations and PPAX8-PPAR gamma rearrangements can be used to distinguish follicular carcinoma from adenoma
Nuclear atypia does not indicate malignancy
Risk factors include iodine deficiency and irradiation exposure

Board review style answer #1

C. Detecting RAS mutations and PAX8-PPAR gamma rearrangements can be used to distinguish follicular carcinoma from adenoma. RAS mutations and PAX8-PPAR gamma rearrangements can be found in follicular adenoma.

Comment Here

Reference: Follicular

Follicular variant

Table of Contents

Definition / general

Follicular variant of papillary thyroid carcinoma (FV-PTC) is defined by 2 features:
- Architecturally, it is composed exclusively or almost exclusively of follicles
- Cytologically, it shows nuclear features of papillary thyroid carcinoma, such as nuclear enlargement, nuclear membrane irregularity and chromatin clearing

Essential features

Exclusive or near exclusive follicular architecture
Nuclear features of papillary thyroid carcinoma
Can be divided into 2 subtypes (Eur J Surg Oncol 2018;44:338, Cancer 2006;107:1255, J Clin Endocrinol Metab 2017;102:15)
- Encapsulated follicular variant is characterized by the presence of a complete capsule or well circumscribed border and usually RAS mutation
- Infiltrative follicular variant is associated with infiltrative growth, risk of nodal metastasis and BRAF V600E mutation, akin to classic type of papillary thyroid carcinoma

Terminology

Two subtypes:
- Encapsulated FV-PTC
- Infiltrative FV-PTC (old terminology: multinodular FV-PTC, diffuse FV-PTC)
Noninvasive encapsulated FV-PTC has been reclassified to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (JAMA Oncol 2016;2:1023)

ICD coding

ICD-O: 8340/3 - papillary carcinoma, follicular variant
ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

In Western countries, frequency of follicular variant among all papillary carcinoma increased over the past few decades from 3.4% to 25.2% (J Clin Endocrinol Metab 2014;99:E276)
In Asia, incidence is much lower (Endocr Pathol 2018;29:276, Thyroid 2017;27:983)
While classic (papillary) pattern used to be the dominant (59% - 76%) architectural pattern of papillary carcinoma diagnosed in the '70s - '90s, follicular patterned papillary carcinoma (regardless of tumor size and cytologic features) became the most prevalent (57%) architecture in papillary carcinoma in 2009 (J Clin Endocrinol Metab 2014;99:E276)
Above shift of diagnosis is in part due to widespread use of follicular variant terminology and decreased threshold for nuclear alterations required to diagnose papillary carcinoma (J Clin Endocrinol Metab 2017;102:15)
- Lowering of PTC nuclei threshold was particularly noted in USA, partially driven by malpractice fears (Am J Clin Pathol 2002;117:19, Arch Pathol Lab Med 2019;143:1171)
Among all papillary thyroid carcinomas, the rate of encapsulated follicular variant without invasion, encapsulated follicular variant with invasion and infiltrative follicular variant were 13.6%, 7.1% and 1.7%, respectively (J Clin Endocrinol Metab 2017;102:15)
Above mentioned data represent epidemiology prior to the creation of NIFTP; since the reclassification of encapsulated follicular variant without invasion as NIFTP in 2016, the epidemiologic data of follicular variant need to be reassessed (JAMA Oncol 2016;2:1023)

Sites

Most commonly affects the thyroid gland
May also occur in thyroglossal duct, lingual thyroid, ectopic thyroid and struma ovarii (Int Surg 2006;91:141, J Oral Maxillofac Surg 2013;71:644)

Etiology

Same etiology as papillary thyroid carcinoma

Diagrams / tables

Images hosted on other servers:

Follicular variant

Clinical features

Painless thyroid mass detected by imaging or palpation
More aggressive invasive subtype may manifest with cervical nodal metastasis or obstructive symptoms

Diagnosis

Diagnostic workup is similar to any thyroid mass / nodule
- Ultrasound with fine needle aspiration cytology
- CT scan may be useful to evaluate extrathyroidal extension and lymph node metastases
Final diagnosis is rendered on histopathological examination of resected tumor, using a combination of nuclear features and follicular architecture
- FV-PTC can be suspected on cytology, but accuracy of preoperative diagnosis in this variant is lower than in classic PTC

Radiology description

Larger size, more benign sonographic features and lower ultrasound imaging score compared to classic PTC (J Ultrasound Med 2009;28:1685)

Prognostic factors

Overall prognosis of follicular variant is excellent (Cancer 2006;107:1255)
Prognosis differs according to the status of encapsulation and invasion
- Encapsulated follicular variant without capsular and vascular invasion is highly indolent, with negligible (zero or near zero) risk of recurrence or metastasis: the majority of such tumors have been revised as NIFTP (JAMA Oncol 2016;2:1023, Cancer 2006;107:1255)
- Risk of nodal metastasis is 65% for infiltrative follicular variant and 7% for encapsulated follicular variant with capsular or vascular invasion (Cancer 2006;107:1255)
Risk stratification as per American Thyroid Association 2015 (Thyroid 2016;26:1)

Case reports

22 year old woman with extension to parapharyngeal space (BMC Ear Nose Throat Disord 2006;6:3)
46 year old man presenting with pleural effusion (Acta Cytol 2007;51:911)
47 year old man with invasive FV-PTC harboring NRAS mutation and presenting with bone metastasis (Int J Surg Case Rep 2017;38:180)
49 year old woman with aggressive metastatic FV-PTC harboring BRAF K601E and BCORL1 mutations (BMJ Case Rep 2020;13:e234208)
56 year old man with glomeruloid growth pattern (Hum Pathol 2008;39:1540)
70 year old man with FV-PTC presented as autonomous functioning thyroid nodule (Cureus 2018;10:e3014)
83 year old woman with diffuse FV-PTC (Rare Tumors 2016;8:6536)

Treatment

Most of the intrathyroidal follicular variant is considered ATA (American Thyroid Association) low risk and can be treated successfully by surgical resection (lobectomy / hemithyroidectomy) alone (Thyroid 2016;26:1)
Total thyroidectomy and postoperative radioactive iodine treatment may be considered if the tumor exhibits additional aggressive features, e.g. extensive vascular invasion, gross extrathyroidal extension or large lymph node metastasis (Thyroid 2016;26:1)

Gross description

Encapsulated follicular variant: well circumscribed solid beige to tan mass with or without a grossly appreciable tumoral capsule
Infiltrative follicular variant has a multinodular to infiltrative tumor border

Gross images

Contributed by Bin Xu, M.D., Ph.D.

Encapsulated follicular variant

Infiltrative follicular variant

Frozen section description

Frozen section is strongly discouraged as frozen artifacts distort the nuclear features necessary to diagnose papillary thyroid carcinoma
Invasion (capsular or vascular) may not be present in the representative section(s) sampled at the time of intraoperative consultation
Standard care is to perform preoperative fine needle aspiration to establish the diagnosis

Microscopic (histologic) description

Nuclear features of papillary thyroid carcinoma should be seen multifocally (at least 2 foci) or diffusely within the tumor; such features include nuclear enlargement, nuclear overlapping, chromatin clearing, nuclear membrane irregularity and nuclear grooves (J Clin Endocrinol Metab 2017;102:15)
- Nuclear score 2 - 3 (JAMA Oncol 2016;2:1023)
- Nuclear pseudoinclusion, a feature commonly seen in classic and tall cell variant, is rarely present in follicular variant
Architecture: exclusively or nearly exclusively follicular
- True papillae with fibrovascular core are in general absent in follicular variant
- Tumors with mixed papillary (≥ 1% of total tumor volume) and follicular architecture should be classified as classic PTC with predominant follicular pattern, given the associated risk of lymph node metastasis (Thyroid 2019;29:1792)
- Solid architecture may be present: tumors with mixed follicular and solid architecture should be classified as follicular variant, whereas those with (almost) exclusive solid growth are classified as solid variant
Encapsulated follicular variant has a complete fibrous tumor capsule or a well circumscribed tumor border
Infiltrative follicular variant shows infiltrative or multinodular growth
- Sprinkling sign refers to the phenomenon that neoplastic follicles are seen scattered within the background of normal follicles
"Bubble gum colloid", i.e. dense homogenous hypereosinophilic colloid, may be seen in the lumen of neoplastic follicles; scalloping of colloid may be seen
Psammoma bodies are exceedingly rare in follicular variant; the identification of psammoma body should promote a search for true papillary (classic) area within the tumor

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.

Follicular architecture & nuclear features

Follicular architecture & nuclear features

Infiltrative follicular variant

Encapsulated follicular variant

Ossification

Cytology description

Hypercellularity
Small, round and dense colloid (hyaline colloid) may be present, sometimes within follicles
Cells arranged in microfollicles or trabecular pattern
Nuclear enlargement but may lack prominent nuclear features of papillary carcinoma (Am J Clin Pathol 1999;111:216)
Highly suggestive of syncytial clusters, microfollicular architecture, chromatin clearing and nuclear grooves (Acta Cytol 2006;50:663)
Classified by Bethesda system as categories III to VI
Cytologically unable to distinguish between noninvasive and invasive

Cytology images

Contributed by Ayana Suzuki, C. T.

Hypercellular aspirate

Microfollicular and trabecular pattern

Microfollicles

Irregular nuclei

Nuclear inclusions

Images hosted on other servers:

Cellular aspirates;
some microfollicular
aggregates, no colloid

Acinar arrangement with intranuclear inclusion

Grape-like nuclei of papillary thyroid carcinoma

Microfollicles in thyroid FNA smears

Comparison of a
tissue proven follicular
adenoma and variant
of papillary carcinoma

Positive stains

Mutated proteins, e.g. BRAF V600E and NRAS Q61R, can be positive in a proportion of cases (see Molecular / cytogenetics description) (Thyroid 2019;29:1792)
Thyroid specific markers: TTF1, thyroglobulin, PAX8
CK19, galectin3, HBME1 produce focal staining, which cannot reliably distinguish FV-PTC from other follicular patterned lesions

Molecular / cytogenetics description

The Cancer Genome Atlas (TCGA) has shown that follicular variant as a group is associated with RAS mutation, high thyroid differentiation score and a RAS-like molecular signature (Cell 2014;159:676)
Overall, encapsulated follicular variant has a genomic profile akin to follicular adenoma / follicular carcinoma, whereas infiltrative follicular variant has molecular alterations similar to classic papillary thyroid carcinoma (Eur J Surg Oncol 2018;44:338, Am J Clin Pathol 2003;120:71, Mod Pathol 2010;23:1191, Thyroid 2013;23:1256)
Encapsulated follicular variant is associated with high frequency (36% - 40%) of RAS mutation and absence of BRAF V600E mutation
- PAX8-PPARgamma fusion may be seen in encapsulated follicular variant
Infiltrative follicular variant has high frequency of BRAF V600E mutation (26%) and low rate of RAS mutation (10%)
- RET / PTC rearrangement may be seen in infiltrative follicular variant

Sample pathology report

Thyroid, right lobe, lobectomy:
- Papillary thyroid carcinoma, infiltrative follicular variant, 3.2 cm (see synoptic report)

Differential diagnosis

Papillary carcinoma, classic type:
- May contain various amounts of follicles
- Tumor with ≥ 1% of papillae should be classified as classic type
NIFTP:
- In 2016, most (but not all) noninvasive encapsulated follicular variant has been reclassified as NIFTP (JAMA Oncol 2016;2:1023)
- See NIFTP for diagnostic criteria of NIFTP
Follicular adenoma and follicular carcinoma:
- Lack nuclear features of papillary thyroid carcinoma
Macrofollicular PTC:
- Macrofollicles (> 200 µm) constitute > 50% of tumor

Additional references

Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017

Board review style question #1

What is the most common molecular alteration seen in follicular variant of papillary thyroid carcinoma?

BRAF V600E mutation
RAS mutation
RET / PTC fusion
TP53 mutation

Board review style answer #1

B. RAS mutation

Comment Here

Reference: Follicular variant

Board review style question #2

A 45 year old woman underwent thyroid lobectomy for a 2.2 cm thyroid mass. The histology of the tumor is shown above. What is the diagnosis of this tumor?

Adenomatoid nodule
Follicular adenoma
Follicular carcinoma
Papillary thyroid carcinoma, follicular variant

Board review style answer #2

D. Papillary thyroid carcinoma, follicular variant

Comment Here

Reference: Follicular variant

Frozen section

Table of Contents

Definition / general | Microscopic (histologic) images | Additional references

Definition / general

Click here for the frozen section procedure topic
Not indicated for most thyroid nodules due to low sensitivity; frequency has been decreasing (Virchows Arch 2008;453:433)
Results may conflict with FNA (Arch Otolaryngol Head Neck Surg 2007;133:874), but see Thyroid 2007;17:557
Well differentiated carcinomas often cannot be diagnosed on frozen section, regardless of experience of pathologist
Intraoperative cytology may be useful to detect nuclear features of papillary carcinoma (Mod Pathol 2000;13:210)
False negatives by frozen section:
- Minimally invasive follicular carcinoma:
  - Sensitivity varies from 17 - 42% (Presse Med 2008;37:949)
  - Need a mean 9 paraffin blocks to identify vascular invasion (Am J Clin Pathol 2001;115:370)
  - Most diagnoses are "follicular lesion - diagnosis deferred to permanent sections"
False positives by frozen section:
- Metastatic papillary carcinoma: apparent metastases may actually be Riedel thyroiditis, diffuse hyperplasia of ectopic thyroid tissue or sequestered thyroid tissue
- Freezing artifact may mimic nuclear features of papillary thyroid carcinoma or parathyroid neoplasms (43% of cases diagnosed as "suspicious for papillary carcinoma" are not papillary carcinoma at permanent section, Thyroid 2008;18:419)
- Post FNA alterations can mimic capsular or vascular invasion

Microscopic (histologic) images

AFIP images

Nuclear features

Images hosted on other servers:

Follicular variant of papillary carcinoma

Additional references

Arch Pathol Lab Med 2005;129:1575

Frozen section-parathyroid

Table of Contents

Definition / general | Cytology description | Differential diagnosis

Definition / general

Click here for the frozen section procedure topic
Communication with surgeon important
Weigh, measure and freeze largest gland
Algorithm: presumed adenoma if rim of normal tissue, diffuse chief cell growth, no fat, bizarre nuclei; if these criteria not met, examine at least one more gland
Oil Red O fat stain may be helpful if little fat in suspect gland and abundant fat in normal appearing gland (Am J Surg Pathol 1981;5:381, Hum Pathol 1985;16:1255)
Density gradient measurements: denser tissue sinks in 25% mannitol solution, implies more parenchymal cells / abnormal glands
Parathyroid tissue usually lacks birefringent calcium oxalate crystals detectable by polarized light microscopy that are present in thyroid tissue (Am J Surg Pathol 2002;26:813)
Fewer thyroid frozen sections are now performed (Virchows Arch 2008;453:433)

Cytology description

In touch preparations, parathyroid tissue appears as clusters of cells vs. discohesive lymphocytes and histiocytes in lymph nodes mistaken as parathyroid gland (Am J Surg Pathol 2000;24:158)
Parathyroid: moderately cellular, small uniform cells in isolation / small groups with round / oval nuclei, salt and pepper chromatin, occasional naked nuclei, delicate vacuoles in cytoplasm and in background (Arch Pathol Lab Med 2003;127:64)
Cytology plus frozen section is more accurate than either alone (Am J Clin Pathol 2002;118:895)
Rapid intraoperative parathyroid hormone assay of needle aspirates is an accurate method of distinguishing parathyroid from nonparathyroid tissues during FNA as well as parathyroidectomy (Am J Otolaryngol 2011;32:574, World J Surg 2010;34:538)

Differential diagnosis

Coexisting parathyroid and nodular thyroid disease
Intrathyroidal parathyroid glands with conspicuous follicle formations or abundant oncocytic cells mimics thyroid tissue
Solitary thyroid nodules with fatty stroma: see Am J Surg Pathol 1998;22:538
Thyroid tissue with parathyroid pattern: see Mod Pathol 2000;13:210

FT-UMP (pending)

[Pending]

Graves disease

Table of Contents

Definition / general

Named after Robert J. Graves (1796-1853)
Commonly seen in middle aged women
Autoimmune disease characterized by hyperthyroidism due to circulating autoantibodies against thyrotropin (TSH receptor) that activates the receptor, leading to increased thyroid hormone synthesis and secretion and growth of the thyroid gland
Associated with diffuse goiter, infiltrative ophthalmopathy and less commonly infiltrative dermopathy, including pretibial myxedema and thyroid acropachy (extremity swelling, clubbing of fingers and toes due to periosteal new bone formation)
Presence of thyrotropin receptor antibody in the serum and orbitopathy on clinical examination distinguishes Graves disease from other causes of hyperthyroidism
Maternal Graves disease may lead to neonatal thyroidism in 1 - 5% of children due to transplacental transfer of antibodies
People with other autoimmune diseases such as type 1 diabetes and rheumatoid arthritis are more likely to be affected

Essential features

Most common cause of hyperthyroidism in United States
Autoimmune disease characterized by hyperthyroidism due to circulating autoantibodies against thyrotropin (TSH receptor) that activates the receptor leading to increased thyroid hormone synthesis and secretion and growth of the thyroid gland
Presence of thyrotropin receptor antibody in the serum and ophthalmopathy on clinical examination distinguishes Graves disease from other causes of hyperthyroidism
Most commonly affects middle aged women, with female to male ratio of 4:1
Associated with HLA class II molecule HLA-DR (HLA-DRB1*08 and DRB3*0202)

Terminology

Also called diffuse toxic goiter, autoimmune hyperthyroidism, Basedow disease (in Europe)

ICD coding

E05.00

Epidemiology

Most common cause of hyperthyroidism in United States, affecting 2% of women and 0.3% of men
85% of patients are women (female to male ratio is 4:1), usually ages 20 - 40 years; men are usually older
60% concordance in identical twins; associated with HLA-B8 and HLA-DR3

Sites

Global involvement of thyroid gland

Pathophysiology

Exact cause is unclear
- It is believed to involve a combination of genetic and environmental factors
- A person is more likely to be affected if they have a family member with the disease
- Onset of disease may be triggered by stress, infection or giving birth
- Smoking increases the risk of disease and may worsen eye problems
Caused by B and T cell mediated immune responses leading to production of autoantibodies to thyrotropin / TSH receptor
- These autoantibodies are IgG1 subclass, mimic the effects of TSH, cause thyroid hormone synthesis and secretion and cause thyroid growth resulting in a diffuse goiter
Stimulatory antibodies increase the synthesis and activity of sodium iodide symporter leading to increased iodide uptake in Graves disease in the absence of TSH and stimulate protein C kinase pathway leading to cell proliferation
Pituitary secretion of TSH is suppressed due to negative feedback of increased thyroid hormones
A variety of immune mechanisms may be involved in the pathogenesis
- Major mechanisms are thyroid cell expression of human leukocyte antigen (HLA) associated molecules associated with bystander activation

Autoantibodies

There are four thyroid antigens: thyroglobulin, thyroid peroxidase, sodium iodide symporter and thyrotropin / TSH receptor
Anti-thyrotropin antibodies are specific for Graves disease
Previously detected long acting thyroid stimulators have now been identified as the auto antibodies
Antibodies can be either stimulatory / inhibitory or neutral, leading to various clinical presentations of hyperthyroidism or hypothyroidism
Main autoantigen is the thyrotropin / thyroid stimulating hormone (TSH) receptor which is expressed primarily in the thyroid but also in adipocytes, fibroblasts, bone cells and a variety of additional sites
Genes associated with autoimmune thyroid disease are: HLA, CD40, CTLA-4, thyroglobulin, TSH receptor and PTPN22
Antibodies to thyroid peroxidase (microsomal antigen) and thyroglobulin are also seen

Ophthalmopathy

Thyroid stimulating antibodies and activated T cell cytokines such as tumor necrosis factor (TNF) alpha and interferon gamma stimulate adipocytes to proliferate and orbital fibroblasts to secrete glycosaminoglycans
Accumulation of hydrophilic glycosaminoglycan causes a change in osmotic pressure, which in turn leads to a fluid accumulation, muscle swelling and an increase in pressure within the orbit
Together with retroorbital adipogenesis, the eyeball is displaced resulting in malfunction of the extraocular muscles as well as the venous drainage

Clinical features

Features of hyperthyroidism: goiter / enlarged thyroid, muscle weakness, tremors, sweating, heat intolerance, oligomenorrhea, weight loss, exophthalmus (ophthalmopathy), tachycardia (atrial flutter or fibrillation), anxiety, congestive heart failure, pretibial nonpitting edema and dermopathy and acropachy (extremity swelling, clubbing of fingers and toes due to periosteal new bone formation)
Progression of ophthalmopathy can lead to compromised vision and blindness
Long standing thyrotoxicosis causes severe weight loss with osteoporosis and muscle protein breakdown
Thyroid storm is associated with mortality rate of 20% even with treatment

Diagnosis

Diagnosed clinically by symptoms, presence of laboratory markers of hyperthyroidism, ophthalmopathy and presence of serum anti thyrotropin antibodies
Most patients have diffuse thyroid enlargement; large or cold nodules should prompt evaluation by fine needle aspiration cytology

Laboratory

Increased T3 / T4, increased uptake of radioactive iodine, decreased TSH and positive thyroid receptor antibodies

Radiology description

Ultrasound

Thyroid gland is often enlarged and can be hyperechoic
Heterogeneous thyroid echotexture
Relative absence of nodularity in uncomplicated cases
Hypervascular; may demonstrate a thyroid inferno pattern on color Doppler

Nuclear medicine

Iodine-123: imaging performed at around 2 - 6 days; classically demonstrates homogeneously increased activity in an enlarged gland
Tc-99m pertechnetate: homogeneously increased activity in an enlarged thyroid gland

Case reports

46 year old woman with case occurring after excision of multinodular goiter (Exp Clin Endocrinol Diabetes 2009;117:95)
Woman with peripartum cardiomyopathy (Int J Cardiol 2010;145:e23)

Treatment

Beta blockers, propylthiouracil or other drugs, radioiodine ablation, rituximab, surgery (subtotal thyroidectomy, Endocr J 2008;55:161, World J Surg 2008;32:1269)
Surgery may improve exophthalmos (Chirurgia (Bucur) 2008;103:291)
Myxedema may persist in spite of treatment

Clinical images

Images hosted on other servers:

Exophalmos, lid retraction

Rodney Dangerfield

Marty Feldman

Gross description

Diffuse and symmetrically enlarged thyroid gland with beefy red cut surface, weight 50 - 150 grams

Gross images

Images hosted on other servers:

Markedly enlarged gland

Microscopic (histologic) description

Hyperplastic thyroid follicles with papillary infoldings
Diffuse hyperplasia and hypertrophy of follicular cells with retention of lobular architecture and prominent vascular congestion
Tall follicular cells with papillae usually lacking fibrovascular cores
Nuclei are round, often basally located, rarely overlap
Colloid is typically decreased, when present shows peripheral scalloping
Colloid may increase after treatment
Variable patchy lymphoid infiltrate in the stroma
Nuclear clearing (15%), florid papillary hyperplasia (13%, may resemble papillary thyroid carcinoma), nuclear grooves or pseudonuclear inclusions (8%), nuclear enlargement, multinucleation, pleomorphism or prominent nucleoli (7%), mitotic figures (6%), psammoma bodies (1%), hyperplastic follicles may extend into adjacent skeletal muscle (1%)
Rarely small clusters of normal thyroid follicles in adjacent lymph node sinuses (Hum Pathol 2008;39:1080)
Note: preoperative potassium iodide to suppress vascularity causes epithelial involution and colloid accumulation
Gland may look normal after 3 weeks of treatment
Preoperative PTU exaggerates the hyperplasia and hypertrophy
Radioactive iodine initially causes dissolution of some follicles, vascular changes, nuclear atypia and stromal fibrosis
- Late changes are follicular atrophy, fibrosis, nodularity and oncocytic changes
Periorbital tissue: lymphoplasmacytic infiltrate present in periorbital soft tissue and extraorbital skeletal muscles
Skin hyperkeratosis: deposition of acid mucopolysaccharides in dermis

Microscopic (histologic) images

Scroll to see all images:

Contributed by Swati Satturwar, M.D., Mark R. Wick, M.D. and Andrey Bychkov, M.D., Ph.D.

Benign thyroid follicles

Radiation changes with stromal fibrosis

Various images

Active tall epithelium with light vacuolated cytoplasm

Small nodule of atypical cells with bizarre nuclei

Large
eosinophilic cells
with prominent
bizarre nuclei

Compensatory nodular hyperplasia

Prominent nuclear atypia / pleomorphism

NIS membranous expression

AFIP images

Diffuse hyperplasia with well developed papillae

Follicular cells lining papillae are tall and columnar

Hyperplastic small follicles

Images hosted on other servers:

Prominent infoldings of hyperplastic epithelium

Epithelium is tall columnar, colloid shows scalloping

No nuclear changes of papillary thyroid carcinoma

Various images

Numerous plasma cells

Follicles with pale colloid

Irregular follicles,
pseudopapillary
epithelium and
sparse colloid

Colloid has scalloped margins

Lobulated parenchyma with irregular follicles

Cytology description

Cytology features are nonspecific and similar to benign follicular lesions such as nodular goiter, adenomatoid nodules or colloid nodules
- Cellular smears with follicular cells in flat sheets and loosely cohesive clusters
- Cells are tall with finely granular cytoplasm, marginal vacuoles and basal nuclei
- Nuclei are enlarged, vesicular and show prominent nucleoli
- Background may show lymphocytes and oncocytes
Flame cells represented by marginal cytoplasmic vacuoles with pink red frayed edges may be prominent, however not specific for Graves disease
After radioactive therapy: prominent microfollicular architecture with significant nuclear atypia, overlapping and crowding

Cytology images

Images hosted on other servers:

Graves disease: flame cells

Positive stains

p27 (Mod Pathol 2000;13:1014) may distinguish it from papillary thyroid carcinoma
HLA-DR in cytoplasm of thyrocytes and lymphocytes

Negative stains

p63 (Hum Pathol 2003;34:764)

Electron microscopy description

Prominent rough endoplasmic reticulum and golgi, well developed nucleoli in enlarged nuclei

Videos

Graves gross and micro

Thyroid: compare and contrast

Histopathology thyroid: Graves disease

Differential diagnosis

DD of thyrotoxicosis (other than Graves disease):
- Amiodarone induced
- Hashitoxicosis
- Struma ovarii
- Toxic follicular adenoma
- Toxic sporadic goiter
- Trophoblastic tumor
Papillary thyroid carcinoma: enlarged overlapping nuclei, nuclear grooves, nuclear inclusions

Additional references

eMedicine: Graves Disease [Accessed 14 November 2017], UpToDate.com: Hyperthyroidism [Accessed 14 November 2017]

Board review style question #1

All of the following statements are true about Graves disease except:

Graves disease is caused by anti-TPO autoantibodies
Associated with HLA-DR
Caused due to anti-thyrotropin antibodies
Most commonly affects middle aged women

Board review style answer #1

A. Graves disease may be associated with anti-TPO anti-bodies but it is caused by anti-thyrotropin / TSH receptor auto-antibody that mimic TSH and stimulate hormone synthesis, secretion and thyroid growth. Most commonly affects middle aged women with female to male ratio of 4:1. It is associated with HLA class II molecule HLA-DR (HLA-DRB1*08 and DRB3*0202).

Comment Here

Reference: Graves disease

Grossing

Table of Contents

Surgical procedures

Note operation records of surgeon and clinical history; this will help guide dissection
- Diagnosis of papillary carcinoma is usually made preoperatively by fine needle aspiration
Describe how specimen is received (fresh or fixed, intact or fragmented)
Procedure
- Lobectomy
- Hemithyroidectomy: lobe with isthmus
- Subtotal thyroidectomy: small portion of uninvolved thyroid gland is left to preserve endocrine function
- Total thyroidectomy: entire gland
- Completion thyroidectomy: second lobe after lobectomy / hemithyroidectomy
- Each type of thyroidectomy can be accompanied by central compartment / modified radical neck dissection (removal of cervical lymph nodes)

Step by step procedure

Measure 2 lobes and isthmus (3 dimensions) and weigh thyroid gland
Describe shape, color, symmetry and consistency of entire specimen before cutting
Ink if tumor is suspected
Section transversely (or longitudinally or frontal / coronally) every 2 - 5 mm
Describe number, size, location, encapsulation, color (fixed specimens are more grayscale than the fresh ones), secondary changes (hemorrhage, calcification, cystic) and the shortest distance to surgical margins for nodules
Describe thyroid tissue away from tumor, other attached tissue (muscle, fat, trachea, esophagus, if any)
Identify candidate parathyroids and lymph nodes
Gross photos can be taken of
1. Fresh specimen
2. Fixed uncut specimen
3. Serially sectioned specimen
Do sampling, as per Sections to obtain below
Keep remaining tissue in formalin until the final histopathological diagnosis is established

Tips

Fix overnight (2 days for large nodules) in 10% buffered formalin; in addition to easier cutting, this may prevent bulging of capsule of the encapsulated nodule and artefactual nuclear atypia (Japanese Society of Thyroid Surgery: General Rules for the Description of Thyroid Cancer, 7th Edition, 2015)
Large specimens (> 4 cm nodules) can be infiltrated with fixative using syringe (Japanese Society of Thyroid Surgery: General Rules for the Description of Thyroid Cancer, 7th Edition, 2015)
Tumor / nodule size is best measured by sonography - refer to clinical records (Eur Thyroid J 2017;6:315)
- Chart with ultrasound mapping can be supplied
Inking is not necessary if proper 3D mapping is done during grossing; see Sampling gross images below (Japanese Society of Thyroid Surgery: General Rules for the Description of Thyroid Cancer, 7th Edition, 2015)
- Identify and mark on gross photo upper and lower poles, medial (isthmic) side, anteriolateral and posterior surfaces
- Anatomic features can be helpful, such as pointed end (upper pole), convex (anterolateral) and concave (posterior) surfaces, attached muscle (anterior), cauterized transected surface (isthmus)
- Check orientation marks made by surgeon (sutures, clips)
- Refer to schematic drawings provided by surgeon
- Some surgeons submit a specimen oriented on a board with schematic drawing of the major neck structures; this is particularly helpful for mapping of lymph nodes (see Gross images below)
Capsular invasion can be detected or suspected on magnification (zoom of digital photo or loupe) - use for large encapsulated nodules with a thick capsule (Japanese Society of Thyroid Surgery: General Rules for the Description of Thyroid Cancer, 7th Edition, 2015)
If searching for microcarcinoma, slice the specimen into 2 - 3 mm sections and transilluminate them to identify discrete white spots / scars (Rosai: Tumors of the Thyroid and Parathyroid Glands, 4th Series, 2016)
Sampling of the lower lobe with attached fibroadipose tissue may yield clinically unrecognized metastatic perithyroidal lymph nodes
Cytologic smears can be done by fine needle aspiration from freshly submitted specimen using syringe (Kakudo: Thyroid FNA Cytology - Differential Diagnoses and Pitfalls, 2nd Edition, 2019)

Sections to obtain

Thyroid without nodules (diffuse inflammatory lesions, i.e. Graves, Hashimoto or completion thyroidectomy):
- 3 sections from each lobe (upper, mid, lower), 1 from isthmus
Multinodular goiter:
- 1 cassette per centimeter of the greatest dimension of the lobe
- Or 1 cassette per 5 g of tissue up to 10 per lobe and 2 for isthmus (total of 22 per case) (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 3rd Edition, 2019)
- Focus on suspicious areas (solid, sclerotic, firm)
Grossly infiltrative lesion (or ill defined edge), usually papillary carcinoma:
- If small, submit entire lesion
- If > 2 cm, submit 1 section per centimeter, including nearest margin and interface with normal thyroid
- Submit other suspicious / discrete lesions
- Submit representative uninvolved thyroid, as for nonnodular thyroid above
Single well circumscribed nodule (encapsulated or well demarcated):
- Submit entire tumor capsule and include nearest inked margins or at least 10 sections
- Submit representative central portion of tumor
- Diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) may require submitting entire tumor, including interface and parenchyma (Mod Pathol 2017;30:810)
- Submit representative uninvolved thyroid, as for nonnodular thyroid above
Medullary thyroid carcinoma:
- Tumor as per recommendations above
- At least 1 extra specimen each of bilateral upper mid poles (to assess for C cell hyperplasia)
MEN syndrome, prophylactic thyroidectomy:
- Submit the entire thyroid sequentially
Thyroidectomy for occult primary (e.g. nodal metastasis without primary on imaging, thyroglossal duct carcinoma):
- Submit the entire thyroid or at least 20 blocks
For all procedures:
- Submit all candidate lymph nodes and parathyroids
- Can put 2 - 3 sections in each cassette
- If ancillary molecular studies needed, tissue should be sampled from the fresh / unfixed specimen
In resource limited settings, a number of sections can be decreased:
- Up front submission of the entire periphery of encapsulated lesion may not be necessary; additional blocks can be prepared from stored specimens
- Single encapsulated nodule: 1 - 2 blocks for each centimeter of diameter (i.e. 10 blocks for a 5 cm nodule) at initial gross examination
- Multinodular goiter: 1 section per nodule up to 5 nodules in a nodular process

Gross appearance of main thyroid lesions

Multinodular goiter:
- Asymmetrically enlarged and distorted thyroid with diffuse heterogeneous nodularity, frequent scarring, hemorrhage, calcifications and cysts
- It is often difficult to distinguish a dominant nodule
Graves disease:
- Gland is symmetrically enlarged, beefy red and homogeneous without nodularity
Hashimoto thyroiditis:
- Diffuse symmetric enlargement, tannish yellow on cut resembling lymph node; may appear multilobular due to parenchymal fibrosis
Papillary thyroid carcinoma:
- White to yellow-white, sometimes cystic, often firm / sclerotic and calcified with a rim of peritumoral fibrosis; multifocality is common
- Papillary projections can be seen in cystic and encapsulated tumors
- May grossly invade the thyroid capsule and adjacent muscle
- Occult microcarcinoma may appear as a tiny pale gray scar
Follicular neoplasm:
- Follicular adenoma: solitary, 2 - 4 cm, completely encapsulated (thin capsule), pale tan to gray mass, soft, gelatinous or fleshy
- Follicular carcinoma: similar to adenoma but larger and has a thick capsule (> 1 mm)
- Widely invasive follicular carcinoma has infiltrative border, sometimes multinodular
Hürthle cell tumor:
- Tan-brown to mahogany brown with frequent parenchymal hemorrhage
Medullary carcinoma:
- Located in the middle and upper third of the central portion of the lobe
- Well circumscribed but nonencapsulated, gray to yellow, with a soft and fleshy or firm and gritty consistency; often multifocal
Anaplastic carcinoma:
- Large, firm to hard, pale gray with areas of necrosis and hemorrhage
- Because of invasive nature, is often submitted with attached adjacent tissues (muscle, trachea); recognizable thyroid may not be present

Gross description template

Blank template (UCLA Pathology & Laboratory Medicine: Head and Neck Pathology Grossing Guidelines [Accessed 25 April 2019])
- Received [fresh / in formalin] is [intact / disrupted] [hemi / total] thyroidectomy specimen
- [Orientation if provided]
- The thyroid measures __ × __ × __ mm [add measurements for lobes, if total thyroidectomy], weight __ grams
- The capsule is [intact, ruptured, smooth] [with / without] adherent skeletal muscle
- The specimen is serially sectioned into __ levels to reveal [describe lesions including size, color, shape, encapsulation, degenerative changes, relationship to margins]
- Nodule #1 is __ × __ mm [encapsulated / well circumscribed / ill defined / infiltrative] and measures __ mm to the closest [anterior, posterior, etc.] margin / surface, [describe color, homo / heterogeneous, degenerative changes]
- Nodule #2 …
- The remaining cut surface is [red-brown, smooth, unremarkable]
Papillary carcinoma (Lester: Manual of Surgical Pathology, 3rd Edition, 2010)
- Received fresh is a 65 g total thyroidectomy specimen consisting of right lobe (6 × 5 × 4 cm), left lobe (5 × 3 × 2.5 cm) and isthmus (2 × 1.5 × 1 cm). Anterior surface has a fragment of attached skeletal muscle. The right upper pole is oriented with a white surgical suture. On cut, there is a 4 × 3 × 2 cm ovoid white-tan firm mass with a finely granular appearance present in the right lobe and extending into the isthmus. The central portion is densely white, firm and focally calcified. The lesion is poorly circumscribed and grossly invades the thyroid capsule at the posterior plane but is 0.1 cm from the inked resection margin. The remainder of the parenchyma is red-brown and homogeneous with a single colloid filled nodule (0.5 cm) in the lower portion of the left lobe. Parathyroid glands are not recognized grossly.
Encapsulated solitary nodule (follicular adenoma, noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP], follicular carcinoma)
- Received in the fresh state is a specimen identified as left hemithyroidectomy (left lobe with isthmus). A black suture is present at the isthmusectomy margin. The specimen weighs 35 g and measures 65 × 40 × 30 mm. The outer surface is smooth and the consistency is homogeneously firm. An ill defined bulging is noted in the lower pole of the left lobe. No parathyroid glands or lymph nodes are identified. Parallel longitudinal sections of the specimen reveal a round nodule in the lower lobe measuring 25 mm in greatest diameter. It is entirely surrounded by a very thin fibrous capsule that shows no gross evidence of invasion. The cut surface of the nodule is solid, slightly bulging and tan, with punctate areas of fresh hemorrhage. The capsule of the nodule is 5 mm distant from the thyroid capsule in anterior and posterior planes and 12 mm distant from the surgical margin at the isthmus. The rest of the thyroid shows no gross abnormalities.

Diagrams / tables

Images hosted on other servers:

Ink color scheme

How to serially section

Gross images

Contributed by Andrey Bychkov, M.D., Ph.D.

Orientation of specimen by surgeon

Sampling encapsulated lesion

Detecting capsular invasion

Sampling papillary carcinoma

Gross appearance of main thyroid lesions: follicular adenoma and papillary carcinoma

Images hosted on other servers:

Orientation of specimen by surgeon

Sampling encapsulated lesion

Videos

Grossing by Weill Cornell

Grossing by Gross Cutting Room

Additional references

The University of Chicago: Gross Pathology Manual - Thyroid [Accessed 2 July 2019]

Hashimoto thyroiditis

Table of Contents

Definition / general

Prototype of autoimmune disease presenting with goiter, elevated circulating antithyroid antibodies, often with hypothyroidism
Histopathologically diffuse lymphoplasmacytic infiltration, lymphoid follicle formation, follicular atrophy, oncocytic metaplasia and fibrosis
First described in 1912 by Dr. Hakaru Hashimoto, who called it struma lymphomatosa (Thyroid 2013;23:142)

Essential features

Most common cause of hypothyroidism in iodine sufficient areas
Infiltration of thyroid parenchyma by mononuclear cells, lymphoid follicles with germinal centers, oncocytic cells lining residual thyroid follicles, fibrosis

Terminology

Also known as Hashimoto disease, struma lymphomatosa, chronic lymphocytic thyroiditis, goitrous thyroiditis, lymphadenoid goitre
Hashitoxicosis: transient thyrotoxicosis due to follicle destruction in Hashimoto thyroiditis

ICD coding

ICD-10: E06.3 - autoimmune thyroiditis

Epidemiology

Incidence per year 0.3 - 1.5/1,000 (Best Pract Res Clin Endocrinol Metab 2019;33:101367)
30 - 50 years (Maedica (Bucur) 2019;14:98)
F:M = 3 - 12:1 (Autoimmun Rev 2014;13:391)
- 3:1 for IgG4 related variant
- 5:1 for Hashitoxicosis form
- 6:1 for juvenile variant
- 10:1 for fibrous variant
- 12:1 for classic variant
Polymorphisms associated with other autoimmune diseases in 20% of cases

Pathophysiology

Breakdown of immune tolerance (Best Pract Res Clin Endocrinol Metab 2019;33:101367)
- Genetic susceptibility
  - Familial aggregation
  - Polymorphisms in human leukocyte antigen (HLA) genes
  - Polymorphisms in genes involved in immune regulation, including cytotoxic T lymphocyte associated antigen 4 (CTLA4), protein tyrosine phosphatase 22 (PTPN22) and interlukin 2 receptor α chain (IL2RA)
- Environmental factors (Autoimmun Rev 2014;13:391)
  - Smoking has a protective effect
  - Increased dietary iodine is associated with increased incidence
- Polymorphisms
- Decrease in Tregs
Autoantibodies against thyroglobulin, thyroid peroxidase (TPO) and antithyroid stimulating hormone (TSH) receptor
CD8+ T cell mediated cytotoxicity, cytokine mediated cell death and antibody dependent cell mediated cytotoxicity

Etiology

Multifactorial; immunological, genetic and environmental

Diagrams / tables

Images hosted on other servers:

Grading of thyroiditis on cytological material

Clinical features

Painless enlargement of thyroid gland
Majority (75%) are euthyroid (Autoimmun Rev 2014;13:391)
Progressively increasing hypothyroidism
May have an initial transient phase of hyperthyroidism
May coexist with other autoimmune diseases, like type 1 diabetes mellitus, Addison disease, systemic lupus erythematosus, Sjögren syndrome, pernicious anemia, myasthenia gravis, vitiligo, celiac disease, chronic active hepatitis
Increased risk of primary thyroid lymphoma and papillary thyroid carcinoma (PTC) (Front Oncol 2017;7:53, Endocr Pathol 2021;32:368)
6 clinicopathologic forms: classic, fibrous variant, IgG4 related variant, juvenile form, Hashitoxicosis and painless (or silent) thyroiditis (Autoimmun Rev 2014;13:391)
Idiopathic myxedema in older patients with fibrous variant
Juvenile variant: Hashitoxicosis variant: initial hyperthyroid phase similar to Graves disease, followed by hypothyroidism
Painless thyroiditis: sporadic or (more commonly) postpartum (within 12 months of delivery); usually self limited

Diagnosis

Diagnostic workup is similar to any thyroid swelling
- Thyroid function test
- Serum antithyroid antibody levels
- Ultrasound neck
- Fine needle aspiration cytology (FNAC) if thyroid nodule present
References: J Endocrinol Invest 2021;44:883, Autoimmun Rev 2020;19:102649

Laboratory

Deranged thyroid function tests
Elevated levels of TSH, with normal or low serum thyroid hormones (T3,T4)
Decreased TSH, with normal or increased serum T3,T4
Elevated serum antithyroid antibodies
- Antithyroglobulin
- Anti-TPO
- Anti-TSH receptor
References: J Endocrinol Invest 2021;44:883, Autoimmun Rev 2020;19:102649

Radiology description

Sonography: diffusely enlarged thyroid gland; diffusely heterogeneous, coarse and hypoechogenic parenchyma with micronodular pattern (Eur J Endocrinol 2019;181:539, AJR Am J Roentgenol 2010;195:208)
IgG4 related variant: more marked hypoechogenicity (Autoimmun Rev 2014;13:391)
Fibrous variant: hypoechogenicity along with prominent nodularity of the parenchyma

Radiology images

Contributed by Ayana Suzuki, C.T.

Isoechoic nodule

Images hosted on other servers:

Ultrasound

Prognostic factors

IgG4 related variant shows a more aggressive clinical course, with more severe and treatment resistant hypothyroidism (Autoimmun Rev 2014;13:391)

Case reports

24 year old woman with Hashimoto thyroiditis associated with inflammatory myopathy (Pathology 2017;49:97)
28 year old woman with RET / PTC1 rearrangement in Hashimoto thyroiditis and in associated papillary thyroid carcinoma and hyalinizing trabecular adenoma (AJSP Reviews & Reports 2019;24:13)
31 year old man with Hashimoto thyroiditis presented with myxedema psychosis (J Am Osteopath Assoc 2017;117:50)
41 year old woman with hypothyroidism and multinodular goiter (Arch Pathol Lab Med 2003;127:e253)
43 year old woman with coexisting affective psychosis and brain perfusion abnormalities (Clin Pract Epidemiol Ment Health 2007;3:31)
46 year old woman with thyroid adenoma and Hashimoto thyroiditis (Rom J Morphol Embryol 2017;58:241)
52 year old woman with Hashimoto thyroiditis involving ectopic cervical thyroid tissue (Head Neck Pathol 2021;15:328)

Treatment

Thyroid hormone replacement if hypothyroid
Subtotal thyroidectomy to relieve compression symptoms (Best Pract Res Clin Endocrinol Metab 2019;33:101367)
Hemitotal or subtotal thyroidectomy in case of oncocytic cell neoplasm or suspicious for malignancy cytology
Short course glucocorticoids in IgG4 related variant (Autoimmun Rev 2014;13:391)

Gross description

Diffuse symmetric enlargement of thyroid gland; occasionally asymmetric enlargement or nodular
Cut surface: pale, yellow-tan, firm, nodular; resembles lymph nodes
May be fibrotic and atrophied

Gross images

Contributed by Mark R. Wick, M.D.

Diffusely enlarged thyroid lobe

Images hosted on other servers:

Atrophic gland

Nodular gland

Microscopic (histologic) description

Classic form: diffuse infiltration of thyroid parenchyma with lymphocytes and plasma cells; lymphoid follicle formation with germinal centers (Best Pract Res Clin Endocrinol Metab 2019;33:101367)
Polymorphic lymphocytic infiltrate, predominantly T cells
Thyroid follicular destruction
Atrophic thyroid follicles; many lined by oncocytic cells / oncocytes having abundant granular eosinophilic cytoplasm; rarely squamous metaplasia
Later fibrosis and nodularity (Virchows Arch 2013;462:557)
Fibrous (or fibrosing) variant: extensive keloid-like fibrosis of thyroid parenchyma, fibrous septa divide the parenchyma into lobules, mononuclear cell infiltration, lymphoid follicles, thyroid follicular atrophy, oncocytic cell and squamous metaplasia (Autoimmun Rev 2014;13:391)
IgG4 related variant: dense lymphoplasmacytic infiltrate, enriched in IgG4 producing plasma cells (> 20 cells per high power field); interstitial fibrosis; often associated with obliterative phlebitis (Autoimmun Rev 2014;13:391)
Juvenile thyroiditis, Hashitoxicosis and painless thyroiditis: rare / absent germinal center formation and follicular atrophy, follicular cell hyperplasia, less pronounced oncocytic cell metaplasia and fibrosis (Autoimmun Rev 2014;13:391)
Variable atypia of follicular cells and oncocytic cells, may mimic and act as a precursor (limited evidence) of papillary thyroid carcinoma (Endocr Pathol 2021;32:368)
Squamous metaplasia of follicular epithelium can be confused with solid cell nests (J Clin Endocrinol Metab 2012;97:2209)
May be associated with colloid goiter, follicular neoplasm, oncocytic cell neoplasm, papillary thyroid carcinoma and primary thyroid lymphoma (Acta Cytol 2009;53:507, Front Oncol 2017;7:53)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and Shipra Agarwal, M.D.

Lymphoid follicles with germinal centers

Diffuse
lymphoplasmacytic
infiltration

Squamous metaplasia: p63+ cells in many follicles

Evolution of squamous metaplasia

Intense immunostaining

Lobulation of thyroid tissue by fibrotic bands

Vesicular nuclei of thyroid follicles similar to PTC nuclei

Aggregation of lymphoid follicles mimic thyroid nodule

Hashimoto thyroiditis with lymphoepithelial cyst

Nodular Hashimoto thyroiditis

Papillary microcarcinoma and Hashimoto thyroiditis

Oncocytic cell nodule

Virtual slides

Images hosted on other servers:

Fibrous variant of Hashimoto thyroiditis

Lymphoid follicles and oncocytic metaplasia

Dense infiltrate and atrophied follicles

Oncocytic metaplasia

Fibrous variant with squamous metaplasia

Oncocytic and adenomatous nodules

Oncocytic nodule

Cytology description

Moderately or highly cellular aspirate
Inflammatory infiltrate
- Variable number of lymphocytes in different stages of development (Cureus 2019;11:e5851, J Thyroid Res 2018;2018:5246516)
- Lymphocytes infiltrating follicular epithelial cells
- Lymphoglandular bodies (Acta Cytol 2009;53:507)
- Plasma cells
- Can grade based on lymphocytic infiltration from 0 to 3+ (see Diagrams / tables) but does not correlate with clinical, biochemical, radionuclide and ultrasonographic parameters (Cytojournal 2007;4:10, J Cytol 2016;33:145)
Aggregates of oncocytic cells / oncocytes
Crushed cells, lymphoid tangles
Absent or scant colloid
Mild anisonucleosis, giant cells, macrophages, epithelioid cells, eosinophils, fire flares
Usually Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category II; can be TBSRTC III / IV / V

Cytology images

Contributed by Shipra Agarwal, M.D. and Ayana Suzuki, C.T.

Cellular aspirate

Crushed cells

Lymphocytes and oncocytes

Images hosted on other servers:

Oncocytic cells with atypical nuclei

Sheet of follicular cells with oncocytic change mixed with benign lymphoid cells

Resembles lymphoma

Grade I: mild lymphocytic inflammatory infiltrate

Grade II: moderate lymphocytic inflammation

Grade III: marked
inflammation with
polymorphous
lymphocytes

ThinPrep versus Pap stain

Lymphocytes and oncocytes

Follicular destruction by lymphocytes

Crushed cells

Grade 1, 2 and 3 thyroiditis

Positive stains

High molecular weight keratin, p63 (Hum Pathol 2003;34:764)
May have elevated kappa/lambda ratio (Am J Clin Pathol 2006;125:42)
Mixture of T and B cells (Indian J Pathol Microbiol 2011;54:464)
HBME-1, cytokeratin 19, cyclin D1, galectin3: variable positivity in case of atypia (Virchows Arch 2013;462:557, Endocr Pathol 2021;32:368)

Electron microscopy description

Oncocytic cells have numerous large mitochondria

Molecular / cytogenetics description

Polyclonal (Hum Pathol 1988;19:1444, Indian J Pathol Microbiol 2011;54:464)
No mutations, gene fusions (previously reported RET / PTC rearrangements were erroneous)

Videos

Thyroid: compare and contrast

Histopathology thyroid: Hashimoto thyroiditis

Sample pathology report

Thyroid, total thyroidectomy:
- Hashimoto thyroiditis

Differential diagnosis

Chronic (focal) lymphocytic thyroiditis:
- Incidental detection of focal aggregates of lymphocytes, with or without germinal center formation, in thyroid parenchyma
- Absent or limited oncocytic metaplasia
- Follicular atrophy and fibrosis
- Usually absent clinical and laboratory indicators of autoimmune thyroid disease
Riedel thyroiditis:
- Hard fixed mass simulating thyroid carcinoma
- Active fibroblastic proliferation; storiform fibrosis
- Inflammation and fibrosis extends beyond the thyroid capsule into perithyroidal tissues
- Associated with fibroinflammatory lesions in other sites
MALT lymphoma:
- Age: > 60 years
- Rapid increase in size of thyroid swelling, hard swelling
- Clonal proliferation of B cells, confirmed on immunostaining and flow cytometry
- Destructive lymphoepithelial lesions (Rom J Morphol Embryol 2017;58:731)
Oncocytic cell neoplasms:
- Well circumscribed lesion within an echonormal background
- Composed mainly of oncocytic cells without (or with minimal) mononuclear cell infiltration (Rom J Morphol Embryol 2017;58:731)
Papillary carcinoma:
- Presence of true papillae, more well developed and diffuse nuclear features, infiltrative borders
Lithium intake:
- Significant clinical history; shows similar morphologic findings (Hum Pathol 1983;14:737)

Board review style question #1

Which of the following is true regarding the thyroid lesion shown above?

Fibrosis extends into perithyroidal soft tissues
Increased risk of follicular thyroid carcinoma
Increased risk of medullary thyroid carcinoma
Increased risk of primary thyroid lymphoma
Shows monoclonal lymphoid cell proliferation

Board review style answer #1

D. Increased risk of primary thyroid lymphoma. Answer A is incorrect because unlike Riedel thyroiditis, in which the fibrosis extends into perithyroidal soft tissues, it is limited to the thyroid gland in Hashimoto thyroiditis. Answers B and C are incorrect because Hashimoto thyroiditis predisposes to papillary thyroid carcinoma and primary thyroid lymphoma. Answer E is incorrect because Hashimoto thyroiditis is characterized by a polyclonal lymphocytic infiltration of the thyroid parenchyma.

Comment Here

Reference: Hashimoto thyroiditis

Board review style question #2

Which of the following is true about Hashimoto thyroiditis?

Common in iodine deficient areas
Mononuclear cell infiltration of the thyroid parenchyma
More common in males
Not a familial disease
Usually presents with hyperthyroidism

Board review style answer #2

B. Mononuclear cell infiltration of the thyroid parenchyma. Histological examination in Hashimoto thyroiditis reveals a mononuclear cell infiltration of the thyroid parenchyma, composed of lymphocytes and plasma cells. Answer A is incorrect because Hashimoto thyroiditis is the most common cause of hypothyroidism in iodine sufficient areas. Answers C and D are incorrect because the disease shows a female preponderance and is often familial. Answer E is incorrect because the patients usually present with painless diffuse thyroid swelling and are mostly euthyroid.

Comment Here

Reference: Hashimoto thyroiditis

Hashimoto-fibrous

Table of Contents

Definition / general

10 - 12% of all cases
Large symptomatic goiter, marked hypothyroidism
Fibrous atrophy variant:
- Similar to fibrous variant but thyroid gland is much smaller (1 - 6 g)
- Elderly patients with marked hypothyroidism and high titers of antithyroid antibodies

Laboratory

Hypothyroidism with increased TSH
Markedly elevated antithyroglobulin antibody

Treatment

Surgery to relieve dysphagia or dyspnea

Gross description

Large goiter does not adhere to surrounding structures
May not be recognizable as thyroid tissue

Microscopic (histologic) description

Extensive dense (keloid-like) hyaline fibrosis within thyroid capsule
Often extensive squamous metaplasia
Marked follicular atrophy, although lobular architecture of gland is maintained

Microscopic (histologic) images

AFIP images

Metaplastic squamous follicles

Dilated lumen of metaplastic follicle

Various images

Differential diagnosis

Carcinoma
MALT lymphoma: (Pathol Oncol Res 2009;15:285)
Riedel’s thyroiditis: adherence to adjacent structures with infiltration into nerve, fat, muscle and parathyroid glands; vasculitis; fibrous tissue is active proliferative type, residual thyroid tissue is relatively normal, phlebitis present (J Endocrinol Invest 2003;26:444, Histopathology 1983;7:739)

Histology

Table of Contents

Definition / general

Divided into lobules of 20 - 40 round to oval follicles, each 50 - 500 microns, with a single layer of cuboidal to low columnar epithelium
Lumen contains colloid, which is scalloped and pale in follicles with active secretory activity, densely eosinophilic in inactive follicles and more flocculent ("like a clump or tuft of wool") and basophilic in elderly
Stroma contains C cells, formerly called parafollicular cells (actually are intrafollicular), derived from neural crest
C cells represent 0.1% of gland, produce calcitonin, are present in middle and upper third of lateral lobes along central axes, are not present in extreme upper and lower poles or in isthmus
Usually 10 C cells per low power field in adults
C cells are more numerous in neonates, decrease in adults, increase and appear as nodular aggregates after age 60 years
C cells have pale / clear cytoplasm, oval nuclei, difficult to identify with H&E, use calcitonin stain
Sanderson polsters: collections of small follicles projecting into lumen of large actively secreting follicles; may resemble papillary carcinoma
Oncocytes (Hürthle cells, oxyphilic cells, Ashkenazy cells): large cells with abundant deeply eosinophilic granular cytoplasm and numerous mitochondria

Physiology

Purpose of thyroid gland is to produce T4 and T3, which regulate metabolism, increase protein synthesis and increase oxygen consumption in all cells in body; T4 and T3 are also important for growth and development, and maturation of peripheral and central nervous system
Hypothalamus releases thyroid releasing factor (TRF) into hypothalamic-pituitary portal blood circulation, which travels to pituitary, which releases thyroid stimulating hormone (TSH) into blood
Follicular cells normally synthesize thyroglobulin and secrete it into follicular lumen
Thyroid peroxidase, found in apical membrane of thyroid follicular cells, catalyzes iodination of tyrosine residues on thyroglobulin molecule and coupling of iodotyrosyl residues to form T4 (thyroxine) and T3, which are still bound to thyroglobulin, making them inactive; they are then stored as colloid
In response to TSH, follicular cells pinocytose colloid, release the thyroglobulin, and secrete now active T4 and T3 into bloodstream
Body needs 100 mg of iodide per day from diet to synthesize adequate T4; iodide uptake is mediated by human sodium iodide symporter, then oxidized to iodine by iodide peroxidase, which binds to tyrosine
Most T4 / T3 is reversibly bound to thyroid binding globulin, which maintains levels within narrow limits
Free T4 / T3 enters cells, binds to nuclear receptors, increases protein synthesis and catabolism of carbohydrates and fats (basal metabolic rate)
Decreased serum T4 / T3 stimulates release of TRF and TSH via negative feedback regulation; elevated levels have opposite effect
Chronically stimulated (hyperplastic) follicular cells are tall and columnar, may be papillary
C cells secrete calcitonin, which lowers serum calcium by promoting bone absorption of calcium and inhibiting bone resorption by osteoclasts; in humans, has only a minor role in calcium homeostasis
Major role of calcitonin may be to protect skeleton during periods of calcitonin stress, such as growth, pregnancy and lactation
Goitrogens: suppress T4 / T3 synthesis by interfering with iodide uptake or other parts of biochemical pathways, causing an increased TSH, which causes goiter (enlargement of thyroid gland); examples include propylthiouracil, which inhibits oxidation of iodide and blocks T4 / T3 production; iodides in large doses, which inhibit thyroglobulin proteolysis; vegetables such as cabbage, turnips and cassava
References: Nussey: Endocrinology, 2001, Wikipedia: Thyroid Hormones [Accessed 19 July 2018]

Clinical features

Adipose metaplasia (mature adipose tissue between follicles or near capsule)
Intrathyroidal cartilage, skeletal muscle or salivary gland
Melanosis of follicular cells in old age (pigment granules also contain colloid, Ultrastruct Pathol 1998;22:401); see also Black thyroid
Calcification is associated with vessels in elderly, has no laminations (in contrast to psammoma bodies)
Squamous metaplasia is rare in normal thyroid, more common in thyroid disorders

Case reports

67 year old woman with thyroid nodule with adipose metaplasia in a nodular goiter (Indian J Pathol Microbiol 2007;50:369)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Perinuclear brown pigment

Oncocytes

Sanderson polster

Thyroid follicular epithelium

Follicular colloid

Normofollicular thyroid

Macrofollicular thyroid

Pyramidal lobe

Microfollicular thyroid

Pericapsular fat

Adipose metaplasia

Perithyroid thyroid follicles

Intrathyroidal muscle

Calcium oxalate crystals in the colloid

PAS staining

Thyroglobulin expression

Mucicarmine staining

TTF1 expression

PAX8 expression

TTF2 nuclear expression

NIS membranous expression

Cluster of C cells

Location of C cells in relation to follicle

Pericapillary location of C cells

Clustered distribution of C cells

Calcitonin IHC

Proliferation in adult thyroid

Prominent vascular network

Capillary network

Solid cell nests

Histologic mimics of SCN

Solid cell nests: p63

Solid cell nests: thyroglobulin-

AFIP images

C cells (calcitonin
stain); cells are
polyhedral and
spindled

Follicles lined by flattened epithelium

Normal adult follicles are round to oval

Follicles lined by cuboidal epithelium

Colloid is flocculent - most likely artifactual, not significant

Tangential section
of normal thyroid
follicle may resemble
C cell hyperplasia

Ectopic cartilage

Skeletal muscle

Squamous metaplasia

Images hosted on other servers:

Follicles lined by flattened epithelium and filled with colloid

Rich vascular supply

Thyroid and parathyroid glands

Papillary structures

C cells (calcitonin stain)

Positive stains

Follicular cells: thyroglobulin (very specific, weaker staining in oncocytic cells), TTF1, low molecular weight keratin; also EMA, vimentin, T3 (triiodothyronine), T4 (thyroxine), ER beta (not alpha), PgR
- Note: thyroglobulin may leak out of follicular cells and create false positivity in adjacent cells
Colloid: thyroglobulin, Alcian blue, PAS, T3, T4
C cells: calcitonin, calcitonin gene related peptide (CGRP), neuron specific enolase, chromogranin A, synaptophysin, CEA, somatostatin; C cells are metachromatic with toluidine blue; C cells are NEGATIVE for thyroglobulin

Electron microscopy description

Follicular cells: abundant granular endoplasmic reticulum, well developed Golgi, prominent lysosomes, luminal (apical) microvilli, well developed desmosomes with terminal bars between cells, small mitochondria, may contain lipofuscin; nuclei are round with homogeneous chromatin
C cells: intrafollicular (separated from thyroid interstitium by follicular basal lamina), numerous dense core neurosecretory granules (type I are 280 nm, moderately electron dense and present in most C cells; type II are 130 nm, more electron dense and rare)

Electron microscopy images

AFIP images

Follicles have luminal microvilli

Intrafollicular C cell

Images hosted on other servers:

Follicular cells

Videos

By John R. Minarcik, M.D.

Hobnail

Table of Contents

Definition / general

Aggressive variant of papillary thyroid carcinoma (PTC) characterized by predominance of cells with a hobnail appearance often arranged in micropapillary pattern (Am J Surg Pathol 2017;41:854)
- Hobnail cell appearance designates a peculiar loss of polarity with apically placed bulging nuclei
- Micropapillary pattern is characterized by cancer cells loosely arranged in small clusters lacking fibrovascular cores, lined by hobnail, cuboidal or flat epithelium often with loss of polarity and cohesiveness
Micropapillary pattern of tumor is recognized in several organs (bladder, breast, colon, gallbladder, kidney, lung, ovary, pancreas and parotid gland), being associated with poor clinical outcome (Rev Endocr Metab Disord 2016;17:521)
Originally established as distinct PTC variant by Asioli et al. in 2010 (Am J Surg Pathol 2010;34:44)
- Hobnail pattern with micropapillary structures was described by Kakudo group as loss of cellular polarity / cohesiveness in early 2000s (Pathol Int 2003;53:204, J Clin Pathol 2004;57:1041, Cancer Sci 2008;99:1908)
- 70+ cases described (Rev Endocr Metab Disord 2016;17:521)

Essential features

Recently described rare variant of PTC with aggressive behavior (extrathyroidal extension, nodal and distant metastasis) and relatively poor prognosis (lower long term survival)
Microscopically characterized by micropapillary growth pattern and hobnail appearance of cells due to apically placed bulging nuclei
Diagnosis of PTC hobnail variant requires at least 30% of hobnail-micropapillary pattern in the tumor, although minor hobnail-micropapillary features (5 - 30%) are of significance and should be noted in pathology report

Terminology

Hobnail variant of PTC = Hobnail PTC = PTC with prominent hobnail features
Previously described as PTC with micropapillary features, micropapillary carcinoma, micropapillary-hobnail variant and loss of cellular polarity / cohesiveness variant
- Term "micropapillary carcinoma" is often confused with papillary microcarcinoma, an indolent thyroid tumor, hence "hobnail" designator is preferred (Am J Surg Pathol 2013;37:1215)
- Hobnail histology is also more consistently observed than the micropapillary pattern, discounting the value of the latter title (Am J Surg Pathol 2017;41:854)

Epidemiology

Rare tumor, < 1% of all PTC
- Range in PTC series from 0.3% (South Korea) to 2.7% (Southern Italy) (Int J Clin Exp Pathol 2015;8:7988, Rev Endocr Metab Disord 2016;17:521)
Older patients: mean age 57 years, range 17 - 87 (Rev Endocr Metab Disord 2016;17:521)
F:M about 3:1, similar to all PTC

Pathophysiology

Hobnail PTC is considered a moderately differentiated thyroid carcinoma placed between well differentiated classic PTC and poorly differentiated thyroid cancer (Am J Surg Pathol 2015;39:260, Am J Surg Pathol 2017;41:854)
BRAF mutation is a likely driver, followed by second hits in TP53, TERT promoter, PIK3CA or CTNNB1 (Endocr Relat Cancer 2017;24:107)
Associated events are epithelial-mesenchymal transition (Cancer Lett 2009;281:188) and activation of mTOR pathway (J Clin Exp Pathol 2013;4:152), both characteristic for aggressive thyroid cancer

Diagrams / tables

Images hosted on other servers:

Summary of patients

Clinical features

Neck mass, sometimes with compressive symptoms (dyspnea, dysphagia, hoarseness) (Am J Surg Pathol 2010;34:44)
Almost half are incidental findings (Int J Clin Exp Pathol 2015;8:7988)
Aggressive tumor with relatively poor prognosis (Thyroid 2014;24:958):
- Extrathyroidal extension
- Lymph node metastasis in up to 75%
- Distant metastases in up to 40% (lung, brain, bones)
- Local recurrence
- Progression to poorly differentiated thyroid cancer
- Advanced clinical stage (AJCC Stage III or IV) at presentation
- Increased mortality rates compared to classic PTC in most but not all cases

Diagnosis

Diagnostic workup is similar to any thyroid mass / nodule:
- Ultrasound with FNA
- CT scan may be useful in locally advanced disease to evaluate extrathyroidal extension and lymph node metastases
Hobnail PTC is a pathological diagnosis rendered on surgical specimens
- FNAC can suspect hobnail variant and influence surgical tactics
- PTC hobnail variant requires at least 30% of tumor having hobnail-micropapillary pattern
- Minor hobnail micropapillary features (5 - 30%) should also be correctly identified and stated in pathology report due to potential aggressive behavior (Hum Pathol 2012;43:1596)

Radiology description

Sonography: oval, solid or heterogeneous, coarsened hypoechoic and vascular mass with irregular margins, often accompanied by ipsilateral cervical lymphadenopathy (J Clin Exp Pathol 2013;4:152, Diagn Cytopathol 2013;41:757)

Prognostic factors

Hobnail PTC itself indicates propensity for higher grade transformation (Am J Surg Pathol 2015;39:260)
Local recurrence rate is 23%, lymph node metastasis 60 - 75%, distant metastasis 25 - 40%
Disease specific survival rates are 83%, 71% and 54% at 5, 10 and 20 years after surgery, respectively (Int J Clin Exp Pathol 2015;8:7988)
Overall survival rates are 69% and 64% at 5 and 10 years, respectively (Endocr Relat Cancer 2017;24:107)
Increased mortality risk in patients harboring multiple mutations, usually BRAF with TP53 or PIK3CA (Thyroid 2014;24:958)

Case reports

17 year old girl with PTC hobnail variant diagnosed by FNA (J Clin Exp Pathol 2013;4:152)
26 year old woman with hobnail PTC suspected on FNA (Diagn Cytopathol 2015;43:990)
31 year old woman with PTC hobnail variant (Diagn Cytopathol 2013;41:757)
53 year old woman and 62 year old man with hobnail PTC which progressed to anaplastic carcinoma (Am J Surg Pathol 2017;41:854)
54 year old woman with preoperative FNA (Am J Clin Pathol 2015;142:A276)
57 year old man with PTC hobnail variant studied by FNA (Acta Cytol 2012;56:560)
57 year old man with recurrent tumor (Thyroid 2009;19:535)
84 year old woman with hobnail PTC presenting as superior vena cava syndrome (Thyroid 2016;26:129, Poster 353)

Treatment

Total thyroidectomy with neck lymph node dissection followed by TSH suppression therapy and radioactive iodine treatment (Thyroid 2018;28:96)

Gross description

Mean size 3.5 cm (larger than average PTC), range 0.5 - 11.0 cm (Int J Clin Exp Pathol 2015;8:7988)
Infiltrative appearance
Multiple nodules in one or both thyroid lobes (Am J Surg Pathol 2010;34:44)
Rarely a single encapsulated nodule

Microscopic (histologic) description

Histologically, this variant has 3 distinctive features (Am J Surg Pathol 2015;39:260):
- Micropapillae lacking true fibrovascular cores
- Hobnail cells with apically placed protruding nuclei and eosinophilic cytoplasm
- Marked loss of cellular cohesion
Main architectural patterns (Am J Surg Pathol 2010;34:44):
- Papillary pattern is the most common, with variably sized edematous papillae having vascular cores, rare psammoma bodies and lined by discohesive hobnail epithelium 1 - 4 cells thick
- Clustered pattern represented by micropapillary structures without fibrovascular cores, lined by hobnail cells
- Follicular pattern is rare with variably sized follicles lined by hobnail cells and little to no colloid
Hobnail cells:
- Cells with apically placed nuclei and protrusion of the apical surface that gives a hobnail appearance
  - Synonyms of hobnailing: tufting, bulging, apocrine snouting; also matchstick, comet tail, teardrop appearance
- Increased N:C ratio
- Characteristic PTC nuclear features are less prominent compared to classic variant
- Dense eosinophilic cytoplasm with well defined cell borders, similar to oncocytes
- Apical position of nuclei (inversion or loss of polarity) is often accompanied by discohesiveness of the epithelial layer with cell shedding
Aggressive morphology:
- Extensively invasive cancer with extrathyroidal extension and multiple areas of vascular invasion
- Moderate to marked cellular pleomorphism
- Increased mitotic figures (often ≥ 3 per 10 HPF, reported mean 2.1, range 0 - 9), including atypical mitoses (Int J Clin Exp Pathol 2015;8:7988)
- Necrosis is rare
- Focal transformation into poorly differentiated and even anaplastic thyroid cancer (Am J Surg Pathol 2015;39:260, Am J Surg Pathol 2017;41:854)
Proportion of hobnail component:
- Presence of at least 30% of cells with hobnail-micropapillary features is required to entitle a tumor as PTC hobnail variant
- In original series, most had 50 - 100% of hobnail component (Am J Surg Pathol 2010;34:44)
- If present, minor hobnail-micropapillary component (5 - 30%) should be correctly identified and stated in the pathology report, because it has adverse prognostic significance (Hum Pathol 2012;43:1596, Hum Pathol 2013;44:320, Endocrine Abstracts 2013;32:P1105, Am J Surg Pathol 2015;39:260, Thyroid 2016;26:129, Poster 198)
- Concomitant patterns are usually represented by classic, tall cell and oncocytic PTC, rarely by PTC follicular and solid variants; all of them can be considered as precursor lesions
- Number of sections studied is critical for evaluation of PTC with hobnail cells, thus increase in the number of sections routinely studied, especially sampling at the tumor infiltrating edge, can likely result in a higher incidence of detection of the hobnail PTC (Hum Pathol 2013;44:320)
Background: often multinodular goiter or chronic thyroiditis (Rev Endocr Metab Disord 2016;17:521), rarely microcarcinoma (Diagn Cytopathol 2015;43:990)
Nodal and distant metastases usually preserve hobnail pattern, sometimes may progress toward anaplastic carcinoma (Am J Surg Pathol 2017;41:854)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Edematous papillae lined by discohesive epithelium

Oncocytic epithelium with loss of cohesiveness

Hobnail cells with apically placed nuclei

Apical decapitation of cells

Images hosted on other servers:

PTC hobnail variant on different magnifications

Group 2 papillary carcinoma of the thyroid

IHC

Cytology description

Aspirate is highly cellular with scant colloid and bloody background (Hum Pathol 2013;44:320)
Patterns:
- Papillary-like clusters with vascular cores, sometimes with central psammoma calciﬁcations (Diagn Cytopathol 2015;43:990)
- Micropapillary groups without fibrovascular cores
- Rarely follicular structures
- Proportion of isolated cells versus clusters can vary
Hobnail cells:
- Medium sized cells with apically placed nuclei, producing surface bulge resulting in hobnail appearance
- Tapered cytoplasm provides "teardrop" or "comet-like" appearance of hobnail cells (Acta Cytol 2012;56:560)
- Severe crowding, high N:C ratio, dense eosinophilic cytoplasm
- Often more than 50% of tumor cells in smear have hobnail morphology
Additional nuclear features:
- Multiple soap bubble-like intranuclear inclusions
- Occasional grooves and pseudoinclusions (J Clin Exp Pathol 2013;4:152)
- Variable degree of atypia
- Sometimes mitotic figures
LBP (liquid based preparation) cytology (Int J Clin Exp Pathol 2015;8:7988):
- Frequent syncytial cell clusters with eccentric nuclei
- Papillary and micropapillary structures are rare than in conventional smears
- Comet-like hobnail cells and multiple soap bubble-like intranuclear inclusions
- Typical nuclear features of PTC
Most of the cases correspond to the Bethesda VI category (Thyroid 2014;24:958)

Cytology images

Images hosted on other servers:

Conventional smear

LBP

Positive stains

Thyroid specific markers: Thyroglobulin, TTF1
Markers of thyroid neoplasia: CK19, HBME-1
Markers of tumor aggressiveness (Endocr Relat Cancer 2017;24:107):
- Ki67 labeling index around 10%, range 2 - 20%
- p53 (> 25% cells) in more than half cases
This immunoprofile is shared with other thyroid tumors, especially aggressive PTC variants
Ancillary markers (rarely used) (Endocr Relat Cancer 2017;24:107):
- E-cadherin and β-catenin with membranous staining
- MUC1 with characteristic "inside out" pattern in micropapillary component
- EMA - membranous or cytoplasmic
- Cyclin D1 (Am J Surg Pathol 2017;41:854)
- Napsin A expression is often found in micropapillary component, can be a pitfall in differentiating from micropapillary lung adenocarcinoma (Am J Surg Pathol 2013;37:1215)

Electron microscopy description

Cytoplasm of oncocytic cancer cells is packed with mitochondria (Am J Surg Pathol 2010;34:913)

Molecular / cytogenetics description

Main: BRAF V600E mutation in most cases (50 - 80%)
Common: TP53 (55%), TERT promoter (45%), PIK3CA (28%)
Rare: CTNNB1 (17%), EGFR (11%), AKT1 (6%) and NOTCH1 (6%)
More than 70% of tumors have concurrent mutations (Endocr Relat Cancer 2017;24:107)
RET / PTC1 is uncommon, up to 20%, based on one study (Thyroid 2014;24:958)
No RAS family mutations
Mutation profile in primary tumor and metastasis is usually maintained

Differential diagnosis

These PTC variants share papillary histoarchitecture with hobnail variant, however they lack hobnailing (apical tufts) feature:
Cytology (Hum Pathol 2013;44:320)
- See above PTC variants, all of them lack cytologic features of hobnail appearance and comet-like cells
- Metastases to the thyroid gland with hobnail or micropapillary growth pattern, e.g. serous and clear cell carcinoma of the female genital tract, lung adenocarcinoma with micropapillary and hobnail features, breast micropapillary cancer - these cases can be distinguished by IHC panels (TTF1, thyroglobulin, PAX8, WT1, Napsin A, GATA3, etc.)
- Medullary thyroid carcinoma with discohesive cells: positive for calcitonin
- Florid variant of thyroid papillary hyperplasia: absence of PTC nuclei and hobnailing
PTC oncocytic variant shares oncocytic (granular eosinophilic cytoplasm) and sometimes micropapillary features with hobnail PTC but it lacks evident hobnailing (> 30%) and loss of cohesiveness

Additional references

Nose: Diagnostic Pathology: Endocrine, 2012, Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015, Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012

Board review style question #1

Which statement is incorrect about hobnail PTC?

Rare variant of papillary thyroid carcinoma
Relatively aggressive clinical behavior
Microscopically characterized by hobnail cells and micropapillary pattern
Common BRAF V600E, TP53 and TERT promoter mutations
High mortality

Board review style answer #1

E. High mortality. Hobnail papillary thyroid carcinoma is an unusual and aggressive variant of PTC characterized by predominance of cells with a hobnail appearance often arranged in micropapillary pattern. Despite multiple mutations and frequent nodal (up 75%) and distant (up to 40%) metastases, mortality is relatively low - disease specific survival rates are 80+% and 70+% at 5 and 10 years after surgery.

Comment Here

Reference: Hobnail

Board review style question #2

What proportion of a hobnail micropapillary pattern in the tumor is required for a diagnosis of PTC hobnail variant?

Board review style answer #2

D. 30%. The presence of at least 30% of cells with hobnail micropapillary features is mandatory to diagnose a tumor as PTC hobnail variant. Nevertheless, a minor hobnail micropapillary pattern (5 - 30%) has prognostic significance and should be noted in the pathology report.

Comment Here

Reference: Hobnail

Board review style question #3

What category of the Bethesda System of Reporting Thyroid Cytopathology corresponds best to FNA smears of hobnail PTC with comet-like cells?

I (non-diagnostic)
III (AUS/FLUS)
IV (FN/SFN)
V (suspicious for malignancy)
VI (malignant)

Board review style answer #3

E. VI (malignant). Cases with diagnostic hobnail cells are easily placed into the Bethesda VI category.

Comment Here

Reference: Hobnail

Hyalinizing trabecular tumor

Table of Contents

Definition / general

Neoplasm of follicular cells showing a trabecular growth pattern of large cells with pale to eosinophilic cytoplasm containing stromal hyaline material; the nuclear features show elongation, grooves and intranuclear inclusions (Am J Surg Pathol 1987;11:583)

Essential features

Trabecular architecture
Yellow bodies
MIB1 membrane staining of tumor cells
GLIS translocation is unique to this thyroid tumor

Terminology

Hyalinizing trabecular neoplasm, hyalinizing trabecular adenoma

ICD coding

ICD-O: 8336/0 - hyalinizing trabecular adenoma

Epidemiology

Hyalinizing trabecular tumor (HTT) comprises fewer than 1% of thyroid neoplasms, shows a female preponderance > 80% and occurs in adults (mean age 50 years) (Am J Surg Pathol 2008;32:1877)

Sites

Thyroid

Etiology

Unknown

Clinical features

HTT occurs in asymptomatic individuals and is usually an incidental finding on ultrasonography or by clinical examination
In approximately 30% of cases, chronic lymphocytic thyroiditis is present (Thyroid 2011;21:253)

Diagnosis

Neither ultrasound nor radioactive scans can diagnose HTT; fine needle aspiration results are often characterized as atypia of undetermined significance; definitive diagnosis is rarely made preoperatively (J Clin Pathol 2017;70:641, Diagn Cytopathol 2015;43:710, Cancer Cytopathol 2019;127:390)

Laboratory

Thyroid function tests are usually within normal limits; no specific preoperative test is definitive

Prognostic factors

Overwhelming majority of HTT are benign neoplasms; very rare examples showing capsular or vascular invasion have been reported (Am J Surg Pathol 2008;32:1877, Histopathology 1996;28:357)

Case reports

44 year old woman with thyroid nodule (Ultrasound Int Open 2017;3:E42)
54 year old woman with chronic lymphocytic thyroiditis (J Surg Case Rep 2021;2021:rjab324)
70 year old woman with incidental right lobe nodule (Thyroid Res 2017;10:7)

Treatment

Surgery with removal of the affected thyroid lobe is curative

Gross description

Lesion is circumscribed or encapsulated without gross evidence of invasion
Tumor ranges in size from 5 mm - 7.5 cm; half of the tumors measure 3 cm or less
On section, the tumor is yellow to white in color
Cut surface is solid, slightly bulging and may show lobulation

Gross images

Images hosted on other servers:

Encapsulated gray white nodular lesion

Gray white with one area showing cystic degeneration

Microscopic (histologic) description

Trabecular growth pattern
Large, elongated cells with voluminous eosinophilic cytoplasm
> 50% of cases show intracytoplasmic 2 - 5 micron yellow perinuclear inclusions (yellow bodies) with surrounding clear halo; these represent giant lysosomes (Am J Surg Pathol 1999;23:118, Arch Pathol Lab Med 2003;127:715)
Nuclei are enlarged and elongated or oval
Nuclear grooves and intranuclear inclusions are seen in all cases
Hyaline material seen in extracellular space
Stromal calcifications are frequent
No vascular or capsular invasions are noted (Am J Surg Pathol 1987;11:583, Arch Pathol Lab Med 2003;127:715, Am J Surg Pathol 1999;23:118, Am J Surg Pathol 2008;32:1877)

Microscopic (histologic) images

Contributed by Virginia A. Livolsi, M.D.

HTT thinly encapsulated

Solid trabecular growth

Trabecular pattern noted

Elongated nuclei

Prominent intranuclear inclusion

Nuclear clearing and grooves

Yellow bodies

Calcification in tumor stroma

Thyroglobulin stain variable

TTF1 decorates nuclei

Ki67 decorates membranes

Cytology description

Usually hypercellular smears
Cells radially oriented around hyaline material
Tumor cells elongated with abundant cytoplasm
Enlarged, elongated nuclei with nuclear clearing, grooves and inclusions; clearing may not be prominent
Cytoplasmic staining by MIB1 is characteristic
Stromal amorphous material may be mistaken for amyloid (Congo red stain negative)
Because of nuclear features and stromal deposits, cytology may be classified as either papillary carcinoma or medullary carcinoma
References: Am J Surg Pathol 2004;28:859, Diagn Cytopathol 2015;43:710, J Clin Pathol 2017;70:641, Cancer Cytopathol 2019;127:390

Cytology images

Contributed by Ayana Suzuki, C.T.

Nuclear pseudoinclusions

Positive stains

Thyroglobulin
TTF1
PAX8
Cytokeratin
Ki67 membrane staining is unique to HTT (MIB1 monoclonal antibody at room temp must be used) (Am J Clin Pathol 2004;122:506, Am J Surg Pathol 2000;24:575, Am J Surg Pathol 2008;32:1877, Head Neck Pathol 2020;14:778)

Negative stains

HBME-1, CK19, calcitonin, chromogranin

Electron microscopy description

Giant lysosomes are found in the cytoplasm

Molecular / cytogenetics description

Characteristic rearrangement of GLIS; only HTT of all thyroid tumors tested thus far demonstrate rearrangement of GLIS (PAX8-GLIS1 and PAX8-GLIS3 [most frequent]) (Cancer Cytopathol 2019;127:560, Mod Pathol 2019;32:1734)
No BRAF mutation (Appl Immunohistochem Mol Morphol 2007;15:220)
No RAS mutations (Appl Immunohistochem Mol Morphol 2007;15:220)
RET / PTC translocations reported but further study makes these reports doubtful (Am J Surg Pathol 2000;24:1615, Eur J Cancer 2005;41:816, Histopathology 2010;56:632)

Sample pathology report

Thyroid, right lobe, lobectomy:
- Hyalinizing trabecular tumor, 2.5 cm nodule (see comment)
- Comment: Specimen weighs 12 g and measures 4.2 x 2.8 x 1 cm. The surface is smooth and shows a bulging nodule in the lower portion of the lobe. On sectioning, the nodule is solid, tan and circumscribed.

Differential diagnosis

Medullary thyroid carcinoma:
- Stains for calcitonin and chromogranin A
- Stromal amyloid is seen in 75% of these cancers
- Nuclei show salt and pepper morphology
Paraganglioma:
- Tumor cells are chromogranin A positive; intermixed S100 positive sustentacular cells should be noted
- Nuclear morphology resembles the salt and pepper nuclei of neuroendocrine cells
Papillary thyroid carcinoma:
- HTT does not show papillary growth and if follicles are produced they tend to be empty
- Most papillary carcinomas show invasive growth pattern

Board review style question #1

This solitary thyroid nodule represents

Hyalinizing trabecular tumor
Medullary thyroid carcinoma
Papillary thyroid carcinoma, trabecular variant
Paraganglioma

Board review style answer #1

A. Hyalinizing trabecular tumor

Comment Here

Reference: Hyalinizing trabecular tumor

Board review style question #2

The molecular signature of the tumor illustrated is

BRAF K601 mutation
BRAF V600E mutation
GLIS rearrangement
NRAS mutation

Board review style answer #2

C. GLIS rearrangement

Comment Here

Reference: Hyalinizing trabecular tumor

Hyperparathyroidism

Table of Contents

Definition / general

Autonomous, spontaneous overproduction of parathyroid hormone / parathormone / PTH by parathyroid tissue, with no evidence of prior parathyroid stimulation by renal or intestinal disease
Important cause of hypercalcemia (0.3 - 5.0 cases/1000 adults)
Higher incidence in women; usually age 50+
Associated with irradiation in some; may be associated with sarcoidosis
Rarely presents with bone disease (Am J Clin Pathol 1993;100:697)
Normocalcemic primary hyperparathyroidism also occurs

Etiology

Adenoma (85%), hyperplasia (15%), carcinoma (~1%)

Clinical features

Often asymptomatic (no skeletal or renal lesions)
Detected via screening studies for serum calcium
To diagnose, PTH level must be elevated inappropriately to level of serum calcium
Associated with low serum phosphorus, high urinary calcium and phosphorus, high serum alkaline phosphatase

Symptoms (due to increased serum PTH and calcium): bones, stones, groans, moans

Bone disease:

Osteoporosis (from osteoclast prominence and remodeling), with later deformities and fractures
Osteitis fibrosa cystica (also called brown tumors, von Recklinghausen disease [not neurofibromatosis]): thin cortex, marrow with increased fibrous tissue, hemorrhage and cysts; often in jaw

Stones:

Renal calcium stones in 20%
Also nephrocalcinosis (calcification of renal interstitium and tubules)
Renal stones cause hypertension, are important cause of death
Renal abnormalities may progress after treatment

Groans from GI distress:

Nausea, peptic ulcers (associated with high serum gastrin that decreases after surgical excision), constipation, pancreatitis, gallstones

Moans from CNS disturbance:

Depression, lethargy, seizures
Also weakness, fatigue, calcifications of aortic and mitral valves; metastatic calcification in stomach, lungs, myocardium, blood vessels

Calciphylaxis

Rare and life threatening condition of vascular calcification, first described in 1962, that causes ischemic damage to skin (usually lower extremity) and other organs (G Ital Nefrol 2012;29:674, Hum Pathol 1995;26:1055)
Also known as calcific uremic arteriopathy (CUA), calcifying panniculitis, vascular calcification-cutaneous necrosis syndrome
Affects 1 - 4% of dialysis patients; associated with primary, secondary or tertiary hyperparathyroidism
60 - 80% mortality
Diagnosis: bilateral, symmetrical, superficial skin lesions with persistence of dorsal pulses; confirm with biopsy
Treatment: parathyroidectomy

Secondary hyperparathyroidism

Hyperparathyroidism due primarily to non-PTH disease
Bone changes usually less severe than primary hyperparathyroidism
Dialysis patients may have discrete, punched out bone lesions with minimal resorption or osteoblast activity (Am J Surg Pathol 1987;11:205)
Due to hypocalcemia, which causes elevated PTH levels; causes of hypocalcemia are renal failure (phosphorus retention directly depresses serium calcium levels), inadequate calcium intake, steatorrhea (failure to absorb vitamin D), vitamin D deficiency or resistance; note:
~60% monoclonal

Tertiary hyperparathyroidism

Autonomous parathyroid hyperplasia / adenoma arising from secondary hyperparathyroidism
Often detected after hemodialysis or transplantation corrects the renal disease
May have 10-40x increase in parathyroid mass
Treatment: surgical excision
Micro description: marked hyperplasia, with predominance of chief cells and abundance of oxyphil cells (Hum Pathol 1985;16:772)

Case reports

69 year old woman with primary hyperparathyroidism due to parathyroid adenoma (Arch Pathol Lab Med 2001;125:1351)
70 year old man with end stage renal failure secondary to IgA nephropathy (J Med Case Rep 2009;3:9297)

Treatment

Surgical excision of enlarged gland plus one additional gland for diagnostic purposes
Use selective venous catheterization to localize abnormal gland preoperatively
Also total parathyroidectomy with autotransplantation of parathyroid tissue into forearm muscle but may get recurrence of hyperparathyroidism and hyperplastic gland may infiltrate the skeletal muscle and look malignant

Clinical images

Images hosted on other servers:

Calciphylaxis

Gross description

Solid and cystic areas, brown due to hemosiderin

Microscopic (histologic) description

Osteoblastic and osteoclastic activity, cysts, hemosiderin laden macrophages
Pale, vacuolated cells arranged in a trabecular pattern are also seen in non-PTH mediated hypercalcemia (Am J Surg Pathol 1985;9:43)

Microscopic (histologic) images

Images hosted on other servers:

Gland composed mainly of chief cells with a rim of normal parathyroid tissue, no stromal fat

Chief cell hyperplasia and oncocytic cells

Calciphylaxis: ischaemic skin changes

Cytology description

FNA shows organoid or trabecular architecture of cellular tissue fragments with epithelial cells arranged around capillary cores and frequent microacini
Cells have round, fairly uniform nuclei 6 to 8 microns
Larger oxyphil cells may show considerable anisonucleosis
No features of thyroid tissue such as hemosiderin laden macrophages, abundant colloid, paravacuolar granules (Hum Pathol 1995;26:338)

Positive stains

Cyclin D1 (61%, Mod Pathol 1999;12:412)

Electron microscopy description

Ribosomal lamellar complexes and groups of centrioles is suggestive of adenoma
Examination of normal appearing glands can detect chief cell activity associated with hyperplasia (Hum Pathol 1986;17:1036)

Molecular / cytogenetics description

~40% monoclonal
95% sporadic; also associated with MEN 1 and MEN 2 / 2A syndromes (usually chief cell hyperplasia)
PRAD1 / cyclin D1 (parathyroid adenoma 1) protein: inversion of gene on #11 puts PRAD1 next to 5'-PTH gene regulatory sequences which are constitutively active; seen in 10% of adenomas
MEN1: loss of 11q13 tumor suppressor gene usually found; also noted in 20% of sporadic adenomas
MEN 2 / 2A: may see chief cell hyperplasia and medullary carcinoma at the same time

Differential diagnosis

Familial hypocalciuric hypercalcemia: young patients with family history, autosomal dominant, usually mild parathyroid hyperplasia (Hum Pathol 1981;12:229)
Giant cell reparative granuloma: similar histology and both in jaw so use laboratory findings to differentiate
Giant cell tumor: evenly spaced giant cells, plump stromal cells, less osteoblastic activity
Also hyperthyroidism, myeloma, sarcoidosis, vitamin A or vitamin D intoxication
Medullary carcinoma of thyroid if intrathyroidal tissue: PTH-, calcitonin+ (Am J Surg Pathol 1983;7:535)
Tumor related hypercalcemia: has PTH related protein, more common in squamous cell carcinomas, renal cell carcinoma, ovarian clear cell carcinoma, rarely leukemia (Am J Clin Pathol 1981;75:149), Kaposi sarcoma (Am J Clin Pathol 1976;66:998)

Hyperthyroidism

Table of Contents

Definition / general

Increased thyroid hormone synthesis and secretion from the thyroid gland (Lancet 2016;388:906)
See also Hyperthyroidism-lab diagnosis

Epidemiology

Approximately 3% of women and 0.5% of men will develop Graves disease during their lifetime (JAMA 2015;314:2544)

Pathophysiology

Depends upon the underlying cause
Graves disease (Cochrane Database Syst Rev 2015 Nov 25;(11):CD010576):
- Autoimmune disease caused by the production of auto antibodies against thyroid stimulating hormone receptors
- Stimulation of follicular cells to produce thyroid hormone

Types:

Primary hyperthyroidism: intrinsic thyroid abnormality
- Low TSH, high free T4, normal TRH stimulation test
Secondary hyperthyroidism: high TSH, abnormal TRH stimulation test
Subclinical hyperthyroidism: low TSH (Eur J Endocrinol 2005;152:1)
- May be due to exogenous thyroid hormone (Hormones (Athens) 2006;5:119), due to TSH suppressive therapy with L-thyroxine or hormone overreplacement (Eur J Endocrinol 2005;152:1)
- Excessive thyroid hormone may be due to differentiated thyroid cancer (Eur J Endocrinol 2005;152:1)
- Patients have increased risk of coronary heart disease (Int J Cardiol 2008;125:41, Eur J Endocrinol 2005;152:1)
T3 hyperthyroidism: 1 - 4% of hyperthyroid patients
- Low TSH, high free T3, normal free T4
- Associated with early treatment of hyperthyroidism with antithyroid drugs
T4 hyperthyroidism: high T4, normal T3
- Due to primary hyperthyroidism causes, also iodine, amiodarone (Arch Pathol Lab Med 2003;127:e275), pregnancy (transient gestational hyperthyroidism syndrome, 1 - 3%, Hormones (Athens) 2015;14:59)

Etiology

Graves disease (85%) or maternal Graves disease, overdose of thyroid hormone, iodide ingestion, hyperfunctioning multinodular goiter or thyroid adenoma, thyroiditis, struma ovarii, choriocarcinoma, hydatidiform mole, pituitary adenoma (Lancet 2016;388:906)
Radiocontrast iodine based agent (Arch Endocrinol Metab 2016;60:287)

Clinical features

Early symptoms: anxiety, palpitations, rapid pulse, fatigue, muscle weakness, weight loss, diarrhea, hyperactive reflexes, increased sweating, heat intolerance, warm skin, excessive perspiration, menstrual changes, hand tremor, polydipsia and increased appetite (J Am Geriatr Soc 1996;44:50)
Late symptoms: cardiac (palpitations, congestive heart failure, cardiomegaly, atrial fibrillation, fatty change), fatty change of skeletal muscle or liver, osteoporosis from bone resorption, generalized lymphadenopathy
Ocular changes: wide staring gaze and lid lag due to sympathetic overstimulation of levator palpebrae superioris
Thyrotoxicosis: hypermetabolic clinical syndrome due to elevated serum T3 or T4
- May be due to hyperthyroidism, thyroiditis or excessive ingestion of thyroid hormone ("factitious hyperthyroidism")
- Includes a wide range of symptoms, such as ophtalmopathy, dermatopathy, fever, marked tachycardia, heart failure, tremor, nausea, vomiting, diarrhea, dehydration, restlessness, extreme agitation, delirium and coma (Endotext - Graves Disease, CMAJ 2003;168:575)
- In severe thyrotoxicosis, death may be secondary to cardiac failure, shock and multiple organ failure (Endotext - Graves Disease)

Laboratory

Low or suppressed TSH, elevated free thyroxine level (FT4) (CMAJ 2003;168:575)
10% of patients have an increased total or free T3 level and normal T4 level with suppressed TSH level, a condition called "T3 toxicosis" (CMAJ 2003;168:575)
In Graves disease, elevated levels of antitopoisomerase antibodies and antithyroglobulin antibodies are found in 80% and 50% of cases, respectively (Mod Pathol 2000;13:1014)
See also Hyperthyroidism-lab diagnosis

Radiology description

Scintigraphy with Tc - 99m pertechnetate shows an enlarged thyroid gland with an increased activity level diffusely through the gland (Radiographics 2003;23:857)

Case reports

11 year old boy with undiagnosed hyperthyroidism presenting with fractures and osteoporosis (Pediatrics 2016;137:e20150169)
18 year old pregnant woman presenting with aortic aneurysm, tachycardia and hyperthyroidism (Ginecol Obstet Mex 2015;83:627)
35 year old man presented with jaundice secondary to Graves disease (BMC Res Notes 2016;9:320)
36 year old man with thyroid hemiagenesis presenting with hyperthyroidism symptoms (Hormones (Athens) 2015;14:451)
66 year old woman with a history of euthyroid multinodular goiter underwent a head and neck computed tomography scan (Arch Endocrinol Metab 2016;60:287)

Treatment

Treatment options for Graves disease include antithyroid drugs (such as carbimazole, methimazole, or propylthiouracil / PTU), radioactive iodine therapy and surgery (Lancet 2016;388:906)
Beta blockers for symptoms, thionamide type drugs to block new hormone synthesis, iodine to block release of T4 / T3, radioactive iodine to destroy thyroid tissue
Thyroidectomy if other treatments fail or are contraindicated, or when goiter is causing compressive symptoms (Am Fam Physician 2005;72:623)

Gross description

Multinodular goiter (CMAJ 2003;168:575)
Symmetrically enlarged thyroid gland

Gross images

Contributed by Andrey Bychkov, M.D., Ph.D.

Enlarged thyroid

Microscopic (histologic) description

Papillary hyperplasia and fronds that may lack true fibrovascular cores (Mod Pathol 2000;13:1014), mimicking papillary thyroid carcinoma
Follicles are hypercellular and lined by tall columnar epithelium
Treatment may cause follicular cells to become cuboidal rather than columnar
Limited to absent fibrosis
Mixed, but predominantly lymphocytic infiltrate, within stroma surrounding follicles
Small or occluded lumens containing pale or little colloid
Scalloping of the colloid
Nuclear features of papillary carcinoma are lacking

Microscopic (histologic) images

Images hosted on other servers:

Diffuse hyperplasia of thyroid gland

Videos

Histopathology Thyroid - Graves Disease

Additional references

Hypothyroidism

Table of Contents

Definition / general

Hypothyroidism is a common endocrine disorder resulting from a deficiency of thyroid hormone (Rev Endocr Metab Disord 2016 May 7 [Epub ahead of print])
Presents as clinical or subclinical disease based on presence of symptoms and levels of serum TSH and free thyroxine / T4
Further classified as primary, secondary and tertiary (Thyroid 2012;22:1200)
Central hypothyroidism refers to decreased production of TSH / TRH due to pituitary or hypothalamic lesions (Thyroid 2012;22:1200)
Complications include myxedema, characterized by thickened, nonpitting edematous soft tissue in markedly hypothyroid patients (J Clin Diagn Res 2014;8:YD01, An Bras Dermatol 2016;91:100)
- Myxedema can also occur in hyperthyroidism, such as Graves disease (J Clin Diagn Res 2014;8:YD01)
- Myxedema crisis / coma; a medical emergency and life threatening condition associated with a high mortality rate, which usually occurs following severe hypothyroidism decompensation (J Thyroid Res 2011;2011:493462)
See also Hypothyroidism-lab diagnosis

Essential features

Hypothyroidism is a common endocrine disorder resulting from a deficiency in thyroid hormone (Rev Endocr Metab Disord 2016 May 7 [Epub ahead of print])
It is imperative to distinguish primary hypothyroidism from secondary / tertiary hypothyroidism (Indian J Endocrinol Metab 2011;15:S99), as the causes are very different
In severe hypothyroidism decompensation, myxedema crisis / coma, a life threatening condition, can occur and prompt medical treatment is recommended (J Thyroid Res 2011;2011:493462)
Myxedema describes thickened, nonpitting edema of soft tissue that may develop in patients with hypothyroidism (J Clin Diagn Res 2014;8:YD01, An Bras Dermatol 2016;91:100)
- Histologically, mucin accumulation is found between collagen fibers of the reticular dermis
- Other findings include perivascular lymphocytes, large fibroblasts and hemosiderin deposits (An Bras Dermatol 2016;91:100)
- Diagnosis relies primarily on clinical findings, biopsy and laboratory findings suggestive of hypothyroidism (Endotext - Severe Hypothyroidism in the Elderly)

Epidemiology

Prevalence: clinical primary hypothyroidism, 0.3%; subclinical disease, 4.3% (Thyroid 2012;22:1200)
Myxedema crisis / coma has a higher incidence among older females, affects about 220,000 people per year (J Thyroid Res 2011;2011:493462)

Sites

Thyroid gland
Involvement of pituitary gland or hypothalamus are usually observed in central hypothyroidism (Hippokratia 2010;14:82, J Clin Endocrinol Metab 2012;97:3068)
Myxedema involves primarily bilateral pretibial areas (Am J Clin Dermatol 2005;6:295)
- Other sites include: cheeks, hands, supraclavicular fossae and soft tissue around the eyes (Ophthal Plast Reconstr Surg 2006;22:457 , Med J Aust 2003;179:211)

Pathophysiology

Secretion of thyroid hormones are regulated by the hypothalamic pituitary thyroid axis
In primary hypothyroidism, the following changes occur:
- Destruction of the thyroid gland leads to decreased secretion of thyroid hormones T3 and T4
- In response, TSH secretion increases (Neth J Med 2009;67:332, Hippokratia 2010;14:82)
Myxedema: dermal mucinosis is caused by increased deposition of connective tissue components (glycosaminoglycans, hyaluronic acid and mucopolysaccharides) within the reticular dermis (Wikipedia - Myxedema)
- Protein mucopolysaccharide complex binds water, resulting in nonpitting edema
Myxedema coma: patients with longstanding hypothyroidism often develop adaptive mechanisms, including chronic peripheral vasoconstriction, diastolic hypertension and diminished blood blood volume to preserve a normal body core temperature
Myxedema coma occurs when a precipitating event disrupts this homeostasis (Endotext - Myxedema and Coma (Severe Hypothyroidism))

Etiology

Primary hypothyroidism:
- Environmental iodine deficiency (most common etiology worldwide, Thyroid 2012;22:1200)
- Destruction or ablation of thyroid gland (surgery, radiation, developmental)
- In the United States, Hashimoto thyroiditis is the most common etiology (Thyroid 2012;22:1200)
- Interference with thyroid hormone synthesis (idiopathic, genetic [J Med Genet 2005;42:379], drugs [lithium, iodide, methimazole, PTU])
- Supraphysiologic Iodine exposure, especially in those with preexisting thyroid disease (Nat Rev Endocrinol 2014;10:136)
- Chronic renal failure (normal TSH, low T3 and T4) (Nucl Recept 2005;3:1)
Secondary hypothyroidism:
- Any pituitary disorder that causes reduced TRF or TSH secretion
- Include genetics, tumors (e.g., pituitary adenoma), infection, autoimmune disorders, drugs, pituitary surgery or radiotherapy, trauma or pituitary apoplexy (Indian J Endocrinol Metab 2011;15:S99, Hippokratia 2010;14:82)
Tertiary hypothyroidism:
- Any hypothalamic disorder that causes reduced TRF secretion
- Includes tumors, surgery or radiotherapy (Indian J Endocrinol Metab 2011;15:S99, Hippokratia 2010;14:82)
Subclinical hypothyroidism:
- High TSH, normal T3 and T4
- No clinical symptoms of hypothyroidism (Am Fam Physician 2005;71:1763) but may have sensory neuropathy (Neurol Sci 2009;30:149)

Clinical features

Most common symptoms are dry skin, fatigue, muscle cramps, cold sensitivity, voice changes and constipation
- In advanced disease: carpal tunnel syndrome, sleep apnea and pituitary hyperplasia (Thyroid 2012;22:1200)
Rarely presents with myxedema pseudovolvulus (J Surg Case Rep 2016 Apr 22;2016(4)) or severe hyponatremia (Eur J Endocrinol 2017;176:R15)
Myxedema coma is characterized by unconsciousness, respiratory failure, bradycardia, hypothermia (Case Rep Endocrinol 2015;2015:169194) and altered mental status (N Engl J Med 2015;372:764), including "myxedema madness" (psychosis due to marked hypothyroidism)
Recently, arrythmias and coagulation disorders have been recognized as part of myxedema crisis (J Thyroid Res 2011;2011:493462)

Diagnosis

For most outpatients with primary thyroid disease, serum thyrotropin (TSH) is the best screening test, although it may not be adequate for hospitalized patients (Thyroid 2012;22:1200)
Primary hypothyroidism is suspected when TSH is elevated, a goitrous thyroid is present, associated pituitary hormone deficiencies are absent and the thyrotropin releasing hormone stimulation test is normal (Indian J Endocrinol Metab 2011;15:S99)
Secondary / tertiary hypothyroidism (central hypothyroidism) is suggested by a normal to low normal TSH and low normal thyroid hormone, confirmed by the thyrotropin releasing hormone stimuation test (Indian J Endocrinol Metab 2011;15:S99)

Laboratory

Low free T3 / T4, high TSH (Endotext - Severe Hypothyroidism in the Elderly)
Elevated serum TPO antibody titers may indicate autoimmune thyroiditis, and provide prognostic information on the risk of developing hypothyroidism (Thyroid 2012;22:1200)
In myxedema, CEA and CA125 may be elevated (Clin Ther 2007;29:2710)
- May have hyponatremia (Eur J Endocrinol 2017;176:R15)
See also Hypothyroidism-lab diagnosis

Radiology description

Primary hypothyroidism:
- Ultrasound reveals a hyperechoic multinodular thyroid (Med J Aust 2016;205:179), with a halo around nodules and no calcifications; benign nodules typically have ill defined margins (AJR Am J Roentgenol 2010;195:216)
Pretibial myxedema:
- Multiple imaging modalities may be helpful in diagnosis
- Echo-Doppler of the lower legs may show venous and lymphatic insufficiency (An Bras Dermatol 2016;91:100)
- Digital infrared thermal imaging, which detects surface temperature (Eur J Endocrinol 2011;164:605), shows an abnormally low focal temperature over the lower legs
- High resolution ultrasonography shows composition changes in pretibial soft tissue (Eur J Endocrinol 2011;164:605)
Increased skin thickness is demonstrated by hypoechoic substance deposition in the cutaneous tissue, and blurred boundary lines between dermal and subcutaneous tissue

Prognostic factors

Poor compliance with thyroid hormone replacement may lead to myxedema coma (Case Rep Endocrinol 2015;2015:169194)
Predictors of mortality in myxedema crisis or coma: bradycardia, hypotension, hypothermia, respiratory failure requiring mechanical ventilation, sepsis, intake of sedative drugs, high APACHE II score, SOFA (Sequential Organ Failure Assessment) scores greater than 6, and no response to treatment (J Thyroid Res 2011;2011:493462)

Case reports

22 year old woman with hypothyroidism due to bromide intoxication (Am J Clin Pathol 1988;89:802)
30 year old man with Graves disease (Dermatol Online J 2008;14:8)
37 year old man with HIV, hemophilia and Pneumocystis carinii infection presenting as thyroid mass with hypothyroidism (Am J Clin Pathol 1991;95:489)
38 year old woman with myxedema coma and cardiac ischemia (Clin Ther 2007;29:2710)
A man in his late thirties with undiagnosed hypothyroidism presenting with sigmoid volvulus (J Surg Case Rep 2016 Apr 22;2016(4))
43 year old woman with cardiac death due to cardiovascular myxoedema and endocardial fibroelastosis (Int J Cardiol 2015;182:281)
54 year old woman with fatal cardiac tamponade due to myxedema pericarditis (Am J Clin Pathol 1986;86:113)
82 year old woman with myxoedema secondary to hypothyroidism treated with intramuscular injection of Levothyroxine (Case Rep Endocrinol 2015;2015:169194)

Treatment

Thyroid hormone replacement therapy (L-thyroxine), tailored for each patient (Drugs Aging 2005;22:23, Thyroid 2012;22:1200)
Pretibial myxedema usually resolves spontaneously
In some cases, topical steroids, intralesional steroids, gamma globulin, pentoxifylline, surgery and radiotherapy may be required (J Clin Diagn Res 2014;8:YD01)
Myxoedema coma can be successfully managed with levothyroxine and hydrocortisone (Case Rep Endocrinol 2015;2015:169194)
Weekly administration of thyroxine may be useful for patients with cognitive deficits, chronic disabilities and poor medical compliance (Case Rep Endocrinol 2015;2015:169194, Postgrad Med J 2007;83:e3)

Gross description

Diffusely enlarged, firm goiter (Thyroid 2012;22:1200)
Pretibial myxedema: well defined, indurated, erythematous skin with large urticarial plaques often involving both legs and sparing the toes (J Clin Diagn Res 2014;8:YD01)

Microscopic (histologic) description

Primary hypothyroidism (J Clin Endocrinol Metab 1993;76:466):
- Hyperplastic follicles, some with papillary folding
- Follicle cells range from cuboidal to columnar with clear cytoplasm and round nuclei
- Scant colloid material
- Lymphocytic infiltrate may be present
Skin myxedema is usually characterised by (J Clin Diagn Res 2014;8:YD01):
- Collagen fibers in reticular dermis are separated by mucin accumulation
- Cutaneous mucinosis (Am J Dermatopathol 2010;32:196)
- Mild perivascular lymphocyte infiltrate
- Epidermis is spared
- Prominent fibroblasts (An Bras Dermatol 2016;91:100)
- Presence of hemosiderin deposits (An Bras Dermatol 2016;91:100)

Positive stains

Pretibial myxedema: Alcian blue reveals mucin deposition across the entire dermal thickness (An Bras Dermatol 2016;91:100)

Electron microscopy description

Primary hypothyroidism: severe interference with thyroid hormone biosynthesis within the follicular cells (J Clin Endocrinol Metab 1993;76:466)

Videos

Endocrinology overview

Additional references

Wikipedia - Hypothyroidism, eMedicine - Hypothyroidism, eMedicine - Hypothyroidism and Myxedema Coma

Intrathyroidal thymic carcinoma

Table of Contents

Definition / general

A malignant epithelial tumor with thymic differentiation occurring within the thyroid gland (WHO 5th edition)
Intrathyroidal (ectopic) thymic carcinoma (ITC)
CArcinoma Showing Thymus-Like differentiation (CASTLE)
- Terminology first used in 1991 (Hum Pathol 1991;22:349)
- Terminology not recommended by WHO 5th edition
Entity first described in 1985 (World J Surg 1985;9:128)

Essential features

Invasive intrathyroidal (ectopic) thymic carcinoma located at the lower pole of thyroid

Terminology

Acceptable: thymic carcinoma
Not recommended: CD5 positive thyroid carcinoma; lymphoepithelioma-like carcinoma of the thyroid; intrathyroidal epithelial thymoma; primary thyroid thymoma; thyroid carcinoma showing thymus-like differentiation; intrathyroidal carcinoma showing thymus-like elements (CASTLE)

ICD coding

ICD-O: 8589/3 - carcinoma showing thymus-like element

Epidemiology

Rare; World J Surg 2018;42:1754)
M:F = 1:1.3; mean age of 48.5 years (Case Rep Med 2016;2016:7962385)

Sites

Commonly involves the lower pole of thyroid lobes or attached to the thyroid (WHO 5th edition)

Etiology

Thought to arise in intra or perithyroidal thymic tissue, vestiges of thymopharngeal duct or branchial pouch remnants (including solid cell nests) (Endocrinol Metab (Seoul) 2020;35:696, Thyroid 2013;23:511)
Higher prevalence in Asian countries suggests that genetic, ethnic or environmental factors may contribute to tumorigenesis (Oncol Lett 2016;11:1321)

Clinical features

Presents with a slow growing neck mass with hard consistency and poor mobility
Some may present with hoarseness due to recurrent laryngeal nerve paralysis (Am J Clin Pathol 2007;127:230)

Diagnosis

Clinical suspicion of thyroid mass followed by a fine needle aspiration may not reach a definitive diagnosis; a diagnosis can be rendered based on histologic examination on resected specimen

Radiology description

Cold nodule on scintigraphy
Ultrasound: solid, heterogenous and hypoechoic mass
CT: well defined soft tissue density without calcification
MRI: isointensity on T1 weighted images and hyperintensity on T2 weighted images
Nodular masses located in the lower neck between the inferior pole of the thyroid and the upper mediastinum (Br J Radiol 2016;89:20150726)

Radiology images

Images hosted on other servers:

CT scan

Ultrasound

Prognostic factors

Good prognosis, with 5 year and 10 year survival of 90% and 82%; poorer prognosis if venus invasion, laryngeal nerve invasion, high proliferation index, extrathyroidal extension (Am J Clin Pathol 2007;127:230, Malays J Pathol 2020;42:259, Front Oncol 2018;8:477, Case Rep Med 2016;2016:7962385)
Rare aggressive cases can occur; brain, liver and lungs are common metastatic sites (Hum Pathol 1991;22:349)
Lymph node metastases are found at initial surgery in 40 - 50% of cases (Am J Clin Pathol 2007;127:230, Surg Today 2013;43:1261)

Case reports

38 year old woman with lenvatinib as salvage therapy in widely metastatic disease (Front Oncol 2022;12:923683)
58 year old woman with lung metastasis and carotid artery invasion (Ear Nose Throat J 2019;98:557)
60 year old woman status post thyroidectomy with recurrence after 5 years (Thyroid Res 2021;14:20)
66 year old man with complete remission after radiotherapy without resection (Strahlenther Onkol 2021;197:847)

Treatment

Total thyroidectomy with selected neck dissection
Adjuvant intensity modulated radiotherapy may improve locoregional control and survival (Endocr Relat Cancer 2021;28:593, Oncotarget 2016;7:81899)
May respond to PDL1 inhibitor if high PDL1 expression in tumor cells (Front Oncol 2019;9:734)

Gross description

Well defined, solid, lobulated pink-white mass with hard texture, fibrous septa; usually lacking calcifications or cysts on cut surfaces

Gross images

Images hosted on other servers:

Lobulated, solid and tan colored

Tumor and trachea

Microscopic (histologic) description

Identical to those of thymic carcinoma of mediastinum (World J Surg 1985;9:128, Am J Surg Pathol 2006;30:994, Hum Pathol 1991;22:349)
Mostly similar to squamous cell carcinoma with lymphocyte rich stroma (Hum Pathol 1991;22:349)
Fibrous bands separating variably sized solid islands / nests of squamoid or syncytial appearing tumor cells, with occasional single cell keratinization
Variable lymphocytes (mixed mature T and B cells versus immature T cells in thymoma) and plasma cell infiltration
Low mitotic count, Ki67 index of 10 - 30% (Surg Today 2013;43:1261)

Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.

Tumor nests and fibrosis

Central necrosis

Tumor and thyroid tissue

Fibrous bands

Squamoid cells

Invasive growth

Cytology description

Nonspecific; features favoring ITC include syncytial or 3 dimensional tissue fragments of round or spindly tumor cells with large nuclei, vesicular chromatin and prominent nucleoli in a background of lymphocytes (Acta Cytol 2016;60:421)
Resembles nasopharyngeal carcinoma (Diagn Cytopathol 1996;15:224)

Cytology images

Images hosted on other servers:

Sheets and clusters with keratin

Discohesive polygonal to ovoid cells

Positive stains

Similar to thymic carcinoma: high molecular weight keratin, p63, p40, CK19, CD5, CD117, MCL1, CEA, GLUT1, polyclonal PAX8 (Am J Clin Pathol 2015;143:223)
BCL2, calretinin, CEA and p53 (APMIS 2013;121:523)
CD5 and CD117 staining of epithelial cells is highly suggestive
Stromal lymphocytes: CD3, CD5 and CD20 (variable)
Scattered cells can be positive for chromogranin or synaptophysin (APMIS 2013;121:523, Pathol Res Pract 2013;209:662)

Negative stains

EBV, thyroglobulin, TTF1, calcitonin, amyloid, monoclonal PAX8 (World J Surg 2011;35:1840, Oncol Lett 2016;11:1321, Endocr J 2018;65:1171)
Stromal lymphocytes: TdT, CD1a

Electron microscopy description

Substantial tonofibril with abundant and well developed intercellular desmosomes, indicative of squamous differentiation (Histol Histopathol 2013;28:543)
Neuroendocrine granules in some cases (Am J Clin Pathol 2015;143:223)

Molecular / cytogenetics description

Similar to thymomas and thymic carcinomas, gains on chromosomal arm 1q and losses on 6p, 6q and 16q are frequent chromosomal imbalances (Virchows Arch 2011;459:221)
EGFR gene amplification and EGFR gene mutations in exon 20 (p.T790M) and exon 21 (p.R841K) were identified in some cases by FISH (Diagn Cytopathol 2018;46:413, Endocr Pathol 2020;31:274)
No mutations in c-kit identified despite c-kit / CD117 immunohistochemistry positivity (Am J Clin Pathol 2015;143:223)
TERT promoter mutation has been identified in some cases (Endocr Pathol 2020;31:274)
Higher mutation rates for N4BP1 and many genetic alterations were related to the NFkB signaling pathway (Virchows Arch 2023;482:813)

Sample pathology report

Thyroid, total thyroidectomy:
- Intrathyroidal thymic carcinoma, 1.2 cm, confined to the thyroid (see comment)
- No lymphovascular invasion
- Negative margins
- Comment: Immunohistochemistry performed on block 1A with adequate controls show that the tumor cells are positive for p63, CD5 and CD117 and negative for thyroglobulin and TTF1. The findings support the diagnosis above.

Differential diagnosis

Anaplastic carcinoma with squamous component:
- High grade carcinoma with tumor giant cells and necrosis
- CD5-, CD117-
- Ki67 index > 50%
- Both tumors can be polyclonal PAX8+
Squamous cell carcinoma:
- Squamous cell carcinoma without obvious lymphocyte infiltration
- CD5-, CD117-
- Ki67 index > 50%
Poorly differentiated thyroid carcinoma:
- TTF1 and thyroglobulin usually positive; CD5, CD117 and squamoid markers usually negative
- Often a component of well differentiated thyroid carcinoma
Adamantinoma-like Ewing sarcoma (Head Neck Pathol 2022;16:679):
- CD99 positive; CD5 and CD117 negative
- EWSR1::FLI1 translocation
Neuroendocrine carcinomas, including Merkel cell carcinoma and medullary thyroid carcinoma:
- Positive for neuroendocrine markers; negative for squamoid markers

Additional references

WHO Classification of Tumours Editorial Board: Endocrine and Neuroendocrine Tumours, 5th Edition, 2022

Board review style question #1

A 40 year old man presented with a mass in the left lower pole of the thyroid. The tumor is shown in the photomicrograph above. The tumor is positive for p63, CD5 and CD117 and negative for thyroglobulin and TTF1. Which of the following is most likely the correct diagnosis?

Follicular carcinoma
Intrathyroidal thymic carcinoma
Medullary carcinoma
Papillary carcinoma
Squamous cell carcinoma

Board review style answer #1

B. Intrathyroidal thymic carcinoma. Intrathyroidal thymic carcinoma often involves the lower pole of thyroid lobes with nests of squamoid epithelial cells, scattered lymphocytes and fibrous bands, along with typical immunohistochemistry phenotype. Answers A, C and D are incorrect because the morphology and immunoprofile are not consistent with this diagnosis. Answer E is incorrect because the immunoprofile shows thymic differentiation.

Comment Here

Reference: Intrathyroidal thymic carcinoma

Board review style question #2

Which of the following is true about intrathyroidal thymic carcinoma?

CD5 in intrathyroidal thymic carcinoma only highlights the lymphocytes
Most commonly located in upper pole of thyroid
Most patients have a poor prognosis and die from this tumor
Nests of squamoid cells with lymphocyte infiltrate is the key microscopic feature
Polyclonal PAX8 can be used to distinguish from thyroid carcinoma

Board review style answer #2

D. Nests of squamoid cells with lymphocyte infiltrate is the key microscopic feature of intrathyroidal thymic carcinoma. Answer A is incorrect because CD5 also highlights the epithelial cells, which is a feature of thymic differentiation. Answer B is incorrect because intrathyroidal thymic carcinoma commonly involves the lower pole of thyroid lobes or attached to the thyroid. Answer C is incorrect because intrathyroidal thymic carcinoma has relatively good prognosis, with 5 year and 10 year survival of 90% and 82%. Answer E is incorrect because intrathyroidal thymic carcinoma arising from the intrathyroidal ectopic thymus also exhibits moderate to strong nuclear reactivity for polyclonal PAX8; thus, this cannot be used to distinguish from thyroid carcinoma. Monoclonal PAX8 was reported to be negative in intrathyroidal thymic carcinoma (Endocr J 2018;65:1171).

Comment Here

Reference: Intrathyroidal thymic carcinoma

Invasive EFVPTC

Table of Contents

Definition / general

Prognostically distinct entity from counterpart NIFTP (noninvasive follicular thyroid neoplasm with papillary-like nuclear features)

Essential features

Same nuclear features and follicular architecture as NIFTP but with vascular or tumor capsule invasion present

Terminology

Encapsulated follicular variant of papillary thyroid carcinoma with invasion

ICD coding

ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

Women are affected more than men (F:M = 3.6:1)
Mean age of patients 44 years (Diagn Histopathol 2016;22:171)

Sites

Thyroid

Pathophysiology

Thyroid parenchymal follicular cells follow well defined tumor progression model (Clin Adv Hematol Oncol 2015;13:3)

Etiology

Exposure to radiation implicated in etiology of thyroid cancer (Clin Adv Hematol Oncol 2015;13:3)

Clinical features

May be found incidentally on imaging or present as a visible or palpable tumor in the thyroid

Diagnosis

Diagnosis made on histology of surgical specimens following submission and examination of entire tumor capsule (Am J Clin Pathol 2002;117:143)

Laboratory

Follicular variants of papillary thyroid carcinoma may be associated with elevated serum thyroglobulin (Thyroid 2016;26:872)

Radiology description

Ultrasound features include solid composition, smooth margins, parallel orientation, round to oval shape and presence of a halo (hypoechoic rim surrounding thyroid nodule) (Thyroid 2017;27:1177)

Prognostic factors

Good prognosis
Based on an international, multidisciplinary, retrospective study in which 101 participants had invasive EFVPTC, 12 patients experienced an adverse event (including 5 patients developing distant metastases and 2 patients dying of the disease) by a median follow up time of 13 years (JAMA Oncol 2016;2:1023)

Case reports

35 year old man with invasive encapsulated follicular variant of papillary thyroid carcinoma metastatic to lung at presentation (Mod Pathol 2010;23:1191)
43 year old patient with encapsulated follicular variant of papillary thyroid carcinoma showing capsular and vascular invasion on histology (ARS Medica Tomitana 2018;24:15)
3 cases of encapsulated follicular variant of papillary thyroid carcinoma with focal vascular invasion and bone metastases (Mod Pathol 2000;13:861)

Treatment

Hemithyroidectomy with or without isthmusectomy, near total thyroidectomy or total thyroidectomy
Depending on size and stage, may consider lymph node dissection and radioactive iodine ablation for subtotal thyroidectomies (Thyroid 2009;19:1167)

Gross description

Well circumscribed encapsulated solid nodules (Head Neck Pathol 2011;5:51)
Capsular invasion may or may not be grossly evident (Head Neck Pathol 2009;3:86)

Frozen section description

Frozen sections generally not recommended on primary thyroid tumors, particularly ones with preoperative cytology diagnoses of follicular patterned lesions, as diagnosis of these requires evaluation of the entire capsule

Microscopic (histologic) description

Tumor invades capsule or extends into adjacent thyroid tissue or has evidence of lymphovascular invasion
Nuclear features of papillary thyroid carcinoma:
- Size and shape: nuclear enlargement / overlapping / crowding, elongation
- Nuclear membrane irregularities: irregular contours, grooves, pseudoinclusions
- Chromatin characteristics: clearing with margination / glassy nuclei
Follicular growth pattern may be microfollicular, normofollicular or macrofollicular with abundant colloid

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and Rachel Jug, M.B.B.Ch., B.A.O.

Vesicular nuclei with irregular membranes

Evident major and minor diagnostic features

Dark colloid with frequent scalloping and clefting

Free floating of small tumor fragment in vascular lumen

Small piece of tumor floats in vascular lumen

Capsular invastion and extrathyroidal extension

Capsular invasion and extrathyroidal extension

Tumor plug is associated with thrombus

Overlapping, elongation and a single mitotic figure

Irregular nuclear contours, grooves, pseudoinclusions

Clear chromatin with margination

Cytology description

FNA samples are usually hypercellular with neoplastic cells containing nuclear features of papillary thyroid carcinoma arranged in microfollicles
Nuclear features are more subtle than conventional papillary thyroid carcinoma (Endocr Pathol 2014;25:257)
Colloid may be present
Cannot distinguish invasive EFVPTC from NIFTP on cytology, as cannot evaluate capsule on FNA

Cytology images

Contributed by Xiaoyin "Sara" Jiang, M.D.

Microfollicles and nuclear enlargement

Positive stains

TTF1, PAX8, thyroglobulin
HBME-1, CK19, Galectin3 (Cancer Sci 2011;102:288)

Negative stains

Calcitonin, parathyroid hormone
BRAF V600E not generally seen in EFVPTC (J Korean Med Sci 2018;33:e75)

Molecular / cytogenetics description

Shares molecular features (RAS type mutations) with follicular adenoma, follicular carcinoma (Mod Pathol 2010;23:1191)
Follicular variants of papillary thyroid carcinoma more commonly harbor RAS type mutations than classic variant of papillary thyroid carcinoma (more BRAF type mutations); however, invasive EFVPTC is associated with more BRAF type mutations than noninvasive EFVPTC (which is associated with more RAS type mutations) (Cell 2014;159:676, Mod Pathol 2010;23:1191)

Sample pathology report

Right lobe, partial thyroidectomy:
- Invasive encapsulated follicular variant of papillary thyroid carcinoma

Differential diagnosis

Encapsulated follicular variant of papillary thyroid carcinoma:
- Tumor lacks evidence of capsular or lymphovascular invasion
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features:
- Same nuclear features and follicular architecture but lacks vascular or tumor capsular invasion
Follicular carcinoma:
- Thyroid carcinoma with capsular or lymphovascular invasion, similarly composed of follicles but lacks papillary nuclear features
Follicular adenoma:
- Thyroid neoplasm without capsular or lymphovascular invasion, similarly composed of follicles but lacks papillary nuclear features

Additional references

Range: Practical Head and Neck Pathology - Frequently Asked Questions, 1st Edition, 2019, Asa: Survival Guide to Endocrine Pathology, 1st Edition, 2020

Board review style question #1

Which histological feature in the image above separates invasive encapsulated follicular variant of papillary thyroid carcinoma from noninvasive follicular thyroid neoplasm with papillary-like nuclear features?

Capsular invasion
Lymph node metastasis
Microfollicular growth pattern
Mitotic figures
Nuclear enlargement

Board review style answer #1

A. Capsular invasion

Comment Here

Reference: Invasive EFVPTC

Board review style question #2

Which of the following histologic descriptions meets the criteria for capsular invasion?

Bosselation on inner aspect of capsule
Follicles aligned parallel to capsule
Follicles aligned perpendicular to capsule
Tumor bud invading into but not through capsule
Tumor transgresses through and beyond outer contour of capsule

Board review style answer #2

E. Tumor transgresses through and beyond outer contour of capsule

Comment Here

Reference: Invasive EFVPTC

Langerhans cell histiocytosis

Table of Contents

Definition / general

Langerhans cell hystiocytosis (LCH) is a clonal neoplastic proliferation of langerin / CD1a / S100 positive dendritic cells (Langerhans-like cells)
- LCH cells initially thought to arise from the epidermal or mucosal derived Langerhans cell due to the morphologic, immunophenotypic and ultrastructural similarities; however, gene expression profiling showed that LCH cells are not derived from terminally differentiated Langerhans cells but rather share a closer kinship with dendritic cells of the bone marrow (Blood 2017;130:176)
Thyroid involvement is rare
- 100+ morphologically verified cases published as case series and case reports
Can occur as a primary disease or secondary involvement in systemic disease

Essential features

Rare histiocytic neoplasm with occasional involvement of thyroid, either a part of systemic dissemination or isolated
Proliferation of LCH cells (CD1a / S100 / langerin positive histiocytes with convoluted nuclei) on inflammatory, typically eosinophil rich background

Terminology

Not recommended / obsolete terminology:
- Morphological: eosinophilic granuloma; histiocytosis X
- Clinical: Hand-Schüller-Christian disease; Letterer-Siwe disease

ICD coding

ICD-O:
- 9751/1 - Langerhans cell histiocytosis, NOS
- 9751/3 - Langerhans cell histiocytosis, disseminated

Epidemiology

Isolated thyroid involvement is extremely rare
Secondary involvement is more common
LCH incidence: 5 - 9 per million children, 1 - 2 per million adults (Blood 2020;135:1319)
Age range: 2 months to 55 years
- Childhood onset and adult onset LCH
- Young age (< 20 years) at initial presentation in systemic disease, older age in isolated disease (Endocr Pathol 2002;13:227)
Slight male predilection (Br J Haematol 2016;174:887)

Sites

Thyroid involvement can be diffuse (59%) or nodular (25.8%) enlargement (Head Neck Pathol 2012;6:279)
Main target organs in systemic LCH are bone, skin, lung and pituitary (N Engl J Med 2018;379:856)

Pathophysiology

Not fully understood
More than half of LCH cases have MAPK pathway alterations: either BRAF V600E or MAP2K1 (MEK1) mutations (BMC Cancer 2019;19:170, Am J Surg Pathol 2014;38:548, Pediatr Blood Cancer 2015;62:173, Eur Respir J 2020;55:1901190)
- Constitutive activation of MAPK pathway results in continuous stimulation of cell proliferation and promotes cell survival
Hypothesis of underlying pathogenesis: interleukin 1 loop activation by Merkel cell polyomavirus infection (Cell Commun Signal 2015;13:13)
Triple risk factor model, including cytogenetic abnormality, stress and reaction (Cell Commun Signal 2018;16:49)

Etiology

Inflammatory myeloid neoplastic origin (Blood 2015;126:26, Adv Immunol 2013;120:127)
Frequent BRAF and MAP2K1 mutations in LCH support neoplastic origin (Blood 2014;124:867, Blood 2014;124:3007)
Findings suggesting inflammatory reactive origin
- Features of IL17A related inflammatory disease (Blood 2014;124:867)
- Identification of Merkel cell polyomavirus DNA in peripheral blood and tissues of LCH patients (Hum Pathol 2014;45:119)
Most cases are sporadic but variant SMAD6 has been associated with susceptibility to LCH (Blood 2020;135:1319)

Diagrams / tables

Images hosted on other servers:

Risk factor model

Clinical features

Diffuse enlargement or unilateral thyroid nodule
Commonly associated with Hashimoto thyroiditis
Presenting features of systemic LCH are variable and depend on the index organ involved: bone pain, fracture, skin rash, lymphadenopathy, diabetes insipidus and more (Blood 2020;135:1319)

Diagnosis

Fine needle aspiration cytology aided by immunostaining
- If immunocytochemistry is not available, immunostaining in suspicious cases can be performed on core needle biopsy
Histologic evaluation of surgical specimen, if surgery performed
History of systemic LCH in multiorgan disease

Laboratory

41% euthyroid, 20% hypothyroid (BMJ Case Rep 2014;2014:bcr2014206760)
Antithyroglobulin or antimicrosomal antibody (AMA) in cases associated with Hashimoto thyroiditis (Head Neck Pathol 2012;6:279)

Radiology description

Cold nodule on thyroid scan
Ultrasonography: heterogeneous or hypoechoic mixed density nodules (Int J Clin Exp Pathol 2014;7:1229)
- Nonspecific
Increased uptake on FDG-PET

Radiology images

Images hosted on other servers:

Ultrasound

MRI

FDG-PET

Prognostic factors

Excellent prognosis in rare cases with isolated thyroid disease
≥ 99% survival for unifocal (single organ) disease
Up to 20% mortality for patients with organ dysfunction (Blood 2020;135:1319)
66% mortality for young children with multisystem involvement who do not respond to therapy (J Pediatr 2001;138:728, Med Pediatr Oncol 2002;39:581, Med Pediatr Oncol 2001;37:108)
High risk factors: involvement of the bone marrow, liver, lung (Med Pediatr Oncol 2002;39:581, Med Pediatr Oncol 2001;37:108)
Patient age is less important than extent of disease (Med Pediatr Oncol 2002;39:581, Med Pediatr Oncol 2001;37:108)

Case reports

5 month old girl with isolated LCH of thyroid (Eur J Pediatr 2007;166:1151)
18 year old man with LCH goiter (Endocr J 2012;59:47)
19 year old woman with LCH involving thyroid and parathyroid (Mod Pathol 2001;14:111)
27 year old woman with thyroid LCH and papillary thyroid carcinoma involving cervical lymph nodes (Gland Surg 2016;5:537)
29 year old woman with thyroid involvement in systemic LCH with EBV infection (Head Neck Pathol 2020 Nov 2 [Epub ahead of print])
35 year old woman with thyroid LCH diagnosed on FNA cytology (Head Neck Pathol 2015;9:496)
36 year old woman with synchronous papillary thyroid carcinoma and LCH with BRAF mutation (BMC Cancer 2019;19:170)
41 year old man with systemic LCH involving endocrine organs (Medicine (Baltimore) 2018;97:e11215)
44 year old woman with solitary LCH of the thyroid (Head Neck Pathol 2012;6:279)

Treatment

Surgical excision for isolated disease
Combination chemotherapy for systemic disease (Head Neck Pathol 2012;6:279, N Engl J Med 2018;379:856)

Gross description

Focal of diffuse involvement
Variable sized nodules
Similar to other noncystic thyroid nodules

Microscopic (histologic) description

Nodular or diffuse proliferation of LCH cells
LCH cells characteristic of disease are histiocytoid cells recognized by their grooved, convoluted, indented or lobed nuclei (Arch Pathol Lab Med 2015;139:1211, Thyroid 2001;11:697, Mod Pathol 1996;9:145)
- Nuclear appearance is often described as resembling coffee beans, horseshoes or kidneys
- Nuclear atypia is absent or minimal
- Mitoses variable, not correlated with aggressiveness
- Cytoplasm is moderately abundant and slightly eosinophilic
- Unlike epidermal Langerhans cells, LCH cells are oval in shape and devoid of dendritic cell processes
Typical background includes eosinophils with a variable amount of neutrophils, lymphocytes and occasional multinucleated giant cells
- Rarely, eosinophilic abscesses may be formed
Temporal trend
- In early lesions, LCH cells predominate, along with eosinophils and neutrophils
- In late lesions, the LCH cells are decreased in number, with more foamy macrophages and increased fibrosis
- In most cases, at least some LCH cells can be found
Effacement of the surrounding thyroid parenchyma due to infiltration of thyroid follicles by LCH cells
Chronic lymphocytic thyroiditis is common
Neoplastic cells can extend beyond thyroid capsule and occasionally spread to cervical lymph nodes (Case Rep Pathol 2014;2014:184237)
Thyroid carcinoma may coexist and even collide with LCH (Endocr Pathol 2010;21:274, Case Rep Pathol 2014;2014:184237)

Microscopic (histologic) images

Contributed by Somboon Keelawat, M.D. and Jijgee Munkhdelger, M.D., Ph.D.

Discrete nodule

Eosinophils

Follicular stuffing

LCH cells

LCH cells and eosinophils

Langerin

CD1a

Thyroglobulin

Virtual slides

Images hosted on other servers:

Thyroid LCH

Cytology description

Variably cellular smears
Aggregates or isolated histiocytoid LCH cells with grooved / contorted nuclei and moderate amount of pale cytoplasm (Acta Cytol 2015;59:418)
Inflammatory background with variable amount of eosinophils (occasional Charcot-Leyden crystals), scattered small lymphocytes, foamy histiocytes and multinucleated giant cells (Acta Cytol 2013;57:406)
FNA samples lack follicular cells and background colloid (Acta Cytol 2017;61:96, Cancer Cytopathol 2021 Jan 25 [Epub ahead of print])

Cytology images

Images hosted on other servers:

FNA smear

S100 and CD1a

Positive stains

CD1a, S100, langerin (Blood 2001;97:1241, BMJ Case Rep 2014;2014:bcr2014206760)
- CD1a or combination CD1a / S100 is most commonly used
- Langerin (CD207) is a prototypic marker immunolocalized in Birbeck granules but less widely used
VE1 immunostaining (anti-BRAF V600E) correlates with the mutation status of BRAF (Am J Surg Pathol 2014;38:548)
Ki67 variable, of no significance

Negative stains

Thyroid specific: TTF1, PAX8, thyroglobulin
Cytokeratins
Most B cell and T cell lineage markers

Electron microscopy description

Birbeck granules are characteristic cytoplasmic inclusions (Blood 2020;135:1319)
- Rod to flask to tennis racket shaped
- 200 - 400 nm long x 33 nm wide
- Zipper-like appearance due to a median striated line
Electron microscopy is less often used today
- Replaced by immunostains
- Birbeck granules present in a variable percentage of LCH cells

Electron microscopy images

Images hosted on other servers:

Birbeck granules

Molecular / cytogenetics description

BRAF V600E mutation in about 50% (Am J Surg Pathol 2014;38:548, Hum Pathol (N Y) 2019;17:200302)
MAP2K1 (MEK1) in about half of remaining cases

Sample pathology report

Thyroid gland, total thyroidectomy:
- Histiocytic proliferation with eosinophil rich inflammatory background, consistent with Langerhans cell histiocytosis (see comment)
- Comment: The immunohistochemical stains are positive for CD1a / S100 and negative for thyroglobulin in the histiocytes. These findings support the above diagnosis. Clinical correlation (history, systemic involvement) is recommended.

Differential diagnosis

Other histiocytic disorders / Rosai-Dorfman disease:
- Prominent emperipolesis
- CD1a, langerin negative
Lymphocytic thyroiditis:
- No LCH cells, no eosinophils
Granulomatous thyroiditis:
- Well formed granulomas
- No LCH cells, no eosinophils
Lymphoma:
- Monotonous population of large atypical lymphoid cells
- Lymphoepithelial lesion
Anaplastic carcinoma:
- Greater degree of pleomorphism
- Necrosis
- No inflammatory background
Medullary thyroid carcinoma:
- Positive for calcitonin, CEA
Papillary thyroid carcinoma:
- Positive for cytokeratin, thyroglobulin, TTF1

Differential diagnosis of thyroid LCH
Entity	Potential pitfall	Morphological hallmark	IHC profile
Rosai-Dorfman disease	Histiocytic origin; S100+	Histiocytes with emperipolesis	CD1a-, CD207-
Lymphoma	Lymphocyte rich neoplasm	Monotonous proliferation of atypical lymphoid cells	B or T lineage markers+; CD1a-, CD207-
Papillary thyroid carcinoma	Grooved and indented nuclei; BRAF mutation	Papillary and follicular patterned epithelial tumor	TTF1 / Tg+; LCH immunophenotype-
Hashimoto thyroiditis	Lymphocyte rich background obscuring LCH cells	Lymphocytic infiltration	LCH immunophenotype-
Anaplastic thyroid carcinoma	Unusual morphology	Marked pleomorphism	LCH immunophenotype-

Additional references

Campo: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Edition, 2017, Nat Immunol 2020;21:1, Lancet 2021 Apr 23 [Epub ahead of print]

Board review style question #1

What is a widely used IHC marker for Langerhans cell histiocytosis?

CD1a
CD20
Cytokeratin
Thyroglobulin
TTF1

Board review style answer #1

A. CD1a

Comment Here

Reference: Langerhans cell histiocytosis

Board review style question #2

What is the most common molecular alteration in Langerhans cell histiocytosis?

BRAF V600E mutation
EGFR mutation
RAS family mutations
TERT promoter mutation
TP53 mutation

Board review style answer #2

A. BRAF V600E mutation

Comment Here

Reference: Langerhans cell histiocytosis

Lateral aberrant thyroid

Table of Contents

Definition / general

Outdated, imprecise term (Surgery 1993;114:1103); should not be used by pathologists
Term "lateral aberrant thyroid" has been known since 1779 (Eur Arch Otorhinolaryngol 2016;273:2867); today it is rarely found in surgical textbooks
Aberrant thyroid is a mass of tissue having the structure of a normal or pathological thyroid gland, but situated at some definite distance from the normal thyroid, with which it has no connection (Schrager, 1906, cited from Ann Surg 1942;115:161) - or, more strictly, lateral to the jugular vein (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)
Collective ("umbrella") term, largely represented by metastatic carcinoma or benign parasitic nodule
Conditions formerly called "lateral aberrant thyroid" are indicated below:
Malignant
- Nodal metastasis of thyroid carcinoma accounts for most of these cases; see also Thyroid inclusions in cervical lymph nodes
- Branchial cleft with thyroid cancer (BMJ Case Rep 2012;2012)
Benign
- Many cases are actually parasitic nodule
- True ectopic thyroid of lateral location is extremely rare compared to midline location
- Displaced thyroid tissue after trauma / surgery (Ann Diagn Pathol 2004;8:61)

Lymphoepithelial cyst

Table of Contents

Definition / general

Rare lesion which may arise from intrathyroidal remnants of branchial apparatus
Originally reported by Louis et al. in 1989 (Am J Surg Pathol 1989;13:45)
Branchial cleft remnants in thyroid become prominent in Hashimoto thyroiditis

Terminology

"Branchial cleft-like cyst": used for unusually located cervical lymphoepithelial cysts / branchial cleft cysts (i.e. not in soft tissue of anterolateral neck)
Also called branchial-like cleft cyst

Epidemiology

F:M = 2:1
Mainly adults (mean age 45 years, range 1 day to 73 years), 2 pediatric cases (see Case Reports section below)
< 40 cases published

Sites

Lateral thyroid
One case had unusual isthmic location (Thyroid 2010;20:111)

Pathophysiology / etiology

Most authors link the origin of thyroid lymphoepithelial cysts to solid cell nests, which are the remnants of the ultimobranchial body
The most likely mechanism is squamous metaplasia and cystic degeneration of solid cell nests of the thyroid (Pathol Res Pract 1997;193:777)
- This has been confirmed by CEA expression (Surg Today 2001;31:477)
The theory that intrathyroidal lymphoepithelial cysts arise from branchial remnants is supported by the occasional intrathyroidal presence of other branchial derived structures, such as thymic and parathyroid tissue (Arch Pathol Lab Med 2003;127:e205)
An association with chronic lymphocytic thyroiditis is strong; immunological mechanisms responsible for the autoimmune thyroiditis may act on metaplastic epithelium or ultimobranchial rests to form the cysts and may explain the associated lymphoid infiltrate (Hum Pathol 1994;25:1238)
Alternatively, lymphoid tissue may be attracted by the presence of solid cell nests rather than by a primary autoimmune thyroidal process, because of their endodermal origin and inherited ability to form lymphoepithelial lesions (Pathol Int 2006;56:150)

Clinical features

Either incidental finding of minimal clinical significance or presenting as a neck mass (Endo Pathol 1993;4:115, Hum Pathol 1994;25:1238)
Only a few cases (all pediatric) were not associated with concomitant thyroid disease, such as Hashimoto thyroiditis / chronic lymphocytic thyroiditis or nodular goiter
May coexist with thyroid cancer, but not related pathogenetically (Thyroid 2010;20:111)
Rarely causes hoarseness due to vocal cord palsy (Ann Acad Med Singapore 2010;39:68)

Diagnosis

Diagnosis occurs only after surgery (AJNR Am J Neuroradiol 2000;21:1340)
Workup includes radiological and pathological examination

Radiology description

TBS / total body scan: cold nodule(s), rarely a hot nodule (Am J Surg Pathol 1990;14:1165)
US: hypoechoic or echogenic with pseudosolid appearance (AJNR Am J Neuroradiol 2000;21:1340), rarely solid (J Clin Ultrasound 2006;34:298)
MRI: multiloculated cystic nodule

Case reports

Infant with intrathyroidal branchial cleft (Korean J Pediatr 2006;49:1005)
7 year old girl with intrathyroidal branchial cleft-like cyst with heterotopic salivary gland-type tissue (Pediatr Dev Pathol 2004;7:262)
36 year old woman with multiple branchial cleft-like cysts with Hashimoto thyroiditis (Endocr J 2000;47:303)
42 year old man with multilocular lymphoepithelial cyst in the thyroid accompanied by a minute thyroid carcinoma (Pathol Int 1995;45:965)
47 year old man with bilateral intrathyroidal lymphoepithelial cysts (Arch Pathol Lab Med 2003;127:251)
50 year old woman with eosinophilic replacement infiltrates in cystic Hashimoto thyroiditis (Endocr Pathol 2014;25:332)
50 year old man with branchial cleft-like cysts (Am J Otolaryngol 2006;27:146)
55 year old woman with lymphoepithelial cysts of the thyroid gland (Arch Pathol Lab Med 2003;127:e205)
54 year old woman with cytological features of a lymphoepithelial cyst (Soonchunhyang Med Sci 2014;20:131)
65 year old man with branchial-like cysts of the thyroid associated with solid cell nests (Pathol Int 2006;56:150)
Intrathyroidal lymphoepithelial cyst (Pathol Res Pract 1997;193:777)
Amyloid goiter associated with intrathyroid parathyroid and lymphoepithelial cyst (Endocr Pathol 2009;20:243)
Bilateral lymphoepithelial cysts of the thyroid gland (Thyroid 2010;20:111)

Treatment

Surgical excision of the cyst; radical thyroid removal is not recommended (Thyroid 2010;20:111)

Clinical images

Images hosted on other servers:

Sonogram and CT

Gross description

Lateral lobe(s) of the thyroid
Solitary / multiple unilocular or multilocular cysts, usually 1 - 2 cm (few mm to 5 cm)
Smooth external surface, 0.1 - 0.2 cm thick wall; light tan glistening lining with cobblestone appearance; clear or yellow viscous fluid (Am J Surg Pathol 1989;13:45)

Microscopic (histologic) description

The cyst structure is identical to branchial cleft cyst (Branchial pouch / cleft anomalies) composed of lymphoid tissue with germinal centers and squamous lining
Epithelial lining is attenuated stratified squamous (one or two cells to approximately seven cells in thickness) or focal respiratory-type epithelium with ciliated or goblet cells
- Focally can be denuded
- Cyst lumen contains keratin / mucin and debris with cholesterol clefts
Abundant adjacent lymphoid tissue, lymphoid follicles with prominent germinal centers common in cyst wall (Hum Pathol 1994;25:1238)
- Old cysts have a rim of fibrous tissue
No thyroid parenchyma within the cyst, may have entrapped follicles in the outer side of cystic wall
Signs of thyroiditis (often florid Hashimoto thyroiditis) in surrounding thyroid (Am J Surg Pathol 1989;13:45)
Solid cell nests, basaloid squamous nests and C cell hyperplasia often found in surrounding parenchyma (Am J Surg Pathol 1989;13:1072, Am J Surg Pathol 1990;14:1165)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Hashimoto thyroiditis with lymphoepithelial cyst

Lymphoepithelial cyst of thyroid

Images hosted on other servers:

H&E, p63, Ki67

Cytology description

Mature superficial squamous cells with intact nuclei, anucleate squames, clusters of neutrophils and lymphocytes, macrophages, amorphous debris in the background (AJNR Am J Neuroradiol 2000;21:1340)
Some cases yield solely lymphocytes (Endocr J 2000;47:303), squamous cells (Am J Otolaryngol 2006;27:146) or respiratory epithelium (J Clin Ultrasound 2006;34:298)

Cytology images

Images hosted on other servers:

FNA

Positive stains

Negative stains

Differential diagnosis

Intrathyroidal thyroglossal duct cyst: midline location, thyroid remnants in cyst wall, no germinal centers (Am J Surg Pathol 1989;13:45)
Cystic tumors:
- Papillary carcinoma
- Follicular carcinoma
- Follicular adenoma (Pathol Int 2000;50:897)
- Cystic goiter
- Cystic thymic remnants: basaloid cells with Hassall corpuscles (Arch Pathol Lab Med 2003;127:251)
- The distinction from branchial cleft cyst rests on the finding of respiratory-type epithelium (Arch Pathol Lab Med 2003;127:251)
Cytology:
- Hashimoto thyroiditis with squamous metaplasia
- Mucoepidermoid carcinoma
- Squamous cell carcinoma
- Warthin-like variant of papillary thyroid carcinoma (Soonchunhyang Med Sci 2014;20:131)

Lymphoma

Table of Contents

Definition / general

Comprises 2.5% of extranodal lymphoma and 4 - 5% of thyroid malignancies
Usually arise on top of Hashimoto thyroiditis or lymphocytic thyroiditis
Most are diffuse large B cell lymphoma, marginal zone B cell / MALT lymphoma or mixtures of these two
- Rarely follicular cell lymphoma
Hong Kong / Chinese cases are only rarely EBV+ (Am J Clin Pathol 1999;112:263)
Follicular lymphoma has two subgroups:
- t(14;18) or bcl2 overexpression, usually CD10+ and WHO grade 1-2
- No t(14;18) or bcl2 overexpression, often CD10- and WHO grade 3 (Am J Surg Pathol 2009;33:22, Mod Pathol 2005;18:1471)
Hodgkin lymphoma: very rare, favorable prognosis, female predominance (Neuroimaging Clin N Am 2003;13:371)

Epidemiology

75% women, usually adults or elderly (Am J Surg Pathol 2000;24:623)

Clinical features

Rapidly growing neck mass
Compression symptoms including dysphagia and hoarseness
Can present with diffuse thyroid enlargement
May be accidentally discovered
Hypothyroid manifestations may develop
Cold nodule
Virtually all primary thyroid lymphomas are MALT-type arising after 20 - 30 years of lymphocytic thyroiditis in older patients (mean age 64 years)
Sequence similarity in clonal IgH bands suggests lymphoma may arise from thyroiditis (J Clin Pathol 2008;61:438)
Secondary involvement seen in 20% dying of generalized lymphoma, although usually does not produce clinical hypothyroidism
Regional lymph node enlargement can be seen
Hodgkin lymphoma: thyroid mass, cervical lymphadenopathy, patient is euthyroid but may be hypothyroid

Prognostic factors

Overall 5 year survival is 80%
Poor prognostic factors: diffuse B cell lymphoma subtype, perithyroidal soft tissue invasion, stage 2E or higher
Good prognostic factors: marginal zone lymphoma subtype or stage IE

Case reports

19 year old woman with syncytial variant of nodular sclerosing Hodgkin lymphoma (Acta Cytol 1995;39:543)
22 and 29 year old women with thyroid nodule as a first manifestation of Hodgkin lymphoma (Diagn Pathol 2013;8:116)
32 year old man with primary T cell lymphoma of thyroid (Med Oncol 2008;25:462)
37 year old woman with nodular sclerosing Hodgkin lymphoma (Ann Endocrinol (Paris) 2012;73:492)
48 year old woman with primary thyroid lymphoma (Diagn Cytopathol 2012;40:444)
54 year old man with primary mediastinal large B cell lymphoma (Int J Clin Exp Pathol 2015;8:5944)
62 year old woman with Hodgkin lymphoma presenting as abscess in thyroid gland (Indian J Pathol Microbiol 2012;55:122)
65 year old woman with thyroid MALT lymphoma (Ann Thorac Surg 2015;100:700)
70 year old man with diffuse large B cell lymphoma of thyroid (Cytojournal 2006;3:23)

Treatment

Often curable by radiation or chemotherapy (particularly MALT), in contrast to anaplastic carcinoma
Surgery is rare (Eur J Surg Oncol 2008;34:576)

Gross description

Variable sized, rubbery / soft mass
White cut surface with fish flesh appearance
Necrosis could be found

Gross images

AFIP images

Diffuse large cell lymphoma: fish flesh cut surface

Hodgkin lymphoma:
nodular sclerosing
subtype

Microscopic (histologic) description

Varies by histologic type
Diffuse large B cell lymphoma:
- Diffuse infiltrate destroying thyroid follicles
- Large cells with moderate amphophilic cytoplasm, vesicular nuclei, prominent nucleoli
- Bizarre cells may be seen
MALT lymphoma:
- Infiltration of thyroid epithelium creates lymphoepithelial lesions (lymphocytes "stuff" glandular lumina, Arch Pathol Lab Med 2007;131:1673)
- May have background lymphocytic thyroiditis
Follicular lymphoma:
- Usually prominent follicular pattern with prominent interfollicular neoplastic infiltrate, lymphoepithelial lesions are common
- May arise on top of thyroiditis

Microscopic (histologic) images

Contributed by Mark R. Wick, M.D.

Large cell type, reticulin stain

AFIP images

Diffuse large B cell lymphoma:

Tumor cells

Follicle in lower right

Fibrous bands

Tumor cells are CD45 (LCA)+

Keratin, thyroglobulin

Hodgkin lymphoma:

Nodular sclerosing subtype

Follicular lymphoma:

Residual thyroid follicles

Images hosted on other servers:

Large pleomorphic cells

Hodgkin lymphoma: nodular sclerosis type

Hodgkin lymphoma: CD30+

Follicular lymphoma: morphology

Follicular lymphoma: negative for bcl2 and IGH-BCL2

Follicular lymphoma: positive for bcl2 and IGH-BCL2

Cytology description

Monotonous population of large atypical lymphoid cells (scant cytoplasm, finely granular chromatin, prominent nucleoli), lymphoglandular bodies present (cytoplasmic fragmentation), karyorrhexis (Cytojournal 2005;2:21)
MALT features: see Acta Cytol 2015;59:26
May be misdiagnosed as lymphocytic thyroiditis
Hodgkin lymphoma: some atypical cells, may have marked fibrosis

Cytology images

Contributed by Ayana Suzuki, C.T. and Mark R. Wick, M.D.

DLBCL

Large cell type

Images hosted on other servers:

Intermediate grade lymphoma

MALT lymphoma

Hodgkin lymphoma: Reed-Sternberg cell

Diffuse large B cell lymphoma:

Large and irregular lymphoid cells

Misdiagnosed as anaplastic carcinoma

High grade lymphoma

CD45 / LCA+, CD20+, keratin-

Positive stains

CD20 and keratin highlight lymphoepithelial lesions
Thyroglobulin stains entrapped follicular epithelium
Also CD45

Molecular / cytogenetics description

t(11;18) is not present in thyroid MALT lymphomas (Mod Pathol 2006;19:1578)

Differential diagnosis

Anaplastic carcinoma
Insular carcinoma
Small cell variant of medullary carcinoma
Thyroiditis (Hashimoto or lymphocytic):
- Diagnosis of lymphoma is supported by the presence of a dense clonal proliferation of lymphoid cells, lymphoepithelial lesions and CD20 positivity (Acta Cytol 2012;56:352)
Undifferentiated carcinoma (Eur Radiol 2016;26:1031)

Additional references

Mod Pathol 2005;18:1577, eMedicine: Thyroid Lymphoma [Accessed 31 July 2018]

Lysosomal storage diseases

Table of Contents

Definition / general

Lysosomal storage disease (LSD) is a subgroup of inherited metabolic disorders, caused by mutations in genes encoding lysosomal enzymes, which results in cell damage due to excessive storage of undegraded substrates
Main target organ / systems are nervous, muscular, reticuloendothelial and liver
Thyroid involvement is uncommon
Major LSDs were first described in the late 19th (Tay-Sachs, Gaucher and Fabry diseases) and early 20th centuries (Niemann-Pick and Pompe diseases); however the lysosomal concept was developed only in the 1960s (Pediatr Endocrinol Rev 2013;11:59)

Terminology

Synonyms: lysosomal storage disease / disorder, lysosomal disease, thesaurismosis, storage disease
Broader category of inherited metabolic disorders is equivalent to metabolic storage disorder or inborn errors of metabolism (Ann Endocrinol (Paris) 2009;70:14)
Approximately 50 diseases are included in the LSD group, similar to the number of different enzymes within a lysosome
Almost all names are eponymous
Classification is based on the nature of the primary accumulated material:
- Lipid storage diseases, including sphingolipidoses (Fabry, Gaucher, Niemann-Pick) and gangliosidosis (Tay-Sachs)
- Mucopolysacharidoses (Hunter, Hurler, Morquio)
- Glycoproteinoses
- Mucolipidoses
- Glycogen storage disease (Pompe)
- Cystinosis

Epidemiology

Although individual LSDs are rare, the aggregate prevalence is 1:5,000 births, which is comparable to that of the most common genetic diseases (Nat Rev Neurol 2013;9:583)
LSDs are the second most common group of inborn errors of metabolism (1:1,500 births) after small molecule diseases, e.g. phenylketonuria and galactosemia (Pediatrics 2000;105:e10)
Some LSDs have ethnic or geographical predilections (Madame Curie Bioscience Database: Lysosomal Storage Disorders [Accessed 30 October 2017]):
- Ashkenazi Jews: Tay-Sachs and Gaucher disease
- French Canadian: Tay-Sachs
- Finnish: aspartylglucosaminuria and Salla disease
- Russian: Hurler syndrome

Sites

Distribution of affected organs in LSDs is dependent on the nature of the substrates that accumulate and their specific cellular distribution, as well as the cell turnover rate in each tissue (Nat Rev Neurol 2013;9:583):
- Sphingolipids: brain and nerves
- Mucopolysaccharides: cardiovascular system and connective tissue, including bones
- Glycogen: muscles
- Cystine: kidney

Pathophysiology / etiology

LSDs are caused by mutations in genes encoding soluble acidic hydrolases, activator proteins, transporter proteins, integral membrane proteins or nonlysosomal proteins that are necessary for lysosomal function (Annu Rev Med 2015;66:471)
Main genes in LSDs: glucosylceramidase beta / GBA (Gaucher), galactosidase alpha / GLA (Fabry), sphingomyelin phosphodiesterase 1 / SMPD1 (Niemann-Pick), hexosaminidase subunit alpha / HEXA (Tay-Sachs), iduronate 2-sulfatase / IDS (Hunter), glucosidase alpha, acid / GAA (Pompe), cystinosin, lysosomal cystine transporter / CTNS (cystinosis)
As a result, metabolic machinery of the cell is impaired by defects in degradative and synthetic enzymes, lysosomal membrane defects, disorders of lysosome biogenesis and endosome lysosome traffic
Pathogenetic cascade leads to intralysosomal accumulation of undegraded substrates in multiple tissues and organs
Excessive storage of a substrate triggers cell damage via several mechanisms: activation of apoptosis, alterations of plasma membrane lipid content (affect receptor responses and downstream signaling), prolonged inflammation, calcium imbalance, dysregulation of autophagy, etc. (Nat Rev Neurol 2013;9:583)
All LSDs are inherited in an autosomal recessive manner, except X linked recessive Fabry, Hunter and Danon diseases
Severity and age of onset in LSDs depend on a range of factors: residual enzyme activity (20% is still enough for normal function), mutant protein size, location of the mutation with respect to catalytic site, distribution of tissue specific and cell specific substrates, cell turnover rate, defective protein expression and other mechanisms that influence the life span of the affected cells (Nat Rev Neurol 2013;9:583)

Diagrams / tables

Images hosted on other servers:

Classification

Clinical features

In LSDs, buildup of material may begin in utero; disease progressively evolves over time, often becoming evident during the newborn period (i.e. infantile form)
Up to 15% of nonimmune hydrops fetalis are due to LSD (Stocker: Stocker and Dehner's Pediatric Pathology, 3rd Edition, 2010)
Presence of residual enzyme activity can result in mild and late onset forms, i.e. juvenile and adult variants (Madame Curie Bioscience Database: Lysosomal Storage Disorders [Accessed 30 October 2017])
Involvement of multiple organs and systems is typical, with variable association of visceral, ocular, hematological, skeletal and neurological manifestations and there is partial phenotypic overlap among different disorders (Nat Rev Neurol 2013;9:583)
About two thirds of patients with LSDs display a significant neurological component, which ranges from progressive neurodegeneration and severe cognitive impairment to epileptic, behavioral and psychiatric disorders (Annu Rev Med 2015;66:471)
Abnormal thyroid function is mainly represented by primary hypothyroidism (Orphanet J Rare Dis 2012;7:11):
- Hypothyroidism due to cystine accumulation in follicles occurs in 50 - 75% of patients with cystinosis, both children and adults (JAMA 1993;270:2200, Orphanet J Rare Dis 2016;11:47)
- Frequent subclinical hypothyroidism was recently reported in Fabry disease (J Inherit Metab Dis 2005;28:715)

Diagnosis

Current guidelines recommend that diagnosis must be established by specific enzyme assays and by mutational analysis (Genet Med 2011;13:457)
Early detection of LSDs via genetic screening programs, prenatal diagnosis and screening of newborns in at risk families has major impact for the long term course and outcome of the disease (National Organization for Rare Disorders: Lysosomal Storage Disorders [Accessed 30 October 2017])

Laboratory

Accumulated substrate can be detected in various clinical samples, such as urine, blood, amniotic fluid and tissue biopsies (Khong: Keeling's Fetal and Neonatal Pathology, 5th Edition, 2015)
Lysosomal enzyme activities are usually determined by a fluorometric assay in cultured fibroblasts and leukocytes (Mehta: Fabry Disease - Perspectives from 5 Years of FOS, 2006)

Radiology images

Images hosted on other servers:

Skeletal deformities in mucopoly-saccharidoses

Prognostic factors

Most early onset (diagnosed in infants) LSDs have a rather predictable clinical course, when neurologic deterioration continues until the death of the child within 5 - 10 years, usually by infection
Predicting the clinical course in later onset patients, especially adolescents and adults, is nearly impossible (Arch Neurol 2003;60:322)

Case reports

Sphingolipidoses
- 20 year old woman with Gaucher disease and symptoms suspicious for thyroid carcinoma (Pol Arch Med Wewn 1998;100:337)
- 48 year old woman with hypothyroidism in Fabry disease (Intern Med 1994;33:172)
- Two patients with thyroid peroxidase deficiency in Batten disease (Arch Pathol 1975;99:430)
- Two patients with Gaucher disease and papillary thyroid cancer (Am J Hematol 2010;85:340)
Mucopolysacharidoses
- 19 year old man with Hunter syndrome and thyroid deposits (Acta Pathol Jpn 1976;26:115)
- 20 year old man with thyroid cell vacuolation in Morquio A syndrome (Mol Genet Metab 2013;109:301)
Glycogenoses
- Two infants with Pompe disease (Arch Pathol Lab Med 1985;109:921)
- Two 15 month old girls with minimal thyroid inclusions in Pompe disease (Am J Dis Child 1964;108:503)
- Family case with Pompe disease and thyroxine binding globulin deficiency (Funct Neurol 1996;11:105)
Cystinosis
- 23 year old man with cystinosis and atrophic thyroid (Acta Pathol Jpn 1985;35:145)
- 23 year old man with cystinotic kidney transplant and hyperthyroidism after radiotherapy for Hodgkin lymphoma (Pediatr Transplant 2011;15:e56)

Treatment

There is no cure for most LSDs; symptomatic treatment is usually provided by a multidisciplinary team (neurologic, orthopedic, cardiologic, etc.)
Early diagnosis with prompt initiation of presymptomatic therapy for defective soluble enzymes in the neonatal period or as early as possible can improve outcome (Nat Rev Neurol 2013;9:583)
Cystinosis is treated with cysteamine, which reduces intracellular cystine
Enzyme replacement therapy is a promising treatment; normal enzyme can be provided by intravenous injection or as a precursor secreted into the circulation by engineered cells from the patient or by an allograft of transplanted cells (Annu Rev Med 2015;66:471)
Other advanced treatment strategies: stem cell therapies, substrate reduction and chaperone mediated delivery (Nat Rev Neurol 2013;9:583)

Clinical images

Images hosted on other servers:

Skeletal deformities in mucopolysaccharidoses

Gross description

Unremarkable thyroid gland
In cystinosis thyroid may be atrophied (Acta Pathol Jpn 1985;35:145), occasionally to degree when it cannot be identified (Am J Med 1970;48:678)

Microscopic (histologic) description

LSDs are characterized by progressive intracellular (rarely extracellular, e.g. mucopolysacharidoses) accumulation of a substrate
Most prominent thyroid abnormalities are observed in cystinosis (Am J Med 1970;48:678, J Pediatr 1977;91:204):
- Destruction and infiltration of thyroid epithelial cells by cystine crystals
- Focal areas of papillary hyperplasia with dilated follicles and focal acute inflammation
- Follicular atrophy with fibrosis and decreased amounts of colloid
- Frozen sections show abundance of birefringent crystals within follicular cells and macrophages but these are usually lost in fixed tissue sections; to preserve crystals, specimens should be fixed in absolute alcohol, not formalin, otherwise cystine may dissolve
Minor changes represented by intracellular deposits are found in thyroid in other LSDs:
- Tay-Sachs: follicular epithelial cells contain yellow, autofluorescent pigmented granules with lipofuscin (Am J Dis Child 1964;108:503)
- Batten: lipofuscin deposits (Lancet 1970;2:296)
- Hunter: cytoplasmic vacuolation (Acta Pathol Jpn 1976;26:115)
- Morquio: vacuolation of follicular and parafollicular cells (Mol Genet Metab 2013;109:301)
- Pompe: intralysosomal glycogen (Arch Pathol Lab Med 1985;109:921)

Microscopic (histologic) images

Case #164

Liver biopsy in Gaucher disease (H&E, PAS)

Images hosted on other servers:

Hepatic glycogenosis (H&E, PAS, Masson)

Niemann-Pick disease (hepatic steatosis)

Virtual slides

Images hosted on other servers:

Niemann-Pick disease (liver biopsy)

Cytology images

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Gaucher cell in bone marrow

Peripheral smear description

Presence of vacuolated lymphocytes is a simple screening test for storage disorders (Gilbert-Barness: Potter's Pathology of the Fetus, Infant and Child, 2nd Edition, 2007)

Positive stains

Accumulated substrates can be confirmed by histochemistry, e.g. PAS stain for glycogen and lipofuscin (Stocker: Stocker and Dehner's Pediatric Pathology, 3rd Edition, 2010)

Negative stains

CD107b helps to differentiate cardiomyopathy due to Danon disease

Electron microscopy description

Cystinosis: numerous square, rectangular or lozenge shaped cystine crystals in the cytoplasm of foam cells, with smaller crystals located within osmiophilic dense bodies (Acta Pathol Jpn 1985;35:145)
Hunter: clear cytoplasmic inclusion bodies containing various amounts of flocculent material representing glycosaminoglycans (Acta Pathol Jpn 1988;38:1175)
Tay-Sachs: osmophilic deposits in cytoplasm of follicular cells is seen in brain, muscle, other tissues (Lab Invest 1974;30:102)
Ultrastructural studies may be used as a screening tool or if a storage disease is suspected (Stocker: Stocker and Dehner's Pediatric Pathology, 3rd Edition, 2010)

Electron microscopy images

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Lamellated "zebra" bodies in Fabry disease (fig 10)

Leukocyte in mannosidosis

Videos

Histopathology of glycogen storage disease (heart, liver)

Primer in inherited metabolic disorders (2013)

Mechanism of LSDs (2014)

Lecture series on LSDs by Excellence in Pediatrics Institute (2014 - 2016)

Additional references

Macrofollicular

Table of Contents

Definition / general

Macrofollicles (large dilated follicles) > 50% of cross sectional area, with papillary nuclear features
Very rare; similar clinical features as classic papillary carcinoma (female predominant, occasional nodal metastases, few deaths)
May have minor (< 5%) insular component that does not appear to affect prognosis (Cancer 1997;80:1110)

Gross description

Mean 3 cm, often encapsulated

Microscopic (histologic) description

Frequent macrofollicles (> 50% of cross sectional area) and foci of follicular variant of papillary carcinoma, all with prominent, large ground glass nuclei and nuclear grooves (Hum Pathol 1991;22:1195)
Also cells with large but less pale nuclei with stippled chromatin, or cuboidal cells with hyperchromatic nuclei

Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D.

Nodal metastasis, macrofollicular variant PTC

Cytology description

Moderate to highly cellular with micro- and macrofollicles with thick colloid
Papillary nuclear changes often absent or focal
May resemble goiter (Diagn Cytopathol 2007;35:560, Cancer 1998;84:235)

Differential diagnosis

Follicular adenoma: lined by flat epithelial cells with hyperchromatic nuclei
Nodular hyperplasia

Malakoplakia

Table of Contents

Definition / general

Rare chronic inflammatory / granulomatous disease that most commonly affects genitourinary tract (see topics in Bladder, Kidney, Prostate, Testis chapters)
Usually in immunocompromised adult women due to inadequate phagocytosis / degradation of gram negative bacteria by macrophages
Microscopic hallmarks are Hansemann cells and Michaelis-Gutmann bodies (see "Micro description" below)

Terminology

Malakoplakia (or malacoplakia) = Greek "malakos" (soft) + "plakos" (plaque)

Epidemiology

< 10 cases of thyroid involvement have been reported, all in women (see below)

Clinical features

Difficulty swallowing, fever, asymmetrical enlargement of the gland and destruction of surrounding tissues (nonspecific)
Diagnosis only after surgical excision

Radiology description

Ultrasound: solid nodule
I-131 scan: low uptake

Case reports

50, 54 and 60 year old women (Am J Clin Pathol 1989;92:813, Int J Surg Pathol 2015;23:308, Acta Cytol 1996;40:970)
64 year old woman with malacoplakia manifesting as a chronic inflammatory mass (Ear Nose Throat J 2003;82:876)
72 year old woman with thyroid gland malakoplakia with autoimmune thyroiditis (Histopathology 1993;23:491)

Treatment

Antibiotics (quinolones, rifampicin and trimethoprim-sulfamethoxazole)
Mass excision

Gross description

Unencapsulated nodule several cm in diameter, yellow to white, usually soft

Microscopic (histologic) description

Sheets of histiocytes with eosinophilic granular cytoplasm containing characteristic basophilic or PAS+ diastase resistant inclusions / bodies loaded with calcium, iron and bacterial debris (Hanseman cells)
Michaelis-Gutmann bodies (calcospherites) are round laminated mineralized concretions, 1 - 10 microns, intra- or extracellular; may be targetoid, with a dense central crystalline core
Inflammatory (neutrophils, plasma cells, lymphocytes and granulation tissue) to fibrotic background

Microscopic (histologic) images

Images hosted on other servers:

Malakoplakia (arrows at Michaelis-Gutmann bodies), bladder

Michaelis-Gutmann
bodies; von Kossa
calcium stain

Cytology description

Numerous histiocytes with abundant eosinophilic granular cytoplasm containing basophilic inclusions (4 - 10 microns) consistent with Michaelis-Gutmann bodies (Acta Cytol 1996;40:970)
The background contains similar round basophilic bodies, blood and inflammatory cells (Int J Surg Pathol 2015;23:308)

Positive stains

Inclusions: calcium (von Kossa), iron (Prussian blue), PAS+ diastase resistant
CD68 for macrophages contained inclusions

Electron microscopy description

Macrophages with numerous phagolysosomes packed with undigested bacteria
Concentric crystalline laminations with dense inner zone containing calcium salts crystals and thin outer zone of amorphous granular material (Histopathology 1993;23:491)

Differential diagnosis

Malignancy of thyroid or neck organs

Additional references

eMedicine - Malakoplakia, Atlas of Granulomatous Diseases - Malakoplakia

Malignant

Table of Contents

Definition / general

Bethesda category VI malignant is used when cytologic features strongly suggest malignancy (Thyroid 2017;27:1341)

Essential features

Used when cytology is strongly suggesting malignancy
Frequency 5 - 10%, resection rate 65 - 78%, risk of malignancy 99% (when noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP] is included in malignant) or 94 - 96% (NIFTP is excluded from malignant)
Most common histological diagnosis is papillary thyroid carcinoma (PTC)

Clinical features

Meta analysis data (Cancer Cytopathol 2020;128:238)
- Frequency: 7.4% (5.4 - 9.3%)
- Resection rate: 72.1% (65.3 - 77.9%)
- Risk of malignancy: 99% when NIFTP is included in malignant, 94 - 96% when NIFTP is excluded from malignant (Ali: Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2018)

Diagnosis

Includes the following malignancies: papillary thyroid carcinoma, poorly differentiated thyroid carcinoma, anaplastic thyroid carcinoma, medullary thyroid carcinoma, lymphoma, intrathyroid thymic carcinoma, mucoepidermoid carcinoma, squamous cell carcinoma and metastatic carcinoma to the thyroid
- Follicular thyroid carcinoma does not belong to this category (usually Bethesda category IV)
- A few cases of NIFTP, a nonmalignant thyroid tumor, may reside in this category, owing to nuclear features of papillary thyroid carcinoma (Endocr Pract 2019;25:491)
If interpreted as malignant, it is implied that the sample is adequate for evaluation irrespective of quantitative criteria of adequacy
Mention the subtype, if identified

Case reports

Primary malignancies:
- 41 year old man with primary thyroid diffuse large B cell lymphoma coexistent with papillary thyroid carcinoma (Head Neck 2015;37:E109)
- 42 year old woman with poorly differentiated carcinoma of the thyroid (J Cancer Res Ther 2018;14:1142)
- 61 year old woman with synchronous papillary thyroid carcinoma and breast ductal carcinoma (Medicine (Baltimore) 2017;96:e6114)
- 62 year old woman with primary squamous cell carcinoma of the thyroid (Rom J Morphol Embryol 2016;57:831)
- 66 year old woman with anaplastic thyroid carcinoma with rapid thyrotoxicosis (Endokrynol Pol 2018;69:28)
- 74 year old man with mucinous carcinoma of the thyroid (Ann Endocrinol (Paris) 2017;78:70)
Metastatic malignancies:
- 53 year old man with metastasis of colon cancer to medullary thyroid carcinoma (J Korean Med Sci 2014;29:1432)
- 55 year old man with thyroid metastasis from small cell lung carcinoma (J Med Case Rep 2015;9:231)
- 62 year old woman with breast cancer metastases to the thyroid gland (J Med Case Rep 2017;11:269)
- 68 year old man with thyroid metastasis from p16+ oropharyngeal squamous cell carcinoma (Endocr J 2018;65:479)

Treatment

Usual management is total thyroidectomy or lobectomy (Clin Endocrinol (Oxf) 2014;81:1)
For nodules indicating metastatic tumor rather than a primary thyroid malignancy, surgery may not be indicated
Papillary thyroid carcinoma:
- Extent of surgery (lobectomy versus total thyroidectomy) depends on the patient's age, overall health status and the size and sonographic characteristics of the tumor
- For low risk cases (≤ 1 cm, without extrathyroidal extension and clinical metastasis), active surveillance is an option (Thyroid 2018;28:23)
Medullary thyroid carcinoma:
- Serum calcitonin level and genetic testing for germline RET mutations are performed (Endocr J 2017;64:1099, Thyroid 2015;25:567)
- Surgical treatment is usually total thyroidectomy with neck dissection
Poorly differentiated thyroid carcinoma:
- If no distant metastasis, external beam radiotherapy in addition to surgery is recommended
Anaplastic thyroid carcinoma:
- Complete surgical resection, with or without preoperative hyperfractionated radiotherapy or chemotherapy (Nat Rev Endocrinol 2017;13:644)
- If potentially incurable, surgery is combined with postoperative radiation or chemotherapy
Lymphoma:
- Combined modality therapy (2 or more of surgery, radiotherapy and chemotherapy)

Cytology description

Papillary thyroid carcinoma (PTC):
- Arrangement: papillae, monolayers, cellular swirls (Acta Cytol 2010;54:939)
- Cytoplasm: hobnail cells, oncocytic metaplasia, squamoid metaplasia, histiocytoid cells
- Nuclei:
  - Enlarged, crowded, molded, oval or irregularly shaped
  - Longitudinal grooves, pseudoinclusions
  - Pale nuclei with powdery chromatin, thick nuclear membranes, marginally placed micronucleoli
- Background: psammoma bodies, multinucleated giant cells, ropy colloid
- Liquid based cytology specimens: convoluted nuclei, eosinophilic nucleoli, perinucleolar halo, intercellular spaces (Diagn Cytopathol 2015;43:108)
- PTC variants:
  - Follicular variant and NIFTP: small to medium sized follicles lined by cells with variable nuclear features of PTC, absence of papillary fragments, multinucleated giant cells, pseudoinclusions, psammoma bodies and marked cystic change
  - Cystic variant: sheets, papillae, follicles, ball-like clusters, septate intracytoplasmic vacuoles, histiocytoid cells, macrophages
  - Oncocytic variant: oncocytic cells arranged in papillae, sheets, microfollicles, diagnostic nuclear changes of PTC
  - Warthin-like variant: oncocytic cells arranged in papillae, lymphoplasmacytic background, nuclear changes of PTC
  - Tall cell variant: polygonal with centrally located nuclei but can be elongated and cylindrical with an eccentrically placed nucleus (tail-like cells or tadpole cells), granular cytoplasm with prominent cytoplasmic borders, nuclear changes of PTC
  - Columnar cell variant: lacking colloid, arranged as papillae, clusters and flat sheets, small tubular structures, elongated and pseudostratified nuclei, hyperchromatic, nuclear features of PTC are much less prominent
  - Solid variant: lack colloid, appear as cohesive, syncytial type 3 dimensional tissue fragments, microfollicles / trabeculae, discohesive, single cells, typical nuclear features of PTC, scant true papillae
  - Diffuse sclerosing variant: scant or absent colloid, arranged in 3 dimensional ball-like clusters and cohesive clusters intermingled with inflammatory cells
  - Cribriform morular variant: absent colloid, tall, columnar cells having papillary arrangement, round to oval slit-like empty spaces formed by spindle to ovoid cells within cell clusters (cribriform pattern), cell clusters with eddy formation (morules), pale staining nuclei with thickened nuclear membranes (peculiar nuclear clearing), nuclear grooves, pseudoinclusions, hyaline material within cell clusters, absence of psammoma bodies and multinucleated giant cells, positive for β catenin (nuclear and cytoplasmic), estrogen receptor, progesterone receptor
  - Hobnail variant: loss of polarity and cohesiveness, single cells with eccentric nuclei and tapering cytoplasm (comet-like or teardrop-like cells), apically or eccentrically placed nucleus (hobnail features) in papillary or micropapillary clusters, multiple soap bubble-like pseudoinclusions, typical nuclear features of PTC
Medullary thyroid carcinoma:
- Arrangement: numerous isolated cells, weakly cohesive clusters
- Cell shape: plasmacytoid, polygonal, round or spindle shaped, long cell processes, bizarre giant cells
- Cytoplasm: granular, small red-purple granules (Romanowsky stains)
- Nuclei: round, oval, elongated, eccentrically placed, finely or coarsely granular (salt and pepper) chromatin, binucleation or multinucleation
- Background: amyloid
- Immunostaining:
  - Positive: calcitonin, CEA, neuroendocrine markers (chromogranin, synaptophysin) and TTF1
  - Negative: PAX8 and thyroglobulin
- Measurement of calcitonin levels in needle washout fluid can be helpful (Endocr J 2017;64:1099)
Poorly differentiated thyroid carcinoma (Cancer Cytopathol 2015;123:82):
- Arrangement: insular, solid or trabecular pattern
- Nuclei: high nuclear/cytoplasmic (N/C) ratio with variable nuclear atypia
- Background: scant colloid, apoptosis and mitotic activity, necrosis
Anaplastic thyroid carcinoma:
- Arrangement: isolated cells or in variably sized groups
- Cell shape: epithelioid, spindle shaped, range in size, could be plasmacytoid, rhabdoid
- Nuclei: enlargement, irregularity, extreme pleomorphism, mitotic figures, multinucleation
- Background: necrosis, extensive inflammation, sometimes osteoclast-like giant cells
- Immunostaining:
  - Positive: pankeratins, PAX8, vimentin (focal)
  - Negative: TTF1, thyroglobulin (Hum Pathol 2018;82:140)
Lymphoma:
- Arrangement: discohesive round to slightly oval cells
- Cell shape: twice the size of a small mature lymphocyte (marginal zone lymphoma), moderate to abundant basophilic cytoplasm (diffuse large B cell lymphoma)
- Nuclei:
  - Vesicular chromatin, small nucleoli (marginal zone lymphoma)
  - Coarse chromatin with 1 or more prominent nucleoli (diffuse large B cell lymphoma)
  - Reed-Sternberg cells, plasma cells, eosinophils, histiocytes, fibroblasts and capillaries (Hodgkin lymphoma)
- Liquid based cytology specimens: large nuclei, elongated nuclei, degenerative nuclei (specific) (Acta Cytol 2018;62:93)
Squamous cell carcinoma:
- Composed exclusively of large, pleomorphic keratinized cells
Metastatic renal cell carcinoma:
- Arrangement: dispersed individually and in small clusters, fragmented papillae, sheets
- Cytoplasm: abundant pale, finely granular, clear, vacuolated
- Nuclei: round to oval, large nucleoli
- Background: bloody

Cytology images

Contributed by Ayana Suzuki, C.T., Andrey Bychkov, M.D., Ph.D.

Papillary thyroid carcinoma

Medullary thyroid carcinoma

Poorly differentiated thyroid carcinoma

Anaplastic thyroid carcinoma

Primary thyroid lymphoma

Videos

Thyroid cytopathology

Sample pathology report

Dx / category: malignant
- Papillary thyroid carcinoma, favor tall cell variant
Dx / category: malignant
- Medullary thyroid carcinoma
- The malignant cells are positive for calcitonin.
Dx / category: malignant
- Poorly differentiated thyroid carcinoma
- Highly cellular aspirate with atypical follicular cells, necrosis and scant colloid, most consistent with poorly differentiated thyroid carcinoma.

Differential diagnosis

Nodular goiter:
- Monolayered sheet-like cluster may mimic papillary thyroid carcinoma (PTC); however, no PTC nuclear features are seen
Hyalinizing trabecular tumor:
- Nuclear grooves and abundant nuclear pseudoinclusions resemble PTC; however, hyaline material inside the clusters and yellow bodies are specific for this low risk neoplasm
Chronic thyroiditis:
- Nuclear changes of follicular cells with focal enlargement, grooves, prominent nucleoli and chromatin clearing mimic PTC; however, no PTC nuclear features are seen
Benign cyst:
- Histiocytes with septate intracytoplasmic vacuoles so-called histiocytoid cells may mimic PTC; however, no PTC nuclear features are seen (Diagn Cytopathol 2003;29:243)
Hürthle cell (oncocytic) neoplasms:
- Discohesive cells with abundant granular cytoplasm resembles medullary thyroid carcinoma; however, no salt and pepper chromatin and amyloid background are seen
Parathyroid adenoma:
- Insular pattern with scant colloid mimics poorly differentiated thyroid carcinoma; however, no irregularity of nuclear membrane is seen

Board review style question #1

Anaplastic thyroid carcinoma
Follicular carcinoma
Medullary thyroid carcinoma
Papillary thyroid carcinoma
Poorly differentiated thyroid carcinoma

Board review style answer #1

C. Medullary thyroid carcinoma. Numerous isolated spindle cells indicate medullary thyroid carcinoma.

Comment Here

Reference: Malignant

Board review style question #2

Chronic thyroiditis
Follicular carcinoma
Hyalinizing trabecular tumor
Nodular goiter
Poorly differentiated thyroid carcinoma

Board review style answer #2

E. Poorly differentiated thyroid carcinoma. Nodular goiter and chronic thyroiditis belong to the benign category, the follicular carcinoma belongs to follicular neoplasm / suspicious for a follicular neoplasm category and hyalinizing trabecular tumor belongs to the suspicious for malignancy category.

Comment Here

Reference: Malignant

Medullary thyroid carcinoma

Table of Contents

Definition / general

Neuroendocrine tumor derived from C cells (formerly called parafollicular cells) of ultimobranchial body of neural crest, which secrete calcitonin
1 - 2% of thyroid carcinomas
Either sporadic (nonhereditary) or familial (hereditary)
- Sporadic: 70%, age 40 - 60, solitary
- Familial: 30%, younger patients (mean age 35)
  - Due to MEN 2A or 2B syndromes, familial medullary thyroid carcinoma (FMTC) syndrome, von Hippel-Lindau disease or neurofibromatosis
  - Caused by gain of function germline mutations in the RET gene
  - Usually bilateral, multicentric with C cell hyperplasia
  - Usually discovered by screening test for serum calcitonin or peripheral blood RET oncogene mutational analysis

Essential features

Thyroid malignant tumor composed of cells with C cell differentiation

Terminology

Synonyms: C cell carcinoma, solid carcinoma with amyloid stroma, parafollicular cell carcinoma
Microcarcinoma:
- 1 cm or less
- Often bilateral, rarely lymph node metastases, usually incidental finding
- Common finding in prophylactic thyroidectomies for high risk patients
Paraganglioma-like variant: rare; may have melanin pigment
Small cell variant: some small cell carcinomas are variants of medullary carcinoma (Am J Surg Pathol 1980;4:333)
Tubular (follicular) variant:
- Resembles follicular carcinoma
- Tumor cells form follicular structures lined by cells resembling those in typical or solid portions of tumor
- Lumina are empty or contain colloid type material

ICD coding

ICD-O: 8345/3
ICD-10: C73

Epidemiology

1 - 2% of thyroid carcinomas (Thyroid 2015;25:567)

Sites

Junction of the upper and mid portions of the thyroid lobes

Etiology

Sporadic: unknown
Familial: germline mutations in the RET gene

Clinical features

Presents with painless thyroid mass, cold on scanning
Up to 75% of patients have nodal metastasis, mostly involving central compartment, ipsilateral and contralateral jugulocarotid chains (Surg Clin North Am 2009;89:1193, J Clin Endocrinol Metab 2003;88:2070); 10% have distant metastasis
Serum calcitonin correlates with tumor burden (Thyroid 2013;23:294)
Patients with metastasis may have severe diarrhea and flushing
Some tumors may produce ACTH or CRH (Cushing syndrome)

Laboratory

High serum calcitonin and CEA levels
Can monitor for recurrence with calcitonin and CEA levels
Only rarely negative for serum calcitonin (World J Surg Oncol 2006;4:97)

Prognostic factors

5 year survival: 65 - 90%
10 year survival: 45 - 85% (Ann Surg 2007;246:815, Clin Investig 1993;71:7)
Poor prognostic factors:
- High stage
- Older age, cervical nodal metastases, male, sporadic form, high mitotic activity and vascular invasion (J Clin Endocrinol Metab 2008;93:682, Ann Surg Oncol 2010;17:2444)
- Patients with MEN 2B have a more aggressive clinical course than those with MEN 2A
- Tumor with RET / m918T mutation has been associated with poor clinical outcome (J Clin Endocrinol Metab 2008;93:682, Eur J Endocrinol 2011;164:971, Br J Cancer 2009;100:1777)
- Tumor with RAS mutation may have a less aggressive clinical course (Endocr Relat Cancer 2015;22:R235)
Favorable prognostic factors: young age, female, familial form, microcarcinoma
Microcarcinoma: poorer outcome is associated with systemic symptoms, metastatic disease at diagnosis, amyloid (Hum Pathol 1999;30:957), desmoplastic stroma (Am J Surg Pathol 2001;25:1245)

Case reports

Teenage boy with Cowden syndrome (Laryngoscope 2007;117:1180)
22 year old man with occult tumor with nodal metastases (Acta Cytol 2008;52:105)
32 year old man with ACTH producing tumor (Hum Pathol 1992;23:592)
34 year old woman and 65 year old man with simultaneous occurrence of medullary and papillary thyroid carcinomas (composite tumors, J Med Case Rep 2007;1:133)
39 year old woman with undetectable serum calcitonin (J Clin Endocrinol Metab 2015;100:337)
42 year old man with ACTH producing tumor (Int Semin Surg Oncol 2007;4:15)
45 year old woman with tumor of lingual thyroid (Singapore Med J 2008;49:251)
46 year old woman treated with apatinib (Medicine (Baltimore) 2017;96:e8704)
48 year old man with metastasizing composite carcinoma with distinct medullary and papillary components (Arch Pathol Lab Med 1994;118:1143)
48 year old woman with solitary thyroid nodule and follicular variant (Endocr Pathol 2002;13:75)
51 year old woman with Hashimoto thyroiditis (Am J Clin Pathol 1983;80:534)
52 year old woman with melanin producing case (Diagn Pathol 2008;3:2)
59 year old woman with papillary and medullary carcinoma as separate / collision tumors (Diagn Pathol 2007;2:39)
66 year old man presenting with enlarged cervical lymph node and microcarcinoma (Am J Clin Pathol 1986;85:247)
66 year old man with thyroid mass (University of Pittsburgh: A Left Thyroid Mass [Accessed 19 March 2018])
75 year old man with oncocytic variant of medullary thyroid carcinoma (Rare Tumors 2016;8:6537)
Encapsulated tumor (Am J Surg Pathol 1991;15:1089)
Encapsulated tumor resembling hyalinizing trabecular (paraganglioma-like) adenoma (Mod Pathol 1990;3:581)
Papillary and medullary carcinoma as separate / collision tumors (Am J Surg Pathol 1996;20:245) and as composite tumors (Hum Pathol 1990;21:1151)

Treatment

Total thyroidectomy (particularly for familial form) with cervical lymphadenectomy for node positive patients
Microcarcinoma: thyroidectomy, central neck dissection, lateral neck dissection based on serum calcitonin (Surgery 2007;142:1003)

Gross description

Sporadic: typically presents as a single circumscribed but nonencapsulated, gray-tan mass
Familial: generally bilateral / multiple foci
Solid, gray-tan-yellow, firm, may be infiltrative
Larger lesions have hemorrhage and necrosis, tumor usually in mid or upper portion of gland (with higher density of C cells)
< 1 cm in size is called microcarcinoma; if < 0.5 cm, associated with a complete absence of clinically detectable metastatic disease (Ann Surg Oncol 2009;16:2875)

Gross images

Contributed by Mark R. Wick, M.D.

Multifocal in MEN 2

AFIP images

MEN 2A patient with multiple tumor foci (arrows)

Nonfamilial tumor replaces entire left lobe and isthmus

Nodal metastasis

MEN 2A patient with single tumor focus

Left lobe tumor: well circumscribed, right lobe tumor: finely granular

Images hosted on other servers:

Large tumor with
hemorrhage, necrosis
and cystic degeneration

Microscopic (histologic) description

Wide variety of morphology, can mimic any other thyroid malignancy
Round, plasmacytoid, polygonal or spindle cells in nests, cords or follicles; often mixtures of these cells
Round nuclei with finely stippled to coarsely clumped chromatin and indistinct nucleoli, occasional nuclear pseudoinclusion
Eosinophilic to amphophilic granular cytoplasm due to secretory granules
Generally low mitotic figures
Stroma has amyloid deposits from calcitonin, prominent vascularity with glomeruloid configuration or long cords of vessels (Am J Surg Pathol 1995;19:642), coarse calcifications, occasional psammoma-like bodies
Mucin in 42% (Arch Pathol Lab Med 1983;107:70)
Often angiolymphatic invasion
Occasionally marked neutrophilic infiltrate, oncocytic tumor cells, papillary patterns
May entrap follicles
C cell hyperplasia present in familial but not sporadic cases
Microcarcinoma:
- Complex microarchitectural pattern with desmoplastic stroma, often focal amyloid deposition
- Usually a solid pattern of round, polygonal, spindled or plasmacytoid cells (Arch Pathol Lab Med 2008;132:1767)
- Often C cell hyperplasia (Am J Surg Pathol 2000;24:853)

Variants (important for differential diagnosis, most are of no prognostic importance):

Amphicrine variant: tumor cells contain mucin and express calcitonin (Ultrastruct Pathol 1985;8:197)
Angiosarcoma-like variant: cleft spaces with hemorrhage (Diagn Cytopathol 2007;35:424)
Clear cell variant (Hum Pathol 1985;16:844)
Encapsulated variant (J Pathol 1971;103:1)
Follicular variant: has follicles containing eosinophilic secretion (Histopathology 1983;7:83)
Giant cell variant: large cells with bizarre nuclei, may be more aggressive (Arch Pathol Lab Med 1978;102:445)
Melanotic variant: with melanin pigmentation (Histopathology 1990;16:227)
Oncocytic variant: mimics Hürthle cell adenoma / carcinoma but has prominent fibrovascular septa (Cancer 1989;63:1183)
Papillary variant (Pathol Res Pract 1988;184:98)
Paragangioma-like variant:
- Nested tumor cells, mimics paraganglioma (Mod Pathol 1990;3:581)
- Nest-like pattern with pigmented dendritic cells resembling sustentacular cells (Arch Pathol Lab Med 1994;118:1041)
Pseudopapillary variant (Diagn Cytopathol 2014;42:823)
Small cell variant: similar to small cell carcinoma of lung, highly aggressive (Semin Diagn Pathol 1985;2:137)
Spindle cell variant: exclusively spindle cells (Adv Anat Pathol 2014;21:26)
Squamous variant: may have focal squamous differentiation (Cancer 1989;63:1183)

Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D., Joseph Christopher Castillo, M.D. and Mark R. Wick, M.D.

Low power

Background of amyloid

Tumor cells with finely stippled chromatin

H&E

Chromogranin

Thyroglobulin

Pseudopapillary variant

Signet ring cell variant

AFIP images

With melanin pigment

Stains

Amyloid

MEN 2A patients with early medullary carcinoma

Paraganglioma-like pattern

Small cell variant

Tubular (follicular) variant

Images hosted on other servers:

Oncocytic variant

Papillary variant

Cytology description

Cellular specimen with round, ovoid, plasmacytoid or spindle cells singly or in small cluster; cells have abundant cytoplasm and eccentric nuclei; chromatin has salt and pepper appearance
May have pink azurophilic granules and intranuclear pseudoinclusions; amyloid present occasionally (Am J Clin Pathol 1984;82:552)
Paraganglioma-like variant:
- Predominantly ovoid to spindled epithelial cells in cohesive three dimensional clusters with sharp margins, rare isolated individual cells, no background colloid or amyloid
- Tumor cells have inconspicuous cytoplasm, significant nuclear atypia with occasional bizarre or binucleated cells, coarse and granular nuclear chromatin with occasional grooves and intranuclear inclusions (Cytopathology 2009;20:188)

Cytology images

Contributed by Ayana Suzuki, C.T. and Shuanzeng Wei, M.D., Ph.D.

Salt and pepper chromatin

Cellular specimen
(Diff-Quik stain)

Plasmacytoid tumor cells
(Diff-Quik stain)

Variable sized plasmacytoid tumor cells
(Pap stain)

Tumor cells with intranuclear pseudoinclusions (Pap stain)

Diff-Quik

Pap

Cell block

Calcitonin

TTF1

Positive stains

Calcitonin, CEA, TTF1 (weak to moderate), PAX8 (variable and weak) (Mod Pathol 2008;21:192), Congo red for amyloid
Calcitonin gene related peptide, ACTH, somatostatin, gastrin releasing peptide, neurotension, low molecular weight keratin, chromogranin A and B, synaptophysin, neuron specific enolase, progesterone receptors (Mod Pathol 1996;9:68)
Immunocytochemistry for calcitonin, CEA and thyroglobulin is useful with thin layer cytology (Appl Immunohistochem Mol Morphol 2008;16:548)
Paraganglioma-like variant: Fontana-Masson (melanin), calcitonin, S100 (Pathol Res Pract 2000;196:55)
Small cell variant: calcitonin (usually)
Tubular (follicular) variant:
- Calcitonin, calcitonin gene related peptide
- Luminal material shows variable staining for calcitonin

Negative stains

Thyroglobulin (entrapped thyroid follicle can be positive), estrogen receptor
Paraganglioma-like variant: HMB45 (Arch Pathol Lab Med 1998;122:555)
Tubular (follicular) variant: thyroglobulin

Electron microscopy description

Single membrane bound electron dense granules in cytoplasm
130 nm and 280 nm secretory granules contain calcitonin
Tubular (follicular) variant: secretory granules, apical microvilli, well developed desmosomes near luminal poles

Electron microscopy images

AFIP images

Amyloid deposits

Numerous large type I granules in some cells

Tumor cells with sparse granules

Molecular / cytogenetics description

Gain of function muations in RET proto-oncogene: in majority of hereditary medullary thyroid carcinoma (MTC), 50% in sporadic MTC
Exon 16 / M918T is the most common mutation
HRAS and KRAS mutation in RET negative MTC
MYH13-RET fusion in rare RET / RAS negative MTC
Other fusion: GFPT1-ALK and EML4-ALK

Videos

Medullary thyroid carcinoma FNA

Medullary thyroid carcinoma

Differential diagnosis

Hürthle cell carcinoma: eosinophilic not amphophilic cytoplasm, no fibrous bands dividing cells into nests
Metastatic neuroendocrine carcinoma: primary often discovered only on followup; primarily interstitial spread, multiple tumor foci, folliculotropism and rosettes, negative for calcitonin, focal / negative for CEA (Am J Surg Pathol 1997;21:754)
Poorly differentiated thyroid carcinoma: thyroglobulin positive, calcitonin negative, no amyloid
Can mimic various tumors (see variants in Microscopic description): calcitonin and CEA are essential in difficult cases
Paraganglioma-like variant mimics paraganglioma: negative for calcitonin and thyroglobulin, positive for S100 in sustentacular cells (Am J Surg Pathol 1980;4:589)

Additional references

eMedicine: Medullary Thyroid Carcinoma [Accessed 14 March 2018], Wikipedia: Medullary Thyroid Cancer [Accessed 14 March 2018]

Board review style question #1

Which statement is not true for medullary thyroid carcinoma (MTC)?

Majority of MTC have translocation involving RET proto-oncogene
MTC can be monitored for recurrence with serum CEA levels
MTC has a wide variety of morphology, can mimic any other thyroid malignancies
MTC is most commonly found at the junction of the upper and mid portions of the thyroid lobes
MTC is positive for TTF1, synaptophysin and chromogranin

Board review style answer #1

A. Majority of medullary thyroid carcinoma (MTC) have translocation involving RET proto-oncogene is false. The majority of MTC have gain of function mutations in RET gene. MYH13-RET fusion can be found in rare RET / RAS negative MTC. RET-PTC rearrangement is found in papillary thyroid carcinoma.

Comment Here

Reference: Medullary

Microcarcinoma

Table of Contents

Definition / general

Papillary thyroid carcinoma (PTC) of ≤ 1 cm
2017 World Health Organization definition based only on tumor size (irrespective of it being incidental or not)

Essential features

The most common variant of papillary thyroid carcinoma in the United States
The majority are indolent but some can exhibit malignant behavior
No definite biological or clinical parameters currently exist to distinguish indolent from potentially aggressive papillary thyroid microcarcinoma
Active surveillance may be considered as an alternative to surgery for a select group of patients with low risk tumors

Terminology

Synonym: papillary microtumor
Formerly called occult sclerosing carcinoma, occult papillary carcinoma and nonencapsulated sclerosing tumor

ICD coding

ICD-10: C73 - malignant neoplasm of thyroid gland
ICD-O: 8341/3 - papillary microcarcinoma

Epidemiology

Very common (~30 - 40% of all papillary thyroid carcinomas)
Incidental finding in 7 - 17% of surgical thyroidectomies performed for benign or malignant thyroid lesions (J Postgrad Med 2007;53:23, BMC Cancer 2015;15:330)
Incidental finding in 6 - 36% of autopsies in adults who died of nonendocrine related causes (Cancer 1985;56:531, Am J Clin Pathol 1988;90:72)
No strong sex predilection (as compared with other thyroid diseases) (BMC Cancer 2015;15:330, Adv Anat Pathol 2006;13:69)
Predominantly adult patients without a specific age category (BMC Cancer 2015;15:330)

Sites

Thyroid
Exceedingly rare at other sites (see Case reports below)

Pathophysiology

Clonal neoplastic proliferation of thyroid follicular cells, usually with a specific driver mutation (see Molecular / cytogenetics description below)

Etiology

Shared risk factors with most other variants of papillary thyroid carcinoma
- Ionizing radiation
- Pre-existing benign thyroid disease (Adv Anat Pathol 2006;13:69)
- Higher body mass index (BMI) in women only (Eur J Endocrinol 2013;168:879)

Diagrams / tables

Images hosted on other servers:

Incidence and prognosis

Clinical features

Usually an incidental finding in a thyroid removed for other reasons or at autopsy (Adv Anat Pathol 2006;13:69)
Increasingly identified by more sensitive imaging techniques, especially ultrasonography (Surg Clin North Am 2004;84:973, Nat Clin Pract Endocrinol Metab 2007;3:240)
May be an occult primary tumor identified following diagnosis of cervical lymph node metastasis (Int J Clin Exp Pathol 2014;7:5210)
Familial form (~6% of cases): often multifocal and bilateral with lymphovascular invasion and lymph node metastases (Endocr Relat Cancer 2016;23:R577, Ann Surg Treat Res 2017;92:129)

Diagnosis

Histopathologic evaluation of thyroid resection specimens
Fine needle aspiration cytology (FNAC)

Laboratory

Recurrent disease (especially after total thyroidectomy) may be monitored by recombinant human TSH (rhTSH) stimulated serum thyroglobulin measurement, with or without neck ultrasound (J Clin Endocrinol Metab 2003;88:3668)

Radiology description

On ultrasonography: irregular nodule shape, aspect ratio (anteroposterior to transverse diameter of the nodule) of ≥ 1, unclear nodule boundary, blurred margins, internal heterogeneous hypoechogenicity, microcalcifications (Oncol Lett 2016;12:2451)

Radiology images

Images hosted on other servers:

Ultrasound

Prognostic factors

Excellent prognosis overall
Most represent a nonprogressive, clinically innocuous disease (self limiting cancer)
- 10 year active surveillance trials showed size enlargement in 7 - 8% and lymph node metastases in 1 - 4% (Eur J Surg Oncol 2018;44:307)
Small proportion have an aggressive clinical behavior; these represent early stages of papillary thyroid carcinoma that would eventually present as larger tumors
Meta analysis of 11 studies showed means of 7.2% for microscopic extrathyroidal extension, 28% for lymph node metastases, 0.7% for distant metastases, 5% for tumor recurrence and 0.3% for tumor related death (Endocr Pract 2007;13:498)
No definite biological or clinical parameters currently exist to distinguish low risk indolent from potentially aggressive tumors
Meta analysis of 17 studies revealed that recurrence was associated with younger age (Eur J Endocrinol 2008;159:659)
BRAF V600E mutation may be associated with aggressive disease but, as an isolated element, cannot identify cases that will spread locoregionally or to distant sites (Ann Surg Oncol 2009;16:240, Eur J Cancer 2020;124:161)
Coexistence of BRAF with other oncogenic mutations (PIK3CA, AKT1, TERT promoter or TP53) mutations may indicate a less favorable outcome (Thyroid 2016;26:1)

Case reports

44 year old woman with a midline neck mass (J Med Case Rep 2008;2:42)
59 year old man with seizures and dysphagia (Ann R Coll Surg Engl 2020;102:e107)
2 cases with suggestion of partial regression (Ann Diagn Pathol 2007;11:97)

Treatment

No consensus on treatment but generally similar to thyroid carcinomas > 1 cm, depending on the lymph node status and other clinical factors
Thyroid lobectomy alone is sufficient treatment for small, unifocal, intrathyroidal carcinomas in the absence of prior head and neck radiation, familial thyroid carcinoma or clinically detectable cervical nodal or distant metastases (Thyroid 2016;26:1)
Active surveillance may be considered as an alternative to surgery in selected patients with low risk tumors without clinically evident lymph nodes metastases or local invasion (Eur J Surg Oncol 2018;44:307, Cancer 2017;123:372, Thyroid 2016;26:1)
Diagnosis of incidental papillary thyroid microcarcinoma in thyroid resection specimens is not, by itself, an indication for additional treatment (i.e. surgery, radioactive iodine)

Gross description

White-gray fibrotic nodule with irregular contours or an ill defined light brown nodule, measuring ≤ 1 cm
Multifocality in 20 - 46% (World J Clin Cases 2020;8:1350, Adv Anat Pathol 2006;13:69)
Due to their small size, these lesions can be easily missed on gross examination and are often identified only microscopically

Gross images

AFIP images

Well circumscribed tumor of

Small irregular fibrotic tumor

Frozen section description

Frozen section is usually not indicated

Microscopic (histologic) description

Defined solely by the ≤ 1 cm size criterion; does not have a unique morphology
Overall varied architectural patterns with characteristic nuclear features of papillary thyroid carcinoma
Typically shows an irregular stellate or scar-like configuration
May be nonencapsulated or encapsulated, with or without a sclerotic rim
Composed of papillary or follicular structures or a mixture of both
Follicular pattern more common than a pure papillary (classical) pattern (Adv Anat Pathol 2006;13:69)
Characteristic nuclear attributes are present at high power: nuclear enlargement and overlapping, chromatin clearing, irregular nuclear contour, nuclear grooves and nuclear pseudoinclusions
May show cytologic or architectural features of several variants, including follicular or tall cell
- Does not usually require subclassification
- However, the tall cell variant should be recognized since it is associated with aggressive features (Oncol Lett 2017;13:3501, Thyroid 2013;23:1525)

Microscopic (histologic) images

Contributed by Nadine Demko, M.D.C.M., M.Sc., Livia Florianova, M.D., M.Sc. and Marc Pusztaszeri, M.D.

Follicular architecture

Nuclear features

Irregular contour with dystrophic calcification

Nuclear features

Infiltrative pattern

Tall cell features

Chronic thyroiditis background

Follicular architecture

Nuclear features

Tall cell features

Minimal extrathyroidal extension

Infiltrative pattern

Nuclear features

BRAF V600E

Contributed by Andrey Bychkov, M.D., Ph.D.

Incidental finding in multinodular goiter

Encapsulated papillary microcarcinoma

CK19, galectin3 and HBME1

Virtual slides

Images hosted on other servers:

Tall cell features

Cytology description

Usually incidental and is not sampled by fine needle aspiration cytology
However, some of these lesions undergo fine needle aspiration cytology because of suspicious radiology findings (multifocality, calcification, etc.) or in patients with a history of radiation to the head and neck region to establish the diagnosis and to determine the most appropriate management
May be accidentally sampled during the aspiration of other clinically significant thyroid nodules (Acta Cytol 2001;45:341)
Cytologic features are essentially the same as for papillary thyroid carcinoma (Int J Surg Pathol 2002;10:133, Acta Cytol 2001;45:341)

Cytology images

Contributed by Nadine Demko, M.D.C.M., M.Sc., Livia Florianova, M.D., M.Sc. and Marc Pusztaszeri, M.D.

Cytological features

Contributed by Grace C.H. Yang, M.D.

Pap stained slides

Positive stains

Same as for papillary thyroid carcinoma > 1 cm
Thyroglobulin, TTF1, PAX8 and low molecular weight cytokeratins (including CK19), broad spectrum cytokeratins (AE1 / AE3, MNF116), HBME, galectin3 (Mod Pathol 2006;19:1631, Head Neck 2010;32:38, Arch Pathol Lab Med 2015;139:67)
BRAF V600E in some cases (Arch Pathol Lab Med 2015;139:67)

Negative stains

Calcitonin, chromogranin and synaptophysin

Molecular / cytogenetics description

Similar mutations as papillary thyroid carcinoma > 1 cm
BRAF V600E mutation in 30 - 67% (Thyroid 2016;26:1)

Videos

Active surveillance

Sample pathology report

Thyroid, right lobe, right hemithyroidectomy:
- Incidental papillary thyroid microcarcinoma, 3 mm, negative for lymphatic invasion and extrathyroidal extension; resection margin negative
Thyroid, total thyroidectomy:
- Papillary thyroid microcarcinomas, x 5, bilateral, measuring up to 8 mm, negative for lymphatic invasion and extrathyroidal extension; resection margin negative

Differential diagnosis

Reactive nuclear changes in chronic lymphocytic thyroiditis:
- Usually associated with a lymphoplasmacytic infiltrate and not associated with sclerosis
Hyperplastic ultimobranchial body rests / solid cell nests:
- Positive for p63 and negative for thyroglobulin and TTF1
Nonneoplastic follicles entrapped in areas with post-FNAC changes / needle tract:
- Fibrosis and chronic inflammation may cause reactive changes in the nuclei

Board review style question #1

Which of the following statements about papillary thyroid microcarcinoma (shown in the image) is correct?

Can always be diagnosed on cytology alone
Can contain tall cell features
More likely to show a pure papillary rather than follicular architecture
Must be incidental and measure ≤ 1 cm
Requires a total thyroidectomy

Board review style answer #1

B. Can contain tall cell features. Papillary thyroid microcarcinoma may show features of other variants including tall cell. Tall cell features should be recognized and reported since they are associated with more aggressive behavior. The other answer choices are incorrect because the 2017 World Health Organization definition is based only on tumor size (irrespective of it being incidental or not), the final size is most often determined on a surgical resection specimen (though it may also be estimated by ultrasound), follicular architectural pattern is more common than pure papillary (classical) pattern and may be managed by a lobectomy or active surveillance.

Comment Here

Reference: Papillary thyroid microcarcinoma (PTMC)

Board review style question #2

Which of the following immunostains is usually not expressed in papillary thyroid microcarcinoma?

BRAF V600E
CK19
Galectin3
HBME
p63

Board review style answer #2

E. p63. Papillary thyroid microcarcinoma is usually negative for p63, in contrast to the mimicker solid cell nests which are usually positive for p63. HBME, galectin3 and CK19 are expressed in most and can be used to support the diagnosis. BRAF V600E immunostain is often expressed and can be used as a reliable surrogate marker for the corresponding BRAF V600E gene mutation, present in 30 - 67%.

Comment Here

Reference: Papillary thyroid microcarcinoma (PTMC)

Mixed medullary-follicular tumors

Table of Contents

Definition / general | Case reports | Microscopic (histologic) images | Positive stains | Differential diagnosis

Definition / general

Aggressive

Case reports

44 year old man with lymph node metastases (Mod Pathol 1996;9:631)
51 year old woman with medullary and follicular carcinoma in the same thyroid lobe (Hum Pathol 1989;20:83)

Microscopic (histologic) images

AFIP images

Tumor cells show lobular growth pattern

Scattered early follicle-like areas

Tumor cells form colloid containing follicles

Many cells have clear cytoplasm

Immunofluorescent staining

Positive stains

Thyroglobulin and calcitonin

Differential diagnosis

Entrapping of thyroid follicles by medullary carcinoma
Medullary carcinoma with glandular growth pattern

Molecular pathology basics

Table of Contents

Definition / general

Thyroid cancer is a genetically simple disease with a relatively low number of mutations in each tumor
Driver mutations and gene fusions are identified in over 90% of thyroid cancers, making it one of the best molecular characterized malignancies in humans
MAPK and PI3K-AKT are 2 main signaling pathways involved in the development of thyroid tumors
- MAPK pathway: activated through point mutations of BRAF or RAS genes and RET / PTC rearrangements; primarily involved in papillary carcinoma
- PI3K-AKT pathway: activated through point mutations in RAS, PIK3CA, AKT1 and PTEN; primarily involved in follicular carcinoma
- Simultaneous activation of both pathways becomes more frequent as the tumor grade increases
Collectively, the most common alterations are BRAF and RAS point mutations and RET / PTC and PAX8 / PPARγ chromosomal rearrangements
Driver gene aberrations in well differentiated thyroid cancer are mutually exclusive (median = 1 mutation per tumor)
Dedifferentiated cancers accumulate additional genetic alterations, so called late events (median = 6 mutations per tumor)
Chromosomal rearrangements (and resultant gene fusions) are associated with radiation
Most somatic mutations are not thyroid specific and are commonly found in various solid cancers
Molecular techniques are typically applied to cytological smears, formalin fixed paraffin embedded and snap frozen tissue
- Mutations are detected with real time PCR and DNA sequencing
- Chromosomal rearrangements are detected with FISH and RT-PCR
- Immunohistochemistry is specific for detecting mutant proteins (BRAF V600E, NRAS Q61R)

Multistep carcinogenesis

Thyroid cancer develops through the accumulation of multiple genetic alterations and progressive derangement of signaling pathways, accompanied by numerous secondary molecular alterations in the cell and tumor microenvironment, which amplify and synergize their impacts
Early (initiating) genetic events are BRAF and RAS mutations and RET / PTC rearrangements, while TP53 mutation is a classic late event
- BRAF mutations occur early in development of papillary thyroid carcinoma / PTC (often found in microcarcinoma); this mutation is sufficient to induce thyroid tumorigenesis
- RAS mutations are found in adenomas and play a role in early thyroid tumorigenesis, but additional genetic alterations are required to transform benign lesions into thyroid cancers, such as PTEN deletion, as shown in mouse models
Activation of the MAPK pathway, e.g., by BRAF V600E mutation, drives carcinogenesis of the thyroid follicular cell towards papillary thyroid carcinoma (PTC)
Activation of the PI3K-AKT pathway by mutations in RAS, PTEN and PIK3CA, primarily drives the development of follicular adenoma (FA) and follicular thyroid carcinoma (FTC) from follicular thyroid cells
- Progression from FA to FTC is largely due to increasing activation of the PI3K-AKT pathway
As genetic alterations accumulate and intensify the signaling of both pathways, PTC and FTC can progress to poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC)
- ATC may simultaneously have BRAF V600E, RAS mutations and RET-PTC fusions, which are otherwise mutually exclusive in well differentiated thyroid cancers
- PDTC and ATC may also develop de novo directly from follicular thyroid cells and ATC can develop from PTC or FTC
C cell hyperplasia is a precursor of hereditary forms of medullary thyroid carcinoma (MTC) driven by activating germline RET mutations; C cell hyperplasia may progress to medullary microcarcinoma and MTC

Pathophysiology

MAPK pathway

MAPK signaling pathway mediates differentiation, survival, cell growth and metabolic activities through regulating the expression of various genes
Also known as RAS-RAF-MEK-MAPK-ERK signaling pathway
- Transmembrane receptor tyrosine kinase RET is the gateway to the MAPK (Mitogen Actvated Protein Kinase)
- RET activation, by binding of growth factors or cytokine ligands to the extracellular domain of the receptor, results in phosphorylation of tyrosine residues in the intracellular domain and initiates a cascade of subsequent phosphorylation events, transducing a downstream signal regulating cell growth
- First targets of the cascade are RAS viral oncogene family (HRAS, NRAS and KRAS); subsequent signaling occurs by activating phosphorylation of the downstream RAF family of proto-oncogen serine / threonine tyrosine kinases (A-RAF, B-RAF and C-RAF), MEK and ERK
- Activated ERK then translocates into the nucleus, where it modulates transcription factors such as PAX8 and hormone receptors such as PPARγ, which are important to thyroid hormone biosynthesis as well as cell growth, survival and apoptosis
In early thyroid cancer, MAPK pathway is driven by activating mutations in BRAF and RAS or by RET / PTC rearrangements, where all of them are mutually exclusive events
Plays key role in development and progression of PTC
Constitutively active MAPK pathway induces secondary molecular alterations that synergize and amplify the oncogenic activity of this pathway
- Upregulation of oncogenic proteins and related pathways, including VEGF, NF-kB, matrix metalloproteinases, HIF1α, TGFβ1 and various chemokines
- Genome wide hypermethylation and hypomethylation
- Collectively, indirect MAPK related events maintain cancer cell proliferation, growth and survival and drive migration, invasion, tumor angiogenesis and metastasis

PI3K-AKT pathway

PI3K-AKT pathway transmits and modulates signals for control of cell growth, survival and migration
- PI3K pathway starts with PI3K (phosphatidylinositol-3 kinase), which initiates downstream PI3K-AKT-mTOR viral oncogene tyrosine kinase cascade
- PI3K is activated both directly by the transmembrane receptor kinase RET and indirectly by RAS
- This pathway is downregulated by PTEN mediated dephosphorylation
Activating mutations in RAS, PIK3CA and AKT genes or inactivating mutations in PTEN tumor suppressor gene can inappropriately stimulate signaling pathway
PI3K-AKT pathway has a central role primarily in FTC and its invasion and metastasis
Secondary molecular alterations, induced by PI3K-AKT signaling, are those of Wnt-β-catenin, HIF1α and NF-kB pathways

Ancillary pathways

TSHR-cAMP pathway
- TSHR (Thyroid Stimulating Hormone Receptor) is a G protein coupled receptor that triggers cAMP signaling to promote growth and differentiation of thyroid cells
- TSHR partially mediates its effects via RAS-MAPK, PI3K and JAK-STAT kinase pathways
- Overstimulation of TSHR signaling through activating mutations in TSHR or Gsα leads to development of hyperfunctional follicular adenoma
- High serum TSH and increased TSH signaling contributes to development of thyroid cancer
NF-kB pathway
- Controls proliferative and anti apoptotic signaling in thyroid cancer cells and has important role in the regulation of inflammatory responses linked to tumorigenesis
- Triggered by activated MAPK and PI3K pathways
Wnt-β-catenin pathway
- Regulates cell growth, proliferation and stem cell differentiation
- β-catenin, when upregulated by upstream Wnt signaling, translocates into nucleus and transcribes various tumor promoting genes
- In thyroid cancer, activation of Wnt-β-catenin signaling is often caused by activating mutations of CTNNB1 (which encodes β-catenin), particularly in PDTC and ATC
- Upregulated PI3K-AKT signaling also causes aberrant activation of this pathway
HIF1α pathway
- Key mediator of the response to hypoxia, when it binds to HIF1β to form the HIF1 transcription factor that induces the expression of various genes associated with cell metabolism and neoangiogenesis (e.g., VEGFA)
- HIF1α is expressed in aggressive thyroid cancers (ATC), which is consistent with a role in thyroid cancer progression
- HIF1 can be upregulated by both MAPK and PI3K-AKT pathways

Diagrams / tables

Images hosted on other servers:

Molecular pathways in thyroid cancer development

Stepwise mechanism of thyroid neoplasia

Progress in identifying
mutational markers
in thyroid cancer

MAPK pathway

PI3K-AKT pathway

Genomic landscape of PTC

Gene mutations in thyroid tumors

Gene fusions in PTC

BRAF vs. RAS in PTC

BRAF V600E and tumor recurrence

BRAF mutation and iodine uptake

TERT mutations

miRNAs in thyroid cancer

Drug targets in thyroid cancer

Uses by pathologists

Preoperative diagnosis of thyroid nodules with indeterminate FNA
Potential prognostic value to predict aggressive disease
Targeted therapy

Molecular / cytogenetics description

Major (driver) gene mutations

BRAF mutations

Basics
- BRAF is a serine-threonine kinase activated by RAS, which triggers MEK phosphorylation and downstream activation of MAPK-ERK cascade
- Point mutations in BRAF lead to constitutive activation of the kinase and stimulation of MAPK pathway, accompanied by the loss of negative feedback control
- Virtually all point mutations of BRAF involve codon 600 and result in the V600E mutation
- Other BRAF mutations (1 - 2%) are K601E and small in frame insertions / deletions
- BRAF V600E contributes to aggressive behavior of thyroid cancer via multiple mechanisms, e.g., induction of genetic instability, aberrant activation of the TGFβ and NF-kB pathways involved in invasion and angiogenesis, promoting of epithelial-mesenchymal transition, aberrant methylation of tumor suppressor genes, NIS inhibition and others
Prevalence
- BRAF V600E is the most frequent genetic alteration found in PTC (40 - 60%), usually in classic and tall cell variants, but not in pediatric / solid PTC
- BRAF V600E is found in 20 - 80% of papillary thyroid microcarcinoma (mPTC), comparable to larger PTC
- There is a geographic variation in BRAF mutation prevalence; Japan and South Korea have high rates of BRAF V600E (70 - 90%) compared to Western countries (30 - 50%)
- BRAF mutations found in 20 - 40% of PDTC, 25 - 40% of ATC, but never in FTC or benign thyroid nodules
- BRAF K601E was reported in follicular variant PTC and rarely in FA
Detection
- DNA based: direct (Sanger) sequencing, realtime PCR, next generation sequencing
- Mutant protein by VE1 immunohistochemistry
  - Absent or faint staining correlates with lack of the BRAF V600E mutation, whereas strong and diffuse staining is specific to the mutation
  - Equivocal cases should be resolved by molecular testing
Utility
- Highly sensitive marker of malignancy in preoperative evaluation of indeterminate thyroid nodules (Bethesda III - V)
- Prognosis: associated with aggressive behavior of PTC (and even mPTC), e.g., extrathyroidal extension, lymph node metastasis, radioresistance, recurrence / persistence and increased mortality

RAS mutations

Basics
- RAS genes are GTPases located at the inner surface of the cell membrane, that transmit signals arising from growth factor bound receptor tyrosine kinases and G protein coupled receptors along the MAPK, PI3K-AKT and other signaling pathways
- Harvey RAt Sarcoma viral oncogene homolog (HRAS), Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) are the most common oncogenes in human cancer
- Point mutations in RAS genes typically occur in codons 12, 13 and 61 and lock RAS into a constitutively active state
- Codon 61 mutations of NRAS and HRAS (3:1) are the most common in follicular derived thyroid tumors
- Although RAS is a classic dual activator of the MAPK and PI3K-AKT pathways, RAS mutations preferentially activate PI3K-AKT pathway in thyroid tumorigenesis
Prevalence
- 30 - 50% of FTC, with lower incidence in oncocytic variant
- 10 - 20% of PTC, virtually all are follicular variant PTC
- PDTC (20 - 40%) and ATC (10 - 50%)
- RAS mutations are also found in 20 - 40% of FA
- HRAS and KRAS mutations occur in MTC (25%)
Detection
- DNA based: direct (Sanger) sequencing, realtime PCR, next generation sequencing
- NRAS Q61R immunohistochemistry, evaluation is similar to the VE1 above
Utility
- Diagnostic value of RAS mutations to predict malignancy in thyroid nodules is lower than that of BRAF, because RAS mutations are also found in benign neoplasms
- Differentiated thyroid cancers harboring RAS mutations alone have excellent prognosis

RET mutations

Basics
- RET (REarranged during Transfection) proto-oncogene encodes receptor tyrosine kinase that is expressed in thyroid C cells, but not in follicular cells
- RET mutation causes sporadic and hereditary / syndromic MTC (prevalence ratio 3:1), the latter is represented by MEN2A (multiple endocrine neoplasia type 2A), MEN2B (multiple endocrine neoplasia type 2B) and familial MTC
Prevalence
- RET gene is mutated in MTC, both familial and sporadic (25 - 70%)
- Somatic RET M918T mutation is the most common mutation in sporadic MTC (75 - 95% of all somatic RET mutations)
- Germline RET M918T mutation is the most common mutation in MEN2B; in MEN2A and familial MTC, mutations in RET typically occur in one of five cysteine codons within the cysteine rich extracellular domain
Detection
- Direct sequencing of the whole RET gene for the detection of germline mutations (DNA is extracted from peripheral blood lymphocytes or buccal swab cells)
- Sequencing or real time PCR for RET M918T detection in sporadic cases
Utility
- Detection of RET M918T in FNA aspirate predicts MTC with high accuracy
- There are several groups of RET mutations based on aggressiveness of MTC: highest risk (RET M918T), high risk (RET C634 and A883F) and moderate risk (including but not limited to RET C609, C611, C618, C620 and V804 mutations)

Major gene fusions (chromosomal rearrangements)

RET / PTC rearrangements

Basics
- RET gene can fuse with various partners, which lead to the constitutive activation of RET kinase and downstream MAPK and PI3K-AKT pathways
- The most common rearrangement types are RET / PTC1 (formed by fusion of RET with the CCDC6 gene) and RET / PTC3 (formed by fusion of RET with the NCOA4 gene)
- 20+ types of RET / PTC translocation have been described
Prevalence
- RET / PTC1 and RET / PTC3 rearrangements are found in 10 - 20% of adult sporadic PTC
- Recent studies found lower incidence of RET fusions in PTC (2 - 7%)
  - Affected by technical issues (applications and sensitivity cutoffs) and geographic variation
- RET / PTC rearrangements are frequently found in children / young adults (40 - 70%); also in radiation induced PTC (50 - 80%), likely due to the young age of this cohort
- RET / PTC rearrangements usually occur in classic PTC, but are also found in follicular variant PTC and in some FA
- The type of RET rearrangement correlates with tumor morphology: RET / PTC1 is typically found in classic PTC and mPTC, while RET / PTC3 is associated with solid pattern (pediatric or radiation induced)
- Not found in follicular tumors, benign thyroid nodules and Hashimoto thyroiditis (contrary to early findings, which were misinterpreted due to technical limitations)
Detection
- RT-PCR (fresh or frozen tissue), FISH (FFPE), Southern blot
  - These ultrasensitive techniques have inherent risk of false positives, which requires cautious evaluation with pre established cutoffs and rigorous quality control
- NGS (e.g., MassArray based)
- Immunohistochemistry: reliable anti-RET antibody is not currently available
Utility
- Diagnostic: presence of RET / PTC rearrangement predicts almost 100% risk of malignancy in thyroid FNA

PAX8 / PPARγ rearrangement

Basics
- PAX8 / PPARγ rearrangement is a fusion between PAX8 (paired domain transcription factor) and PPARγ (peroxisome proliferator activated receptor) genes
- PAX8 / PPARγ exerts a dominant negative effect on the tumor suppressor PPARγ and also transactivates certain PAX8 responsive genes
Prevalence
- 30 - 40% of FTC with lower prevalence in oncocytic variant (5 - 15%)
- Follicular variant PTC (5 - 30%) and FA (5 - 20%)
Detection
- FISH, RT-PCR, NGS
- Immunohistochemistry with anti-PPARγ antibody is an ancillary / screening tool, only strong and diffuse staining should be considered as positive (still requires molecular verification)
Utility
- Diagnostic value to predict malignancy is insufficient for using PAX8 / PPARγ as a sole marker (similar to RAS mutations), can be a part of molecular panel instead

Other mutations and fusions

AKT1 mutations
- Late event
- Reported in metastatic thyroid cancer, PDTC and ATC (5 - 10%)
ALK fusions
- ALK (anaplastic lymphoma kinase) fusion proteins activate different signaling pathways, including PI3K and MAPK pathways
- ALK rearrangements are found in radiation induced thyroid cancer (50% in small series)
- 5 - 10% of ATC / PDTC, 1% of sporadic PTC
- Detected by FISH, RT-PCR, NGS
- ALK immunohistochemistry can be a screening tool
BRAF fusions
- Fusion of BRAF with AKAP9 (A kinase anchor protein 9) is rarely found in sporadic thyroid cancer
- Higher frequencies (up to 11%) in patients with a history of radiation exposure
CTNNB1 mutations
- CTNNB1 proto-oncogene encodes β-catenin, a member of Wnt signaling pathway
- Point mutations in exon 3 of CTNNB1 stabilize the protein by making it insensitive for adenomatous polyposis coli (APC) induced degradation, leading to the accumulation of β-catenin in the nucleus and constitutive transcription of its target genes
- Somatic CTNBB1 mutation is late event, found in up to 25% of PDTC and 60% of ATC, but very rare in well differentiated thyroid cancer, mainly associated with cribriform-morular variant PTC
- Immunohistochemistry with anti-β-catenin shows translocation of the protein from membranous pattern (typical for normal thyroid cells), to cytoplasmic and nuclear staining in tumor cells, which is highly specific for PTC cribriform-morular variant
EIF1A mutations
- Point mutations in EIF1AX (eukaryotic translation initiation factor 1A, X linked) gene were recently identified in 1.5% of PTC in a mutually exclusive fashion with other driver events
- Associated with RAS and adverse prognosis in PDTC and ATC
NTRK rearrangements
- NTRK1 (neurotrophic tyrosine kinase receptor type 1) is a receptor tyrosine kinase, which may activate MAPK signaling when rearranged with one of three potential fusion partners
- NTRK1 rearrangements are found in 1 - 5% of PTC and at higher frequencies in patients with radiation exposure
- ETV6-NTRK3 fusion was found in 2% of sporadic and 15% of radiation associated PTC
- ETV6-NTRK3 rearrangement is an essential feature of the MASC of thyroid
- Detected by FISH, RT-PCR, NGS
PIK3CA mutations
- Activating mutations in PIK3CA typically occur at hotspots within exons 9 and 20
- Late event
- Found in FTC (5 - 10%), PDTC (10%) and ATC (10 - 20%)
PTEN mutations
- PTEN is tumor suppressor gene, whose product terminates PI3K-AKT signaling
- Inactivating somatic PTEN mutations are infrequently found in follicular thyroid tumors (PTC 1 - 2%, FTC 10%) and ATC (10 - 20%)
- Germline mutations of PTEN cause Cowden syndrome, characterized by multiple hamartomas and increased risk of certain cancers, including breast cancer and FTC
- Loss of PTEN expression by immunostaining in adenomatous and neoplastic thyroid nodules is sensitive and specific for Cowden syndrome (can be used as a screening tool prior to genotyping)
RASAL1 mutation
- RASAL1 is a negative modulator of RAS, which suppresses RAS coupled MAPK and PI3K pathways
- RASAL1 can be inactivated via mutations or hypermethylation (mutually exclusive)
- 15% of ATC, rare in PTC and FTC (3 - 5%)
- RASAL1 germline alteration, predicted to be pathogenic, was identified in 1% of patients with Cowden-like syndrome who developed FTC without PTEN germline alteration
TERT promoter mutations
- TERT gene encodes telomerase reverse transcriptase, which adds telomeric repeats to the ends of chromosomes and thus contributes to immortalization of stem or cancer cells
- Mutations in TERT promoter (C228T and C250T) enhance transcriptional activity of the promoter
- TERT C228T and C250T (prevalence 3.5:1) are mutually exclusive
- Associated with BRAF V600E mutation, functionally explained by activation of TERT transcription via MAPK pathway
- PTC 10%, FTC 15%, with lower incidence in Asian series enriched with BRAF V600E, i.e. the higher the rate of BRAF, the lower the TERT incidence
- Highly prevalent in aggressive thyroid tumors, e.g., PDTC (30 - 40%), ATC (30 - 50%), also widely invasive oncocytic carcinoma and tall cell variant PTC (20%)
- Not found in benign thyroid lesions and MTC
- Detected by DNA based techniques (direct sequencing, next generation sequencing)
- Diagnostic value: 100% specific for malignancy
- Prognostic significance: associated with disease persistence / recurrence, distant metastasis, radioresistance and higher mortality in well differentiated thyroid cancer (PTC and FTC)
TP53 mutations
- TP53 / p53 is a tumor suppressor that plays important role in cell cycle regulation and DNA repair
- Most commonly mutated tumor suppressor gene in human cancer
- Wild (nonmutated) gene arrests cell cycle and activates apoptosis in response to DNA damage and diverse cellular stresses
- Virtually all mutations are located in hot spot region between exons 5 and 9, including codon 273, the most commonly affected
- Inactivating mutation in TP53 is a late event in thyroid cancer progression, which determines tumor dedifferentiation
- Occur at high frequency in PDTC (10 - 40%) and ATC (50 - 80%)
- Recently, TP53 mutations were found in some PTC and 22% of oncocytic FTC (small series)
- Detected by DNA based techniques (direct sequencing, realtime PCR, next generation sequencing)
- p53 immunoreactivity represents nuclear accumulation of the mutant TP53 (often evident in PDTC-ATC) and often, but not always, correlates with the molecular detection of TP53 mutation
- Well differentiated thyroid cancers carrying TP53 mutation have a potential for tumor dedifferentiation and more aggressive clinical course
TSH signaling pathway mutations
- Somatic TSHR mutations frequently occur in autonomously functioning thyroid nodules / adenomas (> 50%)
- Also found in extremely rare cases of "toxic" thyroid carcinomas
- Mutations in GNAS, a gene which encodes α subunit of heterotrimeric G protein complexes, occur predominantly in benign hyperfunctioning nodules, but with much lower rate (5%) than TSHR mutations
Rarely reported mutations
- IDH1 in FTC, PTC and ATC (10 - 20% collectively)
- EGFR in classic variant PTC (5%)

Additional mechanisms and events

mRNA expression

Transcriptomic studies (mainly based on DNA chip / microarray technology) found altered mRNA expression profiles in various thyroid tumors
Cancer initiating mutations and subsequent activation of MAPK or PI3K-AKT pathways cause altered expression of hundreds of genes involved in cell differentiation, energy metabolism, cell adhesion, etc.
mRNA microarrays find genes differentially expressed between benign and malignant thyroid and produce a gene signature (set of genes) for differential diagnosis, used in preoperative diagnosis of indeterminate thyroid nodules (e.g., Afirma gene expression classifier)

miRNA

Micro-RNAs (miRNAs) are small, noncoding RNA genes composed of 21 - 25 nucleotides
miRNAs may regulate pathway signaling, cell differentiation, invasion and metastasis by fine tuning gene expression
Overexpression of oncogenic miRNAs (miR-21 and miR-146b) in BRAF V600E PTC and inhibition of tumor suppressor miRNAs (let-7 family, miR-204 and miR-375) are implicated in thyroid cancer
OncomiRNAs miR-221 and miR-222 may play a role in PTC aggressiveness and are associated with less differentiated tumors
High expression levels of miR-146b correlate with lower overall survival in PTC
miRNA expression profiles differ between neoplastic and nonneoplastic thyroid tissue, which may have potential diagnostic utility

lncRNA

Long noncoding RNAs refers to nonprotein encoding transcripts 200 nucleotides in length or larger
Current data on their role in thyroid cancer are scarce, with only a few markers identified (HOTAIR, PTCSC2, PTCSC3)

Copy number variations

Copy number variation / alteration is a genetic aberration in which the copy number of a chromosomal region or gene is different from the normal two copies, due to gene gain or loss (through chromosomal instability, aneuploidy, amplification or deletion)
Detected by array based comparative genomic hybridization (aCGH)
Copy number gains in genes encoding members of the PI3K-AKT pathway may activate downstream signaling
In PTC, copy number alterations are detected with a relatively low frequency (25%) and are more common in PTC follicular variant and NIFTP; gene losses / deletions are more prevalent than gains / amplifications

Epigenetics

Aberrant methylation occurs via promoter hypermethylation (gene silencing) and hypomethylation (gene overexpression)
In PTC, the BRAF V600E mutation drives hypermethylation / silencing of important tumor suppressor genes (TIMP3, SLC5A8, DAPK1, RARB) and genes of iodide handling machinery (e.g., NIS, TSHR)
In FTC and ATC, activation of the PI3K-AKT pathway causes hypermethylation and silencing of PTEN, which in turn leads to failure to terminate the PI3K-AKT signaling and creates a self amplifying loop
Epigenetic events are important drivers of aggressive thyroid cancers, e.g., ATC
Certain methylation markers are useful for early detection of thyroid cancer and its subtypes
Histone modification (aberrant acetylation, methylation) is another epigenetic mechanism implicated in progression of PDTC and ATC, which can be targeted by drugs

Genetic susceptibility

Genome Wide Associated (GWAS) and candidate gene studies found a strong association / inherited predisposition of some single nucleotide polymorphisms (SNPs) with thyroid tumors
These polymorphic sites may affect the enhancer activity of genes or gene regulation
Risk of inherited susceptibility to the cancer increases with the presence of several risk alleles in an individual
SNPs inside (rs1867277) and upstream (rs965513) of FOXE1 gene on chromosome 9q22.33, which encodes thyroid transcription factor TTF2, are strongly associated with sporadic and radiation induced thyroid cancer; the potential mechanism is activation of FOXE1 transcriptional activity by the risk allele
SNPs rs944289 (area of the NKX2-1 gene, which encodes TTF1) and rs116909374 on chromosome 14q13.3 predispose to thyroid cancer, the former locus is also associated with FA risk
More susceptibility SNPs were found at 2q35 (rs966423 in DIRC3), 8p12 (rs2439302 in NRG1) and 8q24 (multicancer SNP rs6983267 in a gene poor region)
Several SNPs in RET gene are implicated in the increase of MTC risk

Molecular / cytogenetics images

Images hosted on other servers:

ALK fusions

β-catenin (nuclear) in cribriform-morular PTC associated with FAP syndrome

BRAF V600E (sequencing)

BRAF V600E (MALDI-TOF)

BRAF K601E

BRAF V600E / VE1

KRAS mutations

NRAS mutations (sequencing)

NRAS mutations (pyrosequencing)

PPARγ IHC in FTC (A)

PTEN IHC (A - C)

PTEN loss in Cowden syndrome

PTEN evaluation (breast cancer)

RET / PTC rearrangements

TERT promoter mutations

Videos

Genetics and genomics of thyroid neoplasms (2013) by Dr. Electron Kebebew, NCI

Integrated genomic characterization of papillary thyroid carcinoma (2014) by Prof. Tom Giordano, University of Michigan

Advances in molecular pathogenesis of thyroid cancer (2014) by Prof. Pilar Santisteban, Universidad Autónoma de Madrid

Molecular influence in thyroid cancer (2014) by The American Head and Neck Society

Understanding the biology of medullary thyroid cancer (2015) by Prof. Gilbert Cote, MD Anderson Cancer Center

Molecular targeted therapeutics for medullary thyroid cancer (2015) by Dr. Ann Gramza, NCI

MAPK pathway

PI3K-AKT pathway

Additional references

Molecular pathology-practical

Table of Contents

Definition / general

Thyroid cancer is a genetically simple disease with a relatively low number of mutations in each tumor
Driver mutations and gene fusions are identified in over 90% of thyroid cancers, making it one of the best molecular characterized malignancies in humans
MAPK and PI3K-AKT are 2 main signaling pathways involved in the development of thyroid tumors
- MAPK pathway: activated through point mutations of BRAF or RAS genes and RET / PTC rearrangements; primarily involved in papillary carcinoma
- PI3K-AKT pathway: activated through point mutations in RAS, PIK3CA, AKT1 and PTEN; primarily involved in follicular carcinoma
- Simultaneous activation of both pathways becomes more frequent as the tumor grade increases
Collectively, the most common alterations are BRAF and RAS point mutations and RET / PTC and PAX8 / PPARγ chromosomal rearrangements
Driver gene aberrations in well differentiated thyroid cancer are mutually exclusive (median = 1 mutation per tumor)
Dedifferentiated cancers accumulate additional genetic alterations, so called late events (median = 6 mutations per tumor)
Chromosomal rearrangements (and resultant gene fusions) are associated with radiation
Most somatic mutations are not thyroid specific and are commonly found in various solid cancers
Molecular techniques are typically applied to cytological smears, formalin fixed paraffin embedded and snap frozen tissue, see details on Molecular pathology basics page
- Mutations are detected with real time PCR and DNA sequencing
- Chromosomal rearrangements are detected with FISH and RT-PCR
- Immunohistochemistry is specific for detecting mutant proteins (BRAF V600E, NRAS Q61R)

Diagrams / tables

Images hosted on other servers:

Progress in identifying
mutational markers
in thyroid cancer

Gene mutations in thyroid tumors

Genomic landscape of PTC

Gene fusions in PTC

BRAF mutation and iodine uptake

BRAF V600E and tumor recurrence

TERT mutations

Drug targets in thyroid cancer

Uses by pathologists

Preoperative diagnosis of thyroid nodules with indeterminate FNA
Potential prognostic value to predict aggressive disease
Targeted therapy

Summary on key mutations within tumor type

Follicular adenoma (FA)
- RAS 20 - 40%
- PAX8 / PPARγ 5 - 20%
- No RET / PTC translocations, BRAF V600E mutation, PTEN mutations (except germline mutations in Cowden syndrome) or PIK3CA / AKT pathway mutations
Hyalinizing trabecular tumor
- Although early reports found RET / PTC somatic translocations with similar frequency as PTC, this was not confirmed with more robust techniques
- Absence / extreme rarity of BRAF and RAS mutations
Follicular thyroid carcinoma (FTC)
- Mutually exclusive RAS point mutations or PAX8 / PPARγ rearrangements in 75%
- RAS 30 - 50%
- PAX8 / PPARγ 30 - 35%
- TERT 10 - 20%
- PTEN < 10%
- PIK3CA 5 - 10%
Hürthle cell carcinoma (oncocytic variant of FTC)
- Alteration of mitochondrial DNA, including deletions, frameshift and missense point mutations
- Lower prevalence of mutations associated with nononcocytic FTC (RAS, PAX8 / PPARγ)
- GRIM19 mutations 10 - 20%
- RAS 10 - 20%
- PAX8 / PPARγ 5 - 15%, associated with follicular architecture
- TERT 15 - 20%
- TP53 up to 20%
- RET / PTC 35%, all with solid pattern of growth (based on one study)
Papillary thyroid carcinoma (PTC)
- Mutually exclusive genetic events found in 75 - 90% cases: point mutations in BRAF and RAS, rearrangements of RET and NTRK1
- BRAF 40 - 50%
- RAS 10 - 20%
- RET / PTC 5 - 20%
- TERT 5 - 10%
- NTRK 5%
Common PTC variants
- Classic variant: BRAF 40 - 70%, RET / PTC 5 - 40%, RAS 3 - 10%, TERT 10%, NTRK 0 - 5%
- Follicular variant: RAS 25 - 50%, PAX8 / PPARγ 5 - 30%, BRAF V600E up to 25% (invasive type), TERT 1 -10%, RET / PTC 5%, NTRK 0 - 10%, BRAF K601E < 1%
- NIFTP: RAS 30 - 45%, PAX8 / PPARγ up to 20%, THADA fusion up to 20%, EIF1AX 5%, absence of BRAF mutation and RET / PTC translocations
- Microcarcinoma: BRAF 20 - 80%, RET / PTC rearrangements and RAS mutations can be found, TERT < 5%
- Tall cell variant: BRAF 80 - 100%, TERT 20 - 30%, RET / PTC3
Rare PTC variants (based on small series)
- Columnar variant: BRAF 33%
- Diffuse sclerosing variant: RET / PTC rearrangement frequently found, while BRAF mutation is uncommon
- Hobnail variant: BRAF V600E mutation in most cases (50 - 80%), RET / PTC1 is much rarer (up to 20%)
- Warthin-like variant: BRAF 65%
- Cribriform-morular variant: RET / PTC rearrangements, RAS mutations and BRAF mutations not identified; germline APC or CTNNB1 mutations in familial adenomatous polyposis coli syndrome
Poorly differentiated thyroid carcinoma (PDTC)
- TERT 30 - 40%
- RAS 20 - 40%
- BRAF 5 - 30%, higher rate if arises from PTC
- EIF1AX 10%
- Rare chromosomal translocations (RET / PTC, PAX8 / PPARγ, ALK1)
- Late genetic events are common: TP53 (10 - 40%), CTNNB1 (0 - 25%) and genes that encode effectors of the PI3K-AKT signaling pathway, including PIK3CA, AKT1 and PTEN (10 - 20% collectively)
Anaplastic thyroid carcinoma (ATC)
- Coexisting mutations (median is 6 per case)
- TP53 50 - 80%
- TERT 30 - 50%
- RAS 20 - 50%
- BRAF 20 - 45%, especially if progress from PTC
- Less common mutations: CTNNB1 5 - 65%, PIK3CA 5 - 25%, PTEN 5 - 20%, RASAL 15%, EIF1AX 10%
- Fusions, e.g., ALK, are infrequent
Medullary thyroid carcinoma (MTC), sporadic
- Mutually exclusive RET or RAS mutations
- RET 30 - 65%, mainly RET M918T
- RAS 25% (HRAS > KRAS)
Medullary thyroid carcinoma (MTC), hereditary
- Germline RET mutations > 95%, with predominant RET C634A in MEN2A, and RET M918T in MEN2B syndromes, respectively

Clinically significant signatures

Diagnostic molecular signatures

Molecular testing is widely used for preoperative triage of patients with thyroid nodules indeterminate on FNA (Bethesda III - V), see Molecular testing in FNA
Presence of certain mutations in a sample has high sensitivity and specificity for malignancy, with recommendation for total thyroidectomy instead of diagnostic lobectomy
- BRAF V600E or RET / PTC rearrangement has virtually 100% risk of malignancy, likely to be conventional or tall cell variant PTC
- RAS, PAX8 / PPARγ or BRAF K601E confers 75 - 90% risk of cancer, most likely follicular variant PTC
- TERT, p53 or PIK3CA mutation predicts thyroid cancer (almost 100% risk), particularly advanced disease with propensity for dedifferentiation and distant metastasis
- RET M918T is associated with MTC (very high accuracy)
Single gene testing (usually BRAF V600E) is inexpensive, and can be performed using in house facilities
Molecular panels provide the best performance
- 4 genes (BRAF V600E, RAS, RET / PTC and PAX8 / PPARγ) are essential for any thyroid panel
- Commercially available panels include early generation (8 and 15 genes) and extended (60+ genes) panels
Mutation / fusion panels are highly sensitive for malignancy, often having over 95% positive predictive value ("rule in" cancer), however negative result of mutation test does not always predicts benign thyroid nodule; gene expression classifiers based on mRNA expression signatures provide 95% negative predictive value ("rule out" cancer)
Combination of rule in (mutation / fusion panel) and rule out (gene expression classifier) tests is potentially the best approach to indeterminate thyroid nodules, however its cost effectiveness is doubtful

Prognostic significance

BRAF V600E is a marker of higher tumor recurrence and tumor related mortality in PTC patients
- These patients may benefit from more extensive initial surgery with central compartment lymph node dissection to prevent tumor recurrence
- BRAF mutation is a sensitive, but not a specific marker of tumor aggressiveness
- Most patients with BRAF V600E mutation do not have recurrent disease and overall survival remains very high in both groups of patients
TERT promoter mutations are associated with aggressive phenotype of PTC and FTC, including high persistence / recurrence and increased mortality
- Recent studies have shown that the prognostic value of TERT mutations is significantly stronger than that of BRAF V600E
Combination of BRAF V600E mutation with TERT, AKT1, PIK3CA or TP53 mutations predicts more aggressive tumor behavior
- Patients with BRAF and TERT mutations alone had recurrence rates of 25% and 50%, respectively, whereas patients with both mutations had a recurrence rate of 70%

Treatment

Therapeutic utility

With a high rate of targetable ("druggable") molecular abnormalities in thyroid cancer, genotyping has diagnostic and possibly therapeutic relevance
Patients who may benefit from targeted therapy
- Radioiodine resistant differentiated thyroid cancer (metastatic PTC or FTC)
- PDTC, ATC
- MTC
The most studied drugs are tyrosine kinase inhibitors (TKI, or MKI, multikinase inhibitors)
- MKIs block various cell surface (growth factor receptor) and intracellular (members of MAPK signaling) kinases
- Inhibition of VEGF (vascular endothelial growth factor) mediated pathways contributes to the antiangiogenic effect of MKI
- Currently, 4 kinase inhibitors are approved for treatment of differentiated thyroid cancer and MTC
  - Sorafenib, an inhibitor of VEGFR1, VEGFR2, VEGFR3, RET (including RET / PTC), RAF (including BRAF V600E), and PDGFRβ (platelet derived growth factor receptor β)
  - Lenvatinib blocks VEGF receptors 1, 2 and 3, FGF receptors 1 - 4, PDGFRα, RET and KIT
  - Vandetanib (VEGFR2, RET, EGFR) and Cabozantinib (VEGFR2, RET, MET) are approved in the USA and EU for treatment of MTC
- MKI treatment is not curative, and patients eventually develop resistance
Other targeted therapies currently in clinical trials:
- Selective BRAF inhibitors (Vemurafenib, Dabrafenib)
- PPARγ agonists
- ALK inhibitors (Crizotinib)
- Highly selective mTOR inhibitors
- PTEN modulators
- NTRK inhibitors
- Immune checkpoint blockade (anti-CTLA4, anti-PD1, and anti-PDL1)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

V600E mutant protein is diffusely expressed in tumor / cancer, but not normal tissue

Diffuse cytoplasmic staining

Molecular / cytogenetics images

Images hosted on other servers:

ALK fusions

β-catenin (nuclear) in cribriform-morular PTC associated with FAP syndrome

BRAF V600E (sequencing)

BRAF V600E (MALDI-TOF)

BRAF K601E

BRAF V600E / VE1

KRAS mutations

NRAS mutations (sequencing)

NRAS mutations (pyrosequencing)

PPARγ IHC in FTC (A)

PTEN IHC (A - C)

PTEN loss in Cowden syndrome

PTEN evaluation (breast cancer)

RET / PTC rearrangements

TERT promoter mutations

Videos

Molecular influence in thyroid cancer (2014)

Biomarkers in thyroid cancer (2015)

Drugs in development for refractory thyroid cancer (2015)

Molecular targeted therapeutics for medullary thyroid cancer (2015)

Additional references

Molecular testing in FNA

Table of Contents

Definition / general

Ancillary molecular testing is used to further stratify the risk of indeterminate thyroid nodules classified as Bethesda III (atypia of undetermined significance [AUS] / follicular lesion of undetermined significance [FLUS]) or IV (suspicious for follicular neoplasm [SFN] / follicular neoplasm [FN]) for clinical decision making (e.g., close follow up versus repeat FNA versus surgical lobectomy versus thyroidectomy) (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2017)
Diagnostic performance of molecular tests is determined by sensitivity, specificity, negative predictive value and positive predictive value (Arch Pathol Lab Med 2018;142:446)
Molecular tests in thyroid FNA evolved from a single gene test (BRAF mutation) and few genes panels to comprehensive molecular classifiers combining next generation sequencing (NGS) detection of multiple mutations / fusions and gene expression with miRNA profiling
- Detection of mutation is considered a rule in approach, i.e., indicative of neoplasia
- Gene expression classifier contributes as a rule out approach, i.e., excluding malignancy
- Combination of both achieves the highest accuracy

Essential features

Molecular testing in thyroid FNA is used for clinical decision making in indeterminate thyroid nodules (Bethesda III - IV)
Molecular tests are based on detection of thyroid tumor specific mutations (rule in malignancy), sometimes added by gene expression profiling (rule out)
Commercially available platforms (ThyroSeq, Afirma and others) are used along with laboratory developed NGS panels

Purpose of molecular tests

Further characterize lesions diagnosed as indeterminate on FNA and aid in clinical decision making
Different molecular platforms will categorize noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) differently; for example, the ThyroSeq v3/GC considers NIFTP together with malignant nodules because both tumor types require surgical excision (Cancer 2018;124:1682)

Diagrams / tables

Images hosted on other servers:

Overview of platforms and workflow

Proposed clinical algorithm

NPV and PPV of ThyroSeq v2.1

Genetics of thyroid tumors

Diagnostic performance

Background - genetic alterations in thyroid lesions

Mutations in papillary thyroid carcinoma: BRAF mutation (29 - 69%), RET rearrangement (13 - 43%), NTRK1 rearrangement (5 - 13%), RAS mutation (0 - 21%)
- NIFTP and invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) possess molecular profiles similar to follicular adenomas / carcinomas (higher rates of RAS than BRAF mutations) (Mod Pathol 2010;23:1191)
- Conversely, the infiltrative follicular variant of papillary carcinoma has a molecular profile that is more similar to that of classic papillary thyroid carcinoma (higher rates of BRAF than RAS mutations)
- Hence, FNA indeterminate diagnoses may suggest the need for molecular testing to further prognosticate thyroid lesions into these molecular / behavioral subsets of lesions
Mutations in follicular thyroid carcinoma: RAS mutation (40 - 53%), PPARG rearrangement (25 - 63%)
References: Cell 2014;159:676, N Engl J Med 2016;375:1054, Annu Rev Pathol 2018;13:141, Cancers (Basel) 2021;14:204

Overview of molecular tests / platforms

Commercial thyroid platforms are widely used in North America but not available abroad
- Outside of North America, molecular testing in thyroid FNA is possible via targeted cancer gene commercial panels, custom laboratory developed NGS panels and single gene tests (BRAF, RAS)
ThyroSeq v3 (UPMC; also known as ThyroSeq GC)
- Sample collection: residual aspirated material collected from routine FNA placed in nucleic acid preservative solution is ideal (J Clin Endocrinol Metab 2011;96:3390)
- Test can be performed on fixed FNA cells from a cytology cell block and on FFPE tissue samples (Cancer 2018;124:1682)
- Test method: DNA and RNA based next generation sequencing assay that detects hundreds of genetic alterations, including point mutations, insertions / deletions, gene fusions, copy number alterations and abnormal gene expression (Cancer 2018;124:1682)
- Genomic classifier (GC) score is calculated as a sum of individual values of detected genomic alterations for each sample to separate malignant lesions from benign lesions (Cancer 2018;124:1682)
- Performance: GC distinguished cancer from benign nodules with a sensitivity of 98.0%, specificity of 81.8% and accuracy of 90.9% in an FNA validation set (Cancer 2018;124:1682)
- Caveats: accurate performance expected with a minimum of 12% tumor cells in a background of nonneoplastic thyroid cells; additionally, a sample is considered adequate with up to 88% blood contamination (Cancer 2018;124:1682)
- Information from UPMC with list of tested mutations: ThyroSeq®
- References: Cancer 2018;124:1682, JAMA Oncol 2019;5:204, Cancer Cytopathol 2019;127:225
Veracyte's Afirma Gene Expression Classifier (GEC)
- Sample collection: 2 needle passes to collect material for testing in addition to the routine FNA sample for cytology
- Test method: proprietary RNA expression molecular profile analysis
- Performance: 92% sensitivity and 52% specificity for classifying nodules as suspicious; 95% negative predictive value (NPV) for Bethesda III category lesions, 94% NPV for Bethesda IV category lesions (N Engl J Med 2012;367:705)
- Additional tests: Afirma MTC tests for genes associated with medullary thyroid carcinoma and BRAF test available on samples as well
- Caveats: reports nodules as benign or suspicious and does not report specific genetic alterations; while benign result has high NPV, suspicious result has poor positive predictive value (PPV) (16 - 61%, with wide variability in reports) (Cancer Cytopathol 2014;122:737, Diagn Cytopathol 2015;43:966, Endocr Pract 2014;20:364, Ann Surg Oncol 2015;22:3996, J Clin Endocrinol Metab 2014;99:4069, Cancer Cytopathol 2016;124:100, Endocr Pract 2016;22:666)
ThyGeNEXT and ThyraMIRv2 (Thyroid 2022;32:1362)
- Sample collection: test fresh FNA samples or direct smears / ThinPrep slides; no special shipping or refrigeration requirements
- Test method: the only testing platform that utilizes both mutational (DNA and RNA) and microRNA markers
- Performance: 98% sensitivity, 98% specificity, 99% negative predictive value, 96% positive predictive value
- Additional tests: medullary thyroid carcinoma profile that uses pairwise microRNA expression to detect medullary thyroid carcinoma, particularly helpful in absence of mutations
- Caveats: limited real world clinical experience / follow up
RosettaGX® Reveal™ thyroid miRNA (Diagn Cytopathol 2018;46:901)
- Sample collection: test material may include ThinPrep prepared slides or a direct smear from a thyroid FNA
- Test method: molecular microRNA analysis
- Performance: overall correct rate of 64.2% and specificity of 60.3% for benign / NIFTP cases and correct rate of 77.8% in malignant cases in a retrospective study
- Caveats: limited real world clinical experience / follow up

Videos

ThyroSeq testing by Y. Nikiforov (2020)

ThyGenX / ThyraMIR panel by Alidad Mireskandari (2018)

Board review style question #1

For which diagnostic category does the American Thyroid Association (ATA) 2015 guideline recommend one can utilize molecular testing results to assess risk of malignancy as an alternative to proceeding directly to surgery?

Benign (II)
Follicular neoplasm / suspicious for follicular neoplasm (IV)
Malignant (VI)
Nondiagnostic (I)
Suspicious for malignancy (V)

Board review style answer #1

B. Follicular neoplasm / suspicious for follicular neoplasm (IV)

Comment Here

Reference: Molecular testing in FNA

Board review style question #2

Which genetic alteration is likely to be detected in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)?

BRAF
NTRK1
P53
RAS
RET

Board review style answer #2

D. RAS

Comment Here

Reference: Molecular testing in FNA

Mucoepidermoid carcinoma

Table of Contents

Definition / general

Rare low grade malignant epithelial neoplasm with epidermoid and mucinous components (WHO: Pathology and Genetics of Tumours of Endocrine Organs, 3rd Edition, 2004)
Two variants of mucoepidermoid carcinoma in thyroid: mucoepidermoid carcinoma (discussed in this section) and sclerosing mucoepidermoid carcinoma with eosinophilia

Essential features

Rare low grade malignant epithelial neoplasm with epidermoid and mucinous components

Epidemiology

Affects all ages, more female than males (F/M = 2/1)
0.5% of all thyroid malignant neoplasms
Shares most of the epidemiological features of papillary thyroid carcinoma

Pathophysiology

Can arise from metaplastic dedifferentiation of papillary thyroid carcinoma, follicular carcinoma or oncocytic carcinoma (Thyroid 2012;22:205)
May arise from thyroid follicular epithelium based on molecular studies (Clin Endocrinol (Oxf) 2002;57:551) or from solid cell nests based on ciliated epithelium (Pathol Int 2008;58:741)

Etiology

May be associated with radiation exposure

Clinical features

Euthyroid with painless "cold / hypofunctioing" mass in the thyroid gland

Radiology images

Images hosted on other servers:

Large tumor with
internal hypodensity
lesion

Prognostic factors

Good long term prognosis; can have extrathyroidal invasion and regional lymph nodes metastasis but distant metastases or death due to disease are uncommon

Case reports

29 year old woman with follicular variant of papillary carcinoma (Am J Surg Pathol 1995;19:1209)
35 year old man with papillary carcinoma with mucoepidermoid differentiation (Am J Clin Pathol 1991;95:175)
50 year old man with composite follicular variant of papillary carcinoma and mucoepidermoid carcinoma (J Korean Med Sci 2010;25:1683)
86 year old man with composite mucoepidermoid carcinoma and columnar cell variant of papillary thyroid carcinoma (Int J Surg Pathol 2016;24:336)
91 year old woman with a rapidly growing mass of the left upper neck (Case Rep Endocrinol 2012;2012:862545)
Case with papillary carcinoma with mucoepidermoid differentiation (Arch Pathol Lab Med 1996;120:397)

Treatment

Surgery or external beam radiation
Radio ablation for cases with extensive invasion

Gross description

Noncircumscribed, firm, white to brownish tan cut surface; may have mucoid or cystic spaces

Gross images

Images hosted on other servers:

White tan cut surface

Microscopic (histologic) description

Similar but not identical to mucoepidermoid carcinoma of the salivary glands
Nests of epidermoid and mucin producing cells (mucocytes) embedded in fibrotic tissue
Medium sized nuclei with pale chromatin mimicking papillary thyroid carcinoma (can show nuclear grooves and pseudoinclusions)
Mucocyte with clear to foamy or vacuolated cytoplasm, can have hyaline bodies (PAS+) in the cytoplasm
Ciliated cells may be seen
Can show extracellular mucin, comedo necrosis and psammoma bodies
Foci of associated papillary thyroid carcinoma in up to 50% of cases
Often with background of lymphocytic thyroiditis
No eosinophils

Microscopic (histologic) images

AFIP images

Solid nest with mucin producing foci

Microcystic pattern of mucin producing cells

Images hosted on other servers:

Partially solid, glandular and papillary

Squamoid nests and
mucin secreting
component

Transition from follicular
variant of papillary carcinoma
to mucoepidermoid carcinoma

Immunohistochemistry
of TTF1 and
thyroglobulin

Cytology description

Epidermoid cells and mucus secreting cells with background cell debris or mucin

Positive stains

Focally positive for Thyroiglobulin and TTF1
Cytokeratin, CAM 5.2, CEA (polyclonal), intracytoplasmic mucin stains with Alcian blue and mucicarmine

Negative stains

Calcitonin, chromogranin

Molecular / cytogenetics description

Can demonstrate t(11;19) and CRTC1 / MAML2 fusion transcript (Genes Chromosomes Cancer 2007;46:708) and have common origin with Warthin tumor (Genes Chromosomes Cancer 2008;47:309)

Differential diagnosis

Anaplastic carcinoma: highly malignant carcinoma with necrosis, can have squamous component
CASTLE: squamoid cells with variable amount of lymphocytes without eosinophils, CD5+ CD117+, can have mucin
Direct extension or metastasis of salivary mucoepidermoid carcinoma: different primary site
Sclerosing mucoepidermoid carcinoma with eosinophilia: sclerosis and brisk infiltrate of eosinophils
Solid cell nests and squamous metaplasia: confined to lateral and upper portion of thyroid lobes; no atypia and invasion, can have cystic change with luminal mucin, however, no mucin secreting cells / mucocytes
Squamous cell carcinoma: sheets of highly atypical squamous cells with necrosis, no mucin, no eosinophils

Board review style question #1

Which statement is not true for mucoepidermoid carcinoma of thyroid?

Comedo necrosis and psammoma bodies may be seen
Foci of associated papillary thyroid carcinoma are often seen
Lymph nodes metastases, extrathyroidal invasion are common
Mucoepidermoid carcinoma of thyroid is associated with lymphocytic thyroiditis
Similar to sclerosing mucoepidermoid carcinoma with eosinophilia, it cannot have t (11;19) - CRTC1 / MAML2 rearrangement

Board review style answer #1

E. Similar to sclerosing mucoepidermoid carcinoma with eosinophilia, it cannot have t (11;19) - CRTC1 / MAML2 rearrangement. Mucoepidermoid carcinoma can have t (11;19) - CRTC1 / MAML2 rearrangement.

Comment Here

Reference: Mucoepidermoid

NIFTP

Table of Contents

Definition / general

Formerly known as "noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC)"
Suggested to rename lesion to NIFTP based on international, multicenter consensus study showing evidence for indolent biological behavior (lack of metastasis or recurrence) (Mod Pathol 2016;29:698)
Discrepancies commonly affecting nuclear feature evaluation were simplified and criteria were established (see Microscopic (histologic) description below) to provide reproducible standards for separating NIFTP from benign hyperplastic nodules and follicular adenoma morphologically with an overall classification accuracy of 94.3% (JAMA Oncol 2016;2:1023)

Essential features

Encapsulated / circumscribed neoplasm with follicular growth pattern and nuclear features of papillary thyroid carcinoma
Diagnosis of NIFTP requires surgical excision specimen with complete evaluation of tumor to normal interface to exclude capsular invasion
Most commonly associated molecular alterations are RAS mutations
Indolent disease course with excellent long term survival (following surgical excision; lobectomy / partial thyroidectomy sufficient)

Epidemiology

Prevalence is 9.1% of all papillary thyroid cancers worldwide (although NIFTP should now be considered a noncancer) based on meta-analysis (Endocr Pathol 2018 Feb 23 [Epub ahead of print])
Very rare in Asian population (1.6%) compared with Western series (13.3%)
- Due to various perceptions of histological diagnostic thresholds, different nature of papillary thyroid carcinoma and different approaches in the management of thyroid nodules (Endocr Pathol 2018 Feb 23 [Epub ahead of print])
Occasionally reported in pediatric population (Cancer Cytopathol 2018;126:27, Pediatr Blood Cancer 2018;65:e26966)

Pathophysiology

NIFTP is considered a borderline RAS lineage tumor between follicular adenoma and follicular carcinoma or invasive EFVPTC

Diagrams / tables

Contributed by David Poller, M.D.

Mutations in various types of thyroid tumors

Putative molecular pathogenesis of thyroid tumors

Indeterminate cytological diagnosis

Images hosted on other servers:

NIFTP incidence

Diagnostic algorithm

History of NIFTP

Diagnosis

Pathologic diagnostic criteria:

Inclusion criteria
- Major features:
  - Encapsulation or clear demarcation
  - Follicular growth pattern with less than 1% papillae (see comment below)
  - If solid, trabecular or insular patterns seen; these in total should be less than 30% of the total tumor volume
  - No psammoma bodies
  - Nuclear features of papillary thyroid carcinoma (enlargement, crowding / overlapping, elongation, irregular contours, grooves, pseudoinclusions, chromatin clearing), nuclear score should be 2 or 3
- Minor features:
  - Dark colloid
  - Irregularly shaped follicle
  - "Sprinkling sign"
  - Follicles cleft from stroma
  - Multinucleated giant cells within follicles
Exclusion criteria:
- Any capsular or vascular invasion but if the whole capsule has not been examined thoroughly then the default diagnosis is still noninvasive encapsulated FVPTC (EFVPTC) and it is NOT a NIFTP
- True papillary structures in more than 1% of tumor volume, psammoma bodies, infiltrative border
- Tumor necrosis (not associated with FNA), increased mitoses (defined as at least 3 per 10 HPF)
- Cell / morphological characteristics of any other papillary thyroid carcinoma variant (e.g., tall cell, columnar cell, cribriform morular, diffuse sclerosing, etc.) or oncocytic lesion (JAMA Oncol 2016;2:1023)
Additional exclusion criteria (2017, Hum Pathol 2018 Jan 12 [Epub ahead of print], Pathol Int 2018 Apr 19 [Epub ahead of print])
- No papillae
- No BRAF^V600E and TERT promoter mutations
- No distant metastasis
Diagnosis of NIFTP is possible only on surgical samples because it requires careful capsule evaluation
No reliable preoperative modalities (sonography, fine needle aspiration cytology (FNAC), molecular testing) are available at this time

Radiology description

Wider than tall shape, smooth borders, occurrence in multinodular glands and no calcifications (Diagn Cytopathol 2018;46:139)
Perinodular and intranodular Doppler flow patterns, minimal Doppler flow grade
Similar to follicular adenoma and minimally invasive follicular carcinoma (Diagn Cytopathol 2017;45:533)

Radiology images

Images hosted on other servers:

Ultrasonography

Prognostic factors

Excellent, based on an international, multidisciplinary, retrospective study in which all 109 participants with noninvasive follicular variant of papillary thyroid carcinoma (EFVPTC) were alive with no evidence of disease at a median followup time of 13 years (JAMA Oncol 2016;2:1023, Mod Pathol 2016;29:698)

Case reports

37 year old woman with NIFTP showing focal spindle cell metaplasia (Int J Surg Pathol 2018;26:261)
76 year old woman with NIFTP and spindle cell metaplasia (Pathol Res Pract 2017;213:416)

Treatment

It is believed that tumor excision is sufficient; no extended surgery (total / completion thyroidectomy, neck dissection), radioiodine ablation and thyroid stimulating hormone (TSH) suppression therapy needed (Endocr Pract 2017 Jul 13 [Epub ahead of print], Endocr Pract 2017;23:1150)

Gross description

Well circumscribed, encapsulated, solid nodules (Head Neck Pathol 2011;5:51)
Average size is 2 - 3 cm; can vary from subcentimeter (Endocrine 2018;59:143) up to 8 cm (Thyroid 2017;27:512)

Gross images

Images hosted on other servers:

Gross and histology of EFVPTC

Microscopic (histologic) description

Nuclear features of papillary thyroid carcinoma present
- Each category is assigned a score of 0 or 1, resulting in an overall score between 0 - 3, where a total of 0 - 1 is not diagnostic of NIFTP and 2 - 3 is diagnostic of NIFTP
- Size and shape: nuclear enlargement, overlapping, crowding, elongation
- Nuclear membrane irregularities: irregular contours, grooves, pseudoinclusions
- Chromatin characteristics: clearing with margination, glassy nuclei
Fibrous capsule may be thick, thin, partial or the lesion may be well circumscribed / clearly demarcated from adjacent thyroid tissue
Follicular growth pattern may be microfollicular, normofollicular or macrofollicular with abundant colloid (JAMA Oncol 2016;2:1023)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and Rachel Jug, M.B.B.Ch.

Circumscribed follicular patterned nodule

Tumor interface with a thin capsule

Microfollicular pattern

Major and minor diagnostic features

Dark colloid with scalloping and clefting

Free floating tumor fragment in vessel

Small piece of tumor floats in vascular lumen

Processing artifact with distorted nuclei

Distorted nuclei due to artifact

Vesicular-like nuclei due to tissue degeneration

Clear circumscription of the encapsulated lesion with a predominantly follicular growth pattern

Nuclear features of PTC

Images hosted on other servers:

Noninvasive follicular thyroid neoplasm

Low power

Medium power

5.6 cm NIFTP

High power

NIFTP vs HCC

NIFTP vs PDTC

NIFTP vs FTC

NIFTP vs FVPTC

Encapsulated follicular patterned lesion

Nuclear features

Cytology description

FNAC samples are usually hypercellular with neoplastic cells possibly with focal nuclear features of papillary thyroid carcinoma arranged in microfollicles
Nuclear features are subtler than those of conventional papillary thyroid carcinoma; nuclear inclusions are very infrequent or absent as compared with classical type papillary carcinoma and papillae are absent
Colloid may be present
Cannot distinguish invasive encapsulated follicular variant of papillary thyroid carcinoma from NIFTP on cytology because the capsule cannot be evaluated by FNA; however NIFTP has few intranuclear inclusions and does not normally show papillae on FNA
Most NIFTP cases are clustered within the categories follicular neoplasm (FN) / suspicious for follicular (SFN), atypia of unknown significance (AUS) / follicular lesion of unknown significance (FLUS) and suspicious for malignancy
In case of cytologic features suggestive of FVPTC / NIFTP, optional notes in cytologic diagnosis may be used to acknowledge NIFTP: "Although the architectural features suggest a follicular neoplasm (or another Dx category), some nuclear features raise the possibility of an invasive FVPTC or its recently described indolent counterpart, NIFTP; definitive distinction among these entities is not possible on cytologic material" (Thyroid 2017;27:1341)
References: Cancer Cytopathol 2016;124:181, Hum Pathol 2016;54:134, Am J Clin Pathol 2015;144:850, Cancer 2016;124:699

Cytology images

Images hosted on other servers:

Microfollicular pattern, nuclear enlargement

Microfolliclar pattern

Microfollicles, nuclear grooves

Enlarged nuclei

Molecular / cytogenetics description

Shares molecular features (RAS mutations) with follicular adenoma, follicular carcinoma and do not show BRAF^V600E mutations, which is a useful diagnostic feature (Mod Pathol 2010;23:1191, Histopathology 2015;67:579)

Videos

Nomenclature change for thyroid tumors: NIFTP (2017) by Prof. Yuri Nikiforov, University of Pittsburg

NIFTP by R. Ghossein (2020)

Diagnostic dilemmas in NIFTP by N. Cipriani (2020)

Additional references

Synopsis for pathologists: Mod Pathol 2018;31:39, Histopathology 2018;72:53
Endocr Pathol 2015;26:191, Wikipedia: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features [Accessed 25 April 2018], Diagnostic Histopathology 2016;22:171
Articles for pathologists: J Clin Pathol 2016;69:947, J Clin Endocrinol Metab 2016;102:15
Articles for cytopathologists: Cancer Cytopathol 2016;124:616, Cancer 2016;124:767
Articles for clinicians: Thyroid 2016;26:869

Board review style question #1

BRAF^V600E
PAX8 / PPAR gamma rearrangement
PIK3CA
RAS family
TERT promoter

Board review style answer #1

D. RAS family. NIFTP shares molecular alterations similar to those seen in follicular lesions (follicular adenoma and follicular carcinoma).

Comment Here

Reference: NIFTP

Board review style question #2

Follicular growth pattern
Nuclear elongation
Nuclear grooves
Thick colloid
True papillae

Board review style answer #2

E. True papillae. The presence of any true papillae is an exclusion criterion for making a diagnosis of NIFTP. Other exclusion criteria include capsular invasion, increased mitotic rate and tumor necrosis.

Comment Here

Reference: NIFTP

Oncocytic

Table of Contents

Definition / general

Rare type of papillary carcinoma (PTC) characterized by nuclear features of papillary carcinoma and oncocytic / oxyphilic / Hürthle cell like cytoplasm (mitochondria-rich)
Oncocytic changes can be seen in other thyroid cancer (Hürthle cell carcinoma, medullary carcinoma) and in other variants of papillary carcinoma (tall cell variant, Warthin-like variant)

Essential features

Papillary carcinoma with oncocytic cytoplasm
Abundant altered mitochondria on ultrastructural examination
Must differentiate from other oncocytic thyroid tumors, especially tall cell papillary thyroid carcinoma

Terminology

Papillary carcinoma, oxyphilic variant
Papillary carcinoma, Hürthle cell variant

ICD coding

ICD-O: 8342/3 - papillary carcinoma, oxyphilic cell
ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

Less than 10% of all papillary carcinomas (Ann Otol Rhinol Laryngol 2009;118:374, Thyroid 2018;28:1462)
- < 0.5% when purely oncocytic without admixture of other patterns (Oncotarget 2017;8:77075, Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)
Age: 20 - 76 years, usually older than patients with conventional papillary carcinoma (Thyroid 2018;28:1462, Ann Otol Rhinol Laryngol 2009;118:374, Oncotarget 2017;8:77075, Eur J Nucl Med Mol Imaging 2019;46:2526)
74 - 86% women (Thyroid 2018;28:1462, Ann Otol Rhinol Laryngol 2009;118:374, Oncotarget 2017;8:77075)

Sites

Either lobe or isthmus of thyroid gland, also in ectopic thyroid tissue, e.g., thyroglossal cyst or struma ovarii

Pathophysiology

Increasing accumulation of somatic mitochondrial DNA mutations, upregulation of energy pathways (pyruvate synthesis, Krebs cycle, electron transport chain) and mitochondrial related pathways (Mitochondrion 2019;46:123)

Clinical features

Painless neck swelling or enlarged cervical lymph node
Associated with lymphocytic / Hashimoto thyroiditis in 38 - 91% (Thyroid 2018;28:1462, Am J Clin Pathol 1995;103:280)

Diagnosis

Preoperative fine needle aspiration cytology
Histopathological examination of tumor post resection

Radiology description

Similar to classic papillary carcinoma on ultrasound
Well lobulated with peripheral calcifications or macrocalcification (J Ultrasound Med 2015;34:1)
Lacks microcalcification (Front Endocrinol (Lausanne) 2018;9:223)

Radiology images

Images hosted on other servers:

Ultrasound

Prognostic factors

Recent series showed that prognosis is similar to classical papillary carcinoma, although earlier reports raised concern about poorer prognosis (Braz J Otorhinolaryngol 2013;79:738, Oncotarget 2017;8:77075, Thyroid 2018;28:1462, Eur J Nucl Med Mol Imaging 2019;46:2526, Ann Otol Rhinol Laryngol 2009;118:374, Clin Endocrinol (Oxf) 2016;85:797)
Radioactive iodine resistance has been reported (Arch Pathol Lab Med 2008;132:1241)
Risk stratification as per American Thyroid Association 2015 guidelines (Thyroid 2016;26:1)

Case reports

28 year old woman with lymphocytic thyroiditis (Asian Journal of Oncology 2016;02:85)
60 year old man with lymph node metastases (Pathology 2015;47:S81)
64 year old woman with multifocal involvement (Türk Onkoloji Dergisi 2010;25:161)
70 year old woman with brain metastasis (Virchows Arch 2013;462:473)

Treatment

Usually surgical excision per American Thyroid Association and The National Comprehensive Cancer Network guidelines (Thyroid 2016;26:1, J Natl Compr Canc Netw 2018;16:1429)

Gross description

Mean size 2.0 - 2.8 cm (Thyroid 2018;28:1462, Eur J Nucl Med Mol Imaging 2019;46:2526)
Solid, firm nodule
Brown in color similar to Hürthle cell tumors
Variable calcification and encapsulation

Microscopic (histologic) description

Usually papillary, can be follicular, rarely solid (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 3rd Edition, 2019, Clin Endocrinol (Oxf) 2016;85:797, Acta Cytol 2019:1)
Composed of oncocytic (oxyphilic, Hürthle) cells
- Polygonal cells with well defined cell borders
- Abundant, dense eosinophilic, granular cytoplasm
- Can be discohesive, similar to Hürthle cell tumors (adenoma / carcinoma)
Nuclear features
- Nuclear enlargement, round to oval nuclei
- Nuclear membrane with irregular contour, nuclear grooves, frequent intranuclear pseudoinclusions
- Chromatin clearing / chromatin margination / Orphan-Annie nuclei / ground glass nuclei
- Prominent nucleoli, may be hidden due to above nuclear changes
- Nuclear overlapping is uncommon (Acta Cytol 2019:1)
Ideally should be purely oncocytic, however cut off of for proportion of oncocytic cells is not established
Psammoma bodies may be found

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Nucleoli and pseudoinclusions

Oncocytic cells with pseudoinclusions

Cytology description

Cellular aspirate
Monotonous population of polygonal cells arranged as sheets, clusters, papillae or single
More than 75% of cells have oncocytic changes of dense cytoplasm and well defined cell borders (Acta Cytol 2019:1)
Nuclear enlargement, fine powdery chromatin, nuclear grooves, prominent intranuclear pseudoinclusions

Cytology images

Contributed by Shipra Agarwal, M.D.

Loose clusters of oncocytic cells

Predominant oncocytic cells

Intranuclear inclusions

Positive stains

Thyroid specific: TTF1, PAX8, thyroglobulin
Cytokeratins: AE1/AE3, CK7, CK19
HBME, galectin3 (Virchows Arch 2004;445:183)
Hürthle cells frequently demonstrate unusual staining pattern (lower intensity for TTF1/PAX8, abnormal positivity of cytoplasmic markers) compared to nononcocytic thyroid tumors due to abundant intracellular biotin

Negative stains

Calcitonin

Electron microscopy description

Dark and clear cells, both having abundant abnormal mitochondria (more so in dark cells), displaying stacks of parallel cristae, filamentous bundles and woolly densities (Ultrastruct Pathol 1985;8:269, Ultrastruct Pathol 1985;8:131)
Small dense bodies (Ultrastruct Pathol 1985;8:269, Ultrastruct Pathol 1985;8:131)
Indented nuclei (Ultrastruct Pathol 1985;8:269, Ultrastruct Pathol 1985;8:131)
Intact autophagosomes (Mitochondrion 2019;46:123)

Molecular / cytogenetics description

Mitochondrial DNA mutations, especially complex I genes of the oxidative phosphorylation, are characteristic (Mitochondrion 2019;46:123, Biochim Biophys Acta 2011;1807:633, BMC Cancer 2012;12:53)
BRAF^V600E mutation in about half of cases in limited series (J Pathol 2004;202:247)
High prevalence of RET⁄PTC in early studies is currently debated (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 3rd Edition, 2019)
Somatic and germline mutations of GRIM-19 involved in mitochondrial metabolism (Br J Cancer 2005;92:1892)

Sample pathology report

Thyroid, total thyroidectomy:
- Papillary thyroid carcinoma, oncocytic variant, left lobe, 1.5 cm (see synoptic report)

Differential diagnosis

Tall cell variant of papillary thyroid carcinoma:
- Height of cells 2 to 3 times the cell width, has adverse prognosis
Warthin-like variant of papillary thyroid carcinoma:
- Dense lymphoplasmacytic rich infiltrate within the vascular cores
Hürthle cell adenoma:
- Encapsulated oncocytic tumor, round nuclei, prominent centrally placed nucleoli, cells lack well developed nuclear features of papillary thyroid carcinoma
Hürthle cell carcinoma:
- Encapsulated oncocytic tumor with capsular or vascular invasion, round nuclei, prominent centrally placed nucleoli
- Cells lack well developed nuclear features of papillary thyroid carcinoma
Oncocytic variant of poorly differentiated thyroid carcinoma:
- Increased mitotic activity of ≥ 3 mitoses per 10 high powered field, necrosis, lack of nuclear features of papillary thyroid carcinoma
Oncocytic variant of medullary thyroid carcinoma:
- Stippled chromatin, amyloid, calcitonin immunoreactivity, scattered enlarged hyperchromatic nuclei, secretory granules on ultrastructural examination
Nodular / adenomatous hyperplasia with oncocytic metaplasia:
- Develops in a background of lymphocytic / Hashimoto thyroiditis / adenomatous goiter, cells lack fully developed nuclear features of papillary carcinoma

Board review style question #1

Abnormal mitochondria
Filament-ribosomal complexes
Membrane bound crystals
Neurosecretory granules
Paranuclear whorls of intermediate filaments

Board review style answer #1

A. Abnormal mitochondria. This is oncocytic variant of papillary thyroid carcinoma. The cells of have abundant abnormal mitochondria, displaying stacks of parallel cristae, filamentous bundles and woolly densities.

Comment Here

Reference: Oncocytic

Board review style question #2

BRAF^V600E mutation
Mitochondrial DNA mutations
PAX8/PPARγ translocation
RAS mutations
TERT promoter mutations

Board review style answer #2

B. Mitochondrial DNA mutations. Oncocytic papillary thyroid carcinomas show accumulation of mitochondrial DNA mutations. BRAF^V600E mutation can be found in oncocytic papillary thyroid carcinoma but is much more prevalent in tall cell variant of papillary thyroid carcinoma. PAX8/ PPARγ translocation and RAS mutations are usually associated with follicular variant of papillary thyroid carcinoma. TERT promoter mutations have been reported to occur with increasing frequency in cases with de-differentiation.

Comment Here

Reference: Oncocytic

Oncocytic (Hürthle cell) tumors

Table of Contents

Definition / general

Follicular neoplasm with more than 75% oncocytic tumor cells
Oncocytic appearance is due to accumulation of dysfunctional mitochondria
Malignant if capsular and / or vascular invasion
- Tumor size, nuclear atypia, multinucleation, pleomorphism, mitoses or histologic pattern of the lesion are not determinants of malignancy (Arch Pathol Lab Med 2008;132:1241)
Hematogenous metastases, 30% to lymph node (in contrast, rare in follicular carcinoma)
No known exogenous risk factors for developing oncocytic tumors

Essential features

Follicular neoplasm composed of more than 75% oncocytes
Malignant if capsular and / or vascular invasion
Malignant tumors have more aggressive behavior than conventional follicular carcinoma

Terminology

Synonym: oncocytic cell is also called Hürthle, Askanazy and oxyphilic cells
- "Hürthle cell" is a misnomer - Dr. Hürthle originally used it to describe C cells instead of oncocytes

Epidemiology

Carcinoma is more common in older men (mean age: 57 years)

Radiology description

Similar to follicular adenoma / carcinoma

Prognostic factors

Oncocytic adenoma is benign, no recurrence after excision
Overall, oncocytic carcinoma is more aggressive than conventional follicular carcinoma, with higher frequency of extrathyroidal extension, local recurrence and metastasis to lymph nodes
Mortality rate: 10 - 80%
Worse prognosis: old age, tumor size > 4 cm and extensive vascular invasion

Case reports

21 year old man with Hürthle cell thyroid carcinoma and parathyroid carcinoma (J Clin Diagn Res 2015;9:OD08)
55 year old man with 3 year history of increasing neck mass (University of Pittsburgh: Neck Mass [Accessed 19 October 2017])
55 year old woman with phyllodes tumor metastatic to Hürthle cell adenoma (Arch Pathol Lab Med 2002;126:1233)
59 year old man with mixed oncocytic and mucinous secreting carcinoma (Arch Pathol Lab Med 2000;124:1547)
77 year old woman with metastasis to breast (Int Semin Surg Oncol 2008;5:14)
79 year old man with rapidly increasing lump on neck and colloid goiter 24 years ago (World J Surg Oncol 2004;2:27)

Treatment

Adenoma: lobectomy
Carcinoma: total thyroidectomy or radiation ablation
Radioactive iodine: resistant compared to conventional follicular carcinoma

Gross description

Most are more than 2 cm
Prone to infarction or hemorrhage, especially after FNA or core biopsy
Solitary, solid, bright brown to mahogany color, mostly encapsulated, lobulated, may have central scar
Widely invasive tumors have irregular borders, may have satellite nodule / multinodular appearance

Gross images

Contributed by Mark R. Wick, M.D. and AFIP

Carcinoma

Adenoma with massive infarct

Carcinoma has focal capsular invasion

Microscopic (histologic) description

At least 75% of tumor cells are oncocytes with large size, distinct cell borders, deeply eosinophilic and granular cytoplasm, large nucleus with prominent nucleolus, complete loss of cell polarity
Follicular, trabecular, solid or papillary growth patterns
Occasional nuclear grooves or nuclear pseudoinclusions
May have psammomatous-like calcifications without lamination in the lumen of follicle (papillary carcinoma has laminated psammoma body in the stroma)
Random nuclear atypia common but not evidence for malignancy
Carcinoma tends to have:
- Thicker capsule than that of adenoma
- Solid / trabecular rather than follicular pattern of growth
- Smaller cells with high N/C ratio, increased mitotic figures
Can have clear cell changes due to dilated mitochondria
Poorly differentiated oncocytic carcinoma: size > 4 cm, with tumor necrosis, numerous mitoses, foci of small tumor cells

Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D., Grace C.H. Yang, M.D. and Mark R. Wick, M.D.

Vascular invasion

Follicular thyroid carcinoma (oncocytic variant)

Oncocytes

Hürthle cell adenoma

Adenoma with atypia

Hürthle cell carcinoma

AFIP images

Adenoma:

Oncocytic adenoma has follicular pattern

Massive infarct due to fine needle biopsy

Pseudo-angiosarcomatous pattern

Well developed papillary growth pattern

Cytoplasm has fine,
homogeneously
distributed
granularity

Psammomatous-like calcifications in follicular lumina

Tumor has hyalinized area near capsule

Tumor has focal cells with large hyperchromatic nuclei

Focal papillary formations

Clear cell change:

Gradual transition from oncocytic to clear cells

Both patterns exist in same cell

Sharp demarcation
between clear
and oncocytic cells

Carcinoma:

Capsular invasion

Vascular invasion

Trabecular pattern

Multinodular pattern

Nesting pattern resembles insular carcinoma

Pseudopapillary formations due to tangential sectioning

Pulmonary metastasis
of tumor with
trabecular
growth pattern

Minimally invasive Hürthle cell carcinoma:

Fine needle biopsy induced necrosis

Images hosted on other servers:

Carcinoma:

Capsular invasion

Oncocytes with abundant eosinophilic granular cytoplasm (far right image is with intraluminal calcifications)

No capsular invasion evident

Tumor in internal jugular vein

Various images

Microfollicles

Metastasis to breast

Cells have
eosinophilic
cytoplasm and
prominent nucleoli

Minimally invasive Hürthle cell carcinoma:

Intracapsular vascular invasion

Vascular invasion

Distant metastasis to femur

Cytology description

Highly cellular, 75% or more Hürthle cells (abundant granular cytoplasm, round nuclei, often prominent nucleoli), often discohesive cells, some enlarged and pleomorphic with intracytoplasmic lumens (empty vacuoles with magenta [Diff Quik], green [Pap] or no material); transgressing vessels (capillaries in clusters of Hürthle cells) (Arch Pathol Lab Med 2001;125:1031)
No colloid, lymphocytes, histiocytes, plasma cells or ordinary follicular cells
Cannot definitively diagnose malignancy based on cytologic material (Am J Clin Pathol 1993;100:231, Acta Cytol 2008;52:659) but malignant cases tend to have small or large cell dysplasia, nuclear crowding and discohesive cells (Diagn Cytopathol 2008;36:149)
Metastatic tumors may have bland cytologic features (Diagn Cytopathol 2007;35:439)

Cytology images

Contributed by Ayana Suzuki, C.T. and Grace C.H. Yang, M.D.

Follicular neoplasm, Hürthle cell type

Hürthle cell adenoma

Images hosted on other servers:

Microfollicles of carcinoma

Positive stains

Thyroglobulin (moderate), TTF1, CK7 (CK20 negative)
Poorly differentiated oncocytic carcinoma may be negative for TTF1 and thyroglobulin

Electron microscopy description

Numerous large mitochondria

Electron microscopy images

Contributed by Mark R. Wick, M.D. and AFIP

Carcinoma

Dilated mitochondria have reduced cristae

Cytoplasm packed
with large mitochondria
with myelin figures

Molecular / cytogenetics description

Aneuploidy is common in oncocytic tumors, including chromosome gains and losses
Deletions or mutation of mitochondrial DNA (mtDNA) coding for oxidative phosphorylation (OXPHOS) proteins, which leads to energy production defects and compensatory mitochondrial proliferation
PTEN and TP53 mutations (Endocr Pathol 2015;26:365)
MEN1 loss of function mutations in 4% of patients diagnosed with oncocytic thyroid carcinoma (J Clin Endocrinol Metab 2015;100:E611)

Videos

Oncocytic lesions by Z. Baloch (2020)

Differential diagnosis

Hashimoto thyroiditis: abundant lymphocytes without distinct nodule
Medullary carcinoma with Hürthle cell-like cells: calcitonin+, CEA+, thyroglobulin-
Nodular goiter with prominent oncocytic cells: abundant colloid, follicular cells and histiocytes mixed with oncocytic cells
Papillary thyroid carcinoma, oncocytic variant, Warthin-like variant, tall cell variant: with nuclear features of papillary carcinoma

Additional references

eMedicine: Hürthle Cell Carcinoma [Accessed 19 October 2017], Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017

Board review style question #1

Which statement is not true for oncocytic carcinoma?

More aggressive compared to conventional follicular carcinoma
More resistant to radioactive iodine compared to conventional follicular carcinoma
Not only metastases to bone or lung; can also spread to lymph node
Oncocytic appearance is due to accumulation of dysfunctional mitochondria
Risk factors include iodine deficiency and irradiation exposure

Board review style answer #1

E. Risk factors include iodine deficiency and irradiation exposure. There are no known exogenous risk factors for developing oncocytic tumors.

Comment Here

Reference: Oncocytic (Hürthle cell) tumors

Oncocytic neoplasm

Table of Contents

Definition / general

Bethesda category IV - Hürthle, “follicular neoplasm, Hürthle cell type / suspicious for a follicular neoplasm, Hürthle cell type (FNHCT/SFNHCT)” is used for cases with a cellular aspirate that consists exclusively of Hürthle cells (Thyroid 2017;27:1341)
Hürthle cells are thyroid follicular cells with oncocytic appearance characterized by large hyperchromatic nuclei with prominent nucleoli and abundant granular eosinophilic cytoplasm
Cases cytologically suspected for Hürthle cell adenoma and Hürthle cell carcinoma are included
- The final diagnosis is made histologically because capsular or vascular invasion are the essential criteria of Hürthle cell carcinoma

Essential features

Includes cases with most of the follicular cells showing abundant fine granular cytoplasm (Hürthle cells)
Frequency 1.2 - 8.75%, resection rate 30.1%, risk of malignancy 10 - 40%
The most common histopathological diagnosis is Hürthle cell adenoma and Hürthle cell carcinoma, followed by multinodular goiter and Hashimoto thyroiditis

Terminology

The term “suspicious for a follicular neoplasm, Hürthle cell type (SFNHCT)” may be more convenient than “follicular neoplasm, Hürthle cell type (FNHCT)” because some nodular goiter or Hashimoto thyroiditis (i.e. nontumor) cases are included in this category
Hürthle cells are also known as oxyphilic, oncocytes or Askanazy cells (Oncologist 2011;16:1380)
In the Bethesda System for Reporting Thyroid Cytopathology, FNA specimens that are suspicious for a Hürthle cell neoplasm are distinguished from those suspicious for a non-Hürthle cell follicular neoplasm (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2018)
- Striking morphologic difference between the cytologic patterns of follicular and Hürthle cell neoplasms
- Follicular and Hürthle cell carcinomas may be genetically different neoplasms (Onco Targets Ther 2016;9:6873)
- WHO histological classification also has a separate chapter for Hürthle (oncocytic) cell tumors

Clinical features

Frequency: 1.2 - 8.75% (J Clin Diagn Res 2013;7:1051, Int J Surg 2013;11:898)
Resection rate: 30.1% (Int J Surg 2013;11:898)
Rate of neoplastic lesion after resection: 75 - 84% (Eur J Endocrinol 2013;169:649)
Risk of malignancy: 10 - 40% (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2018)
The most common histopathological diagnosis is Hürthle cell adenoma and Hürthle cell carcinoma (77.3%), followed by multinodular goiter (13.3%) and Hashimoto thyroiditis (6.6%) (Eur J Endocrinol 2013;169:649)
- Distinction between Hürthle cell adenoma and Hürthle cell carcinoma is based upon histologic evidence of transcapsular or vascular invasion (World J Surg 2010;34:836)
- Hürthle cell carcinomas represent 15 - 20% of all follicular carcinomas (American Registry of Pathology: Tumors of the Thyroid Glands, Atlas of Tumor Pathology, 1st Edition, 2016)

Diagnosis

Aspirates are at least moderately cellular and are composed exclusively of Hürthle cells
Aspirates composed entirely of Hürthle cells with abundant fine granular cytoplasm should be diagnosed as FNHCT/SFNHCT
Excluded from this category:
- Sparsely cellular aspirates composed entirely of oncocytes that could be interpreted as atypia of undetermined significance or follicular lesion of undetermined significance
- Moderately or markedly cellular aspirates composed entirely of non-atypical Hürthle cells with abundant colloid; it is acceptable to interpret the sample as benign
- Specimen with partial or minimal Hürthle cell differentiation should be diagnosed as follicular neoplasm / suspicious for a follicular neoplasm rather than FNHCT/SFNHCT
- Aspirates with Hürthle cells showing nuclear features of papillary carcinoma should be classified as malignant

Case reports

16 year old girl with Hürthle cell carcinoma in an autonomous thyroid nodule (Pediatr Radiol 1995;25:568)
36 year old woman with medullary carcinoma of thyroid mimicking Hürthle cell neoplasm on cytology (Diagn Cytopathol 2019;47:943)
42 year old man with papillary Hürthle cell tumor (Acta Cytol 1996;40:311)
55 year old man with a novel nonsense EIF1AX mutation identiﬁed in a Hürthle cell carcinoma (Endocrine 2018;62:492)
69 year old man with recurrent Hürthle cell carcinoma (Head Neck 1994;16:64)
71 year old woman with EIF1AX mutation in a Hürthle cell carcinoma (Endocr Pathol 2018;29:27)
82 year old man with Hürthle cell carcinoma with extensive tumor necrosis (Zhonghua Yi Xue Za Zhi (Taipei) 1999;62:111)
85 year old woman with anaplastic thyroid carcinoma developing from a Hürthle cell tumor (Acta Cytol 2001;45:761)

Cytology description

Abundant finely granular cytoplasm
- Blue or gray pink (Romanowsky), green (Papanicolaou), pink (H&E)
Nuclei
- Round
- Enlarged, central or eccentrically located
- Prominent nucleolus
- Binucleation (common)
Small cells with high nuclear / cytoplasmic (N/C) ratio (small cell dysplasia) (Cancer 2002;96:261)
Large cells with more than two times anisonucleosis (large cell dysplasia) (Cancer 2002;96:261)
Predominantly isolated cells but sometimes arranged in crowded, syncytial-like clusters
Little or no colloid
No lymphocytes or plasma cells
Transgressing vessels (capillaries passing through clusters of Hürthle cells), seen occasionally (Arch Pathol Lab Med 2001;125:1031)
Sometimes intracytoplasmic colloid inclusions (Arch Pathol Lab Med 2001;125:1031)

Cytology images

Contributed by Ayana Suzuki, C.T.

Follicular neoplasm, Hürthle cell type

Hürthle cell clusters

Oncocytes and histiocytes

Contributed by Grace C.H. Yang, M.D.

Hürthle cell adenoma, Diff-Quik

Hürthle cell adenoma, Pap stain

Treatment

Diagnostic lobectomy (Thyroid 2016;26:1)
Molecular testing with available gene panels is generally not helpful in identifying Hürthle cell carcinomas and distinguishing them from adenomas (Cancer Cytopathol 2018;126 Suppl 8:654)
Patients with FNHCT/SFNHCT who have benign Afirma Gene Expression Classifier (GEC) result may be spared an unnecessary lobectomy (Endocr Pract 2018;24:622)

Sample cytology report

Dx / category: follicular neoplasm, Hürthle cell (oncocytic) type
- Cellular aspirate consisting of abundant isolated oncocytes in the absence of colloid
Dx / category: suspicious for a follicular neoplasm, Hürthle cell (oncocytic) type
- Cellular aspirate of follicular cells with Hürthle cell features, in addition occasional nuclear grooves and focal papillary architecture are seen
- The findings raise the possibility of a Hürthle cell neoplasm with mild nuclear irregularity but a papillary carcinoma cannot be excluded
Dx / category: suspicious for a follicular neoplasm, Hürthle cell (oncocytic) type
- Cellular aspirate composed of cells with abundant granular cytoplasm
- The findings raise the possibility of a Hürthle cell neoplasm but a parathyroid tumor cannot be excluded
- Correlation with clinical findings, imaging and biochemistry might be helpful

Videos

Case 1

Case 2

Oncocytic lesions by Z. Baloch (2020)

Differential diagnosis

Mutinodular goiter:
- Flat, cohesive sheets of Hürthle cell admixed with normal follicular cells and a moderate to abundant amount of colloid (Cancer Cytopathol 2014;122:241)
Chronic thyroiditis:
- Lymphocytes predominate over Hürthle cells
- Data suggest that the criteria for FNHCT/SFNHCT have a lower predictive value for malignancy in the settings of chronic thyroiditis (Am J Clin Pathol 2011;135:139)
Oncocytic variant of papillary carcinoma:
- Nuclear features specific for papillary carcinoma, i.e. nuclear enlargement, pale chromatin, grooves and intranuclear pseudoinclusions
- A few Hürthle cell neoplasms exhibit some of the architectural and nuclear features of papillary carcinoma (diagnosed either as FNHCT/SFNHCT or “suspicious for malignancy”) (Malays J Pathol 2015;37:49)
Medullary carcinoma:
- Presence of salt and pepper chromatin, intranuclear pseudoinclusions but absence of prominent nucleolus; metachromasy on Romanowsky stains
- Calcitonin and chromogranin +, thyroglobulin - (Endocr J 2017;64:1099)
- Calcitonin measurement using needle washout fluid is helpful (Endocr J 2017;64:1099)
Parathyroid adenoma:
- Monomorphous cytoplasm with round nuclei and salt and pepper chromatin
- GATA3, chromogranin, synaptophysin and parathyroid hormone +, thyroglobulin and TTF1 - (Endocr J 2016;63:621)
- Parathyroid hormone measurement using needle washout fluid is helpful
- GEC can recognize the expression profile of parathyroid lesions (Diagn Cytopathol 2017;45:526)
Granular cell tumor (very rare):
- S100 protein + and keratins -

Additional references

Appl Immunohistochem Mol Morphol 2019;27:726, Diagnostic Histopathology 2019;25:154

Board review style question #1

Which finding is not helpful in distinguishing medullary carcinoma from a Hürthle cell neoplasm?

Salt and pepper chromatin
Metachromasia in Romanowsky stain
Calcitonin measurement using needle washout fluid
PTH value measurement using needle washout fluid
Calcitonin immunostaining

Board review style answer #1

D. PTH value measurement using needle washout fluid; PTH value measurement is useful for parathyroid lesions

Comment Here

Reference: Hürthle cell neoplasm

Board review style question #2

What is the most likely diagnosis of this thyroid aspirate?

Chronic thyroiditis
Adenomatous nodule
Hürthle cell neoplasm
Medullary carcinoma
Parathyroid adenoma

Board review style answer #2

D. Medullary carcinoma; salt and pepper chromatin indicates medullary carcinoma

Comment Here

Reference: Hürthle cell neoplasm

Other nonneoplastic parathyroid

Table of Contents

Definition / general

Parathyroid cyst: rare cause of neck swelling, accounting for 0.6% of thyroid and parathyroid lesions (Br J Hosp Med (Lond) 2012;73:108)

Terminology

Parathyromatosis: microscopic foci of hyperplastic parathyroid tissue in neck associated with chief cell hyperplasia and prior surgery (Hum Pathol 1990;21:234)

Clinical features

Parathyroid cyst

Pure cysts are present at any age; contain high levels of parathyroid hormone; can diagnose by FNA via PTH in fluid (Am J Clin Pathol 1986;86:776)
Parathyroid derives from third and fourth branchial pouch, as does thymus
Cysts may be present in low cervical or anterosuperior mediastinum
Patients usually are normocalcemic and present with an asymptomatic mass
May be hyperplastic gland (Am J Clin Pathol 1982;77:104), adenoma with cystic degeneration, heterotopic salivary gland-like tissue (Am J Surg Pathol 2000;24:837)
Can diagnose by FNA if PTH in fluid (Am J Clin Pathol 1986;86:776)
Cystic parathyroid lesions often contain turbid or colored fluid
Functional parathyroid cysts more common than nonfunctional parathyroid cysts (Arch Surg 2009;144:52)
During resection, cyst rupture should be avoided and patients with large cysts should be managed expectantly to forestall the development of symptomatic hypocalcemia

Radiology images

Contributed by Ayana Suzuki, C.T.

Parathyroid cyst: large multilocular cyst

Case reports

40 year old man with amyloid goiter with parathyroid involvement (Arch Pathol Lab Med 2000;124:281)
46 year old woman with thyroid nodule (Indian J Pathol Microbiol 1996;39:297)
50 year old woman with cystic cervical lesion (Med Ultrason 2011;13:157)
57 year old man with renal stones (Am J Clin Pathol 1991;96:348)
58 year old woman with rare case of malignant hypercalcemia (Case Report Med 2012;2012:851941)
66 year old man with a palpable neck mass and hypercalcemia (West J Med 1999;170:118)
2 cases of chronic parathyroiditis associated with parathyroid hyperplasia and hyperparathyroidism (Am J Surg Pathol 1984;8:211)

Treatment

Parathyroid cyst: simple aspiration to diagnosis and treat, ethanol ablation for recurrent cases (Eur J Radiol 2013;82:316)

Clinical images

Contributed by Ayana Suzuki, C.T.

Parathyroid cyst: clear fluid

Gross description

Parathyroid cyst

Usually large, in inferior glands
1 - 10 cm, unilocular, thin walled, clear fluid containing PTH, no nodules

Microscopic (histologic) description

Parathyroid cyst

Lined by flattened parathyroid chief cells, oxyphils, clear cells; no nodules
Cyst wall has uniform thickness
May contain granular material resembling colloid
No cholesterol granulomas, no cartilage, no smooth muscle

Microscopic (histologic) images

Images hosted on other servers:

Parathyroid cyst: islands of parathyroid tissue

CMV
parathyroiditis in
immunosuppressed
child

Positive stains

Parathyroid cyst: Chromogranin A, glycogen, PTH

Negative stains

Parathyroid cyst: Thyroglobulin

Palpation thyroiditis

Table of Contents

Definition / general

Common (85%+ of surgically resected thyroids) but clinically insignificant

Terminology

Also called multifocal granulomatous thyroiditis

Clinical features

More often associated with goiter than autoimmune thyroiditis (J Korean Med Sci 1988;3:27)
May be due to minor trauma, such as vigorous physical examinations (Am J Clin Pathol 1975;64:639)

Case reports

70 year old man with case causing new onset atrial fibrillation (Thyroid 2008;18:571)

Treatment

Self limited, no treatment necessary

Gross description

Normal, or small foci of hemorrhage

Microscopic (histologic) description

Multiple small granulomas centered in disrupted follicles, composed of lymphocytes (usually T cells), macrophages (some foamy), occasional multinucleated giant cells associated with colloid breakdown, usually no necrosis, no neutrophils

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

Superficially
located nodule

Intrafollicular
granulomatous
reaction

Granulomatous folliculitis

Multinucleated giant cells

Histiocytes within follicle

Histiocytes are strongly lysozyme+

Images hosted on other servers:

Granuloma

Differential diagnosis

Fungi: PAS+ / GMS+, necrosis usually present
Sarcoidosis: interstitial granulomas, systemic disease
Subacute thyroiditis: acute inflammatory cells

Papillary thyroid carcinoma - classic

Table of Contents

Definition / general

Classic variant of papillary thyroid carcinoma is characterized by 2 cardinal features:
- The presence of true papillae defined as papillae with a central vascular core
- Nuclear features in the overlying epithelial cells defined by nuclear enlargement, nuclear membrane irregularity and a distinct chromatin pattern

Essential features

Defined by 2 cardinal features: true papillae with a fibrovascular core and nuclear features of papillary carcinoma
One of the most common types of papillary carcinoma
Tendency to spread to regional lymph nodes
High frequency of BRAF V600E mutation

Terminology

Papillary carcinoma, conventional type (variant)
Papillary carcinoma, usual type (variant)

ICD coding

ICD-O: 8260/3 - papillary adenocarcinoma, NOS
ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

One of the most common variants of papillary thyroid carcinoma (J Clin Endocrinol Metab 2014;99:E276)
- Previously was most common type of papillary thyroid carcinoma but now papillary microcarcinoma and papillary thyroid carcinoma, follicular variant are more common
Female predominance; F:M ratio = ~3:1
Median age of diagnosis in 50s

Sites

Most commonly affects the thyroid gland
May also occur in thyroglossal duct, lingual thyroid, ectopic thyroid and struma ovarii (Endocr Pathol 2015;26:75, Endocrine 2016;51:189, Am J Surg Pathol 2007;31:1337)

Etiology

Ionizing radiation is the best established risk factor, including:
- Iatrogenic (e.g., radiation for head and neck cancer)
- Post Chernobyl nuclear accident (Endocr Pathol 2006;17:307)
- Post atom bomb
Can be familial in 4.5% of cases (Surgery 2009;145:100)

Clinical features

Painless palpable thyroid mass

Diagnosis

Typically, the diagnosis is first rendered on ultrasound guided preoperative fine needle aspiration cytology
Surgical pathology report of a resected specimen provides further information about the subtyping (i.e., variant) and microstaging

Radiology description

Diagnostic thyroid ultrasound with survey of cervical lymph nodes is the recommended imaging modality for patients with thyroid nodule(s) (Thyroid 2016;26:1)
The following ultrasound findings are associated with thyroid carcinoma, in particular papillary thyroid carcinoma (Thyroid 2016;26:1):
- Hypoechogenicity compared with surrounding thyroid or strap muscles
- Irregular border
- Microcalcification
- Tall shape (i.e., a nodule that is taller than wide measured on a transverse view)

Radiology images

Images hosted on other servers:

ATA nodule sonographic patterns

Prognostic factors

AJCC pathologic staging and the American Thyroid Association (ATA) initial risk stratification provide prognostic information (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018, Thyroid 2016;26:1)
Pathologic parameters included in the risk stratification for a classic variant of papillary thyroid carcinoma are:
- ATA intermediate risk: microscopic invasion into perithyroidal soft tissue, lymphovascular invasion and > 5 pathologically positive lymph nodes with all involved lymph nodes < 3 cm in size
- ATA high risk: gross extrathyroidal extension, incomplete resection, distant metastasis and pathologic nodal metastasis ≥ 3 cm in greatest dimension

Case reports

7 year old girl with sporadic papillary thyroid carcinoma, classic variant harboring ETV6-NTRK3 fusion (J Pediatr Endocrinol Metab 2018;31:461)
12 and 16 year old boys with papillary thyroid carcinoma arising within thyroglossal duct cyst (Head Neck Pathol 2017;11:442)
48 year old woman with synchronous papillary thyroid carcinoma and non-Hodgkin lymphoma (Medicine (Baltimore) 2018;97:e9831)
61 year old man with papillary thyroid carcinoma metastatic to axillary lymph node (J Med Case Rep 2015;9:181)
72 year old man with metastatic papillary thyroid carcinoma into a clear cell renal cell carcinoma (J Otolaryngol Head Neck Surg 2017;46:17.)

Treatment

Commonly treated with surgical resection (e.g., total thyroidectomy, subtotal thyroidectomy, hemithyroidectomy or lobectomy)
Post operative radioactive iodine treatment may be considered if the tumor exhibits aggressive features (ATA intermediate or high risk) (Thyroid 2016;26:1)

Gross description

Solid or cystic mass with papillary projections

Gross images

Contributed by Bin Xu, M.D., Ph.D.

Thyroid mass

Frozen section description

Frozen section of papillary thyroid carcinoma is strongly discouraged as frozen artifacts distort the nuclear features necessary for diagnosis
The standard care is to perform preoperative fine needle aspiration to establish the diagnosis and to determine the most appropriate surgical procedure

Microscopic (histologic) description

Characterized by 2 cardinal features:
- The presence of true papillae defined as finger-like projection with a fibrovascular core
- The lining cells show nuclear features of papillary carcinoma, defined as 1) nuclear enlargement, 2) nuclear membrane irregularity and 3) chromatin clearing
Lack diagnostic features of other aggressive variants (e.g., tall cell variant, columnar variant and hobnail variant)
Other histologic findings that may be present include:
- Psammoma bodies: laminated microcalcification, common in classic variant
- Prominent cystic degeneration / cystic change
- Ossification or dystrophic calcification

Microscopic (histologic) images

Contributed by Bin Xu, M.D., Ph.D.

Papillary projections

Nuclear features

Psammoma body

Cystic change with BRAF V600E

Osseous metaplasia

Cytology description

Cytology sample shows nuclear features of papillary thyroid carcinoma: oval nuclei, nuclear overlapping, nuclear membrane irregularity, powdery chromatin, chromatin margination, nuclear grooves and nuclear pseudoinclusions
In classic variant, large papillary projections may be seen in cytology samples

Cytology images

Contributed by Bin Xu, M.D., Ph.D.

Papanicolaou stain

Positive stains

Thyroid follicular cell lineage markers: TTF1, thyroglobulin and PAX8
Mutation specific protein: BRAF V600E (VE1 antibody) (Thyroid 2019;29:1792, J Clin Endocrinol Metab 2013;98:E1414)

Negative stains

CK20, calcitonin, synaptophysin and chromogranin

Molecular / cytogenetics description

50 - 77% harbor BRAF mutation, in particular BRAF V600E (J Clin Endocrinol Metab 2014;99:E276, Cell 2014;159:676)
Absence or low frequency (6.3%) of RAS mutation (J Clin Endocrinol Metab 2014;99:E276, Cell 2014;159:676)
8% with RET-PTC rearrangement (Cell 2014;159:676)
Other rare fusions in classic variant include: NTRK3 fusion in 2%, NTRK1 fusion in 1.4%, ALK fusion in 1.1% and PAX8-PPARgamma fusion in 0.8% (Cell 2014;159:676)
TERT promoter mutation is rare; present in

Sample pathology report

Thyroid, left lobe and isthmus, left hemithyroidectomy:
- Papillary carcinoma, classic type, 2.3 cm (see synoptic report)

Differential diagnosis

Papillary foci of Graves disease or other papillary hyperplasia
- May have abundant papillary infoldings and the cytoplasm may be tall or columnar
- However, the nuclei are small and round and lack nuclear clearing
Medullary thyroid carcinoma, papillary variant
- May occasionally contain true papillary architecture (so called papillary variant)
- Lesional cells show nuclear features of neuroendocrine tumors with salt and pepper nuclei
- Positive for calcitonin, synaptophysin and chromogranin

Board review style question #1

A thyroid tumor is resected, as shown above. What is the most common molecular alteration of this tumor?

BRAF V600E mutation
HRAS Q61R mutation
NRAS Q61R mutation
RET-PTC rearrangement

Board review style answer #1

A. BRAF V600E mutation. This is papillary thyroid carcinoma, classic type.

Comment Here

Reference: Classic papillary thyroid carcinoma

Board review style question #2

Which of the following histologic findings is a feature of classic type of papillary thyroid carcinoma?

Composed entirely of follicles
Nuclei of the lesional cells are small and round without nuclear membrane irregularity
Contains well formed papillae with a fibrovascular core
Lesional cells have a cell height at least 2 - 3 times of the cell width

Board review style answer #2

C. Contains well formed papillae with a fibrovascular core

Comment Here

Reference: Classic papillary thyroid carcinoma

Papillary thyroid carcinoma overview

Table of Contents

Definition / general

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma, defined by a set of distinctive nuclear features, including:
- Change of nuclear size and shape: nuclear enlargement, elongation and overlapping
- Chromatin characteristics: chromatin clearing, margination and glassy nuclei
- Nuclear membrane irregularity: irregular nuclear contour, nuclear groove and nuclear pseudoinclusion
There are 15 variants of papillary thyroid carcinoma, including prototypic conventional / classic papillary thyroid carcinoma, as per the 2017 WHO classification (IARC: WHO Classification of Tumours of Endocrine Organs (Medicine), 4th Edition, 2017)

Essential features

Diagnosis is based on nuclear features
Subtyping (i.e., variant) is based on a combination of architecture / pattern, cytologic features, size and encapsulation
BRAF^V600E is the most frequent mutation, particularly in tall cell and classic variants

ICD coding

ICD-O: 8260/3 - papillary carcinoma of thyroid
ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

Predominant form of thyroid carcinoma, accounting for 80 - 93% in contemporary series (IARC: CI5 Cancer Incidence in Five Continents [Accessed 30 September 2019])
- There is a growing number of papillary thyroid carcinoma in the last 15 - 20 years due to increasing recognition of thyroid nodules on imaging (ultrasound and CT), sometimes referred as thyroid cancer epidemics; most of these tumors are of low risk (N Engl J Med 2015;373:2389, N Engl J Med 2016;375:614)
Female predominant with a F:M ratio of ~3:1 (CA Cancer J Clin 2018;68:7)
Most common histological variants are classic PTC, microcarcinoma and follicular variant papillary thyroid carcinoma
Occult tumors in 6% at autopsy (1 - 10 mm), 46% multicentric, 14% with nodal metastases (Am J Clin Pathol 1988;90:72)
Occult tumors in up to 24% with other thyroid disease but with male predominance (Mod Pathol 1996;9:816)

Sites

Predominantly affects thyroid gland proper
May also occur in thyroglossal duct (J Med Case Rep 2008;2:42), lingual thyroid, and other ectopic thyroid tissue, e.g., struma ovarii (Endocrine 2016;51:189, Case of the Week #465)

Etiology

Ionizing radiation before age 20 (for acne, tonsillitis, tinea capitis, enlarged thymus) (Surgery 1991;110:691)
Post Chernobyl (particularly children) or after exposure to nuclear explosions at Marshall Islands (Endocr Pathol 2006;17:307, J Epidemiol 2003;13:99)
Hashimoto thyroiditis, possibly (Cancer 1995;76:2312)
Familial adenomatous polyposis, particularly the cribriform modular variant
Is familial in 4.5%, similar prognosis as sporadic disease (Surgery 2009;145:100)

Clinical features

Usually presents as painless thyroid nodule or mass in neck or cervical node; usually cold on scan
At presentation, 67% in thyroid only, 13% in thyroid and cervical nodes and 20% in nodes only
Nodal involvement is often not clinically apparent due to small size and similar consistency

Diagnosis

Diagnosis is typically rendered using preoperative fine needle aspiration cytology based on the presence of typical cytologic features
- Molecular testing of cytologic aspirates may assist in preoperative diagnosis
Diagnosis in resection specimen is based primarily on nuclear features, including alteration of nuclear size and shape, chromatin pattern and nuclear membrane irregularity
Further subtyping (i.e., variant) is based on a combination of architecture (e.g., solid, classic, follicular and cribriform morular variant), cytologic features (e.g., oncocytic, tall cell, hobnail and columnar cell variant), size (e.g., microcarcinoma) and encapsulation / infiltration (e.g., encapsulated variant, encapsulated follicular variant and infiltrative follicular variant)

Radiology images

Images hosted on other servers:

Invasion of trachea

Enhancing nodular lesion

Diffuse lung metastases

Prognostic factors

Overall excellent prognosis with a life expectancy similar to general population: 5 year, 10 year and 20 year survival is 96%, 93% and > 90% respectively (IARC: WHO Classification of Tumours of Endocrine Organs (Medicine), 4th Edition, 2017)
Disease specific survival is close to 100% if under age 20
Cervical nodal involvement does NOT affect prognosis
5 - 20% have local recurrences, 10 - 15% have distant metastases (lung, bones, CNS)
Adverse prognostic pathologic features recognized by the American Thyroid Association (ATA) Management Guidelines include (Thyroid 2016;26:1)
- Intermediate risk: tall cell / hobnail / columnar cell variant, vascular invasion, pN1 disease with > 5 positive lymph nodes and the largest metastatic focus High risk: gross extrathyroidal extension (strap muscles and beyond), incomplete tumor resection, distant metastasis, pN1 with a metastatic focus ≥ 3 cm in largest dimension
Elder age at diagnosis (≥ 55 years) is a poor prognostic factor, which has been included in the prognostic staging group of AJCC Cancer Staging Manual 8th edition (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018)
Progression to poorly differentiated thyroid carcinoma or anaplastic thyroid carcinoma infers a poor prognosis

Case reports

10 year old girl with cribriform morular variant (Rom J Morphol Embryol 2016;57:531)
40 year old man with a cystic neck mass (Medicine (Baltimore) 2019;98:e16659)
46 year old woman with recurrent tumor (Medicine (Baltimore) 2019;98:e15210)
46 year old woman with multifocal papillary thyroid carcinoma (Endocrinol Diabetes Metab Case Rep 2019 Mar 18 [Epub ahead of print])
56 year old man with follicular variant and multiple metastases (Med Arch 2016;70:314)
61 year old woman with tracheal invasion (Medicine (Baltimore) 2019;98:e17033)
63 year old woman with synchronous and metastatic papillary and follicular thyroid carcinomas (Endocr Pathol 2018;29:9)
69 year old woman with metastatic papillary thyroid carcinoma diagnosed by effusion cytology (Diagn Cytopathol 2018;46:204)

Treatment

Based on ATA risk stratification (Thyroid 2016;26:1)
- High risk: total thyroidectomy and post operative radioactive iodine therapy
- Intermediate risk: subtotal / total thyroidectomy; postoperative radioactive iodine therapy should be considered and discussed with the patient
- Low risk (includes intrathyroidal encapsulated follicular variant and papillary thyroid carcinoma devoid of the aggressive features seen intermediate or high risk groups): lobectomy alone may be sufficient
- Very low risk (i.e., papillary microcarcinomas without clinically evident metastasis, local invasion or convincing cytologic evidence of aggressive disease): active surveillance may be considered as an alternative for surgical approach
Other national guidelines (NCCI, European, Japanese) recommendations may differ from ATA

Clinical images

Images hosted on other servers:

Cystic neck mass

Bulging neck mass

Gross description

Solid, white, firm, often multifocal (20%), encapsulated (10%) or infiltrative
Variable cysts, fibrosis, calcification
Extrathyroidal extension can be readily apparent, if deep (muscles, trachea) or evident only on microscopy (muscles, perithyroidal fat)

Gross images

Contributed by Bin Xu, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D. and Kseniya Korchagina, M.D.

PTC in thyroglossal duct

Peritumoral fibrosis

Grossing and sampling

Extrathyroidal extension

Cystic change

Frozen section description

Frozen section is strongly discouraged as frozen artifacts distort the nuclear features necessary for diagnosis
Standard care is to perform preoperative fine needle aspiration to establish the diagnosis and to determine the most appropriate surgical procedure
Frozen in thyroid surgery is frequently used for detecting parathyroid tissue and, sometimes lymph node metastasis

Microscopic (histologic) description

Nuclear features:
- Change of nuclear size and shape: nuclear enlargement, elongation and overlapping
- Chromatin characteristics: chromatin clearing / optically clear chromatin, chromatin margination, glassy / ground glass nuclei, Orphan Annie nuclei
- Nuclear membrane irregularity: irregular nuclear contour, nuclear grooves and nuclear pseudoinclusions (represent cytoplasmic invaginations)
Variants:
- Classic: complex, branching, randomly oriented papillae with fibrovascular cores
  - Tumors with both papillary and follicular architecture should be classified as classic variant, given the associated risk of nodal metastasis (Thyroid 2019;29:1792)
- Follicular: neoplastic cells arranged as macro or microfollicles with central colloid
- Cribriform morular: cribriform architecture and squamous morules; cytologically, tumor cells usually have columnar / cigar shaped nuclei, sometimes with prominent supra / sub nuclear vacuoles
- Diffuse sclerosing: diffuse involvement of at least one thyroid lobe, in association with fibrosis, frequent psammoma bodies, squamous metaplasia and frequent lymphatic invasion; often present in young patients with a background chronic lymphocytic thyroiditis
- Warthin-like: oncocytic tumor cells with a background of reactive lymphoid stroma resemble Warthin tumor at low power; often occur in the setting of chronic lymphocytic thyroiditis
- Solid: tumor with solid / insular growth pattern
- Different patterns (e.g., papillary and follicular) are frequently coexist within 1 tumor
Cytologic features:
- Tall cell: defined as a cell height at least 2 - 3 times of cell width with distinct cell border; often associated with stretched elongated "tram-track" papillae, eosinophilic cytoplasm (due to the accumulation of mitochondria) and frequent nuclear pseudoinclusions; a tumor can be defined as tall cell variant if at least 30% of the tumor contains tall cells
- Columnar cell: cigar shaped nuclei with nuclear pseudostratification; a tumor can be defined as columnar cell variant if at least 30% of the tumor contains columnar cells
- Hobnail: tumor cells have high nuclear to cytoplasmic ratio with nuclei protruding away from the stalk into the lumen; often with prominent nucleoli
- Oncocytic: tumor cells with abundant eosinophilic cytoplasm
- Other rare cytologic features that have been reported include spindle cell and clear cell
Other pathologic features:
- Colloid is usually dense and hypereosinophilic (inspissated colloid)
- Psammoma bodies defined as laminated microcalcification are frequently associated with classic, tall cell, hobnail and diffuse sclerosing variants; it is postulated that psammoma bodies are formed in the hyalinized core / stalk of papillae
  - Presence of psammoma body alone in lymph node is indicative of metastatic disease and is considered as pN1 by CAP (CAP: Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland [Accessed 1 October 2019]) and AJCC 8th edition (Amin: AJCC Cancer Staging Manual, 8th Edition, 2018)
- Most of papillary thyroid carcinoma are infiltrative while some are encapsulated or well demarkated (usually follicular variant)
- Tumor stroma could be fibrotic (predominant in fibromatosis / fasciitis-like variant) or calcified and ossified
- Cystic changes in primary tumor or in metastasis are not infrequent

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Nuclear features

Nuclear pseudoinclusions

Pseudonuclear inclusions and large vesicular nucleus

Nuclear enlargement, crowding / overlapping

Orphan Annie eye nuclei

Architectural patterns

True papillae with multiple branching

Arborizing papilla

Other histologic features

Psammoma bodies

Psammoma body (HBME1)

Giant cells

Different kinds of giant cells

Deposits in perithyroidal fat

Residual tumor in thyroid bed

Clear cell change

Cystic degeneration

Submucosal spread

Bone involvement

Lymph node replaced by metastasis

Large psammoma bodies

Ossification

Concentric calcium deposition

Mimickers

PTC with Hashimoto thyroiditis

Follicular adenoma, mimic of PTC

Stains

CK19, Galectin3, HBME1

CK19

Galectin3

HBME1

BRAF^V600E

TTF1

PAX8

Virtual slides

Images hosted on other servers:

PTC

Cytology description (Courtesy of Shahid Islam, M.D., Ph.D.)

Cellular aspirate with monolayer sheets of cells, often with three dimensional papillary architecture (thick or thin fragments with fibrovascular cores), multilayered syncytial fragments or branched sheets
May see psammoma bodies
Cells have enlarged overlapping nuclei with irregular contours, intranuclear inclusions, nuclear grooves and pale finely chromatin
No feature by itself is diagnostic, must see a constellation of findings
Addition of BRAF analysis may be useful (Endocr J 2007;54:399)
False negatives usually due to nodule heterogeneity (Cancer 2008;114:27)

Cytology images

Contributed by Andrey Bychkov, M.D., Ph.D.

Papanicolaou stain

Papillary thyroid carcinoma, imprint cytology

Positive stains

Markers of thyroid follicular cells, including cytokeratin AE1 / AE3, CK7, TTF1, thyroglobulin and PAX8
A proportion is positive for mutation specific protein by immunohistochemistry, e.g., BRAF^V600E (VE1 antibody) and NRAS Q61R (Thyroid 2019;29:1792)
Utility of CK19, galectin3 and HBME1 to differentiate from benign mimics remains controversial (Am J Clin Pathol 2002;118:186, Am J Clin Pathol 2001;116:696, Am J Clin Pathol 2006;126:700)
Variant specific immunohistochemistry
- CDX2 for columnar cell variant (positive in 50% of cases, Histopathology 2018;72:40)
- Beta catenin for cribriform morular variant showing abnormal nuclear accumulation
- Ki67 index is low (1 - 5%), > 10% is associated with aggressive histotype and higher recurrence risk (Sci Rep 2017;7:41752)

Negative stains

Electron microscopy description

Highly indented nuclear membrane with pseudoinclusions and multilobation
Clusters of large interchromatin granules, nucleoli have microfibrillar cortex with segregation of their components
Also dense RNA containing microspherules in nucleoli (Arch Pathol Lab Med 1978;102:635)

Electron microscopy images

AFIP images

Tall cuboidal cells

Surface microvilli

Molecular / cytogenetics description

In 2014, The Cancer Genome Atlas (TCGA) published comprehensive genomic alterations (Cell 2014;159:676); key findings are:
- BRAF is the most frequently mutated gene, occurring in 60% of cases
  - Most frequent mutation is BRAF^V600E, which is associated with classic variant and tall cell variant, as well as a low thyroid differentiation score (i.e., less differentiated)
  - BRAF is highly prevalent (80 - 90%) in PTC from coastal Asian countries with high iodine intake (Japan, Korea) (Malays J Pathol 2017;39:95)
- RAS (HRAS, NRAS and KRAS) occurs in 13%, in particular follicular variant; RAS mutation is associated with a high thyroid differentiation score
- Fusions involving BRAF, RET, PPARG, NTRK1, NTRK3, ALK, LTK, MET, FGFR2 or THADA are detected in 15%; among them, RET fusion is the most common, seen in 6%
- TERT promoter mutation is present in 10% and is often associated with aggressive histology, e.g., tall cell variant and poor prognosis (Endocr Relat Cancer 2013;20:603)

Molecular / cytogenetics images

Images hosted on other servers:

TCGA

BRAF mutation

Videos

Papillary thyroid carcinoma: cystic

Thyroid carcinoma

Thyroid: compare and contrast

Histopathology thyroid: papillary carcinoma

Histopathology thyroid: Hashimoto thyroiditis, papillary carcinoma

Integrated genomic characterization of papillary thyroid carcinoma

An alphabet soup of thyroid neoplasms

Sample pathology report

Thyroid, total thyroidectomy:
- Papillary thyroid carcinoma, tall cell variant, 1.2 cm (see synoptic report)

Differential diagnosis

Lymphocytic thyroiditis with reactive nuclear changes:
- Nuclei are round without nuclear pseudoinclusions
- In the context of marked lymphocytic thyroiditis, mild chromatin clearing and nuclear enlargement are not sufficient for a diagnosis of papillary thyroid carcinoma
Papillary foci of Graves disease or other papillary hyperplasia:
- Graves disease may have abundant papillary infoldings and the cytoplasm may be tall/columnar; however, the nuclei are small and round without nuclear features of papillary thyroid carcinoma
Medullary thyroid carcinoma:
- Both may show solid or papillary architecture
- Contains nuclei typical of neuroendocrine neoplasm with salt and pepper chromatin and is positive for synaptophysin and chromogranin and negative for PAX8 and thyroglobulin
Hyalinizing trabecular tumor:
- Also can have frequent nuclear grooves and nuclear pseudoinclusions
- Shows unique architectural patterns with trabecular architecture and tumor cells arranged perpendicularly to the trabeculae
- Has characteristic GLIS rearrangement (Thyroid 2019;29:161)
Hyperplastic ultimobranchial body rests / solid cell nests:
- In lateral lobes
- Round to oval structures, may have chromatin clearing or grooves, central cysts, mucin and squamous metaplasia
- Solid cell nests are usually positive for high molecular weight cytokeratin and p63 but negative for TTF1 / thyroglobulin and papillary thyroid carcinoma associated mutations

Board review style question #1

BRAF^V600E mutation
EGFR mutation
HRAS mutation
TERT promoter mutation
TP53 mutation

Board review style answer #1

A. BRAF^V600E mutation

Comment Here

Reference: Papillary thyroid carcinoma

Board review style question #2

Follicular variant
Oncocytic variant
Papillary microcarcinoma
Tall cell variant
Warthin-like variant

Board review style answer #2

D. Tall cell variant. Tall cell variant is one of the aggressive variants that is considered as intermediate risk by the American Thyroid Association Management Guidelines.

Comment Here

Reference: Papillary thyroid carcinoma

Parasitic nodule

Table of Contents

Definition / general

Peripheral nodule of goiter that is anatomically separate from the main thyroid gland (Arch Otolaryngol Head Neck Surg 1996;122:1409)
Spontaneous detachment of thyroid tissue with subsequent implant in the lateral neck may occur in nodular goiter or Hashimoto thyroiditis
Diagnostic criteria (Histopathology 2006;49:107):
- Parasitic nodule should be in same fascial plane as thyroid gland and exhibit a similar histologic appearance as the main gland
- No evidence of lymph node structures
Similar separated nodules are described in uterine myoma (Obstet Gynecol 2009;114:611)

Terminology

Also called sequestered (i.e. sequestered goiter), detached or accessory thyroid nodule
Recommended to use "parasitic nodule" for separated thyroid nodules in lateral neck, as opposed to midline ectopic thyroid tissue along the thyrothymic tract, which is mainly a developmental abnormality (Virchows Arch 1999;434:241)
Lateral aberrant thyroid often represents parasitic thyroid nodule

Epidemiology

F:M = 4:1, median age is 51 years (range 15 to 83 years)
~100 cases have been reported; the largest series was from Dr. Rosai (Lab Invest 2006;86:96A)

Sites

Perithyroidal, close to the gland (< 1 cm)
Can be located in the lateral neck from the submandibular to the retroclavicular area, the sternocleidomastoid and sternohyoid muscles (Lab Invest 2006;86:96A)
Rarely found in the mediastinum as part of a substernal nodular goiter (Arch Intern Med 1983;143:1015)

Pathophysiology / etiology

Portion of goitrous thyroid extending through the fascia may be separated by the mechanical action of neck muscles, and remains connected to the main gland by a thin fibrous strand of vascular tissue (Boston Med Surg J 1903;149:616)
Split from thyroid gland is due to ablation of pre-existing connection or lack of identification of connection to the main gland (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)
Alternatively, parasitic nodule may represent concurrent hyperplastic changes in accessory thyroid tissue (N Engl J Med 1964;270:927)
Blood supply may be obtained from thyroid via fibrovascular pedicle, or be autonomous, acquired from the surrounding tissues (ISRN Surg 2011;2011:313626)

Clinical features

Palpated in the lateral neck (N Engl J Med 1964;270:927)
The nodule is usually an expression of nodular hyperplasia or nodular Hashimoto thyroiditis, less commonly of Graves disease (Histopathology 2006;49:107)
Benign condition. but some cases of metastatic thyroid carcinoma from occult primary may be initially misdiagnosed as parasitic nodules
- Rodriguez found malignancy without evidence of tumor in the main gland in 10% of studied parasitic nodules, and suggested that parasitic nodule can originate in a primary tumor (Lab Invest 2006;86:96A), but microcarcinoma in the main thyroid cannot be excluded

Diagnosis

On histopathology, after exclusion of metastatic cancer

Radiology description

RAI uptake in a nodule separate from thyroid (N Engl J Med 1964;270:927)
Sonography: the main gland is multinodular, but parasitic nodules imitate enlarged cervical lymph nodes (Endocrinol Diabetes Metab Case Rep 2014;2014:140027)

Radiology images

Images hosted on other servers:

Neck ultrasonography

Color flow Doppler

Tracer uptake, lateral neck

Radiography of mediastinal mass

Case reports

40 year old man with parasitic thyroid nodules and nontoxic multinodular goiter (J Med Case Rep 2014;8:66)
53 year old woman with parasitic thyroid nodule and Hashimoto chronic thyroiditis (Rev Hosp Clin Fac Med Sao Paulo 2000;55:65)
58 year old woman with parasitic thyroid nodules (Endocrinol Diabetes Metab Case Rep 2014;2014:140027)
67 year old woman with parasitic nodule of the thyroid and Graves disease (Virchows Arch 1999;434:241)
80 year old woman with ectopic sequestered thyroid tissue (ISRN Surg 2011;2011:313626)
Young woman with sequestered substernal goiter (Arch Intern Med 1983;143:1015)
Parasitic nodule of thyroid in neck of patient with family history of papillary thyroid carcinoma (Endocr Pathol 2015;26:273)
Scintigraphic demonstration of sequestered nodular goiter (Clin Nucl Med 1992;17:402)
Parasitic nodule of the right carotid triangle (Arch Otolaryngol Head Neck Surg 1996;122:1409)

Treatment

Usually removed surgically to rule out metastasis

Gross description

0.5 - 6.5 cm nodule, separate from thyroid gland, usually single (> 80%)
Fibrovascular pedicle connecting to the main thyroid can be discovered after careful dissection at surgery
Often nodular or shows changes similar to the main thyroid

Gross images

AFIP images

Nodular hyperplasia

Images hosted on other servers:

Mediastinal thyroid mass

Microscopic (histologic) description

Benign appearing thyroid tissue with colloid filled or hyperplastic follicles
Similar features are found in orthotopic gland
Hashimoto thyroiditis in parasitic nodule may simulate lymph node tissue

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

2 perithyroidal lymph nodes

Specimen with signs of Hashimoto thyroiditis

Lymphoid follicles

Patient with Hashimoto

Hyperplastic nodule

Images hosted on other servers:

Parasitic nodule vs lymph node

Thyroid follicles

TTF1, Thyroglobulin

Cytology description

Thyroid follicular cells (Endocr Pathol 2015;26:273)

Negative stains

CK19, Galectin3, HBME1

Molecular / cytogenetics description

No BRAF mutation (Endocrinol Diabetes Metab Case Rep 2014;2014:140027)
Polyclonal on HUMARA assay (Hum Pathol 1998;29:187)

Differential diagnosis

Papillary thyroid carcinoma (nodal metastais) vs. parasitic nodule with Hashimoto thyroiditis:
- Cytological and architectural features of carcinoma
- Primary tumor in the main thyroid
- Lymph node structures, subcapsular sinuses highlighted by reticulin stain (Virchows Arch 1999;434:241)
Displaced / seeded thyroid tissue due to prior surgery or accidental trauma (Ann Diagn Pathol 2004;8:61, Endocrinol Diabetes Metab Case Rep 2014;2014:140027):
- Often multiple and superficial / subcutaneous
- May have suture material, talc crystals, reactive fibrosis

Additional references

Simple goiter and nontoxic multinodular goiter, Arch Surg 1965;90:222

Parathyroid adenoma

Table of Contents

Definition / general

Benign neoplasm derived from parathyroid parenchymal cells
Typically involves one gland

Essential features

Incidence increasing due to biochemical testing
Diagnosis confirmed by a drop in parathyroid hormone (PTH) after surgical removal
Atypical parathyroid adenoma displays histology concerning for but not diagnostic of malignancy and requires clinical follow up after excision
Can be mistaken for thyroid follicular neoplasm by fine needle aspiration

ICD coding

ICD-10: D35.1 - Benign neoplasm of parathyroid gland

Epidemiology

Incidence has increased over the past 50 years due to routine biochemical testing
Accounts for over 85% of cases of primary hyperparathyroidism worldwide (N Engl J Med 2011;365:2389)
Women more frequently affected than men
Age range is broad but commonly 30s - 60s (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

Sites

Parathyroid gland, inferior glands slightly more common than superior
Can also occur where ectopic / supernumerary parathyroid tissue may be found (thyroid gland, thymus, retroesophageal area, mediastinum, vagus nerve, carotid sheath)
Double adenomas can occur, usually involving both superior parathyroid glands (Surg Pathol Clin 2019;12:1007)

Etiology

Most are sporadic cases of unknown etiology
Associated syndromes: hyperparathyroidism jaw tumor syndrome (HRPT2 gene germ line mutation), multiple endocrine neoplasia (MEN1 more likely to have adenomas than MEN2A and MEN2B) (Surg Pathol Clin 2019;12:1007)
Risk factors: radiation exposure, long term lithium therapy (Endocr Rev 2019;40:711, Front Oncol 2019;9:1092)

Clinical features

Often detected early in asymptomatic patients due to routine serologic testing (see laboratory findings below)
Symptoms of hyperparathyroidism: nephrolithiasis, osteopenia, osteitis fibrosa cystica, weakness, fatigue and psychiatric disturbances can occur if not detected early
Rarely presents as a palpable mass (J Med Case Rep 2019;13:332)

Diagnosis

Various imaging techniques can identify parathyroid nodules, including CT, MRI and ultrasound
Technetium 99 sestamibi scintigraphy (99mTc) (see radiology description below)
Intraoperative parathyroid hormone (PTH) rapidly decreases after the abnormal gland is removed

Laboratory

Serum parathyroid hormone (PTH) and calcium elevated, though usually not as high as in parathyroid carcinoma
- Needle washouts after FNA can be used for PTH measurements (Diagn Cytopathol 2020 Aug 24 [Online ahead of print])
Hypophosphatemia and hypophosphaturia (J Med Case Rep 2019;13:332)

Radiology description

Nodule posterior to thyroid gland
99mTc sestamibi:
- Sestamibi accumulates in the mitochondria rich oxyphil cells of the parathyroid
- Increased focal uptake may indicate an adenoma (J Nucl Med 1992;33:1801)

Radiology images

Images hosted on other servers:

99mTc MIBI scintigraphy

Prognostic factors

Normally can be cured by surgical removal but recurrences can happen if not properly localized and excised
Atypical adenomas are considered tumors of uncertain malignant potential and should be followed up clinically (Surg Pathol Clin 2019;12:1007)

Case reports

24 year old pregnant woman with parathyroid adenoma and acute necrotizing pancreatitis (BMC Endocr Disord 2019;19:82)
52 year old woman with giant parathyroid adenoma (J Med Case Rep 2019;13:332)
54 year old woman with parathyroid lipothymoadenoma (Arch Pathol Lab Med 1993;117:312)
56 year old woman with cystic parathyroid adenoma (BMC Endocr Disord 2020;20:53)
57 year old man with a parathyroid adenoma (Endocr J 2019;66:379)
61 year old woman with retrotracheal parathyroid adenoma (Radiol Case Rep 2020;15:672)

Treatment

Parathyroidectomy

Clinical images

Images hosted on other servers:

Giant parathyroid adenoma (intraoperative)

Gross description

Variable size, from < 1 cm to > 10 cm (Rosai: Tumors of the Thyroid and Parathyroid Glands, Series 4)
- Term “microadenoma” has been used to describe tumors measuring < 6 mm
Weight > 40 mg (Endocr Pathol 2018;29:113)
Solid yellow / tan, well circumscribed ovoid nodule
No invasion into adjacent structures

Gross images

Contributed by Mona Kandil, M.D and @Andrew_Fltv on Twitter

Parathyroid adenoma (black arrow) and thyroid

Parathyroid adenoma

Images hosted on other servers:

Right: parathyroid adenoma;
left: thymoma

Frozen section description

Identification of parathyroid tissue is usually sufficient for intraoperative management, rather than trying to distinguish adenoma from hyperplasia

Microscopic (histologic) description

Well circumscribed, frequently with thin fibrous capsule
Absent or reduced stromal adipocytes
Compressed nonneoplastic parathyroid tissue may be seen at edge
Most commonly composed of chief cells (round nucleus, little granular cytoplasm)
Follicle formation is not rare
Mitoses and bizarre nuclei (endocrine atypia) may be focally present
Variants:
- Oxyphilic / oncocytic adenomas: composed entirely of oncocytic cells with abundant, eosinophilic granular cytoplasm (Surg Pathol Clin 2019;12:1007)
- Water clear cell adenoma: cells have clear, glycogen containing cytoplasm (Surg Pathol Clin 2019;12:1007)
- Lipoadenoma (hamartoma): contains stromal (adipose) and parenchymal (usually chief cells) elements; most of the tumor is adipose tissue (Surg Pathol Clin 2019;12:1007)
- Atypical adenoma: contains borderline features concerning for (but not diagnostic of) malignancy (Surg Pathol Clin 2019;12:1007)
  - Dense fibrous bands with hemosiderin
  - Prominent nuclear atypia with spindled nuclei
  - Notable mitotic activity
  - Adherence to adjacent tissue
  - Necrosis
  - Solid or trabecular growth
  - No evidence of lymphovascular invasion, perineural invasion, invasion into adjacent structures or metastasis

Microscopic (histologic) images

Contributed by Diana Murro Lin, M.D. and @Andrew_Fltv on Twitter

Chief cells

Oxyphil adenoma

Oxyphil cells

Atypical adenoma and thyroid

Atypical adenoma fibrous bands

Parathyroid adenoma

Virtual slides

Images hosted on other servers:

Parathyroid adenoma

Cytology description

Cellular aspirates with uniform small cells in sheets, 3D clusters and trabecular arrangements
Round dark nuclei with smooth nuclear borders and without nucleoli
Salt and pepper chromatin (Diagn Cytopathol 2020 Aug 24 [Online ahead of print])
No colloid unless adjacent thyroid tissue is also aspirated
More monotony than normal thyroid tissue
Can be mistaken for a thyroid follicular neoplasm (Diagn Cytopathol 2017;45:526)

Cytology images

Contributed by Ayana Suzuki, C.T.

Sheet of chief cells

Images hosted on other servers:

Microfollicular and trabecular arrangement

Positive stains

Parathyroid hormone, synaptophysin, chromogranin A, GATA3, CAM 5.2, CK7, CK8, CK18 and CK19 (Endocr Pathol 2018;29:113)
GATA3 (Diagn Cytopathol 2020 Aug 24 [Online ahead of print])
Polyclonal PAX8 is nonspecific because monoclonal PAX8 is negative in parathyroid (Endocr Pathol 2018;29:91)
CDC73 (parafibromin)

Negative stains

Electron microscopy description

Oxyphil cells are mitochondria rich (J Nucl Med 1992;33:1801)

Molecular / cytogenetics description

CDC73 (HRPT2) in patients with hyperparathyroidism jaw tumor syndrome (Endocr Pathol 2018;29:113)
MEN1 in multiple endocrine neoplasia and sporadic adenomas
For fine needle aspiration samples, the Veracyte Afirma Gene Expression Classifier contains a cassette to distinguish parathyroid from thyroid tissue (Diagn Cytopathol 2017;45:526)
Mutations in CCND1 (cyclin D1), ZFX, EZH2 (Surg Pathol Clin 2019;12:1007)

Videos

Oncocytic adenoma

Parathyroid pathology

Sample pathology report

Right lower parathyroid, parathyroidectomy:
- Chief cell adenoma, 250 mg

Differential diagnosis

Histology:
- Parathyroid hyperplasia:
  - Typically involves all 4 glands
  - Diffuse enlargement rather than nodular growth with compressed rim of normal tissue
  - Distinction between hyperplasia and adenoma may be difficult on routine histology and definitive diagnosis is based on intraoperative PTH findings
- Parathyroid carcinoma:
  - Definitive evidence of invasion or metastasis (vascular invasion, perineural invasion, invasion into adjacent structure)
  - Atypical mitotic figures
- Paraganglioma:
  - Nested growth wrapped by sustentacular cells with increased vascularity
  - Sustentacular cells identified by S100 immunostain
  - Negative for PTH
Cytology:
- Normal thyroid tissue and follicular neoplasms:
  - Less defined cell membranes with no visible intracellular lipid droplets (Endocr Pathol 2018;29:113)
  - Positive for TTF1 and thyroglobulin and negative for PTH and neuroendocrine markers (Endocr Pathol 2018;29:113)
  - Serum calcium and PTH not elevated

Board review style question #1

What is the best diagnosis for this neck mass?

Parathyroid adenoma, oxyphil type
Oncocytoma
Hurthle cell adenoma
Granular cell tumor

Board review style answer #1

A. Parathyroid adenoma, oxyphil type

Comment Here

Reference: Parathyroid adenoma

Board review style question #2

Which of the following features is seen in parathyroid carcinoma but not adenoma?

Adherence to adjacent thyroid
Nuclear atypia
Necrosis
Perineural invasion

Board review style answer #2

D. Perineural invasion

Comment Here

Reference: Parathyroid adenoma

Parathyroid carcinoma

Table of Contents

Definition / general

Malignant neoplasm originating from parathyroid parenchymal cells

Essential features

90% of patients present with excess parathyroid hormone (PTH)
HRPT2 (CDC73) mutation is strongly associated with familial and sporadic parathyroid carcinoma (> 70%)
One of the following features is necessary for definitive malignancy diagnosis of parathyroid lesion (Endocr Pathol 2022;33:64):
- Angioinvasion (vascular invasion)
- Lymphatic invasion
- Perineural (intraneural) invasion
- Invasion of adjacent structures / organs
- Metastasis
Estimated 5 year and 10 year overall survival rates are 78 - 85% and 49 - 70%, respectively (Ann Surg Oncol 2015;22:3990)

Terminology

Parathyroid carcinoma

ICD coding

ICD-10: C75.0 - malignant neoplasm of parathyroid gland

Epidemiology

M = F
Mean age of 56 years (range: 15 - 89 years)
Usually associated with familial syndromes in younger patients
< 1% of cases of primary hyperparathyroidism (J Bone Miner Res 2008;23:1869)

Sites

Normal parathyroid gland location
Sites of the neck in which parathyroid gland can be seen (e.g., retroesophageal space, mediastinum, thymus and thyroid gland)

Etiology

10 - 15% related to hyperparathyroidism jaw tumor (HPT JT) syndrome (N Engl J Med 2003;349:1722)
Association with familial isolated hyperparathyroidism, multiple endocrine neoplasia types 1 and 2 has been reported (Clin Endocrinol (Oxf) 2016;84:244, Clin Endocrinol (Oxf) 1997;47:747)
Rare sporadic cases have been reported following radiation exposure and in patients with longstanding secondary hyperparathyroidism (see Molecular / cytogenetics description) (Br J Surg 1988;75:873, Tumori 2005;91:558)

Clinical features

Palpable neck mass (30 - 75%)
Symptoms of overt hyperparathyroidism:
- Bone disease (osteitis fibrosa cystica, osteoporosis, fractures)
- Renal disease (nephrolithiasis, nephrocalcinosis)
- Neurocognitive symptoms (fatigue, weight loss, weakness, anxiety, depression, polyuria, polydipsia)
Jaw tumor (if associated with HPT JT)
Neck pain
References: Turk Patoloji Derg 2015;31:80, Endocr Pathol 2022;33:64

Diagnosis

One of the following microscopic features is necessary for definitive diagnosis of parathyroid lesion malignancy (Endocr Pathol 2022;33:64):
- Angioinvasion (vascular invasion)
- Lymphatic invasion
- Perineural (intraneural) invasion
- Invasion of adjacent structures / organs
- Metastasis

Laboratory

PTH levels are usually > 3 times the upper limit of normal (Turk Patoloji Derg 2015;31:80, Nat Rev Endocrinol 2012;8:612)
Hypercalcemia (often > 14 mg/dL) (Turk Patoloji Derg 2015;31:80, Nat Rev Endocrinol 2012;8:612)
Third / second generation PTH assay ratio is usually > 1 (Nat Rev Endocrinol 2012;8:612)
Albumin corrected calcium levels are > 3 mmol/L (85% of patients) (Ann Surg Oncol 2010;17:2156)
Rare nonfunctioning parathyroid carcinomas have also been reported (Endocr Pract. 2007;13:750)

Radiology description

Single gland disease
Infiltration or calcification on neck ultrasound (Eur Radiol 2011;21:1865, Endocr J 2001;48:213)
Suspicion of metastatic disease on sestamibi or CT scan (Head Neck 2016;38:E2159, Semin Ultrasound CT MR 2012;33:123, J Clin Endocrinol Metab 2014;99:4531)

Radiology images

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Xray lytic lesion

Sestamibi scan

Bone scan

Tc MIBI scintigraphy and CT

Tc MIBI SPECT / CT

99mTc MIBI SPECT / CT and MRI

Prognostic factors

The following microscopic features have been reported with aggressive growth in some parathyroid tumors (Am J Surg Pathol 1993;17:820):
- Necrosis
- Macronucleoli
- > 5 mitoses per 10 mm²
Older age at time of diagnosis, larger tumor size and male gender are negative prognostic factors (Ann Surg Oncol 2015;22:3990)
Estimated 5 year and 10 year overall survival rates are 78 - 85% and 49 - 70% respectively (Ann Surg Oncol 2015;22:3990)

Case reports

25 year old man with hyperparathyroidism symptoms and parafibromin deficient parathyroid carcinoma due to a rare germline HRPT2 / CDC73 mutation (Endocr Pathol 2018;29:374)
59 year old man with calcitonin and calcitonin gene related peptide expressing parathyroid carcinoma (Endocr Patho 2019;30:168)
60 year old woman with intrathyroidal parathyroid carcinoma (Diagn Cytopathol 2018;46:47)
61 year old man with multiple endocrine neoplasm type 1 syndrome (Clin Exp Med 2018;18:585)
63 year old man with atypical thyroid nodule and symptomatic hypercalcemia (Front Endocrinol (Lausanne) 2018;9:641)
67 year old man with nonfunctioning parathyroid carcinoma (Surg Case Rep 2017;3:81)

Treatment

En bloc resection with ipsilateral hemithyroidectomy and central lymphadenectomy (Nat Rev Endocrinol 2012;8:612, Ann Endocrinol (Paris) 2015;76:169)
Benefits of adjuvant therapy (chemotherapy and radiotherapy) are unclear (Head Neck 2013;35:35)

Clinical images

Images hosted on other servers:

Intraoperative dissection

Gross description

Typically large, variably encapsulated, poorly circumscribed mass (Cancer 1973;31:600)
Mean diameter of 3.4 cm and weight of 19.2 g (J Clin Pathol 2015;68:771)
Cut section is usually firm, pinkish tan and lobular in appearance (Cancer 1973;31:600)
Variable, sometimes indistinguishable from parathyroid adenoma (Turk Patoloji Derg 2015;31:80)

Gross images

Images hosted on other servers:

Large size and irregular cut surface

Frozen section description

Distinction between parathyroid adenoma and carcinoma is often difficult to make on frozen section if the tumor does not show grossly evident invasion into adjacent structures

Microscopic (histologic) description

Nodular and solid growth pattern is common
Broad fibrous bands can be present
Uniform cells or mild to moderate nuclear atypia
Mostly composed of chief cells; however, oxyphil cells and transitional cells can also be seen
Nuclear atypia, macronucleoli
Increased mitotic activity (> 5/10 mm²) and atypical mitosis may be seen
Necrosis can be present
One of the following features is necessary for definitive diagnosis of parathyroid lesion malignancy (Endocr Pathol 2022;33:64):
- Angioinvasion (vascular invasion)
- Lymphatic invasion
- Perineural (intraneural) invasion
- Invasion of adjacent structures / organs
- Metastasis

Microscopic (histologic) images

Contributed by Mehmet Kefeli, M.D.

Solid and nodular growth

Skeletal muscle invasion

Uniform cytomorphology

Numerous mitoses

Prominent nucleoli

PTH

GATA3

Thyroglobulin

TTF1

Ki67

Virtual slides

Images hosted on other servers:

Parathyroid carcinoma

Cytology description

Cellular, composed of cohesive sheets, ribbon-like cords
Nuclei are uniform or show mild to moderate atypia
Coarsely granular chromatin pattern
Prominent nucleoli
Cytoplasm is moderately abundant and granular
Distinction between parathyroid carcinoma and adenoma is extremely difficult to make on cytology; nuclear pleomorphism, prominent macronucleoli, enlarged uniform hyperchromatic nuclei, mitotic figures favor carcinoma (Diagn Cytopathol 2016;44:688)

Cytology images

Contributed by Mehmet Kefeli, M.D.

Cohesive clusters and sheets of cells

Positive stains

Parathyroid specific markers: PTH, PTH related peptide, GATA3, GCM2 (Endocr Pathol 2018;29:113)
Broad neuroendocrine markers: chromogranin A, synaptophysin
Cytokeratins (Endocr Pathol 2018;29:113)
- CAM 5.2 is the most useful keratin for neuroendocrine tumors
- Keratin 14 may be absent in oxyphil parathyroid carcinoma
Polyclonal PAX8 may be positive (42 - 83%) but monoclonal PAX8 is negative in parathyroid lesions (Am J Surg Pathol 2011;35:816, Mod Pathol 2011;24:751, Endocr Pathol 2022;33:64)
Ki67 is usually elevated > 5% (Endocr Pathol 2022;33:64)

Negative stains

Thyroid specific markers: TTF1, thyroglobulin (Endocr Pathol 2018;29:113)
Calcitonin and calcitonin gene related peptide (usually) (Endocr Patho 2019;30:168)
p27 (CDKN1B): absent or decreased expression (Endocr Pathol 2018;29:113)
Rb, MDM2, BCL2, APC: often loss observed (Endocr Pathol 2018;29:113, Endocr Pathol 2022;33:64)
Parafibromin: often loss observed (Endocr Pathol 2018;29:113)

Molecular / cytogenetics description

HRPT2 (CDC73) mutation (tumor suppressor gene, 1q21-q31, encodes parafibromin) is strongly associated with familial and sporadic parathyroid carcinoma but is uncommon in adenomas, except in the setting of HPT JT (Endocrinol Metab Clin North Am 2017;46:405, N Engl J Med 2003;349:1722, Turk Patoloji Derg 2015;31:80, Mod Pathol 2011;24:S78, Endocr Pathol 2022;33:64)
- 15% with HPT JT (caused by germline HRPT2 inactivating mutation) develop parathyroid carcinoma
- Inactivating mutation of HRPT2 is found in > 70% cases of parathyroid carcinoma
- Complete nuclear loss of parafibromin has shown strong association with HRPT2 mutation; nucleolar loss of parafibromin is an abnormal finding and requires further molecular testing (Endocr Pathol 2022;33:64)
Cyclin D / CCND1 (11q13, parathyroid adenoma oncogene) encodes cyclin D1 which is overexpressed in some parathyroid carcinomas (J Clin Pathol 2015;68:771)
MEN1 mutation (tumor suppressor gene, 11q13) has been reported in rare cases (Clin Endocrinol (Oxf) 2007;67:370)
Additional molecular alterations (nonspecific) also found (CaSR, EZH2, RIZ1, RASSF1, GSK3B, APC, PRUNE2, HIC1, GSK3β, mTOR, MLL2, THRAP3, PIK3CA, WT1) (J Clin Pathol 2015;68:771)

Videos

Parathyroid pathology

Sample pathology report

Right neck, mass, excision:
- Parathyroid carcinoma, oxyphilic type (see comment)
- Comment: There is a cellular malignant tumor with thyroid gland and striated muscle invasion. Tumor cells characterized by eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin and prominent nucleoli. There are 12 mitoses per 10 mm², some of which show atypical features. Lymphatic and vascular invasion are also seen. Immunohistochemically, the tumor cells show strong expression of PTH, GATA3, chromogranin A and synaptophysin while they are negative with thyroglobulin, TTF1, PAX8, CEA and tyrosine hydroxylase. Ki67 index is 16%. Morphological and immunohistochemical features strongly support parathyroid carcinoma, oxyphilic type. Complete nuclear parafibromin loss is detected, which correlates with HRPT2 (CDC73) mutation and also parafibromin deficient parathyroid neoplasm.

Differential diagnosis

Parathyroid adenoma:
- Benign parathyroid neoplasm composed of chief cells, oncocytes or transitional oncocytes or an admixture of these cell types
- Usually asymptomatic, no palpable mass and grossly smaller than parathyroid carcinoma
- Serum calcium level is elevated but often not as high as carcinoma
- Scattered mitosis may be seen but high mitotic rate is rare and usually lacks atypical mitosis
- Lack of definitive diagnostic features of parathyroid carcinoma (invasion or metastases)
Atypical parathyroid tumor:
- Rare type of parathyroid tumor which exhibits some of the features of parathyroid carcinoma such as cytological atypia, mitotic activity, fibrous bands, adherence to adjacent structures, trabecular growth pattern, tumor cells within the capsule
- Lack of definitive diagnostic features of parathyroid carcinoma (invasion or metastases)
- Ancillary immunohistochemical markers could be used for differential diagnosis of parathyroid adenoma and carcinoma (Ki67, parafibromin, galectin3, PGP9.5, E-cadherin, 5-hmC, hTERT, p53, Rb, BCL2, p27, MDM2 and APC) (Endocr Pathol 2018;29:113, Endocr Pathol 2022;33:64)
Well differentiated thyroid carcinoma:
- Well differentiated thyroid malignancy arising from follicular epithelial cells
- Papillary or follicular growth pattern, may have colloid, typical nuclear features for papillary carcinoma, lacks well defined cytoplasmic membrane
- Positive for TTF1, thyroglobulin; negative for PTH, GATA3 (Endocr Pathol 2018;29:91)
- PAX8 expression can overlap between thyroid and parathyroid tumors and should not be considered as a reliable marker for differential diagnosis
Differentiated high grade thyroid carcinoma:
- Invasive high grade malignancy arising from follicular epithelial cells with necrosis or high mitotic count ≥ 5/10 mm² (Endocr Pathol 2022;33:27)
- Growth pattern and nuclear features similar to well differentiated tumors; papillary architecture is more common
- Positive for TTF1, thyroglobulin; negative for PTH, GATA3 (Endocr Pathol 2022;33:27)
Poorly differentiated thyroid carcinoma:
- Follicular cell neoplasm that shows limited evidence of follicular differentiation
- Solid, trabecular or insular growth pattern and lacks well defined cytoplasmic membrane
- Positive for TTF1, thyroglobulin (reduced expression); negative for PTH, GATA3 (Endocr Pathol 2018;29:91)
Medullary thyroid carcinoma:
- Malignant neuroendocrine tumor derived from C cells of thyroid
- Also lacks colloid and is positive for neuroendocrine markers and keratin
- Positive for calcitonin, CEA, TTF1; negative for PTH and GATA3 (Endocr Pathol 2018;29:91)
Paraganglioma:
- Nonepithelial tumor originating from neural crest derived paraganglion cells
- Also positive for neuroendocrine markers and GATA3 (some parasympathetic paraganglioma can be negative for chromogranin A) (Arch Pathol Lab Med 2014;138:182)
- Negative for keratin and PTH; positive for tyrosine hydroxylase (can be negative in parasympathetic paraganglioma) (Endocr Pathol 2018;29:91, Endocr Pathol 2018;29:113)
Metastatic neuroendocrine tumors:
- Clinical history, radiological and laboratory findings are important
- Usually positive for neuroendocrine markers and keratin (Cancer Cytopathol 2016;124:871)
- TTF1 (lung but also positive in medullary carcinoma), CDX2 (gastrointestinal), p16 (cervical), ISL1 and PDX1 (pancreatic) useful for detection of primary tumor site (Cancer Cytopathol 2016;124:871)

Additional references

Mete: Endocrine Pathology, 1st Edition, 2016, Nose: Diagnostic Pathology - Endocrine, 2nd Edition, 2018, Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017

Board review style question #1

Broad fibrous bands
Increased mitotic activity (> 5/10 mm²)
Parafibromin loss
Perineural invasion
Tumor cells within the capsule

Board review style answer #1

D. Perineural invasion of tumor cells is diagnostic of malignancy for parathyroid neoplasm. Although the other options are also atypical features and commonly seen in parathyroid carcinoma, based on the 2022 WHO classification one of the following features is required for definitive malignancy diagnosis of the parathyroid lesion: angioinvasion (vascular invasion), lymphatic invasion, perineural (intraneural) invasion, invasion of adjacent structures / organs, metastasis (Endocr Pathol 2022;33:64).

Comment Here

Reference: Parathyroid carcinoma

Board review style question #2

Isocitrate dehydrogenase 1 (IDH1)
Menin
Parafibromin
SMARCB1 / INI1
Succinate dehydrogenase B (SDHB)

Board review style answer #2

C. Parafibromin. Parafibromin is the protein encoded by the tumor suppressor gene HRPT2 (CDC73). Complete loss of nuclear parafibromin immunoreactivity indicates biallelic CDC73 inactivation and requires routine germline CDC73 mutation testing. Based on the 2022 WHO classification, complete nuclear loss of expression of parafibromin is considered parafibromin deficiency. Parafibromin deficient parathyroid neoplasms may show metachronous disease in the other glands and increased recurrence (Endocr Pathol 2022;33:64)

Comment Here

Reference: Parathyroid carcinoma

Parathyroid gland hyperplasia

Table of Contents

Definition / general

Usually all 4 glands are involved but may be asymmetrical with lower glands being larger
Weight of all glands usually 1 - 3 g
Usually chief cell hyperplasia, occasionally water clear cell hyperplasia; adipose tissue is rare
Some believe adenoma and hyperplasia are different morphologic manifestations of the same process
May show clonality

Water clear cell hyperplasia

Extreme enlargement of all parathyroid tissue with weights up to 100 g; causes primary hyperparathyroidism
Incidence has decreased over past 20 years, now very rare
No familial incidence, not associated with MEN (unlike chief cell hyperplasia)
Associated with blood group O (Hum Genet 1994;94:195)

Case reports

Bilateral primary chief cell hyperplasia associated with loss of APC gene (Am J Surg Pathol 2002;26:103)

Treatment

Primary chief cell hyperplasia

Excise 3 of 4 glands
Some surgeons remove all parathyroid tissue
Can use frozen section, touch prep or intraoperative PTH assay to confirm removal

Gross description

Primary chief cell hyperplasia

Classically, all glands enlarged (up to 10 g) vs. pseudoadenomatous (one gland enlarged) vs. occult (all glands normal size but histologically hyperplastic)

Water clear cell hyperplasia

Superior glands larger than inferior glands
2 giant glands may appear as one
Soft, chocolate brown, with cysts and hemorrhages
Pseudopods also common

Gross images

Images hosted on other servers:

3 and a half glands removed

Microscopic (histologic) description

Usually no rim of compressed normal tissue
May have mitotic activity

Primary chief cell hyperplasia

Sheets of chief cells, minimal fat, rare oxyphils
Usually no rim of normal tissue

Water clear cell hyperplasia

Abundant optically clear cells of variable size (hyperplasia and hypertrophy), with spherical clear vacuoles surrounded by thin eosinophilic material; basal nuclei, compact or alveolar patterns

Microscopic (histologic) images

Images hosted on other servers:

Nodular parathyroid hyperplasia (figures D / E)

Molecular / cytogenetics description

Sporadic or part of MEN 1 or 2A

Primary chief cell hyperplasia

Increased production of PTH; associated with MEN 1, 2A / 2 in 30% of cases (not MEN 2B / 3)
50% have allelic loss on #11 (where MEN1 gene is located)

Differential diagnosis

Adenoma: usually encapsulated, affects one gland with compression of adjacent tissue; most important criterion - no recurrence of hypercalcemia after 5 year followup

Parathyroid tissue

Table of Contents

Definition / general

Caused by aberrant migration of parathyroid (PT) glands during embryogenesis
First described by Lahey in 1926 (J Surg Oncol 1984;27:271)
May undergo same pathologic processes as PT glands (Mod Pathol 1989;2:652, Int Surg 1997;82:87), usually functioning adenoma or hyperplasia
Intrathyroidal PT glands are rare, but intrathyroidal PT tissue is not
A survey of the thyroids of 350 infants and children suggests that the presence of thymus and PT tissue within the thyroid is so common as to be classified as normal (J Anat 1976;122:77)

Terminology

Definition: intrathyroidal PT gland (true intrathyroidal PT gland) is a PT gland, normal or abnormal, situated totally within the thyroid, surrounded on all aspects by thyroid parenchyma and with no capsule
This entity must be clearly distinguished from subcapsular / intracapsular PT gland and those glands located in crevices in the thyroid (Ann Surg 1976;183:271, World J Surg 1987;11:110)

Epidemiology

Intrathyroidal PT tissue was found in 2% - 3% of total thyroidectomy cases (Laryngoscope 1999;109:1238, Arch Otolaryngol Head Neck Surg 2007;133:1105)
The incidence of true functioning intrathyroidal PT glands is < 1% of all hyperparathyroidism cases in large series (Otolaryngol Head Neck Surg 2011;144:867, Surgery 2012;152:1193); an additional 1% - 2% are intrathyroidal PT glands of subcapsular location
F:M = 3:1, mean age is 54 years (Surgery 2012;152:1193)
Adenoma > Hyperplasia > Carcinoma
400+ cases of intrathyroidal PT adenoma have been described in series and case reports, but < 10 cases of intrathyroidal PT carcinoma
Intrathyroidal PT tissue was found in 3% of infants on routine sections, 70% on step sections (J Anat 1976;122:77)

Sites

Superior vs. Inferior = 3:1
R:L = 3:2

Pathophysiology / etiology

A primordium of the superior PT glands (derived from 4th branchial pouch) may become trapped within the thyroid as the lateral and medial lobes fuse, resulting in an intrathyroidal superior PT gland (Ann Surg 1976;183:271)
The inferior PT glands (derived from 3rd branchial pouch) are pulled by the thymus during its descent, and, because of migrating a longer distance, they have an increased chance of becoming entrapped during the fusion of the thyroid lobes (Am J Surg 1992;164:496, Am J Surg 2006;191:418)

Clinical features

30% are asymptomatic (Surgery 2012;152:1193)
Hyperparathyroidism is seen in functioning lesions (adenoma, hyperplasia)
May cause failure in surgical treatment of hyperparathyroidism (World J Surg 1987;11:110)
Conversely, excision during thyroidectomy of intrathyroid PT glands may cause hypoparathyroidism (J Surg Oncol 1984;27:271)

Laboratory

May cause high PTH serum levels, hypercalcemia or hyperphosphatemia in functioning lesions (adenoma, hyperplasia)
PTH immunoassay in FNA aspiration fluid shows higher level than in serum

Radiology description

Detect with 99m Technetium-sestamibi scintigraphy (MIBI scan), MIBI-CT (see Video below)
US: the most characteristic feature of intrathyroidal PT adenoma is a hyperechoic line on the ventral surface of the PT gland (Endocr J 2011;58:989)

Case reports

Nontumor:
- 6 year old boy with intrathyroidal thymic tissue surrounding an intrathyroidal parathyroid gland (Thyroid 2008;18:1125)
- 29 year old woman with ectopic intrathyroidal nonfunctioning parathyroid cyst (Endocr Pract 2007;13:56)
- 41 year old woman with intrathyroidal parathyroid hyperplasia (J Surg Case Rep 2013 May 8;2013(5))
- 52 year old woman with intrathyroidal supernumerary parathyroid gland (Nephrol Dial Transplant 2007;22:293)
- 74 year old man with intrathyroidal parathyroid gland (Endocr Pract 2008;14:80)
- Bilateral intrathyroidal hyperplastic parathyroid glands (J Surg Oncol 1984;27:271)
- Amyloid goiter associated with intrathyroid parathyroid and lymphoepithelial cyst (Endocr Pathol 2009;20:243)
- Ectopic intrathyroidal parathyroid gland and papillary microcarcinoma of the thyroid (Histopathology 2004;44:300)
- Intrathyroid parathyroid gland and neonatal primary hyperparathyroidism (J Pediatr Surg 2000;35:1517)
Adenoma:
- 19 year old woman with giant intrathyroidal parathyroid adenoma (J Emerg Trauma Shock 2012;5:196)
- 22 year old woman with intrathyroidal parathyroid adenoma mimicking lymphocytic thyroiditis (Diagn Cytopathol 1999;21:276)
- 24 year old woman with primary hyperparathyroidism (Endocrinol Diabetes Metab Case Rep 2013;2013:130019)
- 44 year old woman with primary hyperparathyroidism due to intrathyroidal parathyroid adenoma (BMJ Case Rep 2012 Jun 8;2012)
- 48 year old woman with ectopic intrathyroid parathyroid adenoma (Med Ultrason 2011;13:241)
- Intrathyroid parathyroid adenoma (Diagn Cytopathol 2006;34:790)
Carcinoma:
- 40 year old man with intrathyroid parathyroid carcinoma with intrathyroidal metastasis (Jpn J Clin Oncol 2011;41:1142)
- 51 year old woman with intrathyroidal parathyroid carcinoma (Case Rep Pathol 2013;2013:198643)
- 63 year old woman with intrathyroidal parathyroid carcinoma (Diagn Pathol 2008;3:46)
- 67 year old woman with intrathyroidal parathyroid carcinoma as cause of hypercalcemia (Endocr Pract 2007;13:176)

Treatment

Surgical excision
- Thyroid lobectomy for a missing PT tumor is the most common approach (J R Soc Med 1981;74:49)
- Alternatively, thyroidotomy is performed over the lower third of the thyroid only if (a) a lower gland is missing, (b) the ipsilateral thymus is examined and removed, and (c) 3 other glands have been found (Otolaryngol Head Neck Surg 2011;144:867)
Careful search for hidden subcapsular PT glands is mandatory to avoid unnecessary thyroid surgery
Draining and ethanol ablation of a cyst

Clinical images

Images hosted on other servers:

Sonogram

Intrathyroidal PT adenoma

MIBI scan

Technetium sestamibi scan

Parathyroid carcinoma

Parathyroid glands

Coronal oblique slices

Right sided neck mass

Gross description

Yellowish tan soft nodule, completely enveloped by the thyroid
5 mm to 4 cm in size, rarely occupying the whole lobe; mean weight 300 - 400 mg (Surgery 2012;152:1193)
The corresponding normal PT gland is missing
Adenoma may have degenerating cystic center (intrathyroidal PT cyst)

Gross images

Images hosted on other servers:

Excised tissue

Resected thyroid

Parathyroid adenoma

Thyroid lobe

Intrathyroidal PT adenoma

Enlarged right thyroid lobe

Microscopic (histologic) description

Incidental intrathyroidal PT tissue / gland has a typical histology of PT
Ectopic PT gland is completely encased by thyroid parenchyma
Adenoma may consist of any PT cell population and repeats the composition of orthotopic PT adenoma, with a lack of fatty tissue and peripheral rim of compressed PT parenchyma
Carcinoma is diagnosed by the presence of invasion or metastasis

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Parathyroid histology

Images hosted on other servers:

Ectopic thymus and PT within thyroid

Surrounded by thyroid parenchyma

PT hyperplasia

Intrathyroidal PT cystic adenoma

Intrathyroidal PT adenoma

Intrathyroidal PT carcinoma

Cytology description

Monotonous cell population of chief cells appeared as discohesive naked nuclei with coarse granular chromatin mimicking lymphocytes (Surgical Pathology Clinics 2014;7:515)
The cytoplasmic feature unique to PT is the perinuclear oil vacuoles of chief cells, which can be seen on Diff-Quik stain in ~13% of cases (Yang: Thyroid Fine Needle Aspiration, 2013)
Stippled nuclear chromatin (Cytojournal 2006;3:6)
Abundant capillaries with attached epithelial cells corresponded to the highly vascular parenchyma (Diagn Cytopathol 1999;21:276)
The distinction of the different PT lesions including hyperplasia, adenoma and carcinoma cannot be made solely on the basis of cytologic features
PT adenoma aspirate may contain microfollicular, trabecular, or papillary arrangements, colloid-like secretions, and macrophages similar to thyroid (Yang: Thyroid Fine Needle Aspiration, 2013)

Cytology images

Images hosted on other servers:

Common and uncommon FNA features

FNA

Positive stains

PTH
Chromogranin A, synaptophysin

Negative stains

Electron microscopy description

EM can identify hidden chief cells in "pure" oxyphilic adenoma, explaining PTH production

Videos

Sestamibi Scans and How to See Your Parathyroid Glands

Differential diagnosis

Chief cell intrathyroidal PT adenoma
- Thyroid follicular adenoma: less vasculature, larger nuclei, colloid with birefringent oxalate crystals and scalloping
Intrathyroidal PT chief cell hyperplasia
- Lymphocytic thyroiditis (Cancer 2007;111:130)
- Intrathyroidal PT adenoma should be differentiated from thyroid tumors: naked nuclei on FNA, often has an admixture of different PT cell types (chief, oxyphil and clear cells), may have a rim of compressed benign PT tissue at the periphery, PTH+ / TTF1-
Oncocytic / oxyphilic intrathyroidal PT adenoma
- Thyroid Hürthle cell adenoma: large nuclei, more often prominent nucleoli, indistinct cell membrane (Diagn Cytopathol 2004;31:276, Diagn Cytopathol 2010;38:833)
- Thyroid medullary carcinoma: infiltrative growth with sclerosis and prominent amyloid deposition
Water clear-cell intrathyroidal PT adenoma
- Thyroid clear cell adenoma

Plasma cell granuloma

Table of Contents

Definition / general

Marked polyclonal plasma cell infiltration with nodular or diffuse thyroid involvement

Terminology

Also known as plasma cell granuloma type of inflammatory pseudotumor; but sclerosing type of inflammatory pseudotumor of thyroid is mainly composed of spindle cells (Eur Arch Otorhinolaryngol 2009;266:763, Endocr Pathol 2009;20:186)
Note: at other sites, the term inflammatory myofibroblastic tumor (or inflammatory pseudotumor) is usually used because myofibroblasts are common, and it is understood that some variants will have numerous plasma cells; however, in the thyroid gland, these cases are still called plasma cell granuloma because there are usually marked plasma cell infiltrates and myofibroblasts are usually limited

Epidemiology

~ 20 cases reported, mainly middle age and elderly women (range, 18 - 89 years, M/F = 1:4)

Pathophysiology

Excessive immunological reaction due to diverse stimuli, either infectious or noninfectious (Pathol Res Pract 2007;203:813)
Intrinsic abnormal plasma cell differentiation as a consequence of an underlying chronic infection or inflammatory condition (Hum Pathol 1985;16:848)
Autoimmune reactions and a predisposition to autoimmune diseases (J Clin Endocrinol Metab 2004;89:1534)
IgG4-related immunopathologic processes are probably NOT involved (Int J Surg Pathol 2012;20:500)

Clinical features

Neck mass with compression signs
Mainly indolent clinical behavior
Often accompanied by hypothyroidism or Hashimoto thyroiditis

Diagnosis

Histology after biopsy or surgery

Radiology description

Nonspecific; solitary benign nodule or diffuse involvement on ultrasound, cold nodule on scintigraphy

Case reports

29 year old man with hard thyroid mass and type 1 diabetes mellitus (Int J Clin Pract 2001;55:335)
35 year old woman and 41 year old man with plasma cell granuloma of thyroid associated with Hashimoto thyroiditis (J Clin Endocrinol Metab 2004;89:1534, South Med J 2004;97:598)
46 year old woman (Arch Pathol Lab Med 2002;126:595)
46 year old man with plasma cell granuloma of thyroid with Hashimoto thyroiditis (Ear Nose Throat J 2003;82:64)
50 year old man with plasma cell granuloma of thyroid gland mimicking carcinoma (Pathol Res Pract 2007;203:813)
55 year old woman (Endocr Pract 2008;14:611)
75 year old woman with inflammatory pseudotumor of thyroid gland showing fibrohistiocytic proliferation (Endocr Pathol 2009;20:186)
89 year old woman (J Thyroid Res 2010;2010:840469)

Treatment

Lobectomy / partial excision for nodular lesion, total thyroidectomy for diffuse form
Conservative steroid and immunosuppressive therapy (J Clin Endocrinol Metab 2004;89:1534)
No recurrences / metastases after excision

Gross description

Nodular form (50% of cases): well circumscribed, nonencapsulated, white, firm round nodule 2 - 5 cm in diameter (J Clin Pathol 1986;39:1105)
Diffuse form: unencapsulated, firm, gray-white with multinodular appearance (Arch Pathol Lab Med 2002;126:595)
Thyroid may adhere to surrounding tissue (Cancer 1981;48:830, J Surg Oncol 1989;41:139, Int J Clin Pract 2001;55:335)

Gross images

Images hosted on other servers:

Multinodular

Cut surface

Microscopic (histologic) description

Abundant benign plasma cells forming sheets inside cellular fibroblastic stroma with residual thyroid tissue
Variable lymphocytes and histiocytes, and occasional polymorphonuclear leukocytes or eosinophils
Russel bodies (aggregates of immunuoglobulin) within plasma cells; Russel bodies may form grape-like clusters
Mott cells (plasma cells with spherical inclusions packed in their cytoplasm, Endocr Pract 2008;14:611)
Hürthle cell changes of follicular epithelium in thyroid with diffuse involvement
Rare sclerosing subtype is hypocellular with focal uniform spindle cells / myofibroblasts arranged in fascicles; large histiocytes, lymphocytes, plasma cells and scattered eosinophils are in background

Microscopic (histologic) images

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Plasma cells, lymphocytes and fibrous tissue

Clumps of plasma cells

Plasma cells around follicular epithelium

CD79a

Kappa and lambda light chains

Positive stains

Plasma cells: polyclonal kappa and lambda light chains (APMIS 2008;116:167)
Spindle cells: vimentin, smooth muscle actin

Negative stains

ALK1 for spindle cells (no positive cases reported so far)

Molecular / cytogenetics description

No monoclonality by PCR

Differential diagnosis

Plasmacytoma

Table of Contents

Definition / general

Rare tumor of thyroid gland, presenting as a mass
Solitary or associated with multiple myeloma
Diagnosis should be restricted to tumors without a lymphoid component

Case reports

19 year old woman (N Z Med J 2006;119:U2005)
53 , 60, 61 and 71 year old men (Blood Res 2014;49:280, J Cytol 2014;31:53, Arch Pathol Lab Med 1981;105:570, The Internet Journal of Head and Neck Surgery 2007;2(1))
71 year old man with painless right sided neck mass (Case #394)
78 year old woman (Acta Clin Belg 2015;70:133)
Gamma heavy chain disease with primary thyroid plasmacytoma (Arch Pathol Lab Med 1986;110:893)
Plasmacytoma found in goiter (J La State Med Soc 2010;162:338)

Gross images

Images hosted on other servers:

Gray, firm, fleshy

Thyroidectomy specimen

Microscopic (histologic) description

See discussion at Bone marrow neoplastic - Plasmacytoma

Microscopic (histologic) images

Case #394

10×

20×

40×

CD79a

CD138

Kappa

Lambda

Images hosted on other servers:

Mature and immature plasma cells

H&E, CD138+

(A) Kappa light chain+
(B) Lambda light chain-

Cytology description

See discussion at Bone marrow neoplastic - Plasmacytoma

Cytology images

Images hosted on other servers:

Intranuclear inclusion

Congo red+

Positive stains

See discussion at Bone marrow neoplastic - Plasmacytoma

Negative stains

See discussion at Bone marrow neoplastic - Plasmacytoma

Differential diagnosis

Plasmacytoid form of medullary carcinoma
Reactive / inflammatory conditions such as inflammatory pseudotumor
Thyroid involvement with multiple myeloma
Thyroid marginal zone lymphoma with extensive plasmacytic differentiation
Undifferentiated carcinoma

Poorly differentiated thyroid carcinoma

Table of Contents

Definition / general

Malignant follicular cell neoplasm with limited evidence of follicular cell differentiation
Intermediate clinical behavior between well differentiated (papillary and follicular carcinoma) and anaplastic carcinoma (Am J Surg Pathol 2007;31:1256, Surg Pathol Clin 2014;7:475, Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

Essential features

Intermediate grade follicular cell carcinoma with limited evidence of follicular cell differentiation

Terminology

Insular / trabecular carcinoma
Primordial cell carcinoma
Poorly differentiated follicular carcinoma
Poorly differentiated papillary carcinoma
Solid type follicular carcinoma
High risk thyroid carcinoma of follicular cell origin

ICD coding

ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

Older patients, mean age 55 - 63 years
0.3 - 6.7% of thyroid carcinomas
More common in Europe and South America than U.S. (Mod Pathol 2010;23:1269)

Etiology

Iodine deficiency may be a risk factor; no association with radiation exposure (Clin Oncol (R Coll Radiol) 2011;23:261)
Some tumors are de novo; some arise from dedifferentiation of follicular or papillary carcinoma

Clinical features

Large solitary thyroid mass. Patient may have a history of recent growth in a longstanding uninodular or multinodular thyroid (Am J Surg Pathol 1984;8:655)
Intermediate behavior between well differentiated and anaplastic carcinoma (World J Surg 2007;31:934)
Has nodal and hematogenous metastases and 3 year survival of 38% (Langenbecks Arch Surg 2007;392:671)
Extends to perithyroidal soft tissue in 60 - 70% cases
Vascular invasion in 60 - 90% cases
Regional lymph node metastasis in 15 - 65%
Distant metastasis in 40 - 70%

Radiology description

Ultrasound shows inhomogeneous hyoechoic mass (Cancer 2006;106:1286)
Cold on scintigraphy and positive on FDG PET

Prognostic factors

Tumors with overall 5 year survival rate: 60 - 70% (J Clin Endocrinol Metab 2014;99:1245)
Poor prognosis associated with high stage and older age (> 45 years)

Case reports

4 year old girl with metastatic disease (Am J Otolaryngol 2009;30:61)
26 year old African American woman with benign biopsy but compressive symptoms (Case #435)
57 year old woman with unusual short term complete response to chemotherapy (J Clin Endocrinol Metab 2012;97:3046)
60 year old woman with metastatic poorly differentiated thyroid carcinoma within an intracranial meningioma (J Clin Endocrinol Metab 2014;99:3513)
64 year old woman with tumor arising from ectopic thyroid (Am J Clin Pathol 1995;104:408)
75 year old woman with superior vena cava metastasis (J Clin Oncol 2015;33:e119)
80 year old woman with neck mass (University of Pittsburgh: Case 24 - Neck Mass)
82 year old woman with extensive extracellular mucin in tumor (Hum Pathol 2005;36:698)

Treatment

Total thyroidectomy, neck dissection, radioactive iodine and suppressive thyroxine

Gross description

Large (median size: 5 cm), grayish white, some show soft pale areas of necrosis
Pushing margins, may be partially encapsulated
Can have satellite nodules (Am J Surg Pathol 1984;8:655)

Gross images

Contributed by Mark R. Wick, M.D. and AFIP images

Various images

Poorly differentiated thyroid carcinoma

Massive cervical lymph node metastasis

Images hosted on other servers:

A well demarcated tumor

Tumor with invasive growth pattern

Microscopic (histologic) description

Turin consensus diagnostic criteria:
- Solid / trabecular / insular growth pattern
- No nuclear features of papillary carcinoma
- Presence of at least one of following: convoluted nuclei, ≥ 3 mitotic figures/10 HPF, tumor necrosis (Am J Surg Pathol 2007;31:1256)
Other:

Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D.

Nests of tumor with necrosis

Follicular carcinoma with high grade progression

Follicular carcinoma with high grade progression

Case #435

Various images

Cytology description

Highly cellular, crowded cell clusters with solid, trabecular or insular morphology (Cancer 2009;117:185, Cytopathology 2016;27:176)
Background of single cells with high N:C ratio
May have necrotic background and increased mitotic figures

Cytology images

Contributed by Ayana Suzuki, C.T. and Shuanzeng Wei, M.D., Ph.D.

Insular pattern

Diff-Quik stain

Pap stain

Corresponding histology shows mitosis and necrosis

Images hosted on other servers:

Nesting pattern of cells

Overlapping cells with round, regular nuclei

Large clusters and single cells

Cellular nests of loosely cohesive cells

Overlapping cells with mild atypia

Small microfollicle of tumor cells

Vacuolated cytoplasm with round nuclei

Positive stains

Keratin, thyroglobulin (decreased expression), TTF1, Ki67: 10 - 30% (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

Negative stains

Calcitonin, PTH

Molecular / cytogenetics description

Alteration of early event of thyroid carcinogenesis: RAS family and BRAF mutation (Surg Pathol Clin 2014;7:475)
Alteration associated with dedifferentiation: mutation of p53, TERT, CTNNB1 and AKT1 (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

Videos

Poorly differentiated thyroid carcinoma by M. Brandwein (2020)

Differential diagnosis

Anaplastic thyroid carcinoma:
- Completely lacks follicular differentiation, prominent nuclear pleomorphism and necrosis
- Generally thyroglobulin- TTF1- (Surg Pathol Clin 2014;7:475)
Hürthle cell tumors:
- Poorly differentiated thyroid carcinoma can be predominantly composed of oncocytic cells (often with a small cell component) but also has necrosis and ≥ 3 mitoses/10 HPF
Metastatic carcinoma to thyroid:
- Pertinent tumor history
Medullary thyroid carcinoma:
- Also has nesting pattern
- In addition, has prominent vasculature, granular cytoplasm and finely stippled chromatin, calcitonin+ thyroglobulin- with amyloid
Parathyroid carcinoma:
- PTH+
Solid variant papillary thyroid carcinoma:
- Typical papillary nuclear features throughout

Additional references

Front Endocrinol (Lausanne) 2012;3:77

Board review style question #1

Which of the following features are not required for the diagnosis of poorly differentiated thyroid carcinoma?

Absence of conventional nuclear features of papillary thyroid carcinoma
Necrosis / convoluted nuclei / increased mitotic activity
Solid, trabecular or insular growth
Vascular invasion

Board review style answer #1

D. Vascular invasion. The Turin criteria specify solid / trabecular / insular growth, lack of conventional nuclear features of papillary thyroid carcinoma and one of the following: necrosis, convoluted nuclei or increased mitotic activity (3 or more mitoses/10 HPF). Vascular invasion may be seen in a variety of thyroid carcinomas and is an adverse prognostic factor regardless of histologic subtype or grade.

Comment Here

Reference: Poorly differentiated thyroid carcinoma

Postoperative spindle cell nodule

Table of Contents

Definition / general

Occurs after FNA or surgery
Rare, reported in other sites as genitourinary system and breast (Am J Clin Pathol 1999;111:70)

Clinical features

Thyroid mass
History of surgery or FNA

Radiology description

Hypoechoic mass with calcification (Korean J Pathol 2013;47:89)

Case reports

31 year old woman with postoperative spindle cell nodule after thyroidectomy (Head Neck 2013;35:E13)
53 year old woman with postoperative spindle cell nodule in neck after thyroidectomy (Korean J Pathol 2013;47:89)

Microscopic (histologic) description

Spindle cell proliferation
Bland cytology, no pleomorphism
Low mitotic count, no atypical mitoses
Other features may be seen as scattered inflammatory cells and histiocytes, focal myxoid change and delicate blood vessels

Microscopic (histologic) images

Images hosted on other servers:

Gross and microscopic findings

Cytology description

Spindle cells with histiocytes, vague granulomatous pattern

Cytology images

Images hosted on other servers:

Fragments of fibrocollagenous tissue

Positive stains

Vimentin
ALK (50%)

Electron microscopy description

Characteristic myofibroblastic features

Differential diagnosis

Recurrence of the lesion
Spindle cell lesions of the thyroid:
- Medullary carcinoma
- Sarcoma
- Schwannoma

Radiation thyroiditis

Table of Contents

Definition / general | Microscopic (histologic) images

Definition / general

Histologic changes vary with dose and type of radioactive isotope
Low doses to tonsils cause nodular hyperplasia of thyroid, follicular disruption, focal hemorrhagic necrosis, neutrophil infiltration
Radioactive iodine may cause large bizarre cells with hyperchromatic nuclei and prominent nucleoli or nuclear features of papillary carcinoma; cells are in clusters and sheets accompanied by lymphocytes, histiocytes and Hürthle cells (Am J Clin Pathol 1997;107:20)
External radiation (for lymphoma) causes hypercellularity, lymphocyte infiltration, adenomatous nodules, oncocytic metaplasia, fibrosis and atypia; chronic changes include fibrosis, atrophy and vascular change
Post Chernobyl changes include antithyroperoxidase antibodies, but no thyroid dysfunction (J Clin Endocrinol Metab 2008;93:2729)
Childhood radiation is associated with high frequency of allelic loss (Mod Pathol 2008;21:1176)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

Small nodule of atypical cells with bizarre nuclei

Large eosinophilic cells

Small regenerative nodule

Compensatory nodular hyperplasia

Prominent nuclear atypia / pleomorphism

Postnecrotic hyalinosis of colloid nodule

Intact parathyroid versus highly atrophic thyroid follicles

Hyalinized vessel wall

Bizarre nuclear changes

Papillary changes

Images hosted on other servers:

Hyperplastic epithelium and atypia

References

Table of Contents

Main references recommended by editor

Recommended thyroid books
First choice:

Chapters in general pathology books:

Endocrine/Head-Neck volumes:

FNA:

Clinical:

Professional societies
Pathology:

Endocrine Pathology Society - Affiliated Journal: Endocrine Pathology
UK Endocrine Pathology Society

Clinical:

American Thyroid Association - Affiliated Journal: Thyroid
Endocrine Society - Affiliated Journal: Journal of Clinical Endocrinology & Metabolism
Society for Endocrinology - Affiliated Journal: Endocrine-Related Cancer
European Society of Endocrinology - Affiliated Journal: European Journal of Endocrinology

Media
Virtual slides (main):

Virtual slides (more):

Images:

YouTube channels:

Guidelines
Pathology:

Clinical:

Online resources

Thyroid Disease Manager

Literature from 2020

Special issues
- Seminars in Diagnostic Pathology: Thyroid Pathology - Controversies and Best Practices [Accessed 21 January 2021]
- Gland Surgery: Asian and Western Practice in Thyroid Pathology - Similarities and Differences [Accessed 21 January 2021]
Journal articles
- Review on rare thyroid tumors (Endocr Pathol 2020;31:197)
- Dissecting anaplastic thyroid carcinoma (Thyroid 2020;30:1505)
- Grading of medullary thyroid carcinoma based on necrosis and proliferation (Mod Pathol 2020;33:1690, Am J Surg Pathol 2020;44:1419)
- Characterization of metastatic lymph nodes for risk stratification of papillary thyroid carcinoma (Eur J Endocrinol 2020;183:83)
- Papillary thyroid carcinoma with high grade features (Thyroid 2021 Jan 19 [Epub ahead of print])
- DICER1 in pediatric thyroid cancer (Mod Pathol 2020;33:1264) and thyroid teratomas (Am J Surg Pathol 2020;44:826)
- Measures to improve clinical decision making in thyroid FNA (Cancer Cytopathol 2020;128:917)
Books
- Asa: Survival Guide to Endocrine Pathology, Series 1, 2020
Videos
- Histopathology
  
  NIFTP by R. Ghossein (2020)
  
  Diagnostic dilemmas in NIFTP by N. Cipriani (2020)
  
  Extrathyroidal extension by J. Hernandez-Prera (2020)
  
  Poorly differentiated thyroid carcinoma by M. Brandwein (2020)
  
  Oncocytic lesions by Z. Baloch (2020)
  
  Update on thyroid neoplasms by R. Lloyd (2020)
  
  Virtual slides of main thyroid lesions by G. Tranesh (2020)
- Cytopathology
  
  Thyroid cytopathology by S. Ali (2020)
  
  Pediatric thyroid nodules by A. Wassner and A. Bauer (2020)
- Molecular
  
  ThyroSeq testing by Y. Nikiforov (2020)
  
  ThyGenX/ThyraMIR panel by Alidad Mireskandari (2018)
Major updates on PathOutlines
- Bethesda topics (suspicious for malignancy, malignant)
- Papillary carcinoma variants (classic, microcarcinoma, tall cell and others)
- Chemistry pages (thyroid function panel, calcitonin and more)

Literature from 2019

ICCR carcinoma of the thyroid histopathology reporting guide ICCR: Carcinomas of the Thyroid (TNM8) [Accessed 28 January 2020]
Core needle biopsy guidelines J Pathol Transl Med 2020;54:64
Special issues
- Endocrine Pathology (Surg Pathol Clin 2019;12:865)
- Cytology and Surgical Pathology of the Thyroid (AJSP Reviews & Reports 2019;24:39)
- Mini-Symposium Endocrine Pathology (Diagnostic Histopathology 2019;25:143)
Journal articles
- Reviews on evolving concepts (Hum Pathol 2019;95:46), histological classification (Endocrinol Metab Clin North Am 2019;48:1) and follicular-patterned nodules (Arch Pathol Lab Med 2019;143:1472)
- Debates in Archives on role of pathologists in overdiagnosis of thyroid cancer (Arch Pathol Lab Med 2018;142:1018, Arch Pathol Lab Med 2019;143:1171, Arch Pathol Lab Med 2019;143:1171)
- Reviews on molecular testing in indeterminate FNA (Endocr Rev 2018;39:154, Endocrinol Metab Clin North Am 2019;48:85, Acta Cytol 2020;64:40)
- Hyalinizing trabecular tumor decoded (Thyroid 2019;29:161, Mod Pathol 2019;32:1734)
- AI in thyroid histopathology (J Clin Med 2019;8:1675, Ann Transl Med 2019;7:468) and cytology (J Cancer 2019;10:4876)
Books
- Hoda: Atlas of Thyroid Cytopathology on Liquid Based Preparations - Correlation with Clinical, Radiological, Molecular Tests and Histopathology, 1st Edition, 2020
Major updates on PathOutlines
- Grossing guide
- Ultrasound and cytology techniques
- Bethesda topics (adequacy, nondiagnostic, AUS, FN, Hürthle)
- Papillary carcinoma pages

Literature from 2018

Special issue of Endocrine Pathology on IHC biomarkers in endocrine pathology (Endocr Pathol 2018;29)
Journal articles
- Review of the new WHO classification of thyroid tumors (Pathol Int 2018;68:641)
- Revision of NIFTP criteria (JAMA Oncol 2018;4:1125, Cancer Cytopathol 2018;126:897)
- Update on molecular testing (Arch Pathol Lab Med 2018;142:446)
Books
- Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid - A Comprehensive Guide for Practicing Thyroid Pathology, Third Edition, 2019
- Kakudo: Thyroid FNA Cytology - Differential Diagnoses and Pitfalls, Second Edition, 2019
Video
- Histopathology
  
  An alphabet soup of thyroid neoplasms (2018) by L. Thompson
- Cytology
  
  The atypical thyroid FNA (2017) by E. Cibas
  
  Algorithmic approach to thyroid FNA (2018) by Z. Baloch
- Molecular
  
  New molecular platforms (2017) by E. Cibas, P. Sadow, and R. Kloos
  
  Genomic evolution of thyroid nodules and cancer (2018) by Y. Nikiforov

Literature from 2017

Annual review issue of Histopathology on endocrine pathology: Histopathology 2018;72:3
Journal articles
- Practical synopsis on NIFTP: Mod Pathol 2018;31:39, Histopathology 2018;72:53
- Molecular pathology and molecular testing: Annu Rev Pathol 2018;13:141, Endocr Pract 2017;23:979, Arch Pathol Lab Med 2018;142:446, Endocr Pathol 2018 May 9 [Epub ahead of print]
- FVPTC and thyroid cancer: J Clin Endocrinol Metab 2017;102:15, Pathology 2017;49:229
Books

Literature from 2016

Mini symposium on thyroid pathology by Diagnostic Histopathology: Diagn Histopathol (Oxf) 2016;22:171
Journal articles
- Introduction of NIFTP: JAMA Oncol 2016;2:1023
- MASC of the thyroid: Mod Pathol 2016;29:985
- Genotyping of aggressive thyroid cancers (anaplastic and poorly differentiated): J Clin Invest 2016;126:1052
- Thyroid C cells were found to derive from endoderm, not neural crest: Development 2015;142:3519
ATA 2015 guidelines on thyroid nodules and thyroid cancer: Thyroid 2016;26:1
Books (links also available here):
- Rosai: AFIP Tumors of the Thyroid and Parathyroid, 2015 – updated AFIP fascicle
- Wenig: Atlas of Head-Neck Pathology 3rd Edition, 2015 – up-to-date, richly illustrated
- Kakudo: Thyroid FNA Cytology: Differential Diagnoses and Pitfalls, 2016 – a look on thyroid pathology from Asian experts
- Mete: Endocrine Pathology, 1st Edition, 2016
- Wartofsky: Thyroid Cancer – A Comprehensive Guide to Clinical Management, 3rd Edition, 2016

Riedel thyroiditis

Table of Contents

Definition / general

Densely fibrotic inflammatory process involving thyroid gland and adjacent neck tissue
Described in 1896 by German surgeon Bernhard Moritz Carl Ludwig Riedel (Wikipedia)
Rare (0.05% of thyroidectomy specimens)

Terminology

Also called Riedel struma, fibrous thyroiditis

Epidemiology

Slight female predominance, usually age 40 - 60 years

Etiology

Etiology unclear; may be part of generalized fibroinflammatory process also involving other organs (Am J Clin Pathol 2004;121:S50)

Clinical features

Associated with inflammatory fibrosclerosis / multifocal systemic fibrosclerosis (mediastinal or retroperitoneal fibrosis, sclerosing cholangitis, inflammatory pseudotumor of orbit)
65% have antithyroid antibodies
Clinically resembles carcinoma
In one study, 67% had antithyroid antibodies, supporting an autoimmune mechanism of injury (Am J Clin Pathol 1988;90:715)

Case reports

41 year old woman with case resembling anaplastic carcinoma (Int J Surg 2008;6:e24)
44 year old woman with bilateral orbital pseudotumors (J Fr Ophtalmol 2008;31:715.e1)
51 year old woman with prior subacute thyroiditis (Endocr J 2007;54:559)
Two cases of Riedel thyroiditis, one had coexisting retroperitoneal fibrosis (Am J Clin Pathol 1976;65:274)

Treatment

Surgery to decompress, steroids or tamoxifen (Endocr Pract 2004;10:483)

Gross description

Extensive stony hard fibrosis involving a goitrous thyroid gland and infiltration into adjacent muscle and other structures, obliterating tissue planes at surgery
Binds soft tissues of neck in an "iron collar," may compress trachea
Tan / gray, woody and avascular, no lobules apparent

Microscopic (histologic) description

No normal lobular pattern
Follicles are obliterated or compressed by extensive dense fibrous tissue, which also infiltrates adjacent skeletal muscle
Patchy lymphocytes (B & T cells), plasma cells (IgA, lambda) and eosinophils, inflammation in walls of trapped veins
25% have adenoma centrally in fibrous mass
No oncocytic cells, no giant cells

Microscopic (histologic) images

AFIP images

Atrophic thyroid follicles

Resembles papillary microcarcinoma

Follicles within scar irregular

Heavy inflammatory infiltrate, venous wall

Images hosted on other servers:

Massive scarring and lymphohistiocytic infiltrate

Obliterating phlebitis

Virtual slides

Images hosted on other servers:

Invasive fibrous thyroiditis

Cytology description

Moderate cellularity with fragments of fibrous tissue containing bland spindle cells and myofibroblasts (Diagn Cytopathol 2004;30:193)

Differential diagnosis

Fibrous variant of Hashimoto thyroiditis: limited to thyroid, noninfiltrative, less abundant fibrous reaction, oncocytic cells present, more plasma cells, no granulocytes, no monocytes, no eosinophils (J Endocrinol Invest 2003;26:444)
Sarcoma: atypical spindle cells (J Clin Pathol 2001;54:570)
Subacute thyroiditis: late phase (Ann Pathol 2008;28:263)

Additional references

eMedicine - Riedel Thyroiditis

Sarcoidosis

Table of Contents

Definition / general

Idiopathic multisystemic disease with noncaseating granulomas and predominantly pulmonary involvement (see Lung nontumor chapter)

Epidemiology

Clinically recognizable thyroid involvement occurs in < 1% of sarcoidosis patients
Autopsy series reports thyroid involvement in 4% of sarcoidosis patients (Am J Med 1963;35:67)

Clinical features

Hypo- and euthyroidism are more common than hyperthyroidism (Thyroid 2006;16:1175)
May be manifested as or mimic thyroiditis, nodular and diffuse goiter, and thyroid cancer (Arq Bras Endocrinol Metabol 2012;56:209)

Diagnosis

Diagnosis / Radiology

Presence of noncaseating granulomas in the gland and the evidence of generalized sarcoidosis
Isolated sarcoidosis of thyroid is a diagnosis of exclusion - further radiographic evaluation for systemic disease is suggested
Granulomas often occur as cold nodules

Laboratory

Serum angiotensin converting enzyme (ACE) level is elevated and represents total body granuloma load

Case reports

23 year old woman with Graves' thyrotoxicosis and concomitant sarcoidosis (Endocr Pract 2007;13:159)
51 year old man - first report of thyroid sarcoidosis (Arch Intern Med (Chic) 1938;62:285)
59 year old man with granulomatous thyroiditis (Acta Biomed 2004;75:69)
65 year old woman with multinodular goiter as the initial presentation of systemic sarcoidosis (Respir Care 2011;56:1029)
Hürthle cell hyperplasia and sarcoidosis of the thyroid (Arch Pathol Lab Med 1991;115:1044)
Two cases with Graves' disease (Arq Bras Endocrinol Metabol 2012;56:209)

Isolated sarcoidosis of the thyroid:

42 year old woman with sarcoidosis presenting as cold thyroid nodules (Surg Today 2005;35:770)
54 year old man with asymptomatic nontoxic thyromegaly (Endocr Pract 2013;19:e40)
Sarcoidosis of the thyroid gland initially diagnosed as malignancy (Otolaryngol Head Neck Surg 2003;129:154)
Thyroid sarcoidosis as a unique localization (Thyroid 2006;16:1175)
Two cases of thyroid sarcoidosis associated with hyperthyroidism (J Endocrinol Invest 2006;29:834)

Thyroid sarcoidosis with thyroid cancer:

35 year old woman with papillary thyroid carcinoma with sarcoidosis (Neth J Med 2007;65:185)

Thyroid cancer and sarcoidosis (Sarcoidosis Vasc Diffuse Lung Dis 2014;31:239)

Treatment

In patients with compression symptoms, hyperthyroidism, resistance to antithyroid drugs and RAI treatment thyroidectomy is performed

Microscopic (histologic) description

Multiple scattered noncaseating, epithelioid granulomas with Langhans giant cells and lymphocytes, nonspecific
Interstitial (rather than intrafollicular) location, usually not surrounding colloid
Associated sarcoid granulomas in the extrathyroidal tissue such as the lymph nodes, parathyroids and adjacent muscle (Thyroid 2006;16:1175)

Cytology description

Granulomas with multinucleated cells, nonspecific (Respir Care 2011;56:1029)
Epithelioid cells and lymphocytes

Negative stains

GMS; acid fast stains

Differential diagnosis

Granulomatous diseases:
- Tuberculosis: AFB+, caseating necrosis
- Fungi: positive for GMS, PAS
- Other rare lesions: atypical mycobacteria, granulomatous vasculitis
Subacute and palpation thyroiditis with involvement of follicles and engulfment of colloid
Post FNA effects and foreign body granulomas
Sarcoid reaction in thyroid carcinoma: a noncaseating granuloma found in the primary tumor, its vicinity or within the lymph nodes draining the neoplasm when evidence of systemic sarcoidosis does not exist (Endocr J 1997;44:697); may have similar findings in autoimmune thyroiditis (Endocr Pract 2013;19:e40)

Additional references

Sarcoma

Table of Contents

Definition / general

Primary thyroid sarcomas are rare, usually reported only as case reports
Chondrosarcoma: primary thyroid tumors are very rare
Kaposi sarcoma: rare site for this tumor, even in HIV patients (0.9%, J Thyroid Res 2014;2014:364146)
Leiomyosarcoma: malignant mesenchymal tumor of smooth muscle origin; very rare as primary thyroid tumor; has very aggressive clinical course
Synovial sarcoma: distinctive soft tissue neoplasm, 5 - 10% of all soft tissue sarcomas, but very rare in thyroid (Goldblum: Enzinger and Weiss's Soft Tissue Tumors, 6th ed, 2013); presents as rapidly enlarging thyroid mass with normal thyroid function tests
Undifferentiated pleomorphic sarcoma (MFH): extremely rare thyroid tumor with median survival of only 9 months (Eur J Surg Oncol 2009;35:649)

Case reports

15 year old boy with primary thyroid synovial sarcoma (J Korean Med Sci 2007;22:S154)
30 year old man with Kaposi sarcoma (Clin Nucl Med 1987;12:848)
30 year old woman with MFH metastasizing to thyroid (Acta Cytol 2008;52:729)
41 year old HIV+ woman with thyroid Kaposi sarcoma (Acta Cytol 2003;47:645)
41 year old patient with hypothyroidism due to Kaposi sarcoma of thyroid (Rev Infect Dis 1991;13:826)
45 year old HIV- Haitian woman with thyroid Kaposi sarcoma (Acta Cytol 2007;51:421)
49 year old woman and 71 year old man with thyryoid liposarcoma (Sarcoma 2004;8:91)
55 year old man with rapidly growing 7 cm neck mass - synovial sarcoma (Case Rep Oncol 2014;7:6)
56 year old woman with thyryoid liposarcoma (Am J Clin Pathol 1991;95:675)
59 year old woman with primary thyroid myxoid liposarcoma (J Clin Pathol 2009;62:1037)
60 year old man and 72 year old woman with primary thyroid synovial sarcoma (Acta Cytol 2003;47:495, Clin Exp Otorhinolaryngol 2011;4:204)
60 and 75 year old women with primary thyroid osteosarcoma (Diagn Cytopathol 2008;36:589, Contemp Oncol (Pozn) 2013;17:97)
64 and 65 year old women with thyroid leiomyosarcoma (Endocr Pathol 2013;24:136, Thyroid 2008;18:425)
65 year old man with thyroid leiomyosarcoma (Updates Surg 2014;66:165)
65 year old man with thyroid MFH mimicking Riedel thyroiditis (J Clin Pathol 2001;54:570)
67 and 70 year old women with primary thyroid MFH (Thyroid 2008;18:51)
68 year old man with primary myxoid chondrosarcoma (Arch Pathol Lab Med 1988;112:94)
72 year old woman and 77 year old man with thyroid leiomyosarcoma (Diagn Pathol 2013;8:36, Oncol Lett 2014;7:1011
83 year old woman with thyroid leiomyosarcoma (Ann Diagn Pathol 2008;12:50)
Metastasis of uterine leiomyosarcoma to thyroid gland (Thyroid 2007;17:1295)
Mesenchymal chondrosarcoma of thyroid (APMIS 2004;112:384)
Thyroid liposarcoma mimicking retrosternal goiter (Ann Thorac Surg 2003;75:566)

Clinical images

Images hosted on other servers:

Leiomyosarcoma: nodule with heterogeneous uptake

Gross description

Chondrosarcoma: well defined, greyish white, with cartilaginous consistency
Leiomyosarcoma: solid, unencapsulated tumor with hemorrhage and necrosis
Synovial sarcoma: encapsulated mass with lobulated cut surface, grayish tan solid mass with rubbery consistency (J Korean Med Sci 2007;22:S154)

Gross images

Images hosted on other servers:

Synovial sarcoma:
well demarcated
lobulated, tan
solid mass

Microscopic (histologic) description

Chondrosarcoma: lobular appearance with pleomorphic chondrocytes and infiltration of surrounding thyroid tissue; variable calcification
Leiomyosarcoma: spindled cells in fascicular pattern, infiltrating normal thyroid tissue; cells are pleomorphic with abundant eosinophilic fibrillary cytoplasm and irregular intracytoplasmic vacuoles; commonly hemorrhage, necrosis, mitotic figures, atypical mitoses
Liposarcoma: invasive tumor composed of spindle to pleomorphic cells, with variable pleomorphism; may have myxoid stroma with arborizing capillaries
Osteosarcoma: spindled to epithelioid cells invading and destroying adjacent thyroid; pleomorphic with coarse chromatin and multinucleated cells with foci of lace-like osteoid
Synovial sarcoma: biphasic growth pattern with admixture of spindled and epithelial cell components; spindle cell component has fascicles of atypical fibroblast-like cells; epithelial component has solid nests of plump epithelioid cells with well formed glandular structures; cells are pleomorphic and mitotically active

Microscopic (histologic) images

Images hosted on other servers:

Leiomyosarcoma:

Compactly cellular

Cigar shaped nuclei

Invades thyroid parenchyma

CK-

h-Caldesmon

Desmin

ER-

TTF1-

Chromogranin-, synaptophysin-

Liposarcoma

Synovial sarcoma: biphasic growth; cytokeratin & vimentin

UPS / MFH: residual thyroid follicles; intersecting bundles of atypical spindle cells

Cytology description

Kaposi sarcoma: spindled and plasmacytoid cells
Leiomyosarcoma: spindled and plump pleomorphic cells with acidophilic fibrillary cytoplasm in a necrotic / proteinaceous background
Osteosarcoma: hypercellular smears of loosely cohesive cells; spindled to epithelioid cells with scant to moderate amphophilic-basophilic cytoplasm, with occasional small cytoplasmic vacuoles; cells may be multinucleated; nuclei are elongated ovals with coarse chromatin and prominent nucleoli; fibrillar, metachromatic extracellular matrix
Synovial sarcoma: clusters of pleomorphic spindled and epithelioid cells

Cytology images

Images hosted on other servers:

Synovial sarcoma:
spindled and
epithelioid cells

Positive stains

Leiomyosarcoma: vimentin, h-Caldesmon, SMA
Liposarcoma: S100, vimentin
Osteosarcoma: vimentin
Synovial sarcoma: vimentin, EMA, CD99, PAS, Alcian blue

Negative stains

Leiomyosarcoma: Cytokeratin, EMA, TTF1; also CD31, Factor VIII, thyroglobuin
Liposarcoma: cytokeratin
Osteosarcoma: thyroglobulin, calcitonin, cytokeratin, TTF1; also synaptophysin, chromogranin, HMB45
Synovial sarcoma: TTF1, thyroglobulin, synaptophysin, chromogranin, S100

Electron microscopy images

Images hosted on other servers:

Synovial sarcoma:
solid nests of
epithelial cells

Molecular / cytogenetics images

Images hosted on other servers:

Synovial sarcoma:
SYT-SSX fusion
gene transcript

Differential diagnosis

Chondrosarcoma: anaplastic carcinoma with chondrosarcomatous component (Cesk Patol 2005;41:34)
Follicular or papillary neoplasms with spindle cell metaplasia
Medullary carcinoma
Riedel thyroiditis
SETTLE

Sclerosing mucoepidermoid carcinoma with eosinophilia

Table of Contents

Definition / general

Indolent mucoepidermoid carcinoma with fibrosis and eosinophil infiltrate in a background of sclerosing Hashimoto thyroiditis (Am J Surg Pathol 1991;15:438)
Distinct from mucoepidermoid carcinoma of salivary gland (Mod Pathol 2000;13:802, Mod Pathol 2017;30:329)
- May derive from squamous metaplasia or ultimobranchial body rests (Mod Pathol 2004;17:526)
- Death due to disease is uncommon, although lymph nodes metastases, extracapsular spread, vascular invasion and perineural invasion are common
Distinct from thyroid mucoepidermoid carcinoma

Essential features

Squamous and mucus secreting cells with fibrosis and eosinophilic infiltrate in a background of sclerosing Hashimoto thyroiditis

Epidemiology

Almost always women (M:F = 1:16)
Mean age: 55 years
Associated with Hashimoto thyroiditis and solid cell nest hyperplasia

Etiology

Associated with sclerosing Hashimoto thyroiditis
Possibly derives from metaplastic squamous epithelium or solid cell nests
Negative for MAML2 rearrangements, typically seen in salivary mucoepidermoid carcinoma (Mod Pathol 2017;30:329)

Clinical features

Slowly growing thyroid mass in patients with sclerosing Hashimoto thyroiditis
Death due to disease is uncommon, although lymph nodes metastases, extracapsular spread with extensive tumor invasion into the adjacent soft tissues and organs, vascular invasion and perineural invasion are common (Hum Pathol 2015;46:725)

Radiology description

Ultrasound scan: ill defined, heterogeneous and hypoechoic nodule
Cold on radionuclide scan

Case reports

35 year old woman with thyroid swelling and lymph node enlargement (J Cytol 2016;33:37)
38 year old woman diagnosed with sclerosing mucoepidermoid carcinoma (Am J Otolaryngol 2004;25:48)
39 year old woman with a goiter for many years (Am J Clin Pathol 1998;109:294)
44 year old woman with 4 month history of a painless swelling (Int Surg J 2017;4:1780)
45 year old man with a painless mass (Int J Clin Exp Pathol 2015;8:5947)
57 year old woman with right neck mass for 20 years (J Korean Med Sci 1999;14:338)
61 year old man with thyromegaly and vocal cord paralysis (Am J Clin Pathol 1998;109:294)
65 year old woman with thyroid swelling (Indian J Pathol Microbiol 2008;51:34)
65 year old man presented a diffuse neck swelling of rapid onset (Hematology/Oncology and Stem Cell Therapy 2008;1:62)
69 year old woman who had undergone thyroidectomy and 70 year old woman with distant metastasis (Hum Pathol 1997;28:1091)
Middle aged woman with locally recurrent thyroid tumor (Case #230)

Treatment

Total thyroidectomy with/without neck dissection

Gross description

White, homogenous, firm, usually ill defined border

Gross images

Contributed by Mark R. Wick, M.D. and AFIP

Mucoepidermoid
carcinoma,
sclerosing type

Well circumscribed
tumor (not typical)
with dense fibrosis

Microscopic (histologic) description

Infiltrating solid / nested squamous tumor cells with mild to moderate atypia in dense fibrohyaline stroma with marked eosinophil infiltration; keratin pearls and keratin debris can be identified
Mucus secreting cells, small mucin pools present; background of chronic lymphocytic thyroiditis
Lymph nodes metastasis, extracapsular spread, vascular invasion and perineural invasion are common
May have focal clear cells (Ann Diagn Pathol 2003;7:348)

Microscopic (histologic) images

Case #230 and AFIP

Small irregular strands of tumor cells

Images hosted on other servers:

Various images

Cytology description

Atypical squamous cells, mucocytes, mucin and eosinophils; may mimic squamous cell / anaplastic carcinoma (Diagn Cytopathol 1996;15:30, Am J Clin Pathol 1998;109:294)

Cytology images

Images hosted on other servers:

Epithelial pearl-like structure

Cell block

Cell block, p40

Positive stains

Keratin, p63, variable TTF1, CEA (mucus containing cells) (Hum Pathol 2015;46:725)

Negative stains

Thyroglobulin, calcitonin

Differential diagnosis

Anaplastic carcinoma: highly malignant carcinoma with necrosis, can have squamous component
CASTLE: squamous cells with variable lymphocytes without eosinophils, CD5+, CD117+, can have mucin
Direct extension or metastasis of salivary mucoepidermoid carcinoma: keratinization is rare
Nodular sclerosing Hodgkin lymphoma: Reed-Sternberg cells without mucin (Arch Pathol Lab Med 2000;124:446)
Solid cell nest and squamous metaplasia: no atypia, no invasion, no mucin, no eosinophils
Squamous cell carcinoma: sheets of highly atypical squamous cells with necrosis, no mucin, no eosinophils
Papillary carcinoma with squamous metaplasia
Rare neoplastic (medullary carcinoma with squamous differentiation, invading adenosquamous carcinoma) and non-neoplastic (Hashimoto thyroiditis with cyst formation and prominent eosinophilic infiltration, branchial cleft-derived cysts) lesions (Wenig, Bruce: Atlas of Head and Neck Pathology)
Differential diagnosis of FNA cytology includes other primary and metastatic thyroid malignancies, and Hashimoto’s thyroiditis (Diagn Cytopathol 1996;15:301)

Board review style question #1

Which item is correct regarding sclerosing mucoepidermoid carcinoma with eosinophilia?

Sclerosing mucoepidermoid carcinoma with eosinophilia is not associated with Hashimoto thyroiditis
Lymph nodes metastases, extracapsular spread, vascular invasion and perineural invasion are common
Death due to sclerosing mucoepidermoid carcinoma with eosinophilia is common
Eosinophil infiltration is common, and no keratin pearls and keratin debris are seen
The squamous component is highly malignant

Board review style answer #1

B. Lymph nodes metastases, extracapsular spread, vascular invasion and perineural invasion are common. Death due to disease is uncommon, although lymph nodes metastases, extracapsular spread, vascular invasion and perineural invasion are common.

Comment Here

Reference: Sclerosing mucoepidermoid carcinoma with eosinophilia

Secretory carcinoma

Table of Contents

Definition / general

Rare salivary gland type tumor arising in thyroid
First described by Stevens et al. in 2015 (Mod Pathol 2015;28:1084)

Essential features

Recently described rare cancer, originally reported in salivary glands, which is associated with ETV6-NTRK3 translocation
Highly reminiscent of papillary thyroid carcinoma with oncocytic features, can be suspected by the presence of microcystic / cribriform pattern
Important to differentiate from thyroid cancer because of likely aggressive course and ineffectiveness of radioactive iodine / RAI therapy
Diagnosis: Mammaglobin+, Thyroglobulin-, TTF1-; also confirmed by molecular testing

Terminology

MASC: mammary analog / analogue secretory carcinoma

Epidemiology

Very rare; fewer than 10 cases described to date (Head Neck Pathol 2016 Sep 15 [Epub ahead of print])
Middle age (range, 36 - 74 years old, mean 57 years old); F:M is 2.5

Sites

MASC was originally described in salivary glands, and shares the same histology, immunophenotype and molecular background as secretory carcinoma of breast (Am J Surg Pathol 2010;34:599)
Reported in major salivary glands (parotid > submandibular), occasionally in other head / neck locations (lip, palate and thyroid), also in skin

Pathophysiology / etiology

Origin is debated (Head Neck Pathol 2016 Jul 11 [Epub ahead of print], Mod Pathol 2016;29:985):
- Primary thyroid tumor from ectopic salivary gland remnants, intra- or perithyroidal
- Metastatic from occult primary (salivary glands, breast)
- May have the same origin with papillary thyroid cancer, some MASCs coexist with PTC and share molecular aberrations
Initiating molecular event is a chromosomal translocation t(12;15)(p12;q25) resulting in the ETV6-NTRK3 gene fusion
Chimeric protein is a constitutively active protein tyrosine kinase with transformation activity
ETV6-NTRK3 fusion is found in several malignancies other than MASC, e.g., secretory carcinoma of the breast, congenital fibrosarcoma, cellular or mixed mesoblastic nephroma, myeloid leukemias and papillary thyroid carcinoma (2% sporadic, 14% radiation induced) (Head Neck Pathol 2016;10:405)

Diagrams / tables

Images hosted on other servers:

ETV6-NTRK3 fusion

Clinical features

Invasive / locally aggressive growth with nodal metastasis, 2 out of 7 reported cases were disseminated and fatal (in contrast to the indolent MASC of salivary gland)
Frequent recurrences

Diagnosis

On histopathology, confirmed by IHC and molecular testing
Occult primary (breast, salivary glands) should be considered

Laboratory

Recurrence after total thyroidectomy produce no elevated serum thyroglobulin

Radiology description

Non RAI avid, both primary tumor and relapses / metastases

Prognostic factors

Probably more aggressive than follicular derived, well differentiated thyroid tumors

Case reports

36 year old woman with MASC apparently arising in thyroid which progressed to fatal disseminated disease (Head Neck Pathol 2016;10;405)

Treatment

Surgical excision, usually total thyroidectomy with lymph node dissection
Does not respond to RAI (Head Neck Pathol 2016;10;405)
ETV6-NTRK3 is a "druggable" fusion, Trk inhibitors are currently used for MASC patients in clinical trials (Mod Pathol 2016;29:985)

Gross description

Poorly circumscribed solid white tan nodules (Head Neck Pathol 2016 Jul 11 [Epub ahead of print])
Large (range = 2.4 - 7.0 cm, mean = 4.3 cm)
Often extrathyroidal extension (Mod Pathol 2016;29:985)

Microscopic (histologic) description

Invasive growth with multiple nodules in fibrotic stroma
Complex architecture with microcystic / cribriform, solid, trabecular, tubular and papillary growth patterns
Polygonal eosinophilic cells with vacuolated cytoplasm:
- Prominent single centrally placed nucleolus
- Abundant nuclear grooves (in all architectural patterns), rare pseudoinclusions
- Focal vesicular nuclei with chromatin clearing
- Sometimes apocrine-like capitations
- Cellular atypia is mild to focally moderate, rarely may have high grade features (increased mitoses and necrosis)
Intraluminar (sometimes intracytoplasmic) colloid-like mucin secretions, from slightly pink watery to purple dense
Stroma:
- Extensive fibrosis
- Few psammoma bodies
- Lymphoplasmacytic infiltrate and chronic lymphocytic thyroiditis in adjacent thyroid tissue
Minor papillary thyroid carcinoma component can exist, either classic or follicular variant (Mod Pathol 2016;29:985)

Microscopic (histologic) images

Images hosted on other servers:

Morphology

MASC vs. PTC

Immunophenotype

Cytology description

Hypercellular smear with sheets, caps, blunted papillary structures without fibrovascular cores ("tentacular nubbins") and loss of polarity (Diagn Cytopathol 2017;45:45)
Round to oval nuclei with prominent grooves, vesicular to powdery chromatin, single central nucleoli and rare nuclear pseudoinclusions
Abundant granular cytoplasm with vacuolation
No increased colloid

Positive stains

Mammaglobin
GATA3, DOG1
S100 is consistently positive, PAX8 variable, which is overlapped with papillary thyroid carcinoma (not helpful for differential diagnosis)
Mucicarmine, PAS and PASD for secretions (mucin)
Low Ki67 (1 - 7%) (Mod Pathol 2016;29:985)

Negative stains

TTF1 and Tg

Electron microscopy description

Large number of secretory granules with extrusion into the intercellular spaces, well developed endoplasmic reticulum, lipid laden vacuoles and well formed microvilli (Int J Surg Pathol 2017;25:127)

Molecular / cytogenetics description

FISH (on paraffin sections) to detect chromosome translocation t(12;15)(p12;q25)
RT-PCR or NGS (RNA template) to detect ETV6-NTRK3 gene fusion

Molecular / cytogenetics images

Images hosted on other servers:

FISH (separate signals)

Differential diagnosis

Both histology and cytology closely mimics papillary thyroid cancer
Oncocytic PTC:
- Histology rarely shows unusual patterns (cribriform / microcystic), no intracytoplasmic secretions and capitation
- Absence of tentacular nubbins in smears
- Immunophenotype is inconsistent with MASC, IHC panel with mammaglobin and Tg / TTF1 can be used on surgical samples and FNA (cell block)
Poorly differentiated thyroid carcinoma: high grade features like mitoses and necrosis, TTF1+ / Tg+ (evident or residual)
Metastasis from salivary MASC and secretory carcinoma of breast should be excluded clinically (history, imaging)

SETTLE

Table of Contents

Definition / general

Spindle Epithelial Tumor with Thymus-Like Differentiation
Rare initially indolent tumor of neck in young patients (4 - 59 years old, median age 18 years), with delayed (after 5 years) metastases to lymph nodes or lungs, indolent even with metastasis (Head Neck 2015;37:746)

Essential features

Low grade biphasic tumor with metastatic potential which occurs in young patients

Terminology

Terminology first used in 1991 (Hum Pathol 1991;22:349)
Synonym: Thyroid spindle cell tumor with mucinous cysts

Case reports

6 year old boy with circumscribed tumor with slightly gritty whorled appearance (Hum Pathol 2003;34:190)
20 year old woman with enlarged thyroid (Arch Pathol Lab Med 2006;130:405)
59 year old man with enlarged thyroid for adult life and recent rapid enlargement of thyroid (Mod Pathol 2000;13:1150)

Treatment

Thyroidectomy, radiotherapy and chemotherapy are effective in cases with unresectable tumor or metastasis

Gross description

Circumscribed or infiltrative, lobulated, white / tan cut surface

Microscopic (histologic) description

Encapsulated or infiltrative tumor separated by sclerotic stroma
Biphasic pattern: spindle cells and epithelial structures (cords, tubules, papillae or glandular formation)
Rare monomorphic variant can have spindle cells or glandular only (Histopathology 1998;33:71)
No or rare lymphocytes
Mitotic activity or focal necrosis are rare

Microscopic (histologic) images

AFIP images

Spindled cells with mesenchymal appearance

Cytology description

Tumor with minimal epithelial component was moderately cellular with single and loosely grouped spindle cells in homogeneous metachromatic material resembling amyloid (Diagn Cytopathol 2007;35:113)

Positive stains

34betaE12 (diffuse in both spindle and epithelial cells), CK7, CD99, BCL2, CD117, INI1, SMA
EMA (focally), CAM 5.2 (focally), rarely TLE1 (Am J Surg Pathol 2009;33:1179)

Negative stains

CK20, calcitonin, desmin, thyroglobulin, S100, CD34

Differential diagnosis

Synovial sarcoma: translocation t(x;18) (SSX; SS18 / SYT), increased mitotic figures, no / weak cytokeratin staining, no sclerosing stroma, no epithelial component
Medullary carcinoma: not biphasic, amyloid+, calcitonin+, chromogranin+
Anaplastic carcinoma: pleomorphic spindle cells, increased mitotic figures, necrosis
Ectopic thymoma: with TdT+ lymphocytes
Malignant teratoma: with other immature tissue

Silent thyroiditis

Table of Contents

Definition / general

Transient, painless hyperthyroidism that spontaneously resolves

Terminology

Also called painless or sometimes chronic lymphocytic thyroiditis

Epidemiology

Relatively uncommon; usually women

Etiology

Cause unknown, although hyperfunction is due to destruction of thyroid follicles

Clinical features

Rarely recurrent (Thyroid 2007;17:671) or familial (Endocr J 2005;52:617)
Interferon may cause evolution to Graves' disease (Eur J Endocrinol 2006;154:367)

Laboratory

Elevated T3 / T4, low radioactive iodine uptake

Case reports

48 year old patient taking lithium (Rev Med Interne 2007;28:46)

Treatment

Usually none, beta blockers possibly in hyperthyroid phase

Gross description

Diffuse goiter or slightly enlarged thyroid gland

Microscopic (histologic) description

Preserved lobular pattern with follicular destruction, variable lymphocytic infiltrate, rare / no oncocytic change, no / focal fibrosis
T cells present in paracortex, B cells predominate in germinal center

Differential diagnosis

Chronic thyroiditis: usually no follicular destruction
Post-partum thyroiditis: similar but during pregnancy

Solid / trabecular

Table of Contents

Definition / general

Uncommon papillary thyroid carcinoma (PTC) subtype in which > 50% of tumor has solid, trabecular or insular growth but lacks diagnostic features of a higher grade tumor (high grade PTC or poorly differentiated thyroid carcinoma)
Literature on the prognosis and outcomes of solid / trabecular subtype of PTC (S / T PTC) is sparse and conflicting, with some studies reporting it as a clinically aggressive subtype while others did not

Essential features

Rare form of PTC, accounting for 1 - 3% of all PTC subtypes in adults
Proportion of solid component needed to render the diagnosis of (S / T PTC) has been inconsistent in the literature
3rd edition of the WHO classification of endocrine tumors required all or nearly all of a tumor to show solid, trabecular or insular growth, whereas the 4th edition established a cutoff of > 50%
This variation in the proportion of solid component might contribute to the conflicting results regarding the aggressiveness of this subtype, along with other confounding factors including variability in the assessment / diagnosis of nuclear features of PTC, mitotic activity or necrosis and tumor encapsulation / invasiveness
Therefore, a diagnosis of S / T PTC, regardless of the diagnostic criteria used (i.e., % of solid component), should not automatically trigger a more aggressive treatment approach and other clinicopathological features including encapsulation / invasiveness should be considered as well

Terminology

Paraganglioma-like variant or Chernobyl variant

ICD coding

ICD-O: 8260/3 - papillary adenocarcinoma, NOS
ICD-10: C73 - malignant neoplasm of thyroid gland

Epidemiology

Rare: 1 - 3% of all PTC subtypes in adults (Ann Diagn Pathol 2021;52:151737)
Female predominance (F:M = 2 - 9:1), similar to classic PTC (Head Neck 2018;40:1588, Histopathology 2022;81:171, Ann Diagn Pathol 2021;52:151737)
Mean age of 45 - 48 years (range: 7 - 85), similar to classic PTC (ANZ J Surg 2014;84:380, Histopathology 2022;81:171, Ann Diagn Pathol 2021;52:151737)
More common in young patients and in patients with a history of exposure to ionizing radiation
S / T PTC was reported in ~34% of children with PTC after the Chernobyl disaster (Endocr Pathol 2006;17:307, Endocr J 2020;67:241, Ann Diagn Pathol 2021;52:151737)

Sites

Thyroid gland

Pathophysiology

S / T PTC is a heterogeneous group of tumors associated with different etiologies (sporadic and radiation induced) and molecular pathways

Etiology

May be radiation induced or not
Higher radiation doses associated with higher frequency of S / T PTC and diffuse sclerosing PTC subtypes as well as histologic features of cancer aggressiveness, including lymph vascular invasion, intrathyroidal infiltration and multifocality (Cancer 1994;74:748)

Diagrams / tables

Images hosted on other servers:

Immunoprofile of S / T PTC and some mimickers

Clinical features

Not well established, usually similar to classic PTC
See Case reports for various clinical presentations

Diagnosis

Workup is similar to any thyroid mass / nodule
- Ultrasound with fine needle aspiration cytology
- Computed tomography (CT) scan may be useful to evaluate extrathyroidal extension and lymph node metastases
Because of the lack of criteria with high specificity and sensitivity, the preoperative diagnosis of S / T PTC is hardly ever made or suggested on cytology
However, most cases of S / T PTC are diagnosed as malignant or suspicious for malignancy (PTC or FVPTC) by fine needle aspiration biopsy (FNAB)
Molecular testing of cytologic aspirates may assist in preoperative diagnosis
Definitive diagnosis is made via histological examination of a resection specimen, supplemented by immunohistochemistry

Radiology description

Ultrasonography
- Usually well defined solid nodules with hypoechoic rim (Cancer Cytopathol 2015;123:71)
- Tumors with well defined borders with hypoechoic rim correlate with totally encapsulated tumors on histology, which are associated with indolent behavior in the absence of invasion (Cancer Cytopathol 2015;123:71)
- May have irregular borders (J Clin Endocrinol Metab 2023;108:e1186)
- Rarely, knobby or lobulated nodule or conglomeration of nodules replacing a lobe (Cancer Cytopathol 2015;123:71)
- Calcifications (central or coarse) may be present (J Clin Endocrinol Metab 2023;108:e1186, Cancer Cytopathol 2015;123:71)
- Diagnosed as high or intermediate suspicion nodules using ultrasound (US) based on the Korean Thyroid Image Reporting and Data System (Korean J Radiol 2016;17:811)
18F fluorodeoxyglucose positron tomography (PET / CT 18F FDG) may show an hypermetabolic mass (Diagnostics (Basel) 2020;11:4, Indian J Nucl Med 2011;26:196)

Radiology images

Images hosted on other servers:

Ultrasonographic / cytologic features of S / T PTC

Nodule on ultrasound / intranodular or peripheral vascularity on Doppler

Hypoechogenic solid nodule on ultrasound

FDG PET and ultrasound

Prognostic factors

Literature on the prognosis / outcomes of S / T PTC is sparse and conflicting, with some studies reporting it as a clinically aggressive subtype, while others showed that S / T PTC may not be clinically aggressive (Clin Endocrinol (Oxf) 2023;99:335, Histopathology 2022;81:171)
These conflicting results may be due to the fact that S / T PTC is a rare variant with diagnostic criteria that have changed over time
Other confounding factors including variability in the assessment / diagnosis of nuclear features of PTC, mitotic activity or necrosis and encapsulation / invasiveness
Systematic review with meta analysis of 205 cases (with several potential confounding factors) concluded that S / T PTC is an aggressive subtype with higher tumor recurrence and mortality rates (Head Neck 2018;40:1588)
Different clinicopathologic features of S / T PTC appear to influence prognosis
When stringently selected to exclude differentiated high grade thyroid carcinomas, S / T PTC appear to follow an indolent clinical course characterized by a low risk of nodal metastasis (18%) and a very indolent clinical course with a 10 year disease specific survival of 96% and 10 year relapse free survival of 87% (Histopathology 2022;81:171)
Determining factor for nodal metastasis and disease free survival is the encapsulation / infiltration status rather than the solid / trabecular percentage (Histopathology 2022;81:171)
Encapsulated noninvasive tumors follow an indolent course with a very low risk of nodal metastasis and recurrence (Histopathology 2022;81:171)
In contrast, infiltrative S / T PTC had a significantly higher rate of nodal metastasis (33 - 56%) and 10 year recurrence (14 - 26%) (Histopathology 2022;81:171)
Post-Chernobyl radiation induced cases is a distinct subgroup associated with higher frequency of lymph node metastases, angioinvasion, extrathyroidal invasion (Cancer 1994;74:748)
However, among children and young adults with post-Chernobyl PTCs, many of which had S / T PTC, the mortality overall remained at a very low level (< 1%) during the first 10 years of follow up (Cancer 1994;74:748)
Reported rate of distant metastasis varies from 4% to 25% (13.5% in the meta analysis by Vuongg et al.) (Head Neck 2018;40:1588)

Case reports

14 year old girl with multiple cervical lymphadenopathies (BMJ Case Rep 2013;2013:bcr2013010001)
21 year old man with Hashimoto thyroiditis with challenging cytological features (BMJ Case Rep 2019;12:e226153)
22 year old woman with Turner syndrome with chronic thyroiditis (Front Oncol 2023;13:1150002)
47 year old woman with multinodular goiter and S / T PTC with novel BRAF VK600-1E mutation (Hum Pathol 2005;36:694)
61 year old woman with focal differentiated high grade thyroid carcinoma on histology (Ecancermedicalscience 2023;17:1587)
64 year old man with S / T PTC diagnosed by cytology and BRAF mutational analysis (Cytojournal 2008;5:2)
67 year old man with a 4.7 cm adrenal incidentaloma as the initial manifestation of a S / T PTC (AACE Clin Case Rep 2022;8:131)

Treatment

Similar to classic PTC
Management of S / T PTC may include total thyroidectomy, bilateral neck dissection (in cases with cervical lymphadenopathy) and postoperative radioiodine ablation (BMJ Case Rep 2013;2013:bcr2013010001, Ann Diagn Pathol 2021;52:151737)
Diagnosis of S / T PTC, regardless of the diagnostic criteria used, should not automatically trigger a more aggressive treatment approach and other clinicopathological features including invasiveness should be considered as well (Histopathology 2022;81:171)

Gross description

Size ranges from 0.1 cm to 11 cm (Ann Diagn Pathol 2021;52:151737)
Multifocal involvement in 39.3% of cases (Ann Diagn Pathol 2021;52:151737)
Often well circumscribed white-tan nodule in the thyroid gland
Infiltrative nodules and nests may be found (Histopathology 2022;81:171)
Generally no necrosis or hemorrhage (Ann Diagn Pathol 2021;52:151737, Endocr J 2020;67:241)
Cystic changes may be present (Diagnostics (Basel) 2020;11:4)

Gross images

Images hosted on other servers:

3.2 cm tumor

Total thyroidectomy specimen

Microscopic (histologic) description

~67% of tumors are encapsulated while 33% of tumors are invasive; among encapsulated tumors, about half of them lack invasion (either capsular or vascular) (Histopathology 2022;81:171, Ann Diagn Pathol 2021;52:151737)
> 50% of tumor has solid, trabecular or insular growth but lacks diagnostic features of a higher grade tumor (high grade PTC or poorly differentiated thyroid carcinoma)
Other growth patterns may be seen as minor components, including follicular and papillary architecture (Histopathology 2022;81:171)
Tight microfollicles (with or without colloid) and larger colloid filled follicles may be identified
Abortive papillae or well formed papillae can be seen
Nuclear features of PTC are present but may be less obvious than in classic PTC
Stromal component may vary from thin fibrous strands to thick fibrous bands
Solid nests may be separated by thin fibrovascular stroma, creating insular or nested / organoid pattern of growth
No increase in mitotic activity (< 5 mitoses per 10 high power fields [HPF]) and no tumor necrosis
Psammomatous calcifications in 17.9% of tumors (Ann Diagn Pathol 2021;52:151737)
Vascular invasion and extrathyroidal extension can be encountered in 25 - 40% and 14 - 30% of cases, respectively (Histopathology 2022;81:171, Ann Diagn Pathol 2021;52:151737)
Nodal metastases are detected in ~7 - 18% of cases at the time of initial surgery (Histopathology 2022;81:171, Ann Diagn Pathol 2021;52:151737)

Microscopic (histologic) images

Contributed by Marc Pusztaszeri, M.D. (source: World Tumor Registry)

Encapsulated solid PTC

Infiltrative solid PTC

Encapsulated solid PTC with capsular invasion

Solid architecture

Solid and trabecular architecture

Solid and insular architecture

Solid PTC with stromal hyalinization

Solid PTC with minor follicular component

Solid PTC with tight microfollicles

BRAF V600E immunostain

Cytology description

Due to its rarity, reports on the cytological features of S / T PTC are limited
Because of the lack of criteria with high specificity and sensitivity, the preoperative diagnosis of S / T PTC is hardly ever made or suggested on cytology
However, most cases of S / T PTC are diagnosed as malignant or suspicious for malignancy (PTC or FVPTC) by FNAB (Cancer Cytopathol 2015;123:71)
Common cytologic patterns described in the literature include trabeculae, cohesive solid nests, syncytial fragments and 3 dimensional clusters; other possible patterns include microfollicles and scattered single cells (dyshesive) (Cancer Cytopathol 2015;123:71, Ecancermedicalscience 2023;17:1587)
Predominant microfollicular pattern may be seen, which causes difficulty in distinguishing this subtype from the follicular variant of PTC or NIFTP; accordingly, some of these cases are diagnosed as Bethesda IV (Cancer Cytopathol 2015;123:71, Ecancermedicalscience 2023;17:1587, Acta Cytol 2018;62:371)
Nuclear crowding, overlapping, grooving, intranuclear pseudoinclusions and chromatin clearing are seen to a variable extent in S / T PTC (Ecancermedicalscience 2023;17:1587)
However, in some cases, the nuclei might appear round and darker than those of conventional PTC

Cytology images

Images hosted on other servers:

Syncytial, tissue fragment pattern

Microfollicular pattern

Trabecular pattern

Dyshesive single cell pattern

Atypical epithelial cells

Epithelial cell cluster

Cluster of neoplastic cells

Trabeculae and solid nests of tumor cells

Solid aggregates of epithelial follicular cells

Monolayered epithelial cellular sheets

Enlarged nuclei with fine chromatin

Positive stains

Thyroglobulin (may be very focal or limited in extent), TTF1, PAX8, CK7
Galectin3, CK19 and HBME1: less often expressed than in classical PTC (Endocr J 2020;67:241)
Ki67: usually < 10% (Endocr J 2020;67:241)
RAS Q61R (33%) (Histopathology 2022;81:171)
BRAF V600E (VE1) (11%) (Histopathology 2022;81:171)

Negative stains

Calcitonin, synaptophysin, chromogranin and INSM1

Electron microscopy description

Solid / trabecular areas share similar ultrastructural features with poorly differentiated carcinomas (Ultrastruct Pathol 2001;25:13)

Molecular / cytogenetics description

Molecularly heterogeneous group of tumors
RET::PTC3 (NCO4::RET) is strongly associated with pediatric cases that developed after radiation exposure (80% of cases)
RET::PTC1 (CCDC6::RET) and ETV6::NTRK3 may be seen in adult cases with or without radiation exposure
RAS mutations are associated with encapsulated lesions (54%) and an absence of nodal metastasis (Histopathology 2022;81:171)
BRAF V600E mutations are uncommon in the encapsulated form (7%) while they are relatively more common in invasive forms (19%) (Histopathology 2022;81:171)
Noncanonical BRAF mutations have been reported in S / T PTC; a triplet deletion of the BRAF gene leading to the replacement of a valine and a lysine by a glutamate (BRAF V600E + K601) has been reported only in S / T PTC (Endocr Pathol 2009;20:122, Cytojournal 2008;5:2, Hum Pathol 2005;36:694)
TERT promoter mutation is found in ~12% of S / T PTC cases (Eur J Endocrinol 2015;172:403, PLoS One 2016;11:e0153319)
ROS1 gene fusion was identified in a single case of S / T PTC with a locally aggressive presentation (Thyroid 2016;26:794)

Molecular / cytogenetics images

Images hosted on other servers:

BRAF VK600-1E mutation

Gene mutations

Videos

Special types of thyroid cancer with Dr. Virginia LiVolsi

Sample pathology report

Thyroid, right hemithyroidectomy:
- Solid / trabecular papillary thyroid carcinoma, encapsulated, 2.9 cm (see synoptic report and comment)
- Comment: In the absence of high grade features or invasion, the solid / trabecular subtype of PTC follows an indolent clinical course and should not warrant aggressive management (Histopathology 2022;81:171).

Differential diagnosis

Poorly differentiated thyroid (insular) carcinoma:
- Rare tumor type in children, adolescents and young adults, which are typically characterized by DICER1 mutation (Mod Pathol 2020;33:1264)
- Shares growth patterns with S / T PTC
- No nuclear features of PTC
- Presence of at least 1 of following: convoluted nuclei, ≥ 3 mitotic figures/10 HPF, tumor necrosis (Am J Surg Pathol 2007;31:1256)
Differentiated high grade thyroid carcinoma:
- Increased mitotic activity (≥ 5 per 10 HPF) or presence of tumor necrosis
- Follicular or papillary architecture
Medullary thyroid carcinoma:
- Absence of colloid filled follicles
- No nuclear features of PTC; salt and pepper chromatin
- Immunoreactivity for calcitonin, CEA, synaptophysin, chromogranin and INSM1
- Absence of immunoreactivity for thyroglobulin and PAX8
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP):
- Up to 30% solid / trabecular component is allowed in NIFTP
Follicular thyroid carcinoma with a solid growth pattern:
- No nuclear features of PTC
Paraganglioma:
- No nuclear features of PTC
- Immunoreactivity for synaptophysin, chromogranin, INSM1 and S100 in sustentacular cells
- Absence of immunoreactivity for cytokeratins, thyroglobulin, TTF1, PAX8
Hyalinizing trabecular tumor:
- Absence of colloid filled follicles
- Elongated / polygonal cells
- Prominent intratrabecular and intracytoplasmic hyalinization
- Pale yellow cytoplasmic bodies
- Aberrant cytoplasmic reactivity with Ki67 (using MIB1 clone at room temperature)

Additional references

Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015, Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012, Nosé: Diagnostic Pathology - Endocrine, 3rd Edition, 2022

Board review style question #1

Which statement is correct about solid / trabecular papillary thyroid carcinoma (S / T PTC)?

Aggressive subtype of PTC associated with a poor prognosis
Common subtype of PTC
More common in the elderly than in children and young adults
Requires all or nearly all of the tumor to have a solid / trabecular / insular growth pattern for the diagnosis
RET::PTC3 (NCO4::RET) is strongly associated with pediatric cases that developed after radiation exposure

Board review style answer #1

E. RET::PTC3 (NCO4::RET) is strongly associated with pediatric cases that developed after radiation exposure (80% of cases). S / T PTC is a molecularly heterogeneous group of tumors. RET::PTC1 (CCDC6::RET) and ETV6::NTRK3 may be seen in adult cases with or without radiation exposure. In sporadic cases, RAS mutation is associated with encapsulated tumors and an absence of nodal metastasis, while BRAF V600E mutation is associated with infiltrative tumors. Answer B is incorrect because S / T PTC accounts only for 1 - 3% of all PTCs in adults. Answer C is incorrect because S / T PTC is more common in children and young adults where it is commonly associated with ionizing radiation (e.g., following the Chernobyl disaster). Answer D is incorrect because while the diagnostic criteria have varied over time, the latest WHO 2022 classification requires > 50% of solid, trabecular or insular growth pattern for a PTC to be classified as S / T PTC, in the absence of high grade features. Answer A is incorrect because literature on the prognosis / outcomes of S / T PTC is sparse and conflicting, with some studies reporting it as a clinically aggressive subtype, while others showed that S / T PTC may not be clinically aggressive.

Comment Here

Reference: Solid / trabecular papillary thyroid carcinoma

Board review style question #2

What proportion of solid / trabecular pattern in the tumor is required for a diagnosis of solid / trabecular papillary thyroid carcinoma (S / T PTC) according to the latest WHO classification in 2022?

10%
25%
> 50%
> 70%
All or nearly all the tumor

Board review style answer #2

C. > 50%. The presence of at least 50% of solid / trabecular component is required to diagnose a tumor as PTC solid / trabecular subtype according to the latest WHO classification in 2022. The 3rd edition of the WHO classification of endocrine tumors required all or nearly all of a tumor to show solid, trabecular or insular growth, whereas the 4th edition established a cutoff of > 50%. Answer E is incorrect because the WHO criteria for S / T PTC was updated to an established cutoff of > 50% as noted in the 4th edition of WHO released in 2022. Answer D is incorrect because the threshold for diagnosing S / T PTC does not have to be greater than 70% but rather greater than 50%. Answers A and B are incorrect because these percentages are too low and have not been used as a diagnostic cutoff for S / T PTC.

Comment Here

Reference: Solid / trabecular papillary thyroid carcinoma

Solid cell nests / ultimobranchial body remnants

Table of Contents

Definition / general

Small (< 1 mm) interfollicular clusters of epithelial cells resembling squamous / transitional epithelium
First described by Getzowa in 1907 (Virchows Archiv 1907;188:181)
Considered as normal thyroid gland components (J Clin Endocrinol Metab 1997;82:4274, Acta Anat (Basel) 1992;143:79)
Remnants of the ultimobranchial body derived from branchial apparatus (fourth / fifth pharyngeal pouch complexes) and giving rise to C cells (Am J Clin Pathol 1994;101:186, Lab Invest 2011;91:138)

Terminology

Also known as ultimobranchial body remnants, ultimobranchial body nests
Solid cell nests are the ultimobranchial body remnants in postnatal life
Rarely called compact cell nests, solid cell rests

Epidemiology

Adults: from 3% of routinely examined thyroids to 60% of the glands subjected to serial blocking (Acta Anat (Basel) 1986;127:262)
30% to 90% of serially sectioned fetal thyroids (J Pathol 1993;169:465, Arch Pathol Lab Med 1990;114:1049)
Male predominance (Acta Anat (Basel) 1986;127:262, Acta Anat (Basel) 1992;143:79)

Sites

Located in the middle or occasionally in the upper third of the thyroid lateral lobes and placed in a central to paracentral and slightly dorsal longitudinal axis (J Pathol 1988;155:191)

Clinical features

May play a stem cell role in adult thyroid gland (Mod Pathol 2004;17:819, Endocr Pathol 2011;22:35)
May be site of origin of CASTLE tumors (Am J Surg Pathol 2006;30:994, Thyroid 2013;23:511), primary thyroid mucoepidermoid carcinoma (Mod Pathol 2004;17:526)
Histogenetic link to thyroid cancer is debated (Hum Pathol 2004;35:465, Hum Pathol 2005;36:590, Am J Clin Pathol 2012;137:612)

Diagnosis

Usually an incidental microscopic finding

Case reports

47 year old man with ultimobranchial body remnants (J Clin Endocrinol Metab 2012;97:2209)
48 year old man with BRAF mutation in solid cell nest hyperplasia (Hum Pathol 2009;40:1029)
58 year old man with carcinoma showing thymus-like elements arising in close association with solid cell nests (Thyroid 2013;23:511)
65 year old man with branchial-like cysts of the thyroid associated with solid cell nests (Pathol Int 2006;56:150)
70 year old man with absence of the BRAF and GRIM-19 mutations in oncocytic solid cell nests (Am J Clin Pathol 2012;137:612)
70 year old man with thyroid tumor-in-tumor with basaloid differentiation and phenotype similar to solid cell nests (Int J Surg Pathol 2011;19:276)
Giant solid cell rest of thyroid (Int J Surg Pathol 2009;17:268)
Solid cell nest in fine needle aspiration of goiter (Diagn Cytopathol 2002;27:66)
Thyroid type solid cell nests in struma ovarii (Int J Surg Pathol 2011;19:627)

Microscopic (histologic) description

Small cells in solid structures (50 - 1000 μm) interspersed between follicles
Usually surrounded by stroma and demarcated by adjacent thyroid follicles
Lobulated, nested or irregular shape on low power
Multiple foci (2 - 8 per section) are common (Histopathology 2016;68:866)
Composed of two cell populations - predominant main cells and a minority of C cells
- Sometimes with intermingled cystic structures containing mucin and mixed follicles
Main cells:
- Polygonal / elongated to round to spindle cells
- Scant amphophilic or rarely deeply eosinophilic cytoplasm with squamoid features (but no intercellular bridges)
- Nuclei are centrally located, oval to fusiform, with finely granular chromatin, uneven nuclear membrane, occasional nuclear grooves
C cells: minor population of cells with clear cytoplasm and centrally located, small compact nuclei
May contain ciliated columnar cells
May also contain cells with follicular lumen-like pattern (mixed follicles)
Usually have a tropism to lymphocytes because of the common embryologic derivation of SCNs and the thymus (Pathol Int 2006;56:150, Hum Pathol 2009;40:1029)
C cells in small clusters are common in the vicinity of solid cell nests
Cartilage and adipose tissue are rarely seen (Hum Pathol 1994;25:684)
Asioli et al classified SCN based on the solid (types 1 - 2) or cystic (types 3 - 4) patterns (Endocr Pathol 2009;20:197):
- Type 1 (floret-like) is composed of main cells, characterized by round to oval or elongated cells with scant cytoplasm, centrally located oval to fusiform nuclei, and occasional nuclear grooves
  - The cells form round to oval groups, surrounded by lymphocytes
- Type 2 SCN (epidermoid-like) are made of larger, polygonal cells with an epidermoid appearance
- Type 3 has cystic architecture lined by flattened or polygonal cells
- Type 4 SCNs (mixed follicles) have a follicular appearance and contain both follicular epithelium and small main cells

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP

Solid cell nests

Histologic mimics of SCN

Solid cell nests: p63

Solid cell nests: thyroglobulin-

Solid cell nests

Nested pattern

Cystic SCN

Clear cells

Occasional nuclear grooves

Type 1 and 2 solid cell nests

Images hosted on other servers:

Admixture of main and C cell

High mag of solid cell nests

Various stains

Galectin 3, CEA

Conventional solid cell nests

Cytology description

Cohesive cellular group consisting of polygonal squamoid cells with lightly eosinophilic cytoplasm (no intercellular bridges), elongated to columnar shaped cells with clear cytoplasm, and scattered lymphocytes
Nucleus is large and centrally located, slightly irregular with evenly distributed chromatin and chromocenter (Hum Pathol 2004;35:465)

Positive stains

Main cells:
- p63 (Mod Pathol 2003;16:43, Hum Pathol 2004;35:465), p40 (Histopathology 2016;68:866)
- CEA (variable)
- bcl2
- Cytokeratins (AE1 / AE3, CK7, CK19, CAM5.2, 34βE12)
- Galectin 3 (J Clin Pathol 2003;56:142)
C cells:
- Calcitonin (may leak into adjacent cells), calcitonin gene related peptide, chromogranin
- TTF1
Lumina: PAS+ colloid

Negative stains

Main cells:
- TTF1, thyroglobulin
- CK20
- HBME1 (inconsistent across different studies, e.g. Am J Clin Pathol 2010;134:169, Histopathology 2016;68:866)
C cells: p63

Electron microscopy description

Main cells: desmosomes, intermediate filaments, intracytoplasmic vacuoles and projections (Acta Anat (Basel) 1987;129:289)
C cells: neurosecretory granules; also ciliated cells, lymphocytes (Ultrastruct Pathol 2000;24:1)

Molecular / cytogenetics description

No BRAF mutations found (Am J Clin Pathol 2012;137:612, Histopathology 2016;68:866)

Differential diagnosis

C cell hyperplasia and medullary microcarcinoma: uniformly positive for calcitonin; p63 negative
Intrathyroidal thymic remnants: Hassall corpuscles
Papillary microcarcinoma: TTF1 and thyroglobulin positive, p63 negative
- Not recommended to rely on CK19 / galectin 3 (positive in both SCN and papillary microcarcinoma)
Primary or metastatic squamous carcinoma: cellular atypia, mitotic activity, stromal desmoplasia
Squamous metaplasia in Hashimoto thyroiditis: associated with chronic inflammation (p63 positive and TTF1 positive)
Tangential sections of normal follicles
Thyroglossal duct cyst: midline location (e.g. thyroid isthmus)

Additional references

Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012, Sugiyama: Histological Studies of the Human Thyroid Gland, 1967

Solitary fibrous tumor

Table of Contents

Definition / general

Solitary fibrous tumor (SFT) of the thyroid is a fibroblastic mesenchymal neoplasm characterized by NAB2::STAT6 gene fusion
Thyroid SFT is indistinguishable from pleural or other extrapleural solitary fibrous tumors

Essential features

Fibroblastic tumor composed of collagen producing spindle cells arranged in a characteristic vascular pattern
Immunohistochemical nuclear expression of STAT6 is highly sensitive and specific for the presence of the NAB2::STAT6 gene fusion product; STAT6 is a marker for confirming the diagnosis of solitary fibrous tumor

Terminology

Extrapleural solitary fibrous tumor
Not recommended: hemangiopericytoma; giant cell angiofibroma; benign solitary fibrous tumor

ICD coding

ICD-O
- 8815/0 - solitary fibrous tumor, benign
- 8815/1 - solitary fibrous tumor, NOS
- 8815/3 - solitary fibrous tumor, malignant
ICD-10: D48.7 - neoplasm of uncertain behavior of other specified sites

Epidemiology

Rare tumor in thyroid; < 0.1% of SFTs arise in the head and neck area (Thyroid 2010;20:435)
M = F
Median age: 54.4 years (28 - 88 years) (Head Neck Pathol 2019;13:597)

Sites

Entire thyroid

Etiology

Unknown
Not associated with a longstanding pre-existing goiter or thyroid tumor
Possibly primitive mesenchymal cells capable of myofibroblastic, adipose and hemangiopericytic differentiation (Nose: Diagnostic Pathology - Endocrine, 2nd Edition, 2018)

Diagrams / tables

Images hosted on other servers:

4 variable risk stratification

Clinical features

Painless, slow growing neck mass in euthyroid patients (Nose: Diagnostic Pathology - Endocrine, 2nd Edition, 2018)
Tumor may extend inferiorly from the thyroid gland and present as a mediastinal mass (Med J Islam Repub Iran 2014;28:51)
Compressive symptoms and respiratory failure may occur in some rare cases (Ann Thorac Cardiovasc Surg 2014;20:427, Saudi Med J 2004;25:805)

Diagnosis

Based on histological findings and NAB2::STAT6 gene fusion (immunohistochemical or molecular tests)

Laboratory

Serum thyroid function tests such as thyroid stimulating hormone (TSH), triiodothyronine (T3), free thyroxine (T4) and thyroperoxidase (TPO) antibodies are normal (Endocr Pathol 2011;22:165)

Radiology description

Ultrasonography: heterogeneous, mainly hyperechoic nodule (World J Clin Cases 2020;8:782)
Computed tomography (CT): heterogeneous enhanced lesion (Clinical Imaging 2019;53:105)
Magnetic resonance imaging (MRI): fibrous areas have intermediate intensity on T1 while cellular or myxoid zones present as variable hypointensity to hyperintensity on T2 (Trans Gastroenterol Hepatol 2018;3:94)

Radiology images

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Ultrasound: heterogeneous, hyperechoic solitary nodule

CT: heterogeneous enhanced lesion

Prognostic factors

High mitotic index, tumor cellularity, necrosis, nuclear pleomorphism correlated with metastatic or local recurrence potential
Difficult to predict patient's clinical course if based solely on histologic parameters (Ann Surg Oncol 2017;24:3865)
Age ≥ 55, tumor size ≥ 10 cm, mitotic count ≥ 4/10 high power fields, tumor necrosis ≥ 10% are unfavorable prognostic factors in SFTs of all anatomic sites (Mod Pathol 2017;30:1433)
TERT promoter mutations may be associated with a poor prognosis (Mod Pathol 2016;29:1511, Histopathology 2018;73:843)

Case reports

34 year old woman with enlarging thyroid mass (Arch Clin Cases 2021;8:97)
41 and 64 year old men with a firm, painless cervical mass (Pathol Int 2006;56:471)
42 year old woman with a solid nodule in her right thyroid lobe and 61 year old man with a right cervical lump (Head Neck Pathol 2008;2:231)
47 year old woman with a neck mass and 59 year old man with an asymptomatic neck swelling (Endocr Pathol 2011;22:165)
58 year old man presented with worsening respiratory symptoms (Thyroid 2010;20:435)
59 year old man with a large neck mass (World J Clin Cases 2020;8:782)
61 year old man with a slow growing thyroid mass (Diagn Cytopathol 2003;28:213)
68 year old man with a left cervical lump (Pathol Res Pract 2003;199:687)
76 year old woman with an enlarging neck mass (Diagn Cytopathol 2011;39:694)
78 year old man with a right cervical mass (Med Mol Morphol 2014;47:117)

Treatment

Total thyroidectomy or lobectomy (Laryngoscope 2009;119:2306, Med Mol Morphol 2014;47:117)
Roles of chemotherapy or radiation therapy are controversial (Diagn Cytopathol 2011;39:694)
Close follow up after surgery seems to be the most commonly used approach

Gross description

Well circumscribed mass
Relatively large (5 - 10 cm)
White to gray-brown color, usually solid, sometimes with cystic spaces (Head Neck Pathol 2019;13:597)

Gross images

Images hosted on other servers:

Solid, well circumscribed white nodule

Encapsulated, tan-pink to tan-white mass

Microscopic (histologic) description

Similar to SFT of any other organ
Usually unencapsulated
Proliferation of spindled cells with alternating hypo and hypercellular areas
- Tumor cells are spindled with elongated, slender nuclei surrounded by scant cytoplasm; nuclear chromatin is delicate, fine to vesicular
- Patternless architecture interspersed with loosely to densely collagenized or myxoid stroma
Highly vascular, with dilated, branching, hyalinized staghorn-like (hemangiopericytoma-like), thin walled vessels
Infiltration by inflammatory cells (mainly mast cells) can be seen
Mitoses and nuclear atypia are rare; necrosis is absent or rare
Uncommon: cysts, myxoid change, lipomatous features (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
High mitotic index (> 4 mitoses per 10 high power fields); hypercellularity, nuclear atypia; hemorrhage and necrosis are suggestive of malignant transformation (Am J Surg Pathol 1998;22:1501)

Microscopic (histologic) images

Contributed by Truong Phan Xuan Nguyen, M.D.

Well defined border

Entrapped thyroid follicles

Patternless proliferation of spindled cells

Staghorn-like vessels

Collagenous stroma

STAT6

CD34

Virtual slides

Images hosted on other servers:

Solitary fibrous tumor of thyroid

Cytology description

Smears contain loosely cohesive clusters around blood vessels or dispersed cells with bare nuclei; the cells are oval, elongated or rounded with thin cytoplasm and eosinophilic collagenous stroma (Virchows Arch 2023 Apr 20 [Epub ahead of print])
Adjacent follicular epithelium often shows features compatible with atypia of undetermined significance or follicular lesions of undetermined significance (Diagn Cytopathol 2003;28:213, Med Mol Morphol 2014;47:117)
Liquid based cytology specimens show only dispersed monomorphic spindle cells with bland nuclear features (Virchows Arch 2023 Apr 20 [Epub ahead of print])

Cytology images

Images hosted on other servers:

Scattered spindle-like cells with fusiform nuclei

Positive stains

STAT6
- The most sensitive and specific marker for establishing a diagnosis of SFT (Am J Clin Pathol 2015;143:672, Pathology 2014;46:389)
- Strong nuclear expression reflects underlying STAT6 gene fusion
CD34, CD99, BCL2: not specific
Actin, EMA may be focal

Negative stains

Thyroid specific markers: TTF1, thyroglobulin, calcitonin
Cytokeratins
Desmin, CD31, CD117, S100

Molecular / cytogenetics description

Multiple NAB2::STAT6 gene fusion variants detected by whole exome sequencing and RT-PCR (Am J Pathol 2014;184:1209)
Due to the proximity of the 2 genes on chromosome 12, NAB2::STAT6 gene fusion may be missed by fluorescence in situ (J Clin Pathol 2017;70:508)
Moderate to strong and diffuse immunohistochemistry expression of STAT6 correlated with the NAB2::STAT6 gene fusion (Pathol Res Pract 2017;213:1404)

Molecular / cytogenetics images

Images hosted on other servers:

NAB2::STAT6 gene fusion variants

Sample pathology report

Thyroid, completion thyroidectomy:
- Solitary fibrous tumor of thyroid, 35 mm, margins of resection are uninvolved (see comment)
- Comment: The histological sections show a well circumscribed mass made of moderately cellular spindle cells in a collagenous stroma with prominent dilated staghorn type vasculature. No mitosis or necrosis is seen. Benign thyroid parenchyma is uninvolved and compressed at periphery of the tumor. Immunohistochemistry studies show that the tumor cells are positive for STAT6, CD34 and BCL2 and negative for TTF1, thyroglobulin, calcitonin, cytokeratins, desmin and S100. The overall findings favor a solitary fibrous tumor, likely thyroid primary. According to the 2017 risk stratification criteria by Demicco et. al., this should be classified as a low risk solitary fibrous tumor.

Differential diagnosis

Post-fine needle aspiration spindle cell nodules:
- Localized phenomenon adjacent to fine needle aspirated thyroid nodule with hemosiderin, extravasated erythrocytes, reactive vascular pattern
Follicular thyroid adenoma with prominent spindle cells:
- Lacks collagen while showing colloid production (Int J Clin Exp Pathol 2012;5:143)
- Positive: cytokeratins, TTF1, thyroglobulin
Hyalinizing trabecular tumor:
- Hyalinization is intra and intercellular
- Trabecular arrangement of follicular epithelial cells: perpendicular nuclei, inclusions and yellow bodies
- Positive: TTF1, membranous MIB1
Smooth muscle tumors:
- Fascicular pattern of growth comprised of spindle shaped cells with blunt ended nuclei
- Positive: actin, desmin
- Negative: STAT6, CD34, BCL2
Riedel thyroiditis:
- Follicles are compressed by extensive dense fibrous tissue, which also infiltrates adjacent skeletal muscle
- Patchy lymphocytes, plasma cells, eosinophils
- > 40% IgG4 / IgG+ cells and elevated IgG4+ plasma cells
Schwannoma:
- Antoni A and B areas, wavy nuclei and tapered cells
- Positive: S100
Medullary thyroid carcinoma:
- Medullary thyroid carcinoma of spindle cell variant may be similar morphologically to SFT
- Positive: chromogranin, calcitonin, TTF1, cytokeratins
- Presence of amyloid
Spindle epithelial tumor with thymus-like differentiation:
- Biphasic pattern: spindled epithelial cells merge into glandular structures
- Rare monomorphic variant can have spindle cells or glandular only
- Young patients
- Positive: 34 beta E12, CK7
- Negative: CD34
Paucicellular variant of anaplastic thyroid carcinoma:
- Acellular or necrotic fibrous tissue with hypocellular foci of mildly atypical spindle cells obliterating large blood vessels
- Positive: cytokeratins, EMA, p53

Additional references

Braverman: Werner & Ingbar's The Thyroid, 11th Edition, 2020, Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017, WHO Classification of Tumours Editorial Board: Soft Tissue and Bone Tumours, 5th Edition, 2020

Board review style question #1

A 50 year old woman presented with a 4.5 cm, well circumscribed, firm mass in the right lobe of thyroid. Histologic sections showed ovoid to spindled cells arranged haphazardly around prominent thin walled, hyalinized, dilated staghorn type vasculature (see image above). Which of the following is the diagnosis of this thyroid tumor?

Medullary carcinoma
Riedel thyroiditis
Solitary fibrous tumor
Spindle epithelial tumor with thymus-like differentiation
Anaplastic thyroid carcinoma, paucicellular variant

Board review style answer #1

C. Solitary fibrous tumor. This case has gross appearance and histological features consistent with solitary fibrous tumor of thyroid. Differential diagnosis includes other thyroid tumors with the spindle cell pattern.

Comment Here

Reference: Solitary fibrous tumor

Board review style question #2

Which of the following is the most sensitive and specific immunohistochemical marker for solitary fibrous tumor of the thyroid?

CD34
Cytokeratin CAM 5.2
STAT6
Thyroglobulin
TTF1

Board review style answer #2

C. STAT6. STAT6 is a highly sensitive and specific marker for the presence of the NAB2::STAT6 gene fusion product, which is identified to be the pathognomonic molecular aberration in solitary fibrous tumor.

Comment Here

Reference: Solitary fibrous tumor

Solitary papillary hyperplastic nodule

Table of Contents

Epidemiology | Gross description | Microscopic (histologic) description | Cytology description

Epidemiology

Frequently occurs in children and teenagers

Gross description

Encapsulated, tan-brown nodules replace entire thyroid lobe, often central cystic change with brown hemorrhagic fluid

Microscopic (histologic) description

Well circumscribed and encapsulated nodules with central cystic and degenerative changes, prominent papillae with edematous stalks and occasional prominent vessels, lining cells have abundant cytoplasm and round nuclei, occasional prominent nucleoli, nuclear grooves or psammoma bodies, calcification
No intranuclear inclusions or well defined nuclear changes of papillary carcinoma

Cytology description

Pediatric solitary papillary hyperplastic nodules have broad flat sheets and 3D clusters, short nonbranching papillae with transgressing vessels, mild to moderate nuclear pleomorphism and nuclear atypia, occasional nuclear grooves
Unlike papillary thyroid carcinoma, has fire flares, short nonbranching papillae, watery and inspissated colloid
No intranuclear inclusions
Negative for CK19 (Arch Pathol Lab Med 2001;125:1575)

Solitary thyroid nodule

Table of Contents

Definition / general

A discrete lesion within the thyroid gland that is palpably or ultrasonographically distinct from surrounding thyroid parenchyma
Up to 5% are malignant (Oncologist 2008;13:105)
Single and cold (on nuclear scan) nodules are higher risk for malignancy, but 80 - 90% are benign; other risk factors are radiation to head and neck, rapidly enlarging nodule, ipsilateral adenopathy, male patient, age < 20 years or > 70 years
Cysts may represent cystic degeneration of follicular adenoma or portions of multinodular goiters

Epidemiology

Usually > 1 cm
Variable prevalence worldwide, depending on iodine deficiency

Etiology

Colloid nodule (hyperplastic nodule)
Thyroid cysts
Focal / asymmetrical thyroiditis, acute suppurative, granulomatous or Hashimoto's thyroiditis
Thyroid adenoma, ectopic thymic tissue, other benign tumors
Primary thyroid malignancies and metastasis:
- Papillary carcinoma
- Follicular carcinoma
- Medullary carcinoma
- Anaplastic carcinoma
- Primary lymphoma of thyroid
- Metastatic carcinoma (especially breast and renal cell carcinoma)

Diagnosis

Use these factors:
- Asymptomatic
- Pain and rapid enlargement
- Age and sex of patient
- History of prior radiation exposure
- Compression symptoms on surrounding structures
- Lymph node involvement or metastasis
- Hypo-, eu-, or hyperthyroidism
- Thyroid function tests
- Ultrasound, radiologic investigations
Biopsy
Evaluate with ultrasound guided fine needle aspiration (see Cytology: FNA) to rule out malignancy
Nonpalpable nodules greater than 1.0 to 1.5 cm represent an absolute indication to perform an ultrasound guided fine needle biopsy (ANZ J Surg 2006;76:381, Hormones (Athens) 2007;6:101)

Radiology description

Thyroid ultrasound
- Most effective
- Determine size and shape of nodule, presence of associated nodules or lesions
- Determine if cystic or solid
  - Benign lesions are pure cystic, spongiform or septate, multiple
  - Suspicious features are solid, calcification, hypoechoic lesion and increased vascularity
- Radionucleotide scanning
  - Hot, cold and warm nodules
- CT and MRI help evaluate extent of lesion if malignant

Radiology images

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Multiple hypoechoic lesions

Case reports

6 year old girl with ectopic intrathyroidal thymus as cause of a solitary thyroid nodule (An Pediatr (Barc) 2013;78:64)
19 year old woman with paraganglioma of thyroid gland (BMJ Case Rep 2013;2013)
38 year old man with primary cavernous hemangioma of thyroid (J Clin Diagn Res 2014;8:151)
56 year old woman with solitary extramedullary plasmacytoma (Diagn Cytopathol 2014;42:964)
64 year old woman with squamous cell carcinoma of esophagus presenting as solitary nodule thyroid (Indian J Surg Oncol 2012;3:41)
Metastases to thyroid gland from renal cancer (Tumori 2013;99:e107)

Microscopic (histologic) description

Description of histology for primary lesion:
- Hashimoto's thyroiditis: small follicles with Hürthle cell change and marked lymphoplasmacytic infiltrate
- Follicular adenoma / carcinoma: follicular proliferation, variable colloid component, trabecular, solid, micro and macrofollicular architecture; vascular and capsular invasion are diagnostic of malignancy
- Papillary carcinoma: true papillae, cells have characteristic nuclear features, psammoma bodies

Microscopic (histologic) images

Images hosted on other servers:

Hemangioma

Metastatic squamous cell carcinoma

Cytology description

FNAC is gold standard in diagnosis
Cytologic features to evaluate include cellularity, colloid, acinar and papillary formation, nuclear features, Hürthle cells, atypia, inflammatory component
Bethesda system for reporting thyroid lesions:

Positive stains

CK19 staining favors papillary carcinoma and Galectin3 staining favors follicular carcinoma (Histopathology 2002;41:236)
Galectin3 has high sensitivity for differentiation of benign and malignant thyroid lesions (Mod Pathol 2003;16:1117)

Videos

Thyroid cytology: colloid nodule

Solitary thyroid nodule

Thyroid: compare and contrast

Additional references

Solitary thyroid nodule

Table of Contents

Definition / general

A lump in the thyroid gland caused by abnormal cell proliferation, identified by manual examination or detected on imaging tests as an incidentaloma

Essential features

A discrete lesion within the thyroid gland due to the aberrant proliferation of thyroid cells, resulting in the formation of a lump either detected by manual examination or through imaging studies only as incidentaloma (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
~5 - 7% in adults during a physical exam, 70% during imaging studies and 50% reported during autopsy (Int J Gen Med 2024;17:135)
90% are benign, 4 - 6.5% are malignant (StatPearls: Thyroid Nodule [Accessed 17 October 2024])

Terminology

Not relevant to this topic

ICD coding

ICD-10
- C73 - malignant neoplasm of thyroid gland
- D17.0 - benign lipomatous neoplasm of skin and subcutaneous tissue of head, face and neck
- D21.9 - benign neoplasm of connective and other soft tissue, unspecified
- D34 - benign neoplasm of thyroid gland
- D44.0 - neoplasm of uncertain behavior of thyroid gland
- Q89.2 - congenital malformations of other endocrine glands

Epidemiology

Risk increases with age and exceeds 50% by seventh decade of life, F > M, radiation exposure, iodine deficiency (benign lesion) (StatPearls: Thyroid Nodule [Accessed 17 October 2024])

Sites

Thyroid gland

Pathophysiology

Differs among individual lesions
Benign (Endocr Pathol 2022;33:27)
- Toxic adenoma; activating mutations in the TSH receptor proteins, making them independent of thyroid stimulating hormones and 33% cases have enhancer of zeste, homolog 1 (EZH1) mutation that functions as an epigenetic regulator of gene expression
- Follicular adenoma; BRAF K601E, EIF1AX, EZH1, DICER1, PTEN or TSHR, PAX8::PPARG has < 10% mutational changes
- BRAF, RET, NTRK or ALK fusions are not observed
Border line lesions
- Low malignant potential
- BRAF K601E, EIF1AX, EZH1, DICER1, PTEN or TSHR < 10% mutation
- PAX8::PPARG and THADA fusions up to 30%
Malignant
- BRAF p.V600E, RAS, RET, NTRK, ALK, NTRK1 - NTRK3, TERT promotor mutation are most common genetic alterations

Etiology

Factors leading to benign causes (Front Endocrinol (Lausanne) 2023;14:1113977)
- Iodine deficiency
- Increase goitrogenic food intake
- Smoking
- Medications
- Genetic alterations such as DICER1 syndrome, Cowden disease, Carney complex
Factors leading to malignant causes (J Clin Endocrinol Metab 2020;105:2869)
- Obesity
- Iodine deficiency and excess
- Ionizing radiation exposure including 131 Iodine
- Thyroid adenoma
- Multinodular goiter
- Hashimoto thyroiditis
- Graves disease
- Genetic mutations such as MEN2A, MEN2B, FMTC, familial adenopolyposis syndrome, Carney complex, Werner syndrome, DICER1 syndrome, etc.
Benign
- Thyroglossal duct cyst (Diseases 2022;10:7)
- Thyroid follicular adenoma (Semin Cancer Biol 2022;79:180)
- Follicular thyroid adenoma with papillary architecture (Front Endocrinol (Lausanne) 2018;9:737)
- Oncocytic adenoma (Endocr Pathol 2022;33:27)
- Lipoma (Medicine (Baltimore) 2020;99:e20392)
- Hemangioma (Ann Ital Chir 2023;94:557)
- Angiolipoma (Head Neck Pathol 2023;17:246)
- Lymphangioma (J Craniofac Surg 2021;32:1417)
- Leiomyoma (Indian J Otolaryngol Head Neck Surg 2024;76:1998)
- Schwannoma (Medicina (Kaunas) 2022;58:1345)
- Granular cell tumor (Endocrine 2022;76:395)
- Solitary fibrous tumor (Arch Clin Cases 2021;8:97)
Low risk neoplasms (Endocr Pathol 2022;33:27)
- Noninvasive follicular thyroid neoplasm with papillary nuclear-like features
- Hyalinizing trabecular tumor
- Thyroid tumor of uncertain malignant potential
Malignant (Endocr Pathol 2022;33:27)
- Follicular thyroid carcinoma
- Invasive encapsulated follicular variant of papillary thyroid carcinoma
- Papillary thyroid carcinoma
- Oncocytic carcinoma
- High grade follicular cell derived nonanaplastic thyroid carcinoma
- Anaplastic thyroid carcinoma
- Medullary thyroid carcinoma
- Mixed medullary and follicular cell derived thyroid carcinoma
- Mucoepidermoid carcinoma
- Secretory carcinoma
Metastatic (Head Neck Pathol 2023;17:447)
- Melanoma, breast, kidney, lung

Diagrams / tables

N/A

Clinical features

Hypo and hyperthyroidism symptoms (heat and cold intolerance, change in bowel habits, weight change, generalized swelling, mood change, etc.) (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
Radiation exposure, family history of thyroid cancers, symptoms associated with multiple endocrine neoplasia 2a or 2b, Cowden disease (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
Local symptoms (dysphonia, stridor, cough, dysphagia and odynophagia), pain (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
Lump could be cystic to firm in consistency, mobile to fixed to adjacent structures (StatPearls: Thyroid Nodule [Accessed 17 October 2024])

Diagnosis

Workup (S D Med 2022;75:569)
- If nodule is > 1 cm, proceed with thyroid stimulating hormone (TSH) levels
- If TSH levels are low, which indicates a hyperfunctioning nodule (low probability of cancer), no need for fine needle aspiration (FNA), proceed with T3, T4 levels and scintigraphy / radionucleotide iodine 123 scan
- If TSH levels are normal to high, which indicates a hypofunctioning cold nodule (high probability of cancer), proceed with ultrasound
  - TIRADS1 and TIRADS2, FNA is not indicated
  - TIRADS 3 with 1.5 - 2.4 cm nodule, TIRADS4 with 1 - 1.4 cm nodule and TIRADS 5 with nodule 0.5 - 0.9 cm, proceed with follow up
  - TIRADS 3 with ≥ 2.5 cm nodule, TIRADS4 with ≥ 1.5 cm nodule and TIRADS5 with ≥ 1 cm nodule, proceed with FNA
- On cytology (S D Med 2022;75:569)
  - Thyroid Bethesda System (TBS) 1: repeat FNA
  - TBS2: follow up
  - TBS3 and TBS4: molecular testing
  - TBS5: lobectomy or total thyroidectomy
  - TBS6: total thyroidectomy
- Molecular studies (Endocr Pathol 2022;33:27)
  - BRAF, HRAS, KRAS, NRAS, RET, PTEN, TP53, TERT, PAX8::PPARG, GNAS, AKT1, EIF1AX, CD274 (PD-L1) (Endocrinol Diabetes Metab 2021;4:e00241)

Laboratory

Thyroid function test (TSH, T3 and T4), could show hyper, hypo and euthyroid state depending upon the lesion
Molecular studies (see Diagnosis)

Radiology description

Ultrasound (thyroid imaging reporting and data systems [TIRADS], lesion composition, echogenicity, shape, margin and echogenic foci observed) (S D Med 2022;75:569)
- TIRADS 1 (0 points, benign, no FNA)
- TIRADS 2 (2 points, not suspicious, no FNA)
- TIRADS 3 (3 points, mildly suspicious, if ≥ 2.5 cm then FNA and if ≥ 1.5 cm then follow up)
- TIRADS 4 (4 to 6 points, moderately suspicious, if ≥ 1.5 cm then FNA and if ≥ 1 cm then follow up)
- TIRADS 5 (7 + points, highly suspicious, if ≥ 1 cm then FNA and if ≥ 0.5 cm then follow up)
Thyroid scintigraphy / radionucleotide iodine 123 scan (hot nodule is most likely benign and cold nodule could be benign and malignant)
Computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of the extent of the lesion

Radiology images

Images hosted on other servers:

Multiple hypoechoic lesions

Prognostic factors

Variation differs from one lesion to another
Benign lesions most common (~90%), malignant lesions 4 - 6.5% (StatPearls: Thyroid Nodule [Accessed 17 October 2024])

Case reports

24 year old woman with thyroid vein hemangioma in the left lobe (J Int Med Res 2020;48:300060520954718)
51 year old woman with undifferentiated sarcoma in the right thyroid lobe (Asian J Surg 2023;46:5058)
65 year old woman with primary extraskeletal osteosarcoma, osteoblastic type in the right thyroid lobe (ORL J Otorhinolaryngol Relat Spec 2023;85:52)

Treatment

Varies from lesion to lesion such as observation, thyroid lobectomy or total thyroidectomy

Clinical images

N/A

Gross description

Varies depending upon the lesion
Follicular adenoma: solid homogeneous, grayish white, tan or brown cut surface with thick capsule (see Follicular adenoma)
Follicular carcinoma: solid and tan-gray cut surface (see Follicular thyroid carcinoma)
Papillary thyroid cancer: firm and white in color to variegated in appearance (see Papillary thyroid carcinoma overview)

Gross images

Contributed by Sara Conway, M.D. and Momin Iqbal, M.D., M.B.B.S.

Follicular thyroid lesion

Oncocytic tumor

Papillary thyroid cancer

Frozen section description

Not relevant to this topic

Frozen section images

Not relevant to this topic

Microscopic (histologic) description

Varies from lesion to lesion
Papillary thyroid cancer (PTC) (Adv Ther 2020;37:3112)
- Papillary architecture with thin fibrovascular core, the cells can have overcrowded nuclei
- The nuclei have distinct features with elongated to oval nuclei, open chromatin, nuclear grooves and intranuclear cytoplasmic pseudoinclusions
Follicular thyroid cancer: follicular thyroid cancer histologically is very similar to thyroid adenoma except for invasion of capsule or vessels (Endocr Pathol 2022;33:27)
Oncocytic / Hürthle cell tumor: encapsulated lesion with predominantly oncocytic / Hürthle cells with intensely eosinophilic granular cytoplasm (Endocr Pathol 2022;33:27)

Microscopic (histologic) images

Contributed by Momin Iqbal, M.D., M.B.B.S. and Sara Conway, M.D.

Papillary thyroid carcinoma

Mushroom-like capsular invasion

Tall cell variant of PTC

Thyroid oncocytic / Hürthle cell tumor

Angioinvasive Hürthle cell tumor

Follicular thyroid adenoma

Virtual slides

N/A

Cytology description

Features that are pertinent to assess include cellularity, colloid, nuclear features, Hürthle cells, atypical cells, oncocytic cells, inflammatory cells
Reported as TBS classification
- TBS1: nondiagnostic or unsatisfactory (see Thyroid & parathyroid-Unsatisfactory)
- TBS2: benign (see Thyroid & parathyroid-Benign)
- TBS3: atypia of undetermined significance (see Thyroid & parathyroid-AUS)
- TBS4: follicular neoplasm or suspicious for a follicular neoplasm (see Thyroid & parathyroid-Follicular neoplasm)
- TBS5: suspicious for malignancy (see Thyroid & parathyroid-Suspicious for malignancy)
- TBS6: positive for malignancy (see Thyroid & parathyroid-Malignant)

Cytology images

N/A

Immunofluorescence description

Not relevant to this topic

Immunofluorescence images

Not relevant to this topic

Positive stains

Not relevant to this topic

Negative stains

Not relevant to this topic

Electron microscopy description

Similar to normal thyroid gland and hyperplastic nodules
Hyperfunctioning follicular adenomas: organelle rich cytoplasm, especially rough endoplasmic reticulum; numerous, long microvilli on surface (Am J Clin Pathol 1982;78:299)
Clear cell follicular adenomas: cytoplasmic vesicles of variable size; these may be dilated cisternae of the rough endoplasmic reticulum or mitochondria, lysosomes or endocytic vesicles (Virchows Arch A Pathol Anat Histol 1978;380:205)
Hürthle cell tumor: cytoplasm packed with mitochondria (Endocr Pathol 2022;33:27)

Electron microscopy images

Not relevant to this topic

Molecular / cytogenetics description

Molecular studies (Endocr Pathol 2022;33:27)
- BRAF: papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, thyroid follicular adenoma
- HRAS: follicular thyroid carcinoma, follicular thyroid adenoma, anaplastic thyroid carcinoma
- KRAS: papillary thyroid carcinoma, follicular thyroid carcinoma, follicular thyroid adenoma, anaplastic thyroid carcinoma
- NRAS: papillary thyroid carcinoma, follicular thyroid carcinoma, follicular thyroid adenoma, anaplastic thyroid carcinoma
- RET: medullary thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma
- PTEN: follicular thyroid carcinoma, papillary thyroid carcinoma
- TP53: papillary thyroid carcinoma, follicular thyroid carcinoma, anaplastic thyroid carcinoma
- TERT: papillary thyroid carcinoma, follicular thyroid carcinoma, anaplastic thyroid carcinoma
- PAX8::PPARG: follicular thyroid carcinoma, follicular thyroid adenoma
- GNAS: NIFTP, follicular thyroid adenoma
- AKT1: papillary thyroid carcinoma, follicular thyroid carcinoma, follicular thyroid adenoma
- EIF1AX: follicular adenoma, follicular thyroid carcinoma, anaplastic thyroid carcinoma, poorly differentiated thyroid carcinoma (Cancers (Basel) 2022;14:6097)
- CD274 (PD-L1): medullary thyroid carcinoma, follicular thyroid carcinoma, papillary thyroid carcinoma (Endocrinol Diabetes Metab 2021;4:e00241, Theranostics 2021;11:1310)

Molecular / cytogenetics images

Not relevant to this topic

Videos

Solitary thyroid nodule

Thyroid carcinoma I: pathology evaluation

Sample pathology report

Thyroid, total thyroidectomy:
- Follicular thyroid carcinoma (4.8 cm), minimally invasive with capsular invasion (A27, A28, A11), isthmus (see comment)
- Surgical resection margins, negative for tumor. No vascular invasion identified.
- Nonneoplastic thyroid showing thyroid follicular nodular disease with adenomatous nodules and chronic lymphocytic (Hashimoto) thyroiditis.
- 5 lymph nodes (0/5), negative for malignancy.
- AJCC tumor stage: pT3N0a
- Comment: Immunohistochemical stains are performed.

Slide	Immunohistochemical stain	Result
A112	CK19	Focally positive
A113	BRAF V600E	Negative
A182	CD31	Negative

Differential diagnosis

Not relevant to this topic

Additional references

Not relevant to this topic

Board review style question #1

What are the most common associated genetic abnormalities identified in papillary thyroid carcinomas?

BRAF mutation
E1F1AX mutations
PTEN mutations
RAS mutation

Board review style answer #1

A. BRAF mutation. BRAF mutations are frequently linked to papillary thyroid carcinoma. The prevalence of papillary thyroid carcinoma in adults is 80 - 95% of all thyroid cancers and 90% in the pediatric population. Answer D is incorrect because RAS mutation is found in 20 - 30% of follicular adenomas. Answer B is incorrect because E1F1AX mutation is seen in 10 - 20% of follicular adenomas. Answer C is incorrect because PTEN mutation occurs in 10 - 15% of follicular adenomas.

Comment Here

Reference: Solitary thyroid nodule

Board review style question #2

For a patient with TIRADS 4 thyroid nodule, what is the cut off size for subsequent FNA evaluation?

≥ 1 cm
≥ 1.5 cm
≥ 2.0 cm
≥ 2.5 cm

Board review style answer #2

B. 1.5 cm. The ultrasound thyroid imaging reporting and data systems (TIRADS) is based on the lesion composition, echogenicity, shape, margin and echogenic foci observed; based on the scores, thyroid lesion is categorized as the TIRADS 1 (0 points, benign, no FNA), TIRADS 2 (2 points, not suspicious, no FNA), TIRADS 3 (3 points, mildly suspicious, if ≥ 2.5 cm then FNA and if ≥ 1.5 cm then follow up); TIRADS 4 (4 to 6 points, moderately suspicious, if ≥ 1.5 cm then FNA and if ≥ 1 cm then follow up; and TIRADS 5 (7 + points, highly suspicious, if ≥ 1 cm then FNA and if ≥ 0.5 cm then follow up). For a TIRADS 4 thyroid lesion, it is recommended for the ultrasound guided FNA if the lesion is 1.5 cm or bigger.

Comment Here

Reference: Solitary thyroid nodule

Board review style question #3

What is the risk of malignancy in Bethesda category IV thyroid lesion?

< 1 - 3%
5 - 15%
25 - 40%
60 - 75%

Board review style answer #3

C. 25 - 40%. The Bethesda system for reporting thyroid cytopathology has 6 categories with category I as nondiagnostic, category II as benign, category III as atypia of undetermined significance, category IV as follicular neoplasm, category V as suspicious for malignancy and category VI as positive for malignancy. In the risk of malignancy, the Bethesda category IV lesion carries a 25 - 40% risk of malignant neoplasm in subsequent surgical resection, the recommended management is surgical lobectomy. Answer A is incorrect because category II lesions carry 0- 3% risk and are usually managed with clinical follow up. Answer B is incorrect because category III lesions carry 10 - 30% risk of malignancy. Answer D is incorrect because category V lesions carry a 50 - 75% risk of malignancy and are usually managed by surgical lobectomy or total thyroidectomy.

Comment Here

Reference: Solitary thyroid nodule

Squamous cell carcinoma

Table of Contents

Definition / general

Considered a variant of anaplastic thyroid carcinoma in the 2022 WHO
Very rare, highly lethal thyroid carcinoma with pure squamous component
Clinically and pathologically shares features with anaplastic thyroid cancers; can be regarded as a variant of anaplastic thyroid carcinoma
Must rule out:
- Metastasis or direct invasion of squamous cell carcinoma from oropharynx, larynx, trachea, lung, other organs
- Papillary carcinoma with foci of squamous differentiation (occurs in 15 to 45% of papillary carcinomas)
- Anaplastic thyroid carcinoma with squamous differentiation
- Other thyroid carcinomas with squamous differentiation, including mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, CASTLE

Essential features

Squamous cell carcinoma is regarded as a variant of anaplastic thyroid carcinoma
Aggressive clinical behavior

Epidemiology

Similar to anaplastic carcinoma, affects older patients with chronic goiter

Clinical features

Older patients present with a rapidly enlarging neck mass
Patients may have a long history of preexisting thyroid disease
Extrathyroidal extension and cervical nodal metastases are common, distant metastases are rare

Prognostic factors

Poor prognosis with median survival < 6 months
Death in almost all cases, usually due to local progression (Int Semin Surg Oncol 2007;4:8) or airway compression

Case reports

Teenage girl with Hashimoto thyroiditis (Pediatr Dev Pathol 2006;9:496)
49 year old woman without coexisting thyroid carcinoma (Case Rep Pathol 2015;2015:838079)
65 year old woman with a 20 year history of thyroid goiter (J Surg Case Rep 2014 Dec 8;2014(12))
66 year old man with hypercalcemia and leukocytosis (Arch Pathol Lab Med 1987;111:373)

Treatment

Radical resection and radiation (often radioresistant)

Clinical images

Images hosted on other servers:

Ulceroproliferative
growth

Recurrent
ulceroproliferative
growth

Mass pressuring;
infiltrating trachea;
surrounding soft tissue

Gross description

Firm infiltrating mass with necrosis

Gross images

Images hosted on other servers:

Enlarged left lobe

White tumor with central necrosis

Microscopic (histologic) description

Invasive squamous carcinoma, with or without keratinization
High mitotic index
Extrathyroid, vascular and perineural invasions are common

Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D.

Squamous cell carcinoma with necrosis

Images hosted on other servers:

Infiltrating squamous cell carcinoma

Cytology images

Images hosted on other servers:

Atypical squamoid cell

Positive stains

CK5, CK6, CK19
Thyroglobulin (focally), PAX8 (91%), TTF1 (9%) (Endocr J 2015;62:991)
p40, p53 (40 - 50%), p63, high Ki67 proliferation index (Thyroid 2006;16:89)

Negative stains

CK20 (Histopathology 2001;39:279), calcitonin

Differential diagnosis

CASTLE: circumscribed, slowly growing tumor, CD5+, CD117+
Metastasis or direct invasion of squamous cell carcinoma from other organs: history of squamous cell carcinoma, PAX8-
Papillary thyroid carcinoma with squamous differentiation: squamous component is small portion of the well differentiated thyroid carcinoma
Squamous metaplasia: benign squamous cells

Staging-parathyroid

Table of Contents

Definition / general

Applicable to parathyroid carcinoma
First introduced in AJCC 8th edition
There is limited evidence on significant prognostic factors in parathyroid carcinoma
Prognostic significance of tumor size, extent of invasion or regional lymph node involvement is unclear and studies are conflicting
Presence of distant metastasis is the only consistent factor across the literature that is predictive of overall survival
While TNM definitions have been established, no universal staging system is available so far; instead, AJCC / TNM includes recommendations for recording data collection variables in the cancer registry to be used to develop a formal staging system in the future
Microscopic and macroscopic classifications of the primary tumor have not been standardized

Essential features

T, N and M categories are established but no cancer stages defined at the moment
Distant metastasis (M category) is the major predictor of overall survival

ICD coding

ICD-10: C75.0 - Parathyroid gland

Primary tumor (pT)

pTX: primary tumor cannot be assessed
pT0: no evidence of primary tumor
pTis: atypical parathyroid neoplasm (neoplasm of uncertain malignant potential) (see notes below)
pT1: localized to the parathyroid gland with extension limited to soft tissue
pT2: direct invasion into the thyroid gland
pT3: direct invasion into recurrent laryngeal nerve, esophagus, trachea, skeletal muscle, adjacent lymph nodes or thymus
pT4: direct invasion into major blood vessel or spine

Notes:

Atypical parathyroid neoplasm is defined as a tumor that is histologically or clinically worrisome but does not fulfill the more robust criteria (i.e. invasion, metastasis) for carcinoma
- Generally includes tumors that have 2 or more concerning features, such as fibrous bands, mitotic figures, necrosis, trabecular growth or adherence to surrounding tissues intraoperatively
- Usually have a smaller dimension, weight and volume than carcinomas and are less likely to have coagulative tumor necrosis

Regional lymph nodes (pN)

pNX: regional lymph nodes cannot be assessed
pN0: no regional lymph node metastasis
pN1: regional lymph node metastasis
- pN1a: metastasis to level VI (pretracheal, paratracheal and prelaryngeal / Delphian lymph nodes) or superior mediastinal lymph nodes (level VII)
- pN1b: metastasis to unilateral, bilateral or contralateral cervical (level I, II, III, IV or V) or retropharyngeal nodes

Distant metastasis (pM)

pM0: no distant metastasis
pM1: distant metastasis

AJCC prognostic stage groups

Not established in the current AJCC / TNM

Registry data collection variables

Age at diagnosis
Gender
Race
Size of primary tumor in millimeters
Location of primary tumor: left or right and superior (upper) or inferior (lower)
Invasion into surrounding tissue (present or absent)
Distant metastasis
Number of lymph nodes removed (by level)
Number of lymph nodes positive (by level)
Highest preoperative calcium (mg/dL)
Highest preoperative parathyroid hormone (pg/mL)
Lymphovascular invasion (present or absent)
Grade (low or high)
Weight of primary tumor (in milligrams)
Mitotic rate
Time to recurrence (months)

Histologic grade

Low grade: round monomorphic nuclei with only mild to moderate nuclear size variation, indistinct nucleoli and chromatin characteristics resembling those of normal parathyroid or of adenoma
High grade: more pleomorphism, with a nuclear size variation > 4:1; prominent nuclear membrane irregularities; chromatin alterations, including hyperchromasia or margination of chromatin; and prominent nucleoli; high grade tumors show several discrete confluent areas with nuclear changes

Histopathologic type

Apart from parathyroid carcinoma, more descriptive type terminology can be used, such as invasive parathyroid neoplasm, neoplasm of undetermined malignant significance, parathyroid neoplasm with locally invasive or atypical features and parathyroid neoplasm with invasion into connective tissue (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

Board review style question #1

A patient presented with a parathyroid carcinoma directly invading thyroid and adjacent fibroadipose tissue. What is the pT category?

pTis
pT1
pT2
pT3
pT4

Board review style answer #1

C. pT2

Comment Here

Reference: Staging-parathyroid

Board review style question #2

A 72 year old man presented with a 4 cm advanced parathyroid carcinoma invading trachea and thyroid and showing cervical lymph nodes metastasis along with dissemination in the lungs. What is the clinical stage as per the AJCC / TNM 8th edition?

Stage I
Stage II
Stage III
Stage IV
Not applicable

Board review style answer #2

E. Not applicable; no AJCC / TNM staging system for parathyroid carcinoma is available so far, only standalone TNM categories

Comment Here

Reference: Staging-parathyroid

Subacute thyroiditis

Table of Contents

Definition / general

Granulomatous inflammation of the thyroid gland with characteristic clinical and microscopic findings
Most common cause of thyroid related neck pain and typically occurs a few weeks after a viral infection

Essential features

Diagnosed mainly based on clinical findings (e.g. fever, odynophagia, thyroid tenderness)
Histopathologically, characterized by granulomatous inflammation composed of multinucleated giant cells, foamy and epithelioid histiocytes, neutrophils, lymphocytes and plasma cells

Terminology

Historical name: de Quervain thyroiditis
Synonyms: subacute granulomatous thyroiditis, de Quervain thyroiditis, painful subacute thyroiditis, postviral thyroiditis, giant cell thyroiditis, subacute nonsuppurative thyroiditis, pseudotuberculous thyroiditis, struma granulomatosa

ICD coding

ICD-10: E06.1 - subacute thyroiditis

Epidemiology

Mostly seen in middle aged women
Appears to be seasonal, as most cases occur in the summer and fall (Am Fam Physician 2006;73:1769)
Young children affected by subacute thyroiditis have been reported (BMJ Case Rep 2020;13:e236909, Clin Pediatr Endocrinol 2021;30:75)

Sites

Entire gland is usually involved (Heilo: Atlas of Thyroid Lesions, 1st Edition, 2011)

Etiology

Associated with coxsackievirus, echovirus infections, mumps, measles, influenza and other viruses (Rev Endocr Metab Disord 2021 May 5 [Epub ahead of print], Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
May be related to pregnancy (J Endocrinol Invest 2006;29:924)
SARS-CoV-2 can be a potent triggering factor (Rev Endocr Metab Disord 2021 May 5 [Epub ahead of print], SN Compr Clin Med 2021 Apr 29 [Epub ahead of print], Cancer Cytopathol 2021;129:844)
Several human leukocyte antigen (HLA) alleles increase the risk of acquiring and recurrence (HLA-B*35, HLA-B*18:01, -DRB1*01 and HLA-C*04:01) (Rev Endocr Metab Disord 2021 May 5 [Epub ahead of print])

Diagrams / tables

Images hosted on other servers:

Thyroid function

Clinical features

Fatigue, low grade fever, myalgias, along with neck pain and diffuse goiter
Self limited in most of cases, usually resolves in 1 - 2 months
Presence of a deterioration of tachycardia or an occurrence of heart arrhythmias were reported in COVID-19 patients with subacute thyroiditis (Rev Endocr Metab Disord 2021 May 5 [Epub ahead of print])
May occasionally coincide with thyroid malignancy (Arq Bras Endocrinol Metabol 2014;58:851)
26.8% of subacute thyroiditis patients developed permanent hypothyroidism within 3 years of treatment (Exp Clin Endocrinol Diabetes 2020;128:703)

Diagnosis

Mainly based on clinical findings (fever, malaise, fatigue, muscle aches, neck pain, thyroid gland tenderness, odynophagia)
May have hypo or hyperthyroidism symptoms (Int J Endocrinol 2014;2014:794943)
May have atypical symptoms: thyroid storm, fever of unknown origin, solitary painless thyroid nodule (Cureus 2021;13:e16399, Int J Surg Case Rep 2017;33:112)

Laboratory

Thyrotoxic phase: hyperthyroid (suppressed thyroid stimulating hormone [TSH] and elevated T4 and T3) due to follicle destruction and release of hormone
After 4 - 8 weeks: TSH and free T4 levels may be low (Am Fam Physician 2014;90:389)

Radiology description

Sonography: diffuse hypoechoic and confluent areas with characteristic features like lava flow (Acta Radiol 2014;55:429, Cytojournal 2015;12:9)
Radioactive iodine uptake in acute phase is very low (Am Fam Physician 2014;90:389)
Increased ¹⁸F-FDG uptake on PET / CT (Medicine (Baltimore) 2017;96:e7535)

Radiology images

Contributed by Ayana Suzuki, C.T.

Hypoechoic nodule

Images hosted on other servers:

Hypoechoic nodule with poorly defined margin

High ¹⁸F-FDG uptake in enlarged right thyroid lobe

Prognostic factors

Self limited, with patients returning to a euthyroid state within a few months
Up to 2% recurrence (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)

Case reports

3 year old girl with Epstein-Barr virus infection (Thyroid 2005;15:1189)
39 year old woman presented with acute thyroid swelling (Endocr Pathol 2002;13:263)
39 year old woman with thyroid nodule (Head Neck Pathol 2019;13:231)
44 year old man with fever, tenderness in the right neck and odynophagia (Pathology Case Reviews 2015;20:105)
45 year old man with numerous subcutaneous nodules and diffuse muscle pain in the neck (Ann Clin Lab Sci 2017;47:620)
46 year old woman who underwent US-FNA for a suspicious thyroid nodule (Diagn Cytopathol 2015;43:399)
48 year old woman who underwent FNA of a left thyroid mass (Diagn Cytopathol 2016;44:682)
51 year old man with a history of fever, gradual right neck swelling and pain (Diagn Cytopathol 2012;40:433)

Treatment

Anti-inflammatory treatment is the key
In some patients, no treatment is required
Symptoms of hyperthyroidism need to be treated with propranolol or atenolol with close follow up
Therapy with antithyroid drugs is not indicated because the disorder is caused by the release of preformed thyroid hormone from destroyed follicles instead of synthesis of new T3 and T4 (Am Fam Physician 2000;61:1047)

Microscopic (histologic) description

Inflammatory infiltrate composed of multinucleated giant cells, foamy histiocytes, epithelioid histiocytes, neutrophils, lymphocytes, plasma cells
Variable background of fibrosis
Temporal trend
- Early stage (acute; hyperthyroidism):
  - Follicular damage and loss of epithelium and colloid
  - Neutrophils, occasional microabscesses
  - Inflammation (predominantly lymphohistiocytic), which expands into adjacent interfollicular zones
- Mid stage (hypothyroidism):
  - Chronic inflammation: lymphocytes, plasma cells
  - Epithelioid and nonepithelioid macrophages and multinucleated giant cells adjacent to or within disrupted follicles, surround and engulf residual colloid
  - Well formed granulomata are not seen
  - Variable degrees of fibrosis
- Late stage (resolution; recovery):
  - Fibrosis replaces destroyed follicles
  - Follicular tissue is regenerated, restoring normal structure
  - Fibrosis and inflammatory infiltrate resolves
Inflammatory process unevenly affects entire gland (65% bilateral) (Thompson: Diagnostic Pathology - Head and Neck, 2nd Edition, 2016)
Nowadays, rarely seen in resection specimens because of conservative treatment and no need for surgery (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 3rd Edition, 2019)

Microscopic (histologic) images

Contributed by Truong Phan Xuan Nguyen, M.D.

Follicular damage

Granuloma

Multinucleated giant cells

Virtual slides

Images hosted on other servers:

Subacute thyroiditis

Acute (subacute) nonsuppurative thyroiditis

Cytology description

Cellular smears with clustered epithelioid cells, fibrous fragments with enmeshed inflammatory cells, scattered lymphocytes, histiocytes and neutrophils, occasional multinucleated giant cells containing up to 100 nuclei and ingesting colloid or neutrophils (Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2018, J Clin Diagn Res 2017;11:EC09)
Cellular composition also depends on the stage
- Early stage: many neutrophils and eosinophils, similar to acute thyroiditis
- Later stages: hypocellular, giant cells surrounding and engulfing colloid, epithelioid cells, lymphocytes, macrophages and scant degenerated follicular cells (Diagn Cytopathol 2019;47:1251)

Cytology images

Contributed by Truong Phan Xuan Nguyen, M.D. and Ayana Suzuki, C.T.

Cellular smear

Multinucleated giant cells

Epithelioid cells

Giant cell

Positive stains

Histiocytes, including giant cells: CD68 (Pathol Res Pract 2002;198:833)
Small lymphocytes in the granulomas: CD3, CD8, CD45
Colloid: PAS
Immunostains are usually not needed for a diagnostic workup

Sample pathology report

Thyroid, left lobe, fine needle aspiration:
- Benign (Bethesda category II)
- Subacute thyroiditis (see comment)
- Comment: Moderately cellular aspirate with multinucleated giant cells, clustered epithelioid histiocytes, scattered lymphocytes and neutrophils consistent with subacute thyroiditis.
Thyroid, completion thyroidectomy:
- Subacute thyroiditis (see comment)
- Comment: Marked inflammation with granulomas containing multinucleated giant cells and epithelioid histiocytes without caseation necrosis. Areas of fibrosis are patchily distributed. The findings are diagnostic of subacute thyroiditis.

Differential diagnosis

Palpation thyroiditis:
- Also called multifocal granulomatous thyroiditis
- May be distributed throughout gland
- No neutrophils
- Multinucleated giant cells
Sarcoidosis:
- Granulomas usually found in interstitium
- Small, compact aggregates of epithelioid histiocytes
- Giant cells may be present
- Necrosis tends to be absent
Tuberculosis:
- Granulomas with caseation
- Granulation tissue and fibrosis
- AFB positive
Chronic lymphocytic (Hashimoto) thyroiditis:
- Diffuse, nontender thyroid gland
- Primary features: oncocytic epithelium, lymphocytes, germinal centers
- Lacks follicle destruction and giant cells
Thyroid primary and metastatic malignant tumors (BMC Endocr Disord 2019;19:86):
- Tumors sometimes imitate symptoms of subacute thyroiditis, which may lead to delayed diagnosis of the thyroid malignancy
- Neck sonography and thyroid FNA are helpful in identifying invasive growth and atypical malignant cells, respectively

Additional references

eMedicine: Subacute Thyroiditis [Accessed 15 December 2021]

Board review style question #1

A 40 year old woman presented to her family physician with fatigue. Several weeks ago, she had a runny nose and cough. A physical examination reveals a tender thyroid gland. Laboratory testing reveals a TSH of 0.3 mIU/L and T3 of 5 nmol/L, T4 of 4.5 nmol/L. Of the following, what would a cytologic examination of the thyroid gland reveal?

Abscesses
Clear nuclei and psamomma bodies
Clustered epithelioid cells and giant cells
Lymphocyte and oncocytic change
Small follicles

Board review style answer #1

C. Clustered epithelioid cells and giant cells. This case has clinical appearances and cytologic features of subacute thyroiditis.

Comment Here

Reference: Subacute thyroiditis

Board review style question #2

A 45 year old woman reported 1 week symptoms of fatigue, fever, myalgias and neck pain. Neck examination demonstrates significant thyroid gland tenderness. Which histologic changes would likely accompany the above symptoms?

Enlarged cells with large intranuclear inclusions
Foreign material
Granulomas with giant cells and epithelioid histiocytes
Markedly atypical cells
Papillae

Board review style answer #2

C. Granulomas made of giant cells and epithelioid histiocytes are a typical histologic feature of subacute thyroiditis.

Comment Here

Reference: Subacute thyroiditis

Suspicious for malignancy

Table of Contents

Definition / general

Bethesda category V suspicious for malignancy (SM) is used when some cytologic features are strongly suspected of malignancy but are not sufficient for a conclusive diagnosis (Thyroid 2017;27:1341)
Higher suspicion of malignancy than atypia of undetermined significance / follicular lesion of undetermined significance (AUS / FLUS) but lower suspicion than malignant
Molecular testing with mutation panels may be useful, particularly for potential noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) cases
Purpose of separating suspicious for malignancy from malignant is to preserve the very high positive predictive value of the malignant category without compromising the overall sensitivity of fine needle cytology aspiration

Essential features

Used when cytology is strongly suspected of malignancy but is not sufficient for a conclusive diagnosis
Frequency Most common histological diagnosis is papillary thyroid carcinoma (PTC) (Acta Cytol 2014;58:15)

Clinical features

Frequency: 3% (Acta Cytol 2012;56:333, Cancer Cytopathol 2020;128:238)
Resection rate: 70% (Cancer Cytopathol 2020;128:238)
Risk of malignancy: 80% (NIFTP = malignant), 45 - 60% (NIFTP ≠ malignant) (Cancer Cytopathol 2020;128:238, Ali: The Bethesda System for Reporting Thyroid Cytopathology - Definitions, Criteria and Explanatory Notes, 2nd Edition, 2018)
Suspicious for malignancy interpretation allows for more conservative management options (e.g. lobectomy)

Diagnosis

Aspirates where malignancy is suspected but cannot be determined due to:
- Suboptimal sampling
- Poor cellular preservation
- Unusual variant of neoplasm
- Overlapping cytological features with other thyroid lesions
Excluded from this category:
- Specimens suspicious for a follicular or Hürthle cell neoplasm (see FN / SFN and FNHCT / SFNHCT)
- Unequivocally malignant aspirates (see Malignant)
- Specimens with a minor degree of atypia, primarily cytologic or architectural (see AUS / FLUS)
Frozen section has limited utility for suspicious for malignancy nodules (Thyroid 2002;12:619)

Case reports

55 year old man with colon cancer metastasis within a NIFTP which was cytologically suspected of PTC (Head Neck Pathol 2019 Oct 17 [Epub ahead of print])
58 year old woman with mammary analogue secretory carcinoma of the thyroid which was cytologically suspected of PTC (Int J Surg Pathol 2018;26:459)
63 year old man with follicular variant of papillary thyroid carcinoma presenting as a toxic nodule which was cytologically suspected of follicular variant of PTC (Clin Nucl Med 2010;35:770)
63 year old woman with hyalinizing trabecular tumor which was cytologically suspected of hyalinizing trabecular tumor (J Pathol Transl Med 2018;52:252)
71 year old man with mixed medullary and follicular cell carcinoma of the thyroid which was cytologically suspected of thyroid carcinoma (Med Sci Monit 2008;14:CS31)

Cytology description

Suspicious for papillary thyroid carcinoma
- Pattern A (patchy nuclear changes): moderate to high cellularity, nuclei showing enlargement, pallor, grooves, irregularity or molding but absence of nuclear pseudoinclusions, psammoma bodies and papillary architecture
- Pattern B (incomplete nuclear changes): nuclei showing enlargement with mild pallor and grooves, absence of nuclear irregularity, nuclear molding, nuclear pseudoinclusions, psammoma bodies and papillary architecture
- Pattern C (sparsely cellular specimen): poor cellularity, presence of many findings suggesting papillary thyroid carcinoma
- Pattern D (cystic degeneration): cystic degeneration based on foamy histiocytes, scattered clusters of follicular cells with the nuclei showing enlargement, pallor, grooves, absence of nuclear pseudoinclusions, psammoma bodies and papillary architecture, large, atypical, histiocytoid cells with enlarged nuclei and without abundant vacuolated cytoplasm (Ali: The Bethesda System for Reporting Thyroid Cytopathology - Definitions, Criteria and Explanatory Notes, 2nd Edition, 2018)
Suspicious for medullary thyroid carcinoma
- Sparse or moderate cellularity
- Monomorphic population of isolated small or medium sized cells with a high nuclear cytoplasmic ratio
- Nuclei are eccentrically located, with smudged chromatin
- Small fragments of amorphous material
Suspicious for lymphoma
- Numerous monomorphic small to intermediate sized lymphoid cells
- Sparsely cellular and contains atypical lymphoid cells
Suspicious for malignancy, not otherwise specified
- Other primary thyroid malignancies like anaplastic carcinoma and poorly differentiated carcinoma
- Suboptimal cellularity or preservation can lead to uncertainty and result in a suspicious for malignancy interpretation

Cytology images

Contributed by Ayana Suzuki, C.T.

Suspicious for PTC

Hyalinizing trabecular tumor

Suspicious for lymphoma

Images hosted on other servers:

Suspicious for lymphoma

Suspicious for medullary thyroid carcinoma

Suspicious for papillary thyroid carcinoma

Suspicious for metastatic carcinoma

Management

Usually surgical management similar to that of malignant nodules (Thyroid 2016;26:1)
In suspicious for papillary thyroid carcinoma cases with low risk features (≤ 1 cm, without extrathyroidal extension and clinical metastasis), active surveillance is an option (Thyroid 2018;28:23)
Molecular testing with high positive predictive value (BRAF mutation or mutation panel) active surveillance is an option (Thyroid 2016;26:1)
For suspicious for medullary thyroid carcinoma
- Measuring serum calcitonin level or calcitonin immunostaining are recommended (Endocr J 2017;64:1099)
For suspicious for lymphoma
- Repeat fine needle aspiration to obtain cells for flow cytometry (Endocr J 2017;64:859, Endocr J 2019;66:1083)

Sample cytology report

Dx / category: suspicious for malignancy
- Suspicious for papillary thyroid carcinoma
- A few follicular cells showing nuclear enlargement, pale and powdery chromatin and nuclear grooves are present
Dx / category: suspicious for malignancy
- Suspicious for medullary thyroid carcinoma
- Correlation with serum calcitonin level or immunostaining might be helpful for definitive diagnosis if clinically indicated
Dx / category: suspicious for malignancy
- Suspicious for lymphoma
- Re-aspiration for flow cytometry might be helpful to better characterize the lymphocyte population if clinically indicated

Differential diagnosis

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features:
- Microfollicular architecture with minimal nuclear features of papillary thyroid carcinoma, absence of nuclear pseudoinclusions, papillae or psammoma bodies
- Impossible to distinguish from invasive follicular variant of papillary thyroid carcinoma by fine needle aspiration alone
Hyalinizing trabecular tumor:
- Trabecular growth pattern of the cells with nuclear grooves and abundant nuclear pseudoinclusions, intratrabecular hyaline material
- MIB1 membranous positivity is useful to distinguish from papillary thyroid carcinoma (Am J Surg Pathol 2000;24:575)
Chronic thyroiditis (versus papillary thyroid carcinoma):
- Nuclear changes of follicular cells with focal enlargement, grooves, prominent nucleoli and chromatin clearing in the lymphocytic background
- An abundance of lymphocytes and plasma cells does not exclude the possibility of a coexisting papillary thyroid carcinoma (Acta Cytol 2012;56:352)
Chronic thyroiditis (versus MALT lymphoma):
- Numerous lymphocytes, few follicular cells
- Difficult to distinguish from MALT lymphoma without immunophenotyping by flow cytometry
Benign cyst:
- Elongated cells with pale chromatin, nuclear grooves and relatively large nucleoli
- Spindle shaped morphology of the cell and nucleus, reminiscent of reparative epithelium in cervical Pap smears

Board review style question #1

Classic papillary thyroid carcinoma
Follicular adenoma
Follicular variant of papillary thyroid carcinoma
Medullary thyroid carcinoma
Poorly differentiated carcinoma

Board review style answer #1

C. Follicular variant of papillary thyroid carcinoma follicular cells appear as microfollicular pattern. A few follicular cells showing nuclear enlargement, pale and powdery chromatin and nuclear grooves are present.

Comment Here

Reference: Suspicious for malignancy

Board review style question #2

Anaplastic thyroid carcinoma
Follicular carcinoma
Medullary thyroid carcinoma
Papillary thyroid carcinoma
Poorly differentiated thyroid carcinoma

Board review style answer #2

D. Papillary thyroid carcinoma. More than 85% of suspicious for malignancy cases are papillary thyroid carcinoma.

Comment Here

Reference: Suspicious for malignancy

Tall cell

Table of Contents

Definition / general

Papillary thyroid carcinoma (PTC) variant characterized by presence of ≥ 30% of tall cells (2 - 3 times taller than wide) with abundant granular eosinophilic (oncocytic-like) cytoplasm and the typical nuclear changes of PTC
Variable diagnostic criteria over time with significant interobserver variability (Thyroid 2017;27:1498)
Often underrecognized (Thyroid 2008;18:1179, Thyroid 2007;17:655)
First described in 1976 (Cleve Clin Q 1976;43:207)

Essential features

The most common aggressive variant of papillary thyroid carcinoma, characterized by tall cells occupying ≥ 30% tumor and well developed papillary thyroid carcinoma nuclear features
Usually requires more aggressive treatment and closer disease surveillance
BRAF V600E mutation present in most cases
Papillary thyroid carcinomas with tall cell features (≥ 10% tall cells) have worse prognosis than those without tall cells; more than 10% tall cells in a tumor should be reported in final pathology reports

Terminology

2017 WHO classification of tumors of endocrine organs requires ≥ 30% of tall tumor cells to define this variant
Variable diagnostic criteria over time
- WHO 2017 (current): 2 - 3x height / width cells occupying ≥ 30% tumor
- WHO 2004 (outdated): 3x height / width cells occupying ≥ 50% tumor
If tall cell features are > 10% but Endocr Relat Cancer 2015;22:419)

ICD coding

ICD-10: C73 - malignant neoplasm of thyroid gland
ICD-O: 8260/3 - papillary carcinoma of thyroid

Epidemiology

5 - 10% of PTCs (World J Surg 2008;32:1535)
Usually older age patients; exceedingly rare in the pediatric population
F > M (Oncotarget 2016;7:40792, Thyroid 2007;17:655, Laryngoscope 2008;118:32)

Sites

Thyroid
Exceedingly rare at other sites, e.g. ectopic thyroid tissue in thyroglossal duct (see case reports below)

Pathophysiology

Clonal neoplastic proliferation of thyroid follicular cells, usually with a specific driver mutation (see molecular / cytogenetics description below)

Etiology

Sporadic in most cases
Shared risk factors with most other variants of PTC
Ionizing radiation and pre-existing benign thyroid disease

Clinical features

Asymptomatic or enlarging neck mass
May present as an incidental thyroid nodule
Local symptoms (dysphagia, hoarseness, stridor) may be present for more advanced cases with vocal cord paralysis or tracheal compression
Thyroid function tests at the time of diagnosis are typically normal

Diagnosis

Gold standard for the diagnosis of the tall cell variant is histopathologic evaluation of thyroid resection specimens
Nevertheless, tall cell features may be recognized on fine needle aspiration cytology

Laboratory

Persistent or recurrent disease can be monitored by serum thyroglobulin (J Clin Endocrinol Metab 2003;88:3668)

Radiology description

Cold nodules on thyroid scanning
Highly suspicious nodule on thyroid ultrasound in most cases
- Markedly hypoechoic solid nodule with microcalcifications and ill defined spiculated or microlobulated margins (Front Endocrinol (Lausanne) 2018;9:223, Ultrasonography 2017;36:103, J Ultrasound Med 2011;30:853)
Extrathyroidal extension and metastatic lymph nodes are commonly seen

Radiology images

Images hosted on other servers:

Tall cell variant in 19 year old woman

Prognostic factors

Even without extrathyroidal extension, tall cell variant was shown to have a more aggressive behavior than classic PTC independent of age, gender and tumor size (Thyroid 2007;17:655)
Often but not always larger tumor size, more frequent extrathyroidal extension and lymph node involvement as well as a higher stage at presentation than classic PTC (Thyroid 2007;17:655, Laryngoscope 2008;118:32, Hum Pathol 2007;38:212, Oncol Lett 2017;13:3501, Oncotarget 2017;8:6222, Oncotarget 2016;7:40792)
Higher recurrence rate, increased tumor related mortality and more frequent distant metastases compared with classic PTC (Thyroid 2007;17:655, Laryngoscope 2008;118:32, Oncol Lett 2017;13:3501, Oncotarget 2017;8:6222, Oncotarget 2016;7:40792)
Accounts for ~20% of radioiodine refractory thyroid carcinomas (Thyroid 2008;18:1179, Cancer 2008;113:48)
Risk of dedifferentiation into poorly differentiated or anaplastic thyroid carcinoma (tall cell PTC often seen as a component of these tumors) (Mod Pathol 1991;4:637)
The tall cell variant of papillary microcarcinoma (Thyroid 2013;23:1525, Thyroid 2007;17:655)

Case reports

40 year old woman with tall cell PTC in struma ovarii (J Cancer Res Ther 2013;9:119)
51 year old man with hemoptysis, shortness of breath and stridor (Case Rep Endocrinol 2017;2017:4581626)
62 year old man with a metastasis to the pancreas (JOP 2006;7:417)
72 year old man with a combined tall cell and Hürthle cell thyroid carcinoma (Arch Pathol Lab Med 2001;125:541)
75 year old woman with a brain metastasis at initial presentation (Head Neck Oncol 2009;1:23)
77 year old woman with tall cell PTC arising in a thyroglossal duct cyst Ann Med Surg (Lond) 2015;4:129)
80 year old woman with a squamous cell carcinoma arising in a tall cell PTC (J Clin Pathol 2005;58:662)
Man with a thyroid carcinoma with mixed tall cell and columnar cell features (Am J Clin Pathol 1990;94:442)

Treatment

Total thyroidectomy in most cases
With or without neck lymph node dissection with or without radioiodine therapy in selected cases
BRAF targeted therapy may be beneficial in selected advanced cases (J Endocr Soc 2017;1:285, Lancet Oncol 2016;17:e468)

Gross description

Tend to be large (> 5 cm)
Extrathyroidal extension may be grossly apparent

Gross images

Contributed by Andrey Bychkov, M.D., Ph.D.

Entire lobe

Muscular invasion

Frozen section description

Frozen section is usually not indicated
Standard of care is to perform preoperative fine needle aspiration to establish the diagnosis of PTC and to determine the most appropriate surgical procedure

Microscopic (histologic) description

Usually unencapsulated and infiltrative
Growth patterns
- Papillary is the most common
- Trabecular (due to closely packed papillae) and follicular
- Areas of tram track or railroad track-like appearance on lower power
Intricate, well formed, long papillae lined by single layer of tall columnar cells (cell height is 2 - 3 times their width)
- Depending on the plane of sectioning, cells may appear wide rather than tall
- Well developed and easily identifiable nuclear features of PTC: enlarged nuclei with numerous grooves and pseudoinclusions
- Sharply delineated cell borders with intensely eosinophilic and finely granular cytoplasm
Tall cell features / pattern are frequently seen in the areas of extrathyroidal invasion of PTC
Psammoma bodies uncommon
Absent features: nuclear stratification, squamoid morules
May exhibit prominent vascular invasion, mitotic activity
Often found as a well differentiated component within anaplastic (undifferentiated) carcinomas and poorly differentiated thyroid carcinomas (Thyroid 2011;21:493)
May be associated with lymphocytic thyroiditis

Microscopic (histologic) images

Contributed by Livia Florianova, M.D., M.Sc. and Marc Pusztaszeri, M.D.

Tram track pattern

Papillary architecture

Elongated papillae

Solid architecture

Trabecular architecture

Tall cells

Oncocytic-like cytoplasm

Extrathyroidal extension

Microcarcinoma with infiltrative borders

Nuclear features

HBME-1

Galectin 3

Cytokeratin 19

BRAF V600E

Contributed by Andrey Bychkov, M.D., Ph.D.

Long papillae with tall cells

Tram track pattern

Virtual slides

Images hosted on other servers:

Tall cell variant

simple sharing
presentation

Cytology description

Tall cell features may be recognized by cytology (see below) but a definitive diagnosis of a tall cell variant requires histologic evaluation (see definition)
Tall / polygonal cells whose height is 2 - 3 times their width (Diagn Cytopathol 2019;47:452)
Well defined granular eosinophilic or dense cytoplasm
Nuclei with grooves and pseudoinclusions which can resemble soap bubbles due to multiple pseudoinclusions in the same nucleus (Diagn Cytopathol 2002;27:143, Diagn Cytopathol 2019;47:452)
Palisaded arrangement and solid clusters
Cells at the periphery of clusters show a tapering cytoplasmic tail to the outside (cytoplasmic elongation or tadpole cell-like)
Individual detached cells may show a spindle-like shape or tombstone appearance (both luminal and basal cell borders are horizontal) (Diagn Cytopathol 2019;47:452)
Lymphocytes may also be present (Acta Cytol 2004;48:325, Diagn Cytopathol 2019;47:452)

Cytology images

Contributed by Papanicolaou Society and the Bethesda System for Reporting Thyroid Cytopathology, Manon Auger, M.D., C.M., Livia Florianova, M.D., M.Sc. and Marc Pusztaszeri, M.D.

Giemsa

Papanicolaou

Soap bubble nuclear pseudoinclusions

Tall cells

Papillae (cell block)

Tall cells (cell block)

Positive stains

Thyroid specific: Thyroglobulin, TTF1, PAX8
Cytokeratins: CK19, broad spectrum cytokeratins (AE1 / AE3)
HBME, galectin3
BRAF V600E by mutation specific antibody (VE1)
May be positive for napsin A (DDx with metastatic lung carcinoma) (Hum Pathol 2010;41:20, Endocr Pathol 2020;31:39)

Negative stains

Calcitonin, chromogranin, synaptophysin

Electron microscopy description

Intranuclear cytoplasmic inclusions and abundant mitochondria in cytoplasm (Ultrastruct Pathol 1985;8:131)

Molecular / cytogenetics description

Highest mutation density (DNA copy number alterations) of all PTC variants (Cell 2014;159:676)
BRAF V600E mutation in ~80% of cases (Oncogene 2004;23:7436, Endocr Relat Cancer 2005;12:245, J Clin Endocrinol Metab 2003;88:5399)
Higher frequency of TERT promoter mutations than in classic PTC (5 - 30% versus 10%) (Endocr Relat Cancer 2013;20:60)
RAS mutations have not been identified

Videos

High grade and poorly differentiated and anaplastic thyroid carcinoma

Ultrasound of tall cell variant of PTC

Sample pathology report

Thyroid, left lobe, fine needle aspiration:
- Satisfactory for evaluation
- Malignant (Bethesda diagnostic category VI)
- Papillary thyroid carcinoma, favor tall cell variant
Thyroid, left lobe, left hemithyroidectomy:
- Papillary thyroid carcinoma, classic type with tall cell features (20%) (see synoptic report)
Thyroid, total thyroidectomy:
- Papillary thyroid carcinoma, tall cell variant (see synoptic report)

Differential diagnosis

Other papillary thyroid carcinoma variants:
- Classic variant with tall cell features:
  - Columnar cell variant:
    - Nuclear stratification, rare nuclear pseudoinclusions, absence of eosinophilic cytoplasm and distinct cell borders
    - Often CDX2 positive
  - Warthin-like variant:
    - Dense lymphocytic infiltration within vascular cores of stroma, rarely infiltrative
  - Oncocytic variant:
    - No or only rare tall cells, lack of distinct cell borders, prominent nucleoli
- Breast tall cell carcinoma with reversed polarity (very rare):
  - Focal positivity for GATA3, GCDFP-15 and mammaglobin
  - TTF1, thyroglobulin and BRAF V600E consistently negative (Mod Pathol 2018;31:1367, Am J Surg Pathol 2017;41:887, Histopathology 2018;73:339)

Board review style question #1

Which of the following statements concerning the tall cell variant of papillary thyroid carcinoma is correct?

It usually has an indolent clinical course
Most cases are associated with a RAS mutation
Patients are usually older adults
The tumor is positive for TTF1, synaptophysin and calcitonin
Tumor cells are stratified and only focal areas show characteristic papillary thyroid carcinoma nuclear features

Board review style answer #1

C. Patients are usually older adults

Comment Here

Reference: Papillary carcinoma, tall cell variant

Board review style question #2

Which of the following diagnostic features are associated with the tall cell variant of papillary thyroid carcinoma?

A dense lymphocytic infiltration of tumor stroma
Cells with granular eosinophilic cytoplasm and nuclei with a soap bubble appearance on cytology
Focal positivity for GATA3
Infrequent nuclear grooves and pseudoinclusions
High nucleus to cytoplasm ratio

Board review style answer #2

B. Cells with granular eosinophilic cytoplasm and nuclei with a soap bubble appearance on cytology

Comment Here

Reference: Papillary carcinoma, tall cell variant

Teratoma

Table of Contents

Definition / general

Teratoma is a germ cell tumor characterized by the presence of 3 germ cell layers: ectoderm, endoderm and mesoderm
Common in newborns and infants (usually benign), rare in adolescence, usually malignant in adults (Cancer 2000;88:1149)

Sites

Only 3 - 6% of teratomas occur in head and neck region (Endocrine 2006;30:231)

Clinical features

Thyroid mass, usually normal thyroid function

Radiology images

Images hosted on other servers:

Heterogeneously hypoechoic nodule

Large cystic fat-containing mass

Case reports

11 month old boy with thyroid teratoma (Int J Surg 2008;6:462)
16 year old girl with thyroid teratoma (Tunis Med 2014;92:286)
27 year old woman with mature mediastinal teratoma extending into cervical neck (Interact Cardiovasc Thorac Surg 2003;2:265)
31 year old woman with primary malignant teratoma with a primitive neuroectodermal tumor component (J Korean Med Sci 2007;22:568)
54 year old woman with benign teratoma of thyroid gland (Endocrinol Metab (Seoul) 2013;28:144)

Gross description

Usually cystic

Gross images

Images hosted on other servers:

Well encapsulated, mixed solid and cystic mass

Lymph node involvement

Microscopic (histologic) description

Neuro / ectodermal tissue: squamous epithelium, glial tissue
Endodermal tissue: GI epithelium, thyroid and salivary glands
Mesodermal tissue: bone and cartilage
Presence of immature tissue or neuroepithelium makes it a malignant immature teratoma (Am J Surg Pathol 2005;29:700)

Microscopic (histologic) images

AFIP images

Newborn infant

Images hosted on other servers:

Benign thyroid teratoma

Cartilage

Primitive neuroepithelial cells

Thymic tissue

Table of Contents

Definition / general

Ectopic thymic tissue within the thyroid gland due to aberrant migration during embryogenesis
First described by Rossle in 1932 (Virchows Archiv 1932;283:41)
May give rise to thymoma, SETTLE, CASTLE (Hum Pathol 1991;22:349, Am J Surg Pathol 2006;30:994)
A survey of the thyroids of 350 infants and children suggests that the presence of thymus and parathyroid tissue within the thyroid is so common as to be classified as normal (J Anat 1976;122:77)

Terminology

Intrathyroidal thymic tissue, ectopic thymus within thyroid

Epidemiology

Aberrant thymic tissue may be found in the neck of up to 20% of the general population, but intrathyroid ectopic thymic tissue is more rare and is usually found incidentally (Eur J Pediatr Surg 2002;12:327)
Usually found in prepubertal pediatric population, rarely in adults due to age related involution
Detected by ultrasound in 1% of general pediatric population (Thyroid 2015;25:534); increasing use of thyroid ultrasound in children results in an increased detection of intrathyroidal thymic inclusions (Horm Res Paediatr 2011;75:258)
Portions of thymic tissue are present in 70% of normal thyroid glands of infants studied by serial sectioning techniques (J Anat 1976;122:77), 5% of random sections of fetal thyroid (Pediatr Pathol 1993;13:431); 0.1% - 2.6% on random sections of pediatric thyroid (Pediatr Pathol 1993;13:181, J Anat 1976;122:77)
50+ morphologically verified cases have been reported, including < 10 cases in adults; additional 420+ cases were verified by ultrasound
M = F, mean age is 6.5 years at detection

Sites

L > R, bilateral in 5%
Mid to lower portion of thyroid lobes
Often close to the surface

Diagrams / tables

Images hosted on other servers:

Thymus descending path

Pathophysiology / etiology

The closely related descent of the thyroid and parathyroid glands and thymus explains their ectopic location within each other (J Ultrasound Med 2015;34:1651)
As most of the thymus and inferior parathyroid glands are derived from the third pharyngeal pouch, they migrate together, and maldescending thymic portions can be trapped within the thyroid (Int J Clin Exp Pathol 2014;7:6375)
A small and inconstant portion of thymic gland derives from the fourth branchial pouch (thymus IV, accessory thymus), together with the upper parathyroid glands and ultimobranchial body, which may become another source of thymic tissue within thyroid (Pediatr Pathol 1993;13:431)

Clinical features

Rarely symptomatic and may mimic solid (rarely cystic) thyroid nodule found accidentally on US or CT / MRI
Most cases occur in prepubertal children, correlating with a period of maximum growth of the thymus
Adult cases are exceedingly rare, most likely due to age related involution (Arch Pathol Lab Med 2001;125:842)
Thymic remnants are usually found in an orthotopic (normal) position or around the thyroid gland; an intrathyroidal thymus is rarely contiguous with the mediastinal thymus (Horm Res Paediatr 2011;75:258)

Diagnosis

US is a sensitive tool because of the unique echogenicity of thymic tissue
FNAC and flow cytometry may confirm thymic tissue in preoperative settings, although thyroid FNA in children is challenging
Most of the early cases removed surgically were diagnosed only on histopathology

Radiology description

US of ectopic thymus is identical to echotexture of the orthotopic thymus:
- Irregular, triangular, polygonal hypoechoic (rarely hyperechoic) area with punctate, granular or linear bright internal echoes surrounded by normal thyroid tissue (J Clin Ultrasound 2012;40:266, Thyroid 2015;25:534)
- Can show accidental and challenging microcalcification representing Hassall corpuscules (J Pediatr Endocrinol Metab 2012;25:997)
- Hypovascular on Doppler (Endocr Pract 2014;20:e241)
- Can be compared with suprasternal thymus in children
MRI is similar to that of the mediastinal thymus:
- In children, normal thymic tissue is homogeneous and of low signal intensity, though slightly higher than that of muscle on T1-weighted images
- On T2-weighted images, the signal intensity of thymus tissue is less than that of fat, and as the child ages, the thymus becomes infiltrated with more fat, thus increasing the signal of both T1- and T2-weighted images (J Clin Ultrasound 2008;36:443)
RAI scan: cold nodule (Journal of Pediatric Surgery 2013;1:386)

Prognostic factors

Pediatric cases rarely become cystic; most resolve at puberty and do not progress (Pediatr Radiol 2010;40:1774)
Extremely rare to progress to neoplasm

Case reports

2 year old girl with incidental finding of a hypodense, homogeneous thyroid lesion (JAMA Otolaryngol Head Neck Surg 2013;139:87)
2 year old boy and 4 year old girl with ectopic intrathyroidal thymus (Journal of Pediatric Surgery 2013;1:386)
4 year old boy with intrathyroidal thymic tissue mimicking a malignant thyroid nodule (Ultrasonography 2014;33:71)
6 year old boy with intrathyroidal thymic tissue (Thyroid 2008;18:377)
12 year old boy with ectopic thymus presenting as a thyroid nodule (Thyroid 2009;19:293)
16 year old girl with ectopic thymic tissue (Eur J Pediatr Surg 2002;12:327)
22 year old woman with ectopic thymus adjacent to thyroid and parathyroid (Arch Pathol Lab Med 2001;125:842)
27 year old woman with ectopic intrathyroidal thymus (ISPUB 2008:3(1))
29 year old woman with ectopic intrathyroidal thymus accompanied by intrathyroidal parathyroid (Int J Clin Exp Pathol 2014;7:6375)
31 year old woman with intrathyroidal thymic tissue (Korean J Pathol 2011;45:547)
73 year old man with intrathyroidal multiloculated proliferating thymic cyst (Endocr Pathol 2015;26:45)

Treatment

US surveillance of nodule without invasive procedures is advocated in children (Horm Res Paediatr 2011;75:258)
Aggressive approach with surgical excision is uncommon; it is recommended that the presence of a normal mediastinal thymus be confirmed before such surgery to avoid potential immunodeficiency (Journal of Pediatric Surgery 2013;1:386)

Clinical images

Images hosted on other servers:

Ectopic thymic tissue

Sonographic images

Intrathyroidal ectopic thymic tissue

Longitudinal US images

Hyperechoic nodule

CT scan

RAI scan

Gross description

Whitish yellow, well demarcated solid nodule, < 1 cm
May be confused with normal parathyroid gland, if located superficially
Rarely cystic (Endocr Pathol 2015;26:45)

Gross images

AFIP images

Intrathyroidal thymus gland

Images hosted on other servers:

Nodule < 1 cm

Microscopic (histologic) description

Mature lymphoid tissue with numerous Hassall corpuscles embedded within thyroid gland
Extent may vary from a small area of thymic tissue containing one or two Hassall bodies, to complete well differentiated glands with distinct cortex and medulla (J Anat 1976;122:77)
Marked adipose involution in adults (Neuroradiology 2013;55:1405)
Small quantities of thyroid follicular epithelial cells can be embedded in the adipose tissue of the heterotopic thymus (Korean J Pathol 2011;45:547)
Ultimobranchial body remnants or ectopic parathyroid can be found in the vicinity (J Anat 1976;122:77, Thyroid 2008;18:1125)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Hassall corpuscle

Images hosted on other servers:

Intrathyroidal thymic tissue

Degenerated Hassall corpuscle

Ectopic thymus and parathyroid

Subcapsular intrathyroidal thymus (E)

Subcapsular intrathyroid thymus, rats

Ectopic intrathyroidal thymoma

Cytology description

Abundant small and medium sized lymphocytes with a mature chromatin pattern, Hassall corpuscles (Thyroid 2009;19:403, J Clin Ultrasound 2012;40:266)
Relative admixture of epithelial cells and colloid present depends on precise targeting of the nodule (J Pediatr Surg 1997;32:1241, Arch Pathol Lab Med 2001;125:842)

Cytology images

Images hosted on other servers:

Hassall corpuscle (D)

CK+ epithelial cells

Lymphocytes

Positive stains

TdT in thymic lymphocytes
CK5 / CK6 in thymic epithelial cells (J Ultrasound Med 2015;34:1651)

Negative stains

Thyroglobulin, calcitonin

Flow cytometry description

Uniformly maturing T cells (Thyroid 2009;19:403):
- CD4 / CD8 coexpression with trailing expression of either CD4 or CD8
- CD5+ T cells
No clonal B cells

Differential diagnosis

Histology: Hashimoto thyroiditis
Cytology
- Ectopic and hamartomatous thymoma, spindle epithelial tumor with thymus-like differentiation, carcinoma showing thymus-like differentiation: atypical cells (Hum Pathol 1991;22:349)
- Hashimoto thyroiditis: degenerated follicular epithelial cells, metaplastic epithelial cells, plasma cells or lymphoplasmacytic cells (Thyroid 2009;19:403)
- Lymphoma: atypical morphology of lymphoid cells, lymphoblasts

Thyroblastoma (pending)

[Pending]

Thyroglossal duct carcinoma

Table of Contents

Definition / general

Rare malignancy arising from thyroid follicular cells of TGD remnants, first described by Brentano in 1911 (Dtsch Med Wochenschr 1911;37:665)
TGD is the most common site for malignancy in ectopic thyroid tissue
The main type is papillary thyroid carcinoma; medullary carcinoma has not been reported, because C cells are absent in TGD

Terminology

Very recently, a new term of upper neck papillary thyroid carcinoma has been proposed to combine TGD cyst cancer, pyramidal lobe cancer and Delphian (prelaryngeal) lymph node metastasis, which are often difficult to distinguish (Laryngoscope 2016;126:1709)

Epidemiology

Carcinoma found in < 1% of TGD cysts (up to 5% - 7% in large referral centers), however the risk of this developing over time is probably underestimated due to the routine removal of TGD cysts in childhood (Semin Pediatr Surg 2006;15:70)
F:M = 2:1, mean age 40 years (range 6 to 84 years)
Pediatric cases are uncommon (< 15% of all TGD cancers), with mean age 12 years (Thyroid 2004;14:777)
Histopathology (J Clin Endocrinol Metab 2011;96:2684):
- 90% papillary thyroid carcinoma, mainly classic variant, however follicular and tall cell variants are also reported (< 10%)
- 5% squamous cell carcinoma, derived from the actual cyst lining
- 2% - 3% follicular carcinoma
- Rare cancers (anaplastic, mucoepidermoid, adenosquamous) and combinations
250+ cases have been reported (Laryngoscope 2016;126:1709)

Pathophysiology / etiology

Two opposing concepts of TGD carcinoma origin are metastatic and de novo (J Clin Endocrinol Metab 2011;96:2684)
Metastatic: TGD cancer represents a metastasis from an occult primary thyroid carcinoma:
- Coincident orthotopic thyroid gland cancer, mainly papillary microcarcinoma, occurs in 30% - 60% of TGD cyst patients when thyroidectomy is performed (J Clin Endocrinol Metab 2013;98:458)
- Benign tumors are described in TGD, which cannot be explained by metastatic theory
De novo: TGD cancer arises from TGD remnants, based on these observations:
- TGD cancer may arise from thyroid follicles (found in roughly half of TGD remnants) in the same manner as any ectopic thyroid tissue, e.g. lingual, may transform to carcinoma
- TGD carcinoma has peculiar features (age, pattern of nodal involvement) not typical for primary thyroid carcinoma
- Coexisting thyroid carcinoma in TGD and orthotopic may have discordant histotypes (Virchows Arch 2014;465:67)
- High rate of coincident carcinoma in orthotopic thyroid is consistent with the incidence of occult thyroid carcinoma found in autopsy studies of undiagnosed patients
- Another component of TGD, particularly epithelial lining, does transform to squamous cell carcinoma
- C cells are absent in TGD and so far no medullary carcinoma in TGD has been described

Clinical features

Most TGD carcinomas are asymptomatic and are discovered by the pathologist on routine histologic evaluation
Clinically, no clear distinction between a benign cyst and malignancy can be made (Head Neck Surg 1982;5:134)
Cancer can be suspected based on:
- Sudden growth of preexisting cyst, although there is no relationship between size or duration of the cyst and malignant change
- Hard, fixed and irregular mass
- The cyst is associated with enlarged cervical lymph nodes
- There is a history of neck irradiation
Metastatic disease:
- Contrary to early reports, nodal involvement was found to be high; in series with neck dissections can approach 70% (Endocr J 2013;60:665)
- Some studies found preferred lateral involvement without central compartment involvement (J Clin Endocrinol Metab 2013;98:458)
- Distant metastases are extremely rare (Auris Nasus Larynx 2008;35:11)
Coexisting occult carcinoma in normal thyroid gland found in 30% - 60% of TGD cyst cases with thyroidectomy (J Clin Endocrinol Metab 2013;98:458, Endocr Pathol 2015;26:75)

Diagnosis

Preoperative diagnosis of carcinoma in a patient presenting with TGD cyst is unusual
Routine workup is similar to that for TGD cyst, essentially neck ultrasound, which can be complemented by CT, MRI and FNAC
Criteria for diagnosis includes histopathological confirmation of thyroglossal remnants in a specimen with carcinoma, and normal thyroid gland (to exclude a metastasis from a primary lesion in the gland)
Fine needle aspirate of the cyst may be helpful in confirming the clinical suspicion (most efficient in adults), however FNA cytology has relatively low sensitivity, and intraoperative frozen sections are advocated as a more robust diagnostic modality (Endocrine 2014;46:160)

Radiology description

US findings suspicious for cancer: calcification, complex cysts with internal echoes and solid vascularized vegetation (Endocrine 2014;46:160)
CT findings suggestive of malignancy include the presence of a solid component, dense or enhancing mural nodules, calcification, an irregular margin or a thickened cyst wall (AJNR Am J Neuroradiol 2000;21:1547)

Radiology images

Images hosted on other servers:

Neck ultrasound

Multicystic lesion

Calcification

Infrahyoid lesion

Low density

Axial and transverse

Cystic swelling

Thick septae

Solid component

Prognostic factors

Excellent prognosis, similar to that of the usual papillary carcinoma of thyroid gland
Histotype is one of the prognostic factors, with squamous cell carcinoma being the most aggressive tumor

Case reports

Papillary carcinoma
- 20 year old woman with papillary carcinoma arising in TGD cyst (Acta Otorhinolaryngol Ital 2014;34:215)
- 25 year old woman with papillary carcinoma arising from TGD cyst (Indian J Radiol Imaging 2009;19:120)
- 27 year old man with papillary carcinoma arising in a submental-intralingual TGD cyst (Acta Otorhinolaryngol Ital 2010;30:313)
- 28 year old woman with metastatic TGD cyst papillary carcinoma (Int J Surg Case Rep 2013;4:704)
- 31 year old man with TGD cyst papillary carcinoma (Case Rep Oncol 2011;4:39)
- 35 year old woman with bilateral cervical lymph node metastasis of TGD cancer (Auris Nasus Larynx 2003;30:107)
- 39 year old woman with simultaneous papillary carcinoma in a TGD cyst and the thyroid gland (Case Rep Otolaryngol 2015;2015:382760)
- 44 year old woman with invasive TGD cyst papillary carcinoma (J Med Case Rep 2009;3:9308)
- 64 year old man with papillary carcinoma in TGD cyst (Arch Med Sci 2014;10:1061)
- 77 year old woman with tall cell carcinoma arising in a TGD cyst (Ann Med Surg (Lond) 2015;4:129)
Other cancers
- 38 year old man with concurrent papillary and squamous carcinoma in a TGD cyst (Can J Surg 1996;39:328)
- 48 year old man with papillary and squamous carcinoma in TGD cyst (World J Surg Oncol 2003;1:15)
- 61 year old woman with adenosquamous carcinoma arising in a TGD cyst (Surg Today 2011;41:533)
- 62 year old woman with Hurthle cell carcinoma in TGD cyst (Otolaryngol Head Neck Surg 1995;113:153)
- 68 year old woman with anaplastic carcinoma arising in a TGD tract (Otolaryngol Head Neck Surg 1993;109:945)
- 73 year old woman with mucoepidermoid carcinoma in a TGD remnant (Int J Surg Case Rep 2015;13:43)
- 78 year old woman with coexistence of a carotid body tumor and metastatic TGD carcinoma (Clin Exp Otorhinolaryngol 2014;7:69)
- 84 year old woman with anaplastic carcinoma arising from TGD remnant (Cancer 1981;48:2724)

Treatment

Most TGD carcinomas are managed initially by the Sistrunk procedure
Further steps may include:
- Total thyroidectomy
- Neck dissection
- Radioiodine ablation
Currently, there are no specific guidelines on optimal management of TGD cyst cancer, and controversy mostly centers on the role of thyroidectomy (J Clin Endocrinol Metab 2013;98:458, Laryngoscope 2016;126:1709)
Squamous cell carcinoma of TGD seems to be more aggressive than papillary cancer and may warrant more extensive surgery and even postoperative irradiation

Clinical images

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Neck mass

Intraoperative

Gross description

Small mural nodule 1.5 - 2 cm, rarely completely filling the cyst (J Clin Endocrinol Metab 2013;98:458, Laryngoscope 2016;126:1709)

Gross images

Images hosted on other servers:

Thyroidectomy

Total resection

Thyroglossal duct

Thyroglossal cyst

Modified neck dissection

Sistrunk procedure

PTC in TGD cyst

Microscopic (histologic) description

Typical thyroid carcinoma (nuclear features and microarchitecture compartible with specific histotype) in the context of a TGD cyst with epithelial lining
Invasion of the hyoid bone and adjacent soft tissue is common

Microscopic (histologic) images

Scroll to see all images:

Contributed by Andrey Bychkov, M.D., Ph.D.

Cystic papillary carcinoma

Papillary structures

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Papillary carcinoma

TGDC wall

Papillary pattern

Overcrowding nuclei

Columnar epithelium

Cystic neoplasm

Squamous epithelium

Papillary appearance

Irregular nucleus

Microcalcifications

Papillary carcinoma

Normal cyst wall lining

PTC tall cell variant

Squamous cell carcinoma

Mucoepidermoid tumor

TTF1, thyroglobulin

Thyroglobulin

CK19

Cytology description

FNA findings range from a nonspecific cystic lesion to features characteristic of papillary or squamous cell carcinoma (Am J Clin Pathol 1996;106:615)
To increase FNA yield:
- Ultrasound guided biopsy of the solid portion of cystic mass
- Liquid based cytology (LBC) of evacuated cystic fluid (Virchows Arch 2014;465:67)
- Sampling of residual mass after fluid evacuation

Cytology images

Images hosted on other servers:

Papillary carcinoma in TGD cyst aspirate

Positive stains

CK19 and other markers of thyroid carcinoma immunophenotype (Arch Med Sci 2014;10:1061)

Molecular / cytogenetics description

BRAF V600E mutation with a rate comparable to orthotopic papillary thyroid carcinoma (Virchows Arch 2014;465:67)

Differential diagnosis

Distinguishing TGD associated carcinoma from either primary pyramidal thyroid lobe cancer or Delphian node metastasis is critically important for staging and treatment (Endocr Pathol 2015;26:75, Laryngoscope 2016;126:1709)
- Primary cancer of the pyramidal lobe:
  - Papillary carcinoma surrounded by a background of benign thyroid parenchyma
  - Absence of TGD epithelium (respiratory / squamous) and lymph node structures
- Nodal metastasis:
  - Lymph node architecture, including lymphoid stroma and subcapsular sinus
  - Lack of TGD epithelium (respiratory / squamous) and thyroid parenchyma
  - Occult / evident cancer in thyroidectomy specimen

Thyroglossal duct cyst

Table of Contents

Definition / general

The most common developmental anomaly of thyroid gland, and the most common congenital neck mass
Midline neck developmental anomaly due to persistence and cystic dilation of thyroglossal duct
Thyroglossal duct (TGD) is the embryonic tract characterized by the presence of epithelial lined remnants and heterotopic thyroid tissue
May appear as blind tubular structure in mid neck or as sinus tract connected to foramen cecum or suprasternal notch skin

Terminology

Synonyms: TGD anomaly, TGD remnant, thyroglossal or thyreoglossal, thyroglossal duct or thyroglossal tract
Sinus is a blind ending tract lined by granulation tissue leading deep inside from natural / normal epithelial surface, e.g. from cervical skin or foramen cecum to TGD cyst (the latter, even being epithelialized, is not considered as a normal postnatal structure)
Fistula is a communication between two normal epithelialized surfaces, e.g. between skin and oropharynx via TGD tract / cyst, which is extremely rare (Laryngoscope 2009;119:2345)
TGD fistula is often used erroneously to represent the discharging sinus

Epidemiology

TGD cyst is the most common congenital anomaly of the neck in childhood, and the most common developmental neck cyst, accounting for 60% - 70% of all cases (Head Neck Surg 1982;5:134, Auris Nasus Larynx 2008;35:11)
Mean age 30 - 40 years old, with 65% of cases being diagnosed before 30 years of age, and up to 25% in 50+ year old patients (Am J Surg 1988;155:741)
Ratio of nondraining cyst to sinus or fistula is 4:1
- Discharging sinuses manifest at younger age (Eur Arch Otorhinolaryngol 2015;272:2513)
M:F = 1:1 (Head Neck Surg 1982;5:134)
Serial sections on autopsy identified TGD remnants in 7% of both adult and pediatric cohorts (Laryngoscope 1977;87:765, Ann Otol Rhinol Laryngol 2000;109:1135)
Scintigraphy after TSH stimulation found TGD remnants in > 40% of thyroidectomized patients (Clin Radiol 2015;70:638)
Out of several thousand TGD cysts described in series and case reports, only 20+ familial cases were published (Pediatr Surg Int 2005;21:593, OMIM - 188455)

Sites

Appears in midline neck anywhere along path of TGD, from foramen cecum in tongue base to suprasternal region
Most TGD cysts are connected to hyoid bone, which is excised during TGD excision (Sistrunk procedure)
Prevalence (J Pediatr Surg 1984;19:555, Int J Pediatr Otorhinolaryngol 2003;67:1285):
- 75% thyrohyoid (between hyoid bone and thyroid cartilage)
- 25% suprahyoid, including submental
- 2% - 4% intralingual (base of tongue)
- Rare sites: suprasternal, intrathyroid, mediastinal
TDG cysts may present lateral to midline in 1 - 2% but never lateral to large neck vessels
Mainly deviate to the left, because levator glandulae thyroideae is ordinarily found to the left (Surg Clin North Am 1953:633)
Often in the region of thyroid cartilage which moves superficial cyst from the median
Can be dislocated due to inflammation / fibrosis or previous surgery (Int J Pediatr Otorhinolaryngol 2003;67:1285)

Diagrams / tables

Images hosted on other servers:

Thyroglossal tract

Thyroglossal duct cyst

Management algorithm

Sistrunk procedure

Pathophysiology / etiology

During embryonic development, thyroid gland remains connected to the foramen cecum (floor of primordial pharynx) and hyoid bone by TGD; the duct gradually disappears by the 10th week of development
If involution fails, TGD remnants may persist anywhere along the pathway of thyroid descent
The only normal remnant of the duct is the pyramidal lobe of the thyroid gland, which is seen in about 40% of the population (Thyroid 2013;23:84)
Cystic dilation is a result of secretion from the lining epithelial cells
Inflammation of lymphoid tissue adjacent to the TGD (repeated respiratory infections) may stimulate the epithelial remnants of thyroglossal tract to undergo cystic changes (BJS 1925;12:561)
Sinus is formed secondary to trauma, inadequate surgery drainage or spontaneous rupture of infected TGD cyst, e.g. due to microbial contamination from oral cavity via foramen cecum

Clinical features

Most patients are asymptomatic, with a slowly enlarging painless cystic mass in the midline anterior neck (perihyoid), 2 - 4 cm in size (Auris Nasus Larynx 2008;35:11)
On physical examination, the cyst can be soft or firm and move upward on swallowing or protrusion of tongue
Infected TGD cyst occurs in 30% of patients, who present with pain, local inflammation, sometimes with draining sinus or fistula (Semin Pediatr Surg 2006;15:70)
After radiation therapy for unrelated head and neck cancer, TGD may enlarge and undergo cystic transformation (AJNR Am J Neuroradiol 2009;30:800)
Lingual TGD cyst may cause dysphagia, choking and cough; in neonates, may cause feeding problems, respiratory compromise and even sudden death
Rarely (< 1%), TGD may give rise to tumors, usually papillary thyroid carcinoma, but also benign follicular adenomas, including Hurthle cell adenoma

Diagnosis

Based on typical clinical manifestations supported by radiological findings and confirmed by postoperative histopathology
Ultrasound is the preoperative investigation of choice (Radiographics 2014;34:37):
- Echogenic characteristics of TGD cyst are cyst location, relation to the hyoid bone and echotexture of thyroid gland
CT and MRI play a supplementary role to more accurately delineate anatomy of large cysts, and MRI may be utilized to define a residual fistulous tract in recurrent disease (Auris Nasus Larynx 2008;35:11)

Radiology description

Ultrasound (Korean J Radiol 2015;16:419, Clin Radiol 2005;60:141):
- Midline (just under the hyoid bone) well circumscribed anechoic cystic lesion in simple TGD cyst
- Pseudosolid appearance, when the cyst contains a proteinaceous fluid, cholesterol crystals and keratin
- Heterogeneous pattern with internal echoes in cases of previous infection or hemorrhage
- Most pediatric TGD cysts have a pseudosolid appearance
- True solid component suggests risk of TGD malignancy
CT with contrast shows a well delineated cystic lesion with capsular enhancement (especially in infected cysts), and its relation to hyoid bone (Indian J Surg 2011;73:28)
MRI demonstrates low signal intensity with T1 weighted sequences and high signal intensity with T2 weighted sequences which do not restrict diffusion; expansion and destruction of the cartilaginous structure of the hyoid (Radiographics 2014;34:37)
Scintigraphy potentially can detect functioning thyroid tissue in TGD (Thyroid 2007;17:341)

Radiology images

Contributed by Ayana Suzuki, C.T.

Large cyst

Images hosted on other servers:

Neck ultrasound

Neck CT

Scintigraphy

Prognostic factors

Excellent prognosis after complete excision, even if carcinoma is present
Recurrence rate after Sistrunk procedure is less than 5%; however, if the central hyoid bone is not removed, TGD cyst may recur in 25% cases (Surg Gynecol Obstet 1949;89:727)
Risk factors for complications and recurrence are young age (< 10 y.o.), lobulated, infected or ruptured cyst, skin involvement and failure to excise the midportion of the hyoid bone and the suprahyoid tract (Am J Surg 1986;152:602)

Case reports

Various locations
- Newborn with TGD cyst on the tongue base (Case Rep Obstet Gynecol 2016;2016:781630)
- Infant with lingual TGD cyst (Respir Care 2014;59:e98)
- 10 year old girl with intrahyoid TGD cyst (Indian J Otolaryngol Head Neck Surg 2007;59:366)
- 28 year old man with migratory TGD cyst (Indian J Radiol Imaging 2010;20:115)
- 31 year old man with intralaryngeal TGD cyst (Pan Afr Med J 2015;22:294)
- 40 year old woman with TGD cyst within the mediastinum (J Thorac Cardiovasc Surg 2007;133:1671)
- 45 year old woman with intrathyroid TGD cyst (Int J Clin Exp Pathol 2015;8:7229)
Complications
- Infant died of fatal asphyxia by a TGD cyst (Am J Forensic Med Pathol. 2008;29:251)
- 6 year old girl with hypothyroidism after excision of TGD cyst (J Pediatr 2013;162:427)
- 14 year old girl with infected TGD cyst (Case Rep Dent 2011;2011:978263)
- 18 year old man with follicular adenoma in TGD (Braz J Otorhinolaryngol 2007;73:430)
- 18 year old woman with Hurthle cell adenoma arising in a TGD cyst (Head Neck 1993;15:348)
- 23 year old woman with infected TGD cyst (West J Emerg Med 2009;10:205)
- 28 year old man with follicular adenoma in TGD cyst and papillary carcinoma in the thyroid (Am J Otolaryngol 2005;26:348)
- 40 year old man with ruptured TGD cyst leading to xanthogranulomatous inflammation (Head Neck Pathol 2015;9:530)
- 46 year old woman with extravasation mucocele arising from a lingual TGD remnant (Case Rep Otolaryngol 2015;2015:326251)
- 55 year old man died of fatal asphyxia by a TGD cyst (J Clin Forensic Med 2006;13:349)
- 65 year old man with giant TGD cyst (Indian J Otolaryngol Head Neck Surg 2011;63:27)
Unusual combinations
- 7 year old boy with double cyst originated from a single TGD (J Pediatr Surg 2008;43:748)
- 15 year old girl with cartilage within a TGD anomaly (Int J Pediatr Otorhinolaryngol 1988;15:205)
- 18 year old woman with epidermal, TGD and lymphoepithelial neck cysts (J Oral Maxillofac Pathol 2013;17:479)
- 20 year old man with ectopic thyroid in the floor of the mouth and functioning TGD cyst without orthotopic thyroid gland (Singapore Med J 2013;54:e149)
- 35 year old woman with metachronous TGD cyst and inferior parathyroid cyst (Kaohsiung J Med Sci 2008;24:487)
- 52 year old woman with ectopic thyroid nodule in TGD (Korean J Intern Med 2011;26:218)
- 85 year old woman with large TGD cyst and lingual hemangioma (BMJ Case Rep 2011;2011)

Treatment

Surgery is routinely recommended for all patients with TGD cysts
The treatment of TGD remnants, whether cyst or sinus / fistula, is a complete surgical excision using the Sistrunk procedure
- This consists of a block excision of the entire TGD to the foramen cecum, and removal of the middle third of the hyoid bone (Operative Techniques in Otolaryngology 2004;15:220)
Incision / draining or sclerotherapy is strictly discouraged

Clinical images

Contributed by Ayana Suzuki, C.T.

Flocculated appearance

Images hosted on other servers:

Neck mass

TGD cyst in children

Intra-operative

Gross description

The thyroglossal duct is a continuous tract from the base of tongue, but occasionally is multiple and aborizing, with a dominant cyst and smaller cysts that are identified microscopically (J Pediatr Surg 1984;19:506, J Pediatr Surg 1991;26:766)
Cysts are unilocular or multilocular with rounded, smooth external surfaces
Cyst has a mean diameter of 2 cm, range 0.2 - 7 cm (J Am Coll Surg 2002;194:274, Endocr Pathol 2015;26:75), giant cysts >10 cm are also described (Ann Surg 1954;139:123)
Cystic content includes clear mucinous or viscous fluid / gel having a broad range of color (clear, yellowish tan, reddish brown and grayish white) and degree of opacity; infected cysts contain purulent exudate

TGD is often firmly embedded in the surrounding strap muscles and soft tissues of the neck without a plane of cleavage around it

Sinus tract or fistula may have openings to pharynx or skin

Thyroid tissue is usually not grossly evident, but if present appears as a reddish tan or reddish brown focus (Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid, 2nd Edition, 2012)

The hyoid bone is part of the surgical specimen (since TGD is always attached to the hyoid) and should be examined for microscopic remnants of the cyst within the bone or immediately adjacent to it (Int J Pediatr Otorhinolaryngol 1998;44:47)

Gross images

AFIP images

TGD cyst

Images hosted on other servers:

In situ

Microscopic (histologic) description

Type of epithelial lining varies by site, and combinations of the types below can be seen in a single cyst (Head Neck Pathol 2013;7:50):
- Ciliated pseudostratified columnar (respiratory) epithelium in lower neck, perhaps due to its close proximity to upper respiratory tract
- Nonkeratinizing squamous epithelium in higher neck (near tongue and foramen cecum), also can be of metaplastic origin in inflammatory settings
- Stratified cuboidal epithelium at level of hyoid bone
- Very often the cyst is denuded of epithelium, at least focally, which reflects epithelial damage by inflammation
Secondary inflammation is common, especially in sinus tract (J Pediatr Surg 1984;19:506):
- Intense lymphocytic infiltration, rarely arranged into lymphoid follicles
- Admixture of neutrophils (if the cyst is infected)
- Granulation tissue and fibrosis
Thyroid follicles in the cyst / duct wall:
- Found in 30% - 60%, with higher yield on serial sections
- More common in infra- versus suprahyoid remnants, on the right paramedian side (Ann Otol Rhinol Laryngol 2000;109:1135)
- Seen in small irregular groups
- Thyroid epithelium may be normal or rarely hyperplastic or neoplastic
- Thyroid tissue often hidden by inflammation (Laryngoscope 2001;111:1002)
- Absence of thyroid tissue does not exclude the diagnosis of TGD cyst
Mucous salivary-type glands can be found in the cyst wall, frequently in lingual and suprahyoid locations (Ann Otol Rhinol Laryngol 1996;105:996)
Occasional inclusions:
- Skin adnexal structures (J Laryngol Otol 2004;118:996)
- Gastric mucosa (Gnepp: Diagnostic Surgical Pathology of the Head and Neck, 2nd Edition, 2009)
- Cartilage (Int J Pediatr Otorhinolaryngol 1988;15:205)
- Bone (J Laryngol Otol 1994;108:168)
- Cholesterol granuloma (Eur Arch Otorhinolaryngol 2009;266:1775)
One study found that specimens clinically diagnosed as TGD cyst were classified based on histology as true cysts (50%), ducts without evidence of cysts (40%) and fibrous tracts (10%) (J Laryngol Otol 2000;114:128)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D., Mark R. Wick, M.D. and AFIP

Perihyoid cystic and arborized tubular structure

Perihyoid cystic structures

Thyroglossal duct penetrates hyoid bone

Denuded TGD, perihoid location

Variable epithelial lining

Ciliated versus squamous epithelium

Thyroid follicles under ciliated epithelium

Thyroid follicles of various size

Thyroid follicles embedded within skeletal muscles

Seromucous glands

Rupture of the cyst wall

Cyst rupture

Thyroglobulin expression by thyroid follicles

Strong TTF1 expression

Thyroglossal duct cyst

Epithelium

Papillary changes

Images hosted on other servers:

Squamous epithelium

Pseudostratified

Cuboidal epithelium

Squamous stratified epithelium

Cyst wall

Epithelial lining

Respiratory epithelium

Thyroid follicles

Thyroglossal tract cyst

Cyst wall

With mucocele

Cytology description

Preoperative FNA is moderately sensitive but with many false negatives (Diagn Cytopathol 2005;33:365)
FNA smears are of low cellularity, with predominant inflammatory cells outnumbering epithelial cells, similar to branchial cleft cyst:
- Macrophages, either foamy or hemosiderin laden
- Mature lymphocytes and neutrophils (predominantly if the cyst is infected)
- Squamous or ciliated columnar epithelium
Colloid is common, ranging from thick and fragmented to thin and watery
Admixture of cholesterol crystals
Thyroid tissue found in < 10% of aspirates, likely due to deep embedding in the cyst wall

Cytology images

Contributed by Andrey Bychkov, M.D., Ph.D., Ayana Suzuki, C.T., Ram Kumar Kurpad R, M.B.B.S., M.D. and Y. C. Spoorthy Rekha, M.B.B.S., M.D.

Sparsely cellular aspirate

Benign squamous cell

Histiocytes and squame

Ciliated epithelium and macrophages

Ciliated epithelium

Foamy macrophages

Images hosted on other servers:

Squames

Neutrophils and macrophages

Epithelial sheet

Negative stains

Thyroglobulin negative epithelial lining, either respiratory or squamous (Virchows Arch 2005;447:9)
Calcitonin, since C cells are absent in median anlage derivatives (Mills: Histology for Pathologists, 4th Edition, 2012)

Videos

Sistrunks Procedure for Thyroglossal Duct Cyst

Differential diagnosis

Cystic lesions
- Dermoid cyst: filled with sebaceous material, lined by keratinizing epithelium, and having skin appendages in the wall, none of these is observed in TGD (J Pediatr Surg 1984;19:506), in addition, rarely inflamed; aspirate enriched with anucleated squames
- Epidermoid cyst / epidermal inclusion cyst: similar to dermoid cyst, but without skin adnexa
- Branchial cleft cyst: lateral location, lymphoid follicles in the wall; aspirate is more cellular with abundant squamous epithelium
- Lymph node metastasis of papillary thyroid carcinoma with cystic degeneration
- Rare developmental cysts: lymphangioma, lymphoepithelial cyst, thymic cyst (suprasternal), bronchogenic cyst, midline cervical cleft, teratoma
- Rare nondevelopmental cysts: ranula (upper neck), laryngocele, cystic degeneration of a colloid nodule
Solid lesions
- Lingual thyroid: resolved by clinical and radiological modalities, orthotopic thyroid is often absent
- Pyramidal lobe of thyroid gland
- Lymph node with reactive hyperplasia
- Lipoma
- Squamous cell carcinoma: atypical cells
- Rare intrathyroidal TGD cysts can be confused with primary thyroid carcinoma
Histopathological diagnosis of TGD requires optimally evidence of respiratory / squamous epithelial lining and thyroid follicles, which sometimes can be difficult to find due to inflammation and fibrosis; in these situations, a diagnosis of developmental cyst with comment (favor TGD cyst or branchial cleft cyst, etc.) may be an option

Additional references

Barnes: Surgical Pathology of the Head and Neck, 3rd Edition, 2008, Radiopaedia - Thyroglossal duct cyst, eMedicine - Thyroglossal Duct Cyst Imaging, PatientInfo - Thyroglossal Cysts

Thyroid cancer-general

Table of Contents

Definition / general

1% of all cancer in U.S., 0.2% of all cancer deaths
Estimated 56,000 new cases and 1800 deaths in U.S. in 2012 (SEER)
Increasing incidence due to new diagnostic practices which detect smaller tumors (Cancer Causes Control 2008;19:585, BMC Cancer 2006;6:284, BMC Cancer 2006 Apr 24;6:102), although increase may be abating (Eur J Endocrinol 2009;160:71)

Epidemiology

Often estrogen receptor positive, which may explain female predominance of tumors in reproductive years (for other ages, incidence in males and females is similar, Mod Pathol 2003;16:437, Arch Pathol Lab Med 1991;115:1203)
More common in U.S. whites than blacks, for unknown reasons (Ann Surg Oncol 2008;15:1169)
Increased risk for children exposed to ionizing radiation (Cancer Causes Control 2009;20:75), particularly under age 1 year (Best Pract Res Clin Endocrinol Metab 2008;22:1061), women atomic bomb survivors in Japan (Epidemiology 2009;20:181)

Prognostic factors

20 year survival is 90%, because most are indolent papillary carcinomas
Good prognostic factors:
- Men under age 40 years or women under age 50 / 60
- Favorable histologic types
Poor prognostic factors:
- Men age 41+ or women 51+
- Large tumor size, nuclear pleomorphism, tumor necrosis, vascular invasion, increased mitotic activity, higher stage, unfavorable subtypes (Am J Surg Pathol 2002;26:1007)
Death usually from undifferentiated, poorly differentiated, Hürthle cell or medullary carcinoma, due to distant metastases
Poor survival in those with bone metastases (5 year: 29%, 10 year: 13%, Arch Pathol Lab Med 2000;124:1440)

Treatment

See also subtypes - either lobectomy, subtotal thyroidectomy or total thyroidectomy; also postoperative radioiodine therapy, TSH suppressive therapy, new molecular therapies (Ther Clin Risk Manag 2008;4:935)
Can assess for recurrence with serum thyroglobulin levels (different assays show good agreement between themselves, Clin Biochem 2009;42:416), calcitonin (medullary carcinoma)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Diffuse positive staining for CK19, Galectin3 and HBME1

Positive stains

Thyroglobulin (even if tumor is necrotic, Hum Pathol 1999;30:1373), TTF1

Negative stains

P504S (Hum Pathol 2003;34:792)

Molecular / cytogenetics description

Rearrangements of RET-PTC in 40% of papillary carcinomas, rearrangements of PAX8-PPARy in 40% of follicular carcinomas, BRAF mutations in 40 - 60% of papillary carcinomas (Arch Pathol Lab Med 2008;132:164)

Videos

Thyroid carcinoma

Advanced thyroid carcinoma

Differential diagnosis

Post iodine 131 treatment for hyperthyroidism: see Radiation thyroiditis

Additional references

National Cancer Institute (U.S.), eMedicine

Thyroid follicular nodular disease (multinodular goiter)

Table of Contents

Definition / general

Most common disease of thyroid gland
Diffuse or nodular enlargement with distorted outer surface
Grossly visible mass / nodule in 10% of thyroid glands at autopsy but microscopic nodularity is present in 40%
3 - 5% risk of thyroid cancer, predominantly follicular variant of papillary thyroid carcinoma or up to 17.5% with papillary microcarcinoma (S Afr J Surg 2014;52:5, Int J Surg Open 2018;15:18)

Essential features

Majority asymptomatic and euthyroid
Asymmetric diffuse or nodular enlargement of thyroid gland with distorted outer surface
Iodine deficiency is most common cause worldwide; however, in the U.S., most goiters are due to autoimmune thyroiditis (i.e. Hashimoto disease) (Endotext: Multinodular Goiter [Accessed 23 December 2020])
Histologically, multiple variably sized dilated follicles lined by flattened to hyperplastic epithelium, with or without degenerative changes

Terminology

Goiter is clinical term meaning enlarged thyroid, which can be either diffuse or nodular (e.g. multinodular or solitary / dominant nodule)
Appropriate morphological term is nodular / multinodular hyperplasia
- Synonyms: adenomatous / adenomatoid hyperplasia / nodule, colloid goiter, simple goiter, colloid / hyperplastic nodule
Simple goiter: also called diffuse nontoxic goiter or colloid goiter
- Thyroid gland usually 40 g or more
- Eventually converts into multinodular goiter
Multinodular goiter: irregular enlargement of thyroid gland due to repeated episodes of hyperplasia and involution (degeneration) of simple goiter
- Thyroid gland often 100 g or more; may resemble a neoplasm, particularly if a single firm dominant nodule is present
- Nodules are clonal or polyclonal and are due to heterogeneous responses of follicular epithelium to TSH
Nontoxic goiter: no hyperthyroidism present

ICD coding

ICD-10: E04.2 - nontoxic multinodular goiter

Epidemiology

90% of those affected are women (F > > > M)
Variable age; develops more frequently during adolescence and pregnancy

Sites

Involves entire thyroid gland

Etiology

Increase in TSH secretion is the main cause in iodine deficiency related goiter and in autoimmune (Hashimoto) thyroiditis; in persons with normal TSH, oxidative damage to follicular cells and then damage to DNA leads to hyperplasia
In individuals with normal TSH, thyroid enlargement is caused by multiple growth factors, including TSH
Genetic factors:
- DICER1 syndrome: germline mutations in DICER1 gene in familial and childhood multinodular goiter (J Clin Endocrinol Metab 2016;101:1, Head Neck 2013;35:E369); patients also at increased risk of Sertoli-Leydig cell tumor, cystic nephroma and pleuropulmonary blastoma
- PTEN hamartoma tumor syndrome: autosomal dominant disorder with germline mutation of PTEN tumor suppressor gene manifesting as multiple carcinomas and hamartomas in variety of organs, including thyroid, presenting with multinodular goiter (J Clin Endocrinol Metab 2011;96:34, Thyroid 2011;21:135)
  - Promoter hypermethylation of tumor suppressor gene RASSF1A: (Ras association domain family 1 isoform A) is a tumor suppressor gene whose inactivation is implicated in the development of many human cancers
  - Promoter hypermethylation leads to loss of function of RASSF1A
  - Other ways it can get inactivated is by gene deletion or point mutations (JAMA Surg 2014;149:1146)
Some nodules eventually become autonomous due to activating mutations in the TSH receptor or G proteins within the thyroid follicular cells
Drug induced goiter: sulfonamides and phenylbutazone inhibit organification of iodine
- Iodine containing drugs such as amiodarone interfere with thyroglobulin proteolysis
- Iodine or lithium interfere with thyroglobulin breakdown and release of T3 / T4
Goitrogens: cassava, cabbage, cauliflower, Brussels sprouts and turnips interfere with T3 / T4 synthesis
- Cassava contains a thiocyanate which inhibits iodide transport within the thyroid
Hereditary: see dyshormonogenetic goiter
Plummer syndrome: hyperfunctioning thyroid nodule within a goiter, without ophthalmopathy or dermopathy of Graves disease
Plummer-Vinson (Paterson-Kelly) syndrome: iron deficiency anemia, glossitis, esophageal dysphasia related to webs, may have thyroid enlargement (Orphanet J Rare Dis 2006;1:36)

Clinical features

Thyroid enlargement (goiter); neck mass
Majority asymptomatic and euthyroid
Hypothyroidism due to decreased production of T3 and T4 hormones
Hyperthyroidism due to autonomous transformation
Pressure symptoms due to compression of trachea and esophagus (uncommon since enlargement is mainly towards strap muscle and subcutaneous tissue); compression of recurrent laryngeal nerve with hoarseness, phrenic nerve paralysis and Horner syndrome
Subacute obstructive symptoms with or without pain due to secondary hemorrhage into a nodule
Exertional dyspnea when tracheal diameter is less than 8 mm with stridor or wheezing when the diameter is less than 5 mm
References: Otolaryngol Clin North Am. 2003;36:35, BMC Emerg Med 2019;19:18, J Endocrinol Invest 2016;39:357

Diagnosis

Clinical examination
Thyroid function tests: TSH, T3, T4
Thyroid peroxidase antibodies
Thyroid ultrasound
CT or MRI to evaluate extent of goiter
Fine needle aspiration is indicated if:
- History of rapid growth
- Pain or tenderness
- Unusually firm areas in the nodule
- Suspicious sonographic features

Laboratory

Usually normal T3 / T4, TSH, normal radioactive iodine uptake, thyroglobulin may be elevated

Radiology description

Upper limits of normal for thyroid gland volume:
- Adult men: 25 mL
- Adult women: 18 mL
- 13 - 14 years: 8 - 10 mL
- 3 - 4 years: 3 mL
- Neonate: 0.8 - 1.5 mL
Ultrasound:
- Wide variety of appearances which include:
  - Enlarged iso / hyperechoic gland with surrounding hypoechoic halo
  - Sponge-like / honeycomb pattern
  - Anechoic areas may contain colloid
  - Internal calcification
Nuclear medicine:
- ^99mTc pertechnetate or radioiodine (¹²³I) demonstrate an enlarged gland, with heterogeneous uptake
References: Horm Metab Res 2004;36:645, Clin Endocrinol (Oxf) 1987;26:273

Radiology images

Contributed by Mark R. Wick M.D.

Intrathoracic (ectopic) goiter

Prognostic factors

Size
Excellent prognosis with either surgery or radioiodine therapy, depending on comorbidities

Case reports

31 year old pregnant woman with cervical goiter developing acute respiratory failure (BMC Emerg Med 2019;19:18)
48 year old woman with rapid enlargement of a preexisting goiter due to disseminating tuberculosis (Case Rep Endocrinol 2018;2018:4369531)
51 year old woman with intrathoracic goiter who needed sternotomy for excision (Asian Cardiovasc Thorac Ann 2016;24:207)
56 year old woman with airway obstruction (Tokai J Exp Clin Med 2016;41:181)
63 year old woman with hemorrhage of goiter causing acute respiratory distress (Medicine (Baltimore) 2016;95:e2777)
78 year old man with giant goiter (J Endocr Soc 2018;2:290)

Treatment

Asymptomatic, euthyroid patients with multinodular goiters (< 80 mL): monitor by annual neck exam, TSH level and thyroid ultrasound as required
For very large goiters (> 80 - 100 mL) or goiters that continue to grow: thyroidectomy
Nontoxic goiters that continue to grow in poor surgical candidates or those who prefer to avoid surgery: radioiodine therapy
References: J Endocrinol Invest 2016;39:357, World J Surg 2008;32:1301, Endokrynol Pol 2015;66:301, J Endocrinol Invest 2001;24:820

Clinical images

Images hosted on other servers:

Large goiter

Giant goiter

Gross description

Simple goiters are usually firm with amber cut surface
Multinodular goiters are asymmetric, large, 200 - 700 g (up to 2 kg)
Increased size: lobe 8 - 15 cm, dominant nodules up to 10 cm
Nodular and bumpy outer surface and variegated cut surface, cystic and hemorrhagic with brown gelatinous colloid nodules with focal calcification
Reference: Diagn Cytopathol 2007;35:579

Gross images

Contributed by Swati Satturwar, M.D. and Andrey Bychkov, M.D., Ph.D.

External surface

Cut surface

Nodular thyroid

AFIP images

Various sized nodules

Nodular hyperplasia

Numerous poorly circumscribed nodules

Nodular hyperplasia with clear cell change

Images hosted on other servers:

Colloid cyst

Colloid goiter

Nodular goiter

Retrosternal goiter

Microscopic (histologic) description

Variable sized dilated follicles with flattened to hyperplastic epithelium
Nodules may be present but without thick capsule
Nodules with variable histological patterns: from colloid and microfollicular to hypercellular / microfollicular
Secondary changes may be seen, including foci of fresh or old hemorrhage, rupture of follicles with granulomatous response, fibrosis, calcification and even osseous metaplasia
Some of the cystically dilated follicles may show papillary projections (Sanderson polsters) that may mimic papillary carcinoma; however, they lack the nuclear features of papillary carcinoma
Cytologic atypia (in the form of highly atypical nuclei) if exposed to radioactive substances
Non nodular thyroid is reduced and compressed
Incidental papillary thyroid microcarcinoma may coexist
References: Neuro Endocrinol Lett 2015;36:48, Eur Endocrinol 2020;16:131

Microscopic (histologic) images

Contributed by Swati Satturwar, M.D., Andrey Bychkov, M.D., Ph.D. and Rajeshwari K. Muthusamy, M.D.

Dilated follicles

Nodule

Degenerative changes

Reactive fibrosis

False angioinvasion

Sanderson polsters

Adipose metaplasia

AFIP images

No capsule identified

Sanderson polster

With hypercellular focus

With adipose metaplasia of stroma

Papillary area

Clear cell change

Focal squamous metaplasia

Cytology description

Sparse to moderately cellular smears with abundant thin or thick colloid, flat sheets with evenly spaced follicular cells, pigment laden macrophages and oncocytic cells
Rare microfollicles
No cytologic features of papillary thyroid carcinoma (nuclear pseudoinclusion, nuclear elongation, nuclear overlap, finely dispersed chromatin)
Mainly classified as category II (Benign) of The Bethesda System for Reporting Thyroid Cytopathology (Thyroid 2017;27:1341)
- Nodules with abundant cystic fluid can be classified as category I (Nondiagnostic / Cyst fluid only)

Cytology images

Contributed by Ayana Suzuki, C.T.

Watery colloid

Cracking colloid

Follicular clusters

3D structures

Paravacuolar granules

Cyst fluid only

Images hosted on other servers:

Watery colloid and focal dense colloid

Large amounts of background colloid

Positive stains

Thyroid specific markers: thyroglobulin, TTF1, PAX8

Negative stains

Loss of PTEN protein in patient with PTEN hamartoma syndrome

Molecular / cytogenetics description

Promoter hypermethylation of tumor suppressor gene RASSF1A (Thyroid 2017;27:1341)
DICER1 mutation
PTEN mutation
Thyroid hormonogenesis related protein mutations (dyshormonogenetic goiter)

Videos

Thyroid multinodular goiter

Histopathology thyroid: nodular goiter

Histopathology thyroid: colloid goiter

Sample pathology report

Thyroid, partial / total thyroidectomy:
- Multinodular hyperplasia
Thyroid, partial / total thyroidectomy:
- Adenomatoid nodule in a background of diffuse hyperplasia
Thyroid, partial / total thyroidectomy:
- Hemorrhagic nodule in background of multinodular hyperplasia
Thyroid, partial / total thyroidectomy:
- Colloid nodule

Differential diagnosis

Adenoma:
- Usually single, totally surrounded by capsule, dissimilar from remaining parenchyma, compresses adjacent tissue and composed of follicles smaller than normal gland
- Can mimic monoclonal dominant nodule in nodular goiter
- Clonal event, such as RAS mutation or PPARG fusion
Dyshormonogenetic goiter:
- Increased cellularity is usually diffuse
Follicular carcinoma:
- Has vascular or capsular invasion, although multinodular goiter may have vascular invasion at periphery of nodule
Papillary carcinoma:
- Distinct nuclear features seen in papillary carcinoma; lacks the Sanderson polsters found in goiters
Toxic goiter:
- Clinical hyperthyroidism

Additional references

Int J Surg 2014;12:S98, UpToDate: Clinical Presentation and Evaluation of Goiter in Adults [Accessed 20 February 2018], Best Pract Res Clin Endocrinol Metab 2008;22:929

Board review style question #1

Which of the histological features is seen in nodular goiter?

Nodules with distinct thick capsule
Papillary projections of the epithelium with nuclear features of papillary thyroid carcinoma
Variably sized follicles with flattened hyperplastic epithelium, cysts, hemorrhage, granulomatous response, fibrosis, calcification or osseous metaplasia
Vascular invasion

Board review style answer #1

C. Variably sized follicles with flattened hyperplastic epithelium, cysts, hemorrhage, granulomatous response, fibrosis, calcification or osseous metaplasia. Nodules may or may not be present in nodular goiter but generally lack a thick capsule. Prominent features are variably sized dilated follicles with flattened hyperplastic epithelium. Secondary changes include foci of fresh or old hemorrhage, rupture of follicles with granulomatous response, fibrosis, calcification and even osseous metaplasia. Some of the cystically dilated follicles may show papillary projections (Sanderson polsters). Cytologic atypia in the form of highly atypical nuclei occurs in patients exposed to radioactive substances.

Comment Here

Reference: Multinodular goiter

Board review style question #2

These images from a thyroid nodule belong in what category of The Bethesda System for Reporting Thyroid Cytopathology?

Category I
Category II
Category III
Category IV
Category V

Board review style answer #2

B. Category II (benign). These images represent a colloid nodule / benign thyroid nodule. They are typically managed by clinical and sonographic followup.

Comment Here

Reference: Multinodular goiter

Thyroid inclusions

Table of Contents

Definition / general

Thyroid tissue incidentally discovered in cervical lymph nodes during histological examination of neck dissections performed for non thyroid disease, e.g. head and neck cancer (Eur Arch Otorhinolaryngol 2016;273:2867)
May represent metastatic carcinoma or benign thyroid tissue; evaluate with extreme caution (Laryngoscope 2005;115:470)
- Metastatic carcinoma accounts for most of the cases: main primary is papillary thyroid carcinoma, often occult
  - Much rarer sources of primary tumor mimicking thyroid follicles in cervical metastasis can be salivary gland, lung, thymus and struma ovarii (Rosai: Rosai and Ackerman's Surgical Pathology, 10th Edition, 2011)
- Heterotopic thyroid: true benign thyroid inclusions due to developmental abnormalities or benign lymphatic transport (Cancer 1967;20:103)
  - Some authors suggested all thyroid tissue within lymph nodes was metastatic thyroid cancer (Cancer 1967;20:103); however the possibility of benign inclusions is widely accepted today (Eur Arch Otorhinolaryngol 2016;273:2867)
  - Benign nodal thyroid inclusions are not unique; similar benign foci of parathyroid, salivary gland tissue and nevus cells are described in cervical lymph nodes (Diag Histopath 2010;16:265)
  - Benign epithelial inclusions are found in axillary (breast) and pelvic (endometrium) lymph nodes (Miranda: Atlas of Lymph Node Pathology, 2013)

Terminology

Ectopic thyroid tissue in cervical lymph nodes; benign thyroid inclusions in cervical lymph nodes
Lateral aberrant thyroid: usually due to metastatic thyroid carcinoma in cervical lymph nodes

Epidemiology

Incidence of unsuspected benign thyroid tissue in lymph nodes of patients with head and neck carcinoma treated with neck dissection is 0.6% - 1.5% (Clin Endocrinol Metab 1981;10:337, Laryngoscope 2005;115:470)
Meticulous study of cervical lymph nodes found benign thyroid inclusions in 4.7% of unselected autopsies (Cancer 1969;24:302)
Total number of well proven cases of benign nodal thyroid inclusions is < 30

Sites

Benign thyroid inclusions involve medial inferior neck lymph nodes, whereas any thyroid tissue found lateral to large neck vessels (carotid artery or jugular vein) should be considered metastatic tumor rather than a developmental anomaly (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)
However, there are occasional cases of benign inclusions in lateral (up to level II) lymph nodes (Eur Arch Otorhinolaryngol 2016;273:2867)

Pathophysiology / etiology

Aberrations during migration of embryonic thyroid may result in entrapment of structures that terminally differentiate to thyroid follicles and remain quiescent in lymph nodes (heterotopia)
- In addition, hypothetically, enlarging lymph node may enclose neighboring ectopic islet of thyroid tissue
May be explained by benign lymphatic transport ("benign metastasis"), when tiny fragments of ruptured thyroid tissue float into sentinel lymph nodes (JAMA 1965;194:1); similar to proposed mechanism for endometriosis
Theoretically, may represent nodal metastasis of occult thyroid carcinoma with further complete regression of the primary (Head Neck 2001;23:885, J Oral Maxillofac Surg 2008;66:2566)

Clinical features

Asymptomatic and incidental by definition
Some authors propose that primary papillary carcinoma can arise in ectopic intranodal thyroid tissue, regardless of the main thyroid (J Oral Maxillofac Surg Med Pathol 2015;27:240)
Potentially may mimic thyroid cancer in thyroglobuin+ washouts of cervical lymph nodes (J Clin Endocrinol Metab 2013;98:1061)

Diagrams / tables

Contributed by Andrey Bychkov, M.D., Ph.D.

Differential diagnosis

Diagnosis

Only after exclusion of suspected primary thyroid carcinoma on extensive workup (imaging and even surgery)

Radiology description

It is believed that current imaging modalities are unable to detect true benign nodal thyroid inclusions (Eur Arch Otorhinolaryngol 2016;273:2867)
Features suggestive of metastatic lymph nodes from papillary thyroid carcinoma (Head Neck 2015;37:E106):
- US: focally or diffusely increased nodal echogenicity, intranodal calcifications, intranodal cystic component(s) and an abnormal vascular pattern (a chaotic or peripheral vascular pattern)
- CT: strong enhancement without hilar vessel enhancement, heterogeneous enhancement, intranodal calcifications and intranodal cystic component

Prognostic factors

The prognosis for benign nodal thyroid inclusions is excellent
Similarly, occult papillary thyroid carcinoma with incidental nodal micrometastasis usually does not progress

Case reports

13 year old boy with ectopic thyroid in lateral lymph nodes (J Pediatr Endocrinol Metab 2015;28:227)
41 year old man with apparent primary papillary thyroid carcinoma in lateral cervical lymph node (Exp Mol Pathol 2007;82:91)
50 year old woman with primary papillary carcinoma arising from ectopic thyroid tissue in the cervical lymph node (J Oral Maxillofac Surg Med Pathol 2015;27:240)
51 year old woman with benign intranodal thyroid tissue mimicking nodal metastasis in a patient with papillary thyroid carcinoma (Head Neck 2015;37:E106)

Treatment

Thyroid imaging is mandatory for all cases with thyroid inclusions in cervical lymph nodes
- If primary thyroid carcinoma is detected, the extent of further thyroid surgery depends on age, comorbidities, control of primary upper aerodigestive cancer and patient preference
"Wait and watch" is recommended if imaging is negative
Option of further surgery can be considered as well
Unequivocally benign inclusions confirmed by morphology and negative thyroid imaging may require no further action but clinical correlation and follow up is advisable (Eur Arch Otorhinolaryngol 2016;273:2867)

Gross description

Lymph nodes are unremarkable, < 5 mm (range 2 - 15 mm)

Microscopic (histologic) description

Inclusions are 0.1 to 2.3 mm and contain up to 100 (average 30) normal appearing thyroid follicles, usually arranged in a wedge shaped focus with the base adjacent to the nodal capsule and the apex directed towards the cortex (Eur Arch Otorhinolaryngol 2016;273:2867)
Benign inclusion should be located within the nodal capsule or in the marginal sinus (subcapsular) and in not more than two cervical lymph nodes
Metastatic papillary carcinoma is suspected by the large extent of thyroid tissue replacing lymph node (often cystic) and the presence of papillary structures, psammoma bodies, grooved nuclei, marginated chromatin, intranuclear pseudoinclusions
The same features of papillary cancer can be found in the thyroidectomy specimen, which may require exhaustive sectioning, including multiple levels and "flipping" of paraffin blocks (Wenig: Atlas of Head and Neck Pathology, 3rd Edition, 2015)

Microscopic (histologic) images

AFIP images

Ectopic thyroid follicles

Images hosted on other servers:

Subcapsular nodal thyroid inclusion

Lymph node with metastatic papillary thyroid carcinoma

Thyroglobulin+ lymph node (potential pitfall)

Cytology description

The probability of obtaining tiny benign thyroid inclusions during cervical lymph node aspiration is extremely low, with only one case reported (Head Neck 2015;37:E106)
As such, the presence of thyroid follicles in cervical lymph node aspirate should be considered to be metastatic thyroid carcinoma or a technical error (if orthotopic or heterotopic thyroid/parasitic nodule is sampled instead of the lymph node)
Metastases in lymph nodes are identified by papillary fragments, psammoma bodies and classic nuclear features of papillary thyroid carcinoma

Positive stains

Thyroglobulin and TTF1, with these limitations:
- Macrophages in lymph nodes draining thyroid tumors may engulf thyroglobulin (J Clin Pathol 2001;54:314)
- TTF1 is not entirely thyroid specific, e.g. TTF1+ lung cancer can metastasize to cervical lymph nodes

Negative stains

Immunomarkers of papillary thyroid carcinoma: CK19, galectin 3, HBME1 (APMIS 2001;109:875)

Molecular / cytogenetics description

Benign inclusions are typically negative for molecular markers of thyroid cancer (BRAF and RAS mutations, RET / PTC rearrangements), although one study found BRAF mutation in "benign" inclusions (Endocr Pathol 2006;17:183)
Benign inclusions, as with normal or ectopic thyroid, are polyclonal on HUMARA assay, but metastatic tumor is monoclonal (Hum Pathol 1998;29:187)

Differential diagnosis

Metastatic carcinoma:
- Metastasis of conventional papillary thyroid carcinoma, often from occult primary, see table for details
- Other types of metastatic thyroid cancer: medullary, follicular and follicular variant of papillary carcinoma
- Metastasis from extrathyroid primary: salivary gland, lung, thymus and struma ovarii
Conditions unrelated to lymph node that can be detected by the absence of typical nodal structures, e.g. subcapsular sinuses:
- Parasitic nodule with Hashimoto thyroiditis
- Heterotopic thyroid
- Branchial cleft cyst

Additional references

Arch Pathol 1964;77:633, Int J Surg Pathol 2012;20:564

Thyroid metastases

Table of Contents

Definition / general

Tumors arising in thyroid by direct extension from adjacent structures or by vascular spread from nonthyroidal sites (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)
Despite being highly vascularized, the thyroid is a rare site for distant metastases
The frequency of metastasis in routine practice is < 0.2% of thyroid malignancies (Endocr Pathol 2017;28:112)
Direct extension common from tumors of larynx, pharynx, trachea, esophagus and neck - usually are squamous cell carcinoma
FNA is useful for diagnosis of solitary metastases (Cytojournal 2007;4:5)
More than 1400 cases have been published in series and individual case reports (Endocr Pathol 2013;24:116)
Tumor to tumor metastasis localized within a primary thyroid neoplasm are very rare with 30+ cases reported

Essential features

Thyroid is highly vascularized but secondary metastases to the gland are very uncommon
Secondary tumors arise from direction extension of head and neck squamous cell carcinoma and distant metastases from kidney, lung, GI and breast
Tumors preoperatively diagnosed by FNA, cytology, histopathology and immunophenotype are matched with a primary tumor

Epidemiology

Recent series found metastases in up to 0.5% of surgical specimens of thyroid cancer, 0.15% of thyroidectomies, 0.07% of thyroid FNA and in 0.2% of hospital autopsies (Endocr Pathol 2013;24:116, Clin Endocrinol (Oxf) 2007;66:565, Cytojournal 2017;14:16, Am J Clin Oncol 2015;38:338)
- Old series reported higher prevalence - 0.5% of thyroidectomies and 1.2 - 3% of thyroid malignancies are metastases (Cancer 1997;79:574, Arch Pathol Lab Med 1998;122:37)
- Metastases were found in autopsy of thyroid in up to 25% of patients dying of disseminated malignancies
Slight predominance in women (1.2:1), mean age over 60 years (Am J Clin Oncol 2015;38:338)

Sites

Direct invasion of thyroid by head neck malignancies
- Squamous cell carcinoma originated from the adjacent organs (larynx, esophagus, hypopharynx and trachea)
- Soft tissue malignancies of the neck
- Parathyroid carcinoma
Primary sites for distant metastases to thyroid are kidney (34%), lung (15%), gastrointestinal tract (14%) and breast (14%) (Endocr Pathol 2013;24:116)
- Lung cancer is the most common primary for thyroid metastasis in Asian series (Arch Pathol Lab Med 1998;122:37, Endocr Pathol 2015;26:80)
Infradiaphragmatic primaries are more common than supradiaphragmatic (Endocr Pathol 2017;28:11)
Renal cell carcinoma is the most common primary in clinical series, while lung cancer is the most common in autopsy studies (Ann Surg Oncol 2017;24:1533)

Pathophysiology

Two major hypotheses explain the rarity of metastases in the highly vascularized thyroid (Thyroid 2012;22:258):
1. Relatively rapid arterial flow through the thyroid may discourage adhesion and seeding of metastases
2. High oxygen saturation and iodine content of the thyroid gland itself may directly inhibit the growth of malignant cells

Diagnosis

Fine needle aspiration after incidental discovery by ultrasound (Ann Surg Oncol 2017;24:1533)
Accurate morphological diagnosis is facilitated by clinical history
Discovered at the time of diagnosis of the primary tumor, after preoperative investigation of a neck mass, on histologic examination of a thyroidectomy specimen or at autopsy (Ann Surg Oncol 2017;24:1533)

Clinical features

Most nodules are asymptomatic
Solitary metastasis to the thyroid gland may be the initial presentation of malignancy
- Nonspecific symptoms of neck mass and compression, including dysphagia, dysphonia, pain and airway compromise (Otolaryngol Head Neck Surg 2016;155:961)
When widespread metastatic disease is present, manifestations in the thyroid gland are typically clinically insignificant (Wartofsky: Thyroid Cancer - A Comprehensive Guide to Clinical Management, 3rd Edition, 2016) )
Metachronous vs. synchronous metastases = 2:1 (Endocr Pathol 2017;28:11)
Latency (time from diagnosis of primary tumour to detection of thyroid metastasis) is 20 - 24 months (Clin Endocrinol (Oxf) 2007;66:565)
Metastases from kidney are generally solitary, occurring a mean 9.2 years after nephrectomy; in 36%, metastasis to thyroid was initial presentation of renal cell carcinoma (Cancer 2002;95:1869)

Radiology description

Solitary hypofunctioning nodule on RAI scan
Sonographic characteristics are similar to benign and malignant thyroid diseases (J Ultrasound Med 2017;36:69)

Radiology images

Images hosted on other servers:

CT scan

Sonography

PET - CT

Metastatic renal cell carcinoma

Prognostic factors

Determined by the underlying primary tumor (site of origin, aggressiveness, extent of metastatic spread), time interval between initial diagnosis and metastasis, extrathyroidal extent of disease and completeness or resection (Ann Surg Oncol 2017;24:1533)
- Metachronous / delayed presentation is associated with improved survival duration (Otolaryngol Head Neck Surg 2016;155:961, Endocr Pathol 2015;26:80)
Overall 5 year survival after detection of thyroid metastasis or postthyroidectomy is 20 - 30%
Median survival: 20 months
- Patients who undergo thyroid resection: 30 - 39 months
- Without thyroid surgery: 12 - 24 months
In one study survival was not different from patients diagnosed with the same primary tumours but without thyroid metastases (Clin Endocrinol (Oxf) 2007;66:565)

Case reports

Supradiaphragmatic primaries
- 37 year old woman with metastatic breast carcinoma (Arch Pathol Lab Med 2004;128:804)
- 50 year old woman with severe thyrotoxicosis induced by thyroid metastasis of lung adenocarcinoma (Thyroid 2001;11:883)
- 54 year old woman with intrathyroidal metastasis of breast carcinoma (Int J Surg Pathol 2017;25:319)
- 59 year old man with thyroid metastasis from pulmonary adenocarcinoma (BMC Res Notes 2017;10:130)
- 61 year old man with a solitary thyroid metastasis of nasopharyngeal carcinoma (Indian J Palliat Care 2017;23:104)
- 64 year old man with a metachronous solitary metastasis to the thyroid gland from squamous cell carcinoma of the lung (Tumori 2017;103:e12)
- 85 year old woman with thyroid metastasis of malignant melanoma of the nasal mucosa (Arch Endocrinol Metab 2017;61:193)
Infradiaphragmatic primaries
- 28 year old woman with thyroid metastasis as initial presentation of cervical carcinoma (Indian J Pathol Microbiol 2017;60:298)
- 42 year old woman with a colon cancer metastasis to the thyroid gland (Clin Case Rep 2016;4:549)
- 50 year old woman with metastasis of tibial osteosarcoma to the thyroid gland (JAMA Oncol 2017;3:853)
- 51 year old Caucasian woman with metastases of renal cell carcinoma (Case Rep Oncol Med 2013;2013:485025)
- 54 year old woman with 2 thyroid nodules-uterine leiomyosarcoma (Case of the Week #342)
- 54 year old woman with metastatic endometrial carcinosarcoma (Gynecol Endocrinol 2007;23:562)
- 54 year old man with metastatic hepatocellular carcinoma (World J Surg Oncol 2007;5:144)
- 54 year old man with multinodular goiter as initial presentation of renal cell carcinoma (BMC Endocr Disord 2006;6:6)
- 55 year old woman with metastatic ovarian carcinoma (Gynecol Oncol 2006;102:394)
- 56 year old woman with thyroid metastasis from cancer of the uterine cervix (Acta Medica (Hradec Kralove) 2016;59:97)
- 64 year old woman with colon cancer metastatic to the thyroid gland (Int J Surg Case Rep 2017;37:221)
- 64 year old man with thyroid metastasis of prostate adenocarcinoma (J Clin Diagn Res 2017;11:ED19)
- 65 year old man with renal cell carcinoma metastic to thyroid (Univ Pittsburgh: Case #454 [Accessed 16 October 2017])
- 67 year old man presented with a thyroid mass (Case of the Week #461)
- 71 year old woman with intrathyroidal metastasis of renal clear cell carcinoma in goiter (Thyroid Res 2008;1:6)
Tumor to tumor metastases
- 52 year old man with rectal carcinoma metastatic to poorly differentiated thyroid carcinoma (World J Surg Oncol 2008;6:122)
- 55 year old man with small cell carcinoma of lung metastasizing to follicular adenoma of thyroid (Indian J Pathol Microbiol 2017;60:133)
- 65 year old man with poorly differentiated carcinoma of lung metastatic to follicular adenoma (Patholog Res Int 2011;2011:238693)
- Two cases of prostatic and breast carcinoma metastasizing to follicular adenoma (Arch Pathol Lab Med 1994;118:551)
- Three patients with tumor to tumor metastases to follicular variant of papillary thyroid carcinoma (Arch Pathol Lab Med 1999;123:703)
- Patient with history of melanoma presented with a thyroid nodule and had a total thyroidectomy (Case of the Month #513)

Treatment

Surgical resection (total or subtotal thyroidectomy) if patient presents with an isolated metastasis diagnosed during followup of indolent disease (Thyroid 2007;17:49)
For patients with widespread metastases in the setting of an aggressive malignancy, surgery is rarely indicated (Ann Surg Oncol 2017;24:1533)

Gross description

Single, more often than multiple, diffuse or bilateral (Arch Pathol Lab Med 1998;122:37)
Gross features consistent with the primary tumour (e.g., yellow, hemorrhagic appearance of a renal cell primary or mucin pools of a gastrointestinal primary) may be helpful to suspect metastasis (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)
If primary arises from an adjacent structure, direct invasion is generally clear
Multinodular metastasis may be indistinguishable from a nodular goiter (Ann Surg Oncol 2014;21:434)

Gross images

Contributed by Mark R. Wick, M.D., Jose G. Mantilla, M.D. (Case #513) and AFIP

Metastatic renal cell carcinoma

Melanoma in OFA

Melanoma metastatic from skin primary

Images hosted on other servers:

Invasion by squamous cell carcinoma of larynx

Renal papillary carcinoma

Metastatic renal cell carcinoma

Surgical specimens

Microscopic (histologic) description

May involve multiple areas of thyroid gland
Can be small deposits within lymphovascular spaces or large mass
Often moderate or poorly differentiated adenocarcinoma (Arch Pathol Lab Med 1998;122:37)
Tumor to tumor metastasis appears as thyroid neoplasm (usually follicular adenoma) containing a nodule with contrasting morphology

Microscopic (histologic) images

Scroll to see all images:

Contributed by Mark R. Wick, M.D.

Metastatic renal cell carcinoma

CD10, Keratin 8, RCC, thyroglobulin

Contributed by Jose G. Mantilla, M.D. (Case #513)

HCA capsule

Interface between components

Pigmented component

Hürthle cell component

Melanoma in OFA interface

Melanoma in OFA SOX10

Case #461

Clear cell RCC metastatic to the thyroid

CD10, 400x

RCC, 400x

Case #342

Metastatic leiomyosarcoma (frozen section slides)

Metastatic leiomyosarcoma (permanent sections)

AFIP images

Clear cell type

Cytoplasm is abundant and completely clear

Oil Red O stains cytoplasm strongly

False positive thyroglobulin staining

Breast carcinoma:

Lobular carcinoma and entrapped thyroid follicles

ER stains breast tumor but not papillary carcinoma

Falsely positive thyroglobulin staining

Lung:

Carcinoid tumor with well defined nesting pattern

Carcinoma metastatic to mediastinal thyroid gland

Skin:

Melanoma

Images hosted on other servers:

From rectum

Metastatic HCC in the thyroid gland

HCC stains for AFP

Clear cell type

Metastasis to goiter

Concurrent RCC and thyroid carcinoma

Central lesions inside
hyperplastic adenomatoid
nodules

FNA, histology and stains

CD10 and H&E

Tumor to tumor metastases

Lung-small cell carcinoma

Lung-squamous cell carcinoma

Melanoma

Parotid adenoid cystic carcinoma

Rectal carcinoma
to poorly
differentiated
thyroid carcinoma

Cytology description

Presence of unusual cells, not typical for thyroid, admixed with normal thyroid follicular cells (Yang: Thyroid Fine Needle Aspiration, 1st Edition, 2013)
Cytological features of keratin, mucin or melanin are the clues to the extrathyroidal origin of the tumor

Cytology images

Contributed by Mark R. Wick, M.D.

FNA: metastatic renal cell carcinoma

Images hosted on other servers:

Kidney: metastatic renal cell carcinoma, clear cell type

Kidney: bloody background with clusters of atypical cells; nuclei are somewhat pleomorphic with prominent nucleoli

Lung squamous cell carcinoma

Melanoma

Melanoma - HMB45

Parotid gland adenoid cystic carcinoma

Positive stains

Primary tumor specific markers e.g. Napsin A for lung, RCC for kidney, mammaglobin and BRST2 for breast, CK20 and CDX2 for gastrointestinal cancers
Mucin+ in metastatic adenocarcinoma, which is not seen in primary thyroid tumor

Negative stains

Thyroglobulin (may be spuriously positive due to the permeating colloid), TTF1 (but is positive in lung or small cell carcinoma)

Molecular / cytogenetics description

Secondary tumors have genetic signature matching with primary sites and mutation testing or miRNA profiling may be helpful (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)

Differential diagnosis

Various primary thyroid tumors with clear cell changes vs. clear cell renal cell carcinoma: RCC has sinusoidal blood vessels and hemorrhage in lumen, is RCC+, CD10+, CAIX+, TTF1-, thyroglobulin-; note that PAX8 is positive in both tumors
Medullary carcinoma vs neuroendocrine neoplasm: calcitonin can be seen in small cell carcinoma
Poorly differentiated metastatic carcinoma vs. Poorly differentiated thyroid carcinoma: the latter is thyroglobulin+, TTF1+, PAX8+ (may be focal)
Undifferentiated metastatic carcinoma vs. Undifferentiated thyroid carcinoma: the latter is PAX8+/-, thyroglobulin+/-, TTF1+/-

Additional references

DeLellis: Pathology and Genetics of Tumours of Endocrine Organs [OP] (IARC WHO Classification of Tumours), 1st Edition, 2004, Nikiforov: Diagnostic Pathology and Molecular Genetics of the Thyroid: A Comprehensive Guide for Practicing Thyroid Pathology, 2nd Edition, 2012

Board review style question #1

Which statement is false regarding metastatic clear cell renal cell carcinoma to the thyroid?

Metastasis from renal cell carcinoma is generally a solitary mass
Metastatic clear cell renal cell carcinoma can have a very long latency after nephrectomy
Metastatic clear cell renal cell carcinoma can have a spurious thyroglobulin stain
TTF1 and PAX8 can be used to differentiate tumors of renal and thyroid origins
Metastatic tumor to the thyroid gland is the initial manifestation of renal cell carcinoma in 33% of cases

Board review style answer #1

D. TTF1 and PAX8 can be used to differentiate renal and thyroid origins. Tumors from both thyroid and kidney can be positive for PAX8.

Comment Here

Reference: Secondary tumors / metastases

Board review style question #2

Which of the following statements is true?

Metastases to the thyroid are a common finding
Most patients with thyroid metastases have no known primary
Melanoma is a common primary that metastasizes to the thyroid
PAX8 may be positive in both thyroid and renal tumors

Board review style answer #2

D. PAX8 may be positive in both thyroid and kidney tumors.

Comment Here

Reference: Secondary tumors / metastases

Board review style question #3

Which of the following is true regarding tumor-to-tumor metastasis in general?

Carcinomas of the breast are among the most common "donor" tumors
Melanoma is the most common "recipient" tumor
Most "recipient" tumors are benign
Sarcomas are the most common "donor" tumor
Their definition includes metastasis to lymph nodes affected by lymphoma

Board review style answer #3

A. Carcinomas of the breast are among the most common "donor" tumors

Comment Here

Reference: Secondary tumors / metastases

Toxic goiter

Table of Contents

Definition / general

Multinodular goiter plus hyperthyroidism ("toxic")
#2 cause of hyperthyroidism after Graves disease, #1 in elderly, particularly in iodine deficient areas (J Endocrinol Invest 2002;25:16)

Terminology

Also called Plummer's disease (particularly if single nodule)
Toxic nodular goiter: also called toxic adenoma, may arise in background of multinodular goiter

Epidemiology

Usually older patients rather than those with nontoxic multinodular goiter, with long evolution time (Surg Today 2005;35:901)

Clinical features

Associated with atrial fibrillation, tachycardia, weakness and muscle wasting, only rarely with eye disease

Laboratory

Slight increase in T3 / T4 (less than Graves disease), reduced TSH

Treatment

Radioactive iodine, total thyroidectomy if obstructive symptoms or large (World J Surg 2008;32:1278)

Gross description

Enlarged thyroid gland with multiple nodules exhibiting fibrosis, old and new hemorrhage and dystrophic calcification

Microscopic (histologic) description

Hyperplastic nodules with discrete fibrous capsule, composed of follicles with papillary hyperplasia and tall columnar cells
Nonfunctioning nodules may appear inactive and have degenerative changes of fibrosis, calcification and hemorrhage (old and new)

Molecular / cytogenetics description

Monoclonal or polyclonal

Differential diagnosis

Dyshormonogenetic goiter: diffuse changes compared to focal changes in toxic multinodular goiter
Follicular carcinoma: vascular invasion or invasion beyond thyroid gland
Graves disease: uniformly enlarged gland with uniformly diffuse hyperplasia and no nodules
Nontoxic multinodular goiter: difficult to distinguish histologically, need imaging studies and clinical correlation

Additional references

eMedicine

Ultrasound

Table of Contents

Definition / general

Ultrasound is an imaging modality based upon sound waves that has several modes that are helpful to visualize thyroid anatomy and blood flow
Basic physics principles:
- Ultrasound probe both emits and receives sound waves
- Medical ultrasound: 2 - 20 MHz
- Lower frequencies: better penetration, lower resolution
- Higher frequencies: lower penetration, higher resolution
B mode (brightness mode):
- 2D black and white image in Emitted waves are reflected back from the target material relative to the degree of the material's acoustic impedance, which is dependent on density
- Higher density materials generally reflect more and look brighter
  - For example, bone is more reflective than soft tissue; thus, bony structures appear brighter on ultrasound images in contrast to darker surrounding tissue
Doppler mode:
- Measures direction and speed of tissue / blood motion
M mode (motion mode):
- Pulses are emitted in quick succession and each time, an image is taken; over time, this is analogous to recording a video in ultrasound (used for heart valves)
References: Arch Pathol Lab Med 2010;134:1541, Radiol Clin North Am 2011;49:417

Essential features

Ultrasound is an imaging modality based upon sound waves that has several modes that are helpful to visualize thyroid anatomy and blood flow
Benign thyroid nodules appear small or large with predominant cystic change, fluid filled (as opposed to solid), hyperechoic or honeycomb morphology
Thyroid nodules suspicious for malignancy are solid, are taller than they are wide, contain microcalcifications and are hypoechoic, with thin capsules or irregular borders and intramodular vascularity

Terminology

Anechoic: black (e.g., blood, cystic fluid)
Azimuthal plane: midsagittal plane of transducer; beam used to guide needle in ultrasound guided fine needle aspiration (UGFNA)
Hyperechoic: brighter than surrounding tissue (e.g., bone)
Hypoechoic: darker than surrounding tissue (e.g., soft tissue versus bone)
Isoechoic: same intensity as surrounding tissue
Ultrasound artifacts:
- Posterior (acoustic) shadowing: strong reflectors (air) or absorbers (stones, bones) block visualization of structures beyond them in relation to the beam
- Posterior (acoustic) enhancement: anechoic structures (cysts) show brighter signals from areas beyond them in relation to the beam
- Eggshell calcification: nodules surrounded by a layer of calcium have bright anterior and posterior walls due to a reflection from the surface but posteriorly there is acoustic shadowing; this phenomenon also leads to edge artifact in which parallel dark lines extend posteriorly from the sides of nodules
- Reverberation artifact: sound waves reflect off a very reflective surface and are re-reflected from the skin, resulting in phantom images behind the target image
- Comet tail artifact: reverberation artifact from front and back of a very strong reflector / absorber (air bubble, metal fragment) - can also happen with dense colloid
Bayonet sign:
- Due to speed propagation artifact, machines use average speed of sound to calculate depth
- If sound actually travels faster in the tissue (anechoic or hypoechoic structures), a reflector will appear closer to the transducer than its actual depth and vice versa
- Needle with its tip in a cyst or nodule with differing echogenicity from surrounding tissue will appear to have its tip bent due to this artifact, looking like a bayonet
References: Arch Pathol Lab Med 2010;134:1541, Radiol Clin North Am 2011;49:417, Korean J Radiol 2014;15:267, Endotext: Ultrasonography of the Thyroid [Accessed 12 October 2022], Radiol Clin North Am 2020;58:1033, Radiol Clin North Am 2020;58:1041, Milas: Advanced Thyroid and Parathyroid Ultrasound, 1st Edition, 2017, Halenka: Atlas of Thyroid Ultrasonography, 1st Edition, 2017

Diagrams / tables

Contributed by Rachel Jug, M.B.B.Ch.

Ultrasound FNA techniques

Images hosted on other servers:

Risk of thyroid cancer

ATA algorithm for
patients with
thyroid nodules

ATA association

ACR TI-RADS chart

Comparison of systems

Typical appearances of diffuse thyroid diseases

Thyroid disorder	Grayscale ultrasound	Color Doppler	Key features
Graves thyroiditis	Enlarged, mildly hypoechoic, heterogeneous	Markedly ↑	Markedly hyperemic; proptosis; hyperthyroid; + antithyroid antibodies
Hashimoto thyroiditis	Enlarged, heterogeneous with lobular margins; hypoechoic and micronodular, septal lines	Highly variable: both ↑ and ↓ flow possible	+ Antithyroid antibodies, hypothyroidism; cervical adenopathy
Subacute lymphocytic thyroiditis (painless)	Hypoechoic	Insufficient data	+ Antithyroid antibodies; postpartum; transient
De Quervain thyroiditis (subacute granulomatous)	Painful patchy areas of hypoechogenicity	↓ in the hypoechoic patch	Thyroid pain over area of hypoechogenicity; ↑ erythrocyte sedimentation rate (ESR)
Acute suppurative thyroiditis	Abscess or infected linear tract in the thyroid	Normal background; no flow within an abscess	Acute presentation with signs of infection and pain; ↑ ESR; possible pyriform sinus fistula
Riedel thyroiditis	Large hypoechoic thyroid with coarse parenchyma	Insufficient data	Large, rock hard gland; encases adjacent structures
Medication induced (i.e., amiodarone induced thyrotoxicosis [AIT])	Type 1: abnormal thyroid; type 2: normal thyroid	Type 1: ↑; type 2: absent	History of current or recent amiodarone use; hyperthyroid
Atrophic thyroiditis	Small, hypoechoic thyroid	↓	+ Antithyroid antibodies; usually hypothyroid
Radiation thyroiditis	Small, hypoechoic thyroid	Variable	Known external beam or I131 administration
Thyroid lymphoma	Large, ill defined, markedly hypoechoic nodules or masses with ↑ through transmission on background of Hashimoto thyroiditis	↓ in the hypoechoic mass	Rapidly enlarging neck mass in patient with history of Hashimoto, with or without adenopathy
Multinodular goiter	Closely opposed or interspersed, similar appearing nodules replace parenchyma, coarse calcifications, variable cystic changes in nodules	Variable	Confluent nodules in a normal or enlarged thyroid; with or without abnormal thyroid function tests

Reference: Radiol Clin North Am 2011;49:391

Sonographic features of thyroid nodules and lymph nodes

Sonographic features of benign thyroid nodules:
- Small size (Fluid filled
- Honeycomb morphology
- Hyperechoic (colloid nodule or focal nodular Hashimoto thyroiditis)
- Large nodules if they are predominantly cystic (cystic change accounts for > 50% of nodule)
Sonographic features of thyroid nodules suspicious for malignancy (Diagn Cytopathol 2008;36:390, Eur J Endocrinol 2009;161:103):
- Solid oval nodules (anterior - posterior dimension: transverse dimension ratio is > 1)
- Presence of discrete coarse echogenic foci or microcalcifications
- Hypoechoic (medullary and papillary thyroid cancers)
- Thin capsules or irregular borders (suggestive of extracapsular spread)
- Intranodular vascularity
- Nodal metastases
Sonographic features of benign lymph nodes:
- Oval shape (short axis:long axis ratio ≤ 0.5)
- Hypoechoic cortex and echoic hilum (due to adipose tissue)
- Clearly demarcated margin from surrounding tissue
- Central vascularization
Sonographic features of lymph nodes suspicious for malignancy (Eur J Endocrinol 2009;161:103):
- Round shape (short axis:long axis ratio > 0.5)
- Echogenic heterogeneity of cortex and absent fatty hilum
- Irregular margin with surrounding tissue
- Increased or abnormally located vascularity
- Features suggestive of metastatic thyroid cancer: cystic appearance, hyperechoic punctations / calcifications
2015 American Thyroid Association (ATA) Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer (Thyroid 2016;26:1):
- Strongly recommends ultrasonic examination of thyroid and cervical lymph nodes if thyroid nodules; fine needle aspiration (FNA) for sampling is recommended if > 1 cm in greatest dimension and high suspicion sonographic pattern (estimates a 70 - 90% risk of malignancy), including:
  - Solid hypoechoic nodule or nodule that is partially solid and hypoechoic and partially cystic with 1 or more of the following features:
    - Irregular margins (infiltrative, microlobulated)
    - Microcalcifications
    - Oval (taller than wide) shape
    - Rim calcifications with an extrusive soft tissue component
    - Evidence of extrathyroidal extension

Reporting systems

American College of Radiology (ACR) Thyroid Imaging, Reporting and Data System (TI-RADS) categorizes lesions based on ultrasound features and provides recommendations for whether or not to FNA the lesion:
- Benign (TR1): no FNA
- Not suspicious (TR2): no FNA
- Mildly suspicious (TR3): FNA if ≥ 2.5 cm; follow if ≥ 1.5 cm
- Moderately suspicious (TR4): FNA if ≥ 1.5 cm; follow if ≥ 1 cm
- Highly suspicious (TR5): FNA if ≥ 1 cm; follow if ≥ 0.5 cm
See ACR TI-RADS chart
Modifications of TI-RADS:
- European: EU TI-RADS (Eur Thyroid J 2017;6:225)
- Korean: K TI-RADS (Korean J Radiol 2021;22:1569)
- Chinese: C TI-RADS (Endocrine 2020;70:256)

Advanced imaging approaches

Thyroid elastography: characterizes thyroid nodules by determining hardness / stiffness; can be integrated into the conventional thyroid ultrasound (Ultraschall Med 2009;30:175)
- Stiffness measured in kPa and elasticity ratios comparing cancerous to benign tissue
- Lesions with low stiffness are considered to be benign, while stiff lesions are considered to be malignant (Diagn Interv Imaging 2013;94:535, Ultraschall Med 2009;30:175)
Contrast enhanced ultrasound (CEUS): qualitative and quantitative approach to analyze the microvascular patterns of thyroid nodules and lymph nodes to characterize them as benign or malignant
- Method increases diagnostic accuracy of ultrasonography (J Clin Med 2021;10:4559)

Clinical features

Indications for UGFNA:
- Nonpalpable or difficult to palpate nodules, most commonly of the thyroid
- Targeting specific areas in complex and cystic nodules, such as solid areas
- Repeat FNA, when a prior palpation guided FNA sample was insufficient (Diagn Cytopathol 2008;36:390)
- Follow up for patients postpartial or total thyroidectomy for malignancy, e.g., to sample thyroid bed (J Ultrasound Med 2013;32:1319)
Benefits of UGFNA compared to conventional FNA alone:
- Higher rates of successful biopsy (J Clin Ultrasound 1994;22:535, Thyroid 1998;8:15, Thyroid 1998;8:283)
- Potentially lowers risk of damage to surrounding structures, which can be visualized
- Varying reports on cost effectiveness (BMC Endocr Disord 2009;9:14, Thyroid 2006;16:555)
- Efficacy of UGFNA is improved by the presence of a cytopathologist onsite, decreasing the overall inadequacy rate from 9.3% to 6% (Br J Radiol 2014;87:20130571)
Complications and contraindications: same as conventional FNA
Overview of procedure - focused thyroid ultrasound and biopsy:
- Image each thyroid lobe in the transverse and longitudinal planes to determine the overall appearance and locate nodules
- After completing ultrasonic assessment of the thyroid, relocate the position and measure size of the suspicious nodules
Approaches to UGFNA relative to the transducer beam (azimuthal plane):
- For each approach, orient the needle with the bevel tip up to create the greatest reflection
- Parallel approach (in beam):
  - Point the needle down, along the plane of the beam, toward the nodule
  - Maintain needle and transducer in the same plane, parallel to the plane of the transducer, then advance the needle into the nodule
  - Advantage: entire length of needle can be seen
- Perpendicular approach (out of beam):
  - Point the needle toward the midpoint of the transducer's side (long axis)
  - Perpendicular approach will result in visualization of the needle as it transversely crosses the plane of the beam at 90 degrees
  - Nodule and needle point will be centered in the midpoint of the transducer's long axis
  - Advantage: desirable, due to anatomy in some locations
  - Disadvantage: entire length of needle is not visualized
Needle based sample collection techniques:
- With aspiration / suction:
  - 27 or 25G needle attached to a 10 cc syringe (with or without extension tubing) withdrawn so that 1 - 2 cc of negative pressure induces aspiration
- Without aspiration / nonsuction:
  - 27 or 25G needle (with or without stylet; may attach open syringe) is introduced into nodule and capillary action causes uptake of cellular material into the needle
Sample preparation: same as for palpation guided FNA

Radiology description

See Sonographic features of thyroid nodules and lymph nodes

Radiology images

Images hosted on other servers:

Calcified nodule

Complex cystic thyroid nodule

Multinodular goiter

17 year old girl with Graves disease

35 year old woman
with diffuse
Hashimoto
thyroiditis

50 year old woman
with colloid
multinodular
goiter

Hypoechoic nodule

Microcalcifications in a thyroid nodule

Intranodular vascularity in thyroid nodule

Oval shaped thyroid nodule

Case reports

18 year old woman with a mass in her left neck with stiffness and normal thyroid function (Medicine (Baltimore) 2021;100:e25517)
24 year old woman with a palpable painless mass in the left thyroid lobe (J Int Med Res 2020;48:300060520954718)
71 year old woman with swelling of the anterior neck and history of airway obstruction (J Ultrasound 2018;21:165)

Videos

Fine needle aspiration (FNA) biopsy techniques - Dr. Britt Marie Ljung playlist

Neck ultrasonography basics

Thyroid ultrasound course

Additional references

Baskin: Thyroid Ultrasound and Ultrasound-Guided FNA, 3rd Edition, 2013

Board review style question #1

Which of the following sonographic features of a thyroid nodule would increase suspicion for malignancy?

Cystic change accounting for > 50% of nodule
Fluid filled
Honeycomb morphology
Hyperechoic
Presence of discrete coarse echogenic foci or microcalcifications

Board review style answer #1

E. Presence of discrete coarse echogenic foci or microcalcifications

Comment Here

Reference: Ultrasound guided FNA

Board review style question #2

What is the typical appearance of chronic lymphocytic (Hashimoto) thyroiditis on a grayscale ultrasound?

Abscess or infected linear tract in the thyroid
Enlarged, heterogeneous with lobular margins; hypoechoic and micronodular, septal lines
Enlarged, mildly hypoechoic, heterogeneous
Large, ill defined, markedly hypoechoic nodules or masses
Small, hypoechoic thyroid

Board review style answer #2

B. Enlarged, heterogeneous with lobular margins; hypoechoic and micronodular, septal lines

Comment Here

Reference: Ultrasound guided FNA

Unsatisfactory

Table of Contents

Definition / general

At the 2007 National Cancer Institute Thyroid Fine Needle Aspiration (FNA) State of the Science conference, the terms nondiagnostic and unsatisfactory were equated and recommended for the category that conveys an inadequate / insufficient sample (Diagn Cytopathol 2008;36:425, Ali: The Bethesda System for Reporting Thyroid Cytopathology, 2nd Edition, 2018)
- Laboratory should choose the one preferable term and use it exclusively for this category
Meta analysis reported 10 - 12% frequency of nondiagnostic / unsatisfactory (ND / UNS) (Acta Cytol 2012;56:333)
- Ideally should be limited to ≤ 10% of thyroid FNAs, excluding cyst fluid only samples (Am J Clin Pathol 2009;132:658)
- Nondiagnostic rate of > 20% may require an audit of thyroid FNA workflow
Resection rate is 7 - 15% (Acta Cytol 2012;56:333)
Risk of malignancy of surgically resected ND / UNS nodules is 9 - 32%
- This relatively high risk of malignancy is likely influenced by selection bias because only clinically suspicious nodules are resected (Acta Cytol 2012;56:333)
- A reasonable extrapolation of the overall risk of malignancy for ND / UNS nodules is 5 - 10% (Thyroid 2016;26:1)

Essential features

ND / UNS aspirates include inadequate by cellularity, unsatisfactory by quality and cyst fluid only specimens
Frequency 10 - 12%, resection rate 7 - 15%, risk of malignancy 5 - 10% of all nodules and up to 30% of resected nodules

Diagnosis

< 6 groups of well preserved, well stained follicular cell groups with 10 cells each
Poorly prepared, poorly stained or significantly obscured follicular cells
Cyst fluid, with or without histiocytes and < 6 groups of 10 benign follicular cells

Management

ND / UNS nodules should be reaspirated except for pure cyst (Thyroid 2016;26:1, Endocr Pract 2007;13:735, Contemp Oncol (Pozn) 2016;20:491)
- Reaspiration can be done 3 weeks after the first aspiration (Kakudo: Thyroid FNA Cytology, 2nd Edition, 2019)
- Ultrasound guidance with immediate on site adequacy evaluation is recommended (Acta Cytol 2012;56:333)
  - If on site evaluation for adequacy is not available, obtain a minimum of 3 separate samples of the nodule (Can Assoc Radiol J 2013;64:220)
  - This approach results in a diagnostic interpretation in 60 - 80% of cases (Am J Clin Pathol 2010;134:450, Acta Cytol 2014;58:229, Thyroid 2016;26:1, Endocr Pract 2007;13:735)
- Close clinical and ultrasound followup or surgery for cases with 2 consecutive ND / UNS
Rapid on site evaluation can help decide whether to reaspirate the nodule immediately
Additional liquid based preparations may be useful (Cytopathology 2010;21:97)
- Cell block from the residual liquid based preparation sample can convert some ND / UNS cases into satisfactory (Diagn Cytopathol 2016;44:737)
Cysts
- If the cyst has solid area, FNA should be performed from it
- Possibility of a cystic papillary thyroid carcinoma cannot be excluded
- Specimens from simple and unilocular cyst may be considered clinically adequate, even though they are reported as ND / UNS
- Simple cysts and < 3 cm cysts have low risk of malignancy (Diagn Cytopathol 2008;36:407, Cancer 2009;117:305, ANZ J Surg 2005;75:537, Pathol Annu 1991;26:63)
- Younger patients with only cystic fluid have a slightly higher risk of malignancy contributed by papillary thyroid carcinoma (Pathol Annu 1991;26:63, Thyroid 2009;19:341, Endocrine 2011;39:33)
- In some local reporting systems (Japan), cyst fluid only cases are reported as "adequate, cyst fluid only" because their risk of malignancy is almost the same as benign category and lower than ND / UNS category (Endocr J 2017;64:759)

Case reports

19 year old woman with intrathyroidal parathyroid cyst (Endocr Pathol 2011;22:108)
42 year old woman with intrathyroidal foregut cyst (Acta Cytol 2009;53:584)
45 year old woman with intrathyroidal thyroglossal duct cyst (Int J Clin Exp Pathol 2015;8:7229)
49 year old woman with a 4 cm autonomously hyperfunctioning cystic nodule harboring thyroid carcinoma (Int J Surg Case Rep 2018;42:287)
55 year old woman with cervical paraganglioma mimicking thyroid nodule (Case Rep Endocrinol 2016;2016:8527279)
Patient with intrathoracic goiter (Acta Cytol 1987;31:694)

Cytology description

Nondiagnostic / unsatisfactory sample

Gross of aspirated sample
- Invisible
- Abundant fresh blood
Cytology
- Poor cellularity causes difficulty in interpretation
- Abundant blood contamination causes difficulty in observing cytological findings
- Poor staining causes misinterpretation of the cytoplasmic and nuclear findings
- Air dried artifact causes difficulty in observing 3D structure and detailed nuclear findings

Cyst fluid only sample

Gross of aspirated sample
- Brownish liquid, sometimes glittering because of cholesterol crystals
Cytology
- Histiocytes and denatured red blood cells, sometimes cholesterol crystals, calcium oxalate crystals

Cytology images

Contributed by Ayana Suzuki, C.T.

Hemorrhagic background

Muscle

Respiratory epithelium

Air dried smear

Cyst fluid only

Images hosted on other servers:

Hemorrhagic background

Muscle

Air dried smear

Cyst fluid only

Poor staining

Videos

Thyroid FNA and smearing techniques

Essential thyroid cytopathology

Head and tail of the Bethesda system for thyroid

Thyroid cytology - Bethesda classification

Sample pathology report

Diagnosis / category: nondiagnostic
- Nondiagnostic specimen due to insufficient cellularity
- Note: a repeat FNA should be considered
Diagnosis / category: nondiagnostic
- Unsatisfactory aspirate due to poor fixation and preservation
- Note: a repeat FNA should be considered
Diagnosis / category: nondiagnostic, cyst fluid only
- Aspirate consists almost exclusively of histiocytes; interpretation is limited by insufficient follicular cells and / or colloid
- Note: can be rendered as benign after clinical and radiological correlation; a repeat FNA from the solid area can also be considered
Diagnosis / category: nondiagnostic
- Obscured by blood, no follicular cells seen
- Note: a repeat FNA should be considered

Board review style question #1

Which thyroid FNA cytologic appearance is classified as nondiagnostic / unsatisfactory?

≥ 6 groups of well visualized follicular cells
Abundant thick colloid
A few cells with cytological atypia
Foamy histiocytes only
Numerous inflammatory cells

Board review style answer #1

D. Foamy histiocytes only. When the aspirated material contains only foamy histiocytes and no follicular epithelium or colloid, it is qualified as nondiagnostic / unsatisfactory. However, in some local reporting systems (e.g. Japanese), these cases are reported as "adequate, cyst fluid only" because their malignancy risk is almost the same as the benign category and lower than the nondiagnostic / unsatisfactory category.

Comment Here

Reference: Nondiagnostic / unsatisfactory

Warthin-like

Table of Contents

Definition / general

Rare histological variant of papillary thyroid carcinoma (PTC), having favorable prognosis
Characterized by papillae lined by large oncocytic cells with nuclear features of PTC and prominent lymphoplasmacytic infiltrate within the papillary cores
Proposed by Apel et al. in 1995 (Am J Surg Pathol 1995;19:810)

Essential features

Histopathologically mimics Warthin tumor of salivary glands, i.e. the lining oncocytic epithelial cells and the abundant lymphoid stroma
Commonly associated with lymphocytic / Hashimoto thyroiditis

Terminology

Papillary carcinoma, Warthin-like variant
Microscopically resembles Warthin tumor of salivary glands, hence the name

ICD coding

ICD-O: 8260/3 - Papillary carcinoma of thyroid
ICD-10: C73 - Malignant neoplasm of thyroid gland

Epidemiology

Rare, 0.06 - 1.9% of all PTC (Med Ultrason 2019;21:152, Endocr J 2016;63:329)
Age: 18 - 77 years (Int J Endocrinol 2015;2015:456027)
Female preponderance, similar to other PTC (Int J Endocrinol 2015;2015:456027, ANZ J Surg 2016;86:492)

Sites

Either lobe or isthmus of thyroid gland

Clinical features

Usually asymptomatic / palpable neck mass (Med Ultrason 2019;21:152)
May also manifest with cervical nodal metastasis

Diagnosis

Diagnostic workup is similar to any thyroid mass / nodule
- Ultrasound with fine needle aspiration cytology (FNAC)
- CT scan may be useful to evaluate extrathyroidal extension and lymph node metastases
Final diagnosis is rendered on histopathological examination of resected tumor
- Accurate diagnosis of Warthin-like variant may not be possible on FNAC; however, preoperative recognition of Warthin-like PTC does not influence treatment decisions

Radiology description

Sonography:
- Solid, wider than tall and hypoechoic nodules (Med Ultrason 2019;21:152, Endocr J 2016;63:329)
- Margins: smooth / irregular / microlobulated
- Less commonly, punctate echogenic foci; taller than wide shape; cystic component
- American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) category 4 or 5 (Med Ultrason 2019;21:152)
  - Occasionally misdiagnosed as benign (Endocr J 2016;63:329)
- Color Doppler ultrasound: little or no internal vascularity
- Thyroid parenchyma: heterogeneous echogenicity, indicative of diffuse thyroiditis

Radiology images

Images hosted on other servers:

Ultrasound

Prognostic factors

Prognosis similar to classic PTC of similar size and stage or a more favorable prognosis (ANZ J Surg 2016;86:492, Int J Endocrinol 2015;2015:456027, Endocr J 2016;63:329, Med Ultrason 2019;21:152)
Rare reports of aggressive behavior in case of dedifferentiation (Case Rep Med 2010;2010:495281, Endocr Pathol 2005;16:83)
Risk stratification as per American Thyroid Association 2015 (Thyroid 2016;26:1)

Case reports

21 year old woman with Graves disease and a solitary thyroid nodule (J Cancer Res Ther 2015;11:652)
22 year old woman with a hypoechoic thyroid nodule (Case Rep Oncol Med 2012;2012:689291)
30 year old woman (Diagn Cytopathol 2017;45:837)
31 year old woman with a hypoechoic solid nodule (Korean J Pathol 2014;48:170)
36 year old woman with right neck tumor (Case Rep Endocrinol 2015;2015:251898)
47 year old woman with neck swelling (Cytopathology 2012;23:408)
50 year old woman with left lobe thyroid mass (Acta Cytol 1998;42:1437)
51 year old woman with simultaneous MALT lymphoma in a background of Hashimoto thyroiditis (J Clin Pathol 2010;63:662)
74 year old woman with anaplastic changes (Endocr Pathol 2005;16:83)
79 year old woman with a dedifferentiated component (Case Rep Med 2010;2010:495281)

Treatment

Based on American Thyroid Association guidelines (Thyroid 2016;26:1)
Also based on National Comprehensive Cancer Network guidelines (J Natl Compr Canc Netw 2018;16:1429)
Usually surgical excision, such as lobectomy or total thyroidectomy with or without neck dissection

Gross description

Usually solitary nodule, well circumscribed, unencapsulated and limited to the thyroid gland
Solid, red-brown to tan or gray-white, 3 - 50 mm (Case Rep Oncol Med 2012;2012:689291)
Variable cystic change, hemorrhagic areas, calcification
Background thyroid parenchyma: pale yellow to tan, variable nodularity (consistent with Hashimoto thyroiditis)

Gross images

Images hosted on other servers:

Solid, gray-white

Microscopic (histologic) description

Papillary architecture (Int J Endocrinol 2015;2015:456027)
- Heavy lymphoplasmacytic infiltrate in fibrovascular cores of papillae
Lining cells
- Oncocytic
- Large, polygonal
- Abundant eosinophilic cytoplasm
Nuclear features
- Prominent nuclear features of PTC
- Nuclear enlargement, grooves, chromatin clearing, intranuclear pseudoinclusions
- Inconspicuous nucleoli
Associated thyroiditis in 53 - 93% (J Pathol Transl Med 2018;52:105, ANZ J Surg 2016;86:492, Int J Endocrinol 2015;2015:456027)
Proportion of Warthin-like pattern to classify tumor as Warthin-like variant of PTC is not defined; supposed to be predominant
Variable psammoma bodies (J Cytol 2017;34:183)

Microscopic (histologic) images

Contributed by Andrey Bychkov, M.D., Ph.D.

Enlarged papillae

Lymphoid follicle

Oncocytic epithelium

Background thyroiditis

Ki67

Cytology description

Cellular aspirate with absent or scant colloid (Diagn Cytopathol 2019;47:1293)
Patterns (J Pathol Transl Med 2018;52:105, Acta Cytol 2019 Oct 21 [Epub ahead of print], Diagn Cytopathol 2019;47:1293)
- Papillary fragments
- Monolayered macrofollicular sheets
- Lymphocytes within the tumor cell clusters and in papillary stalks
Tumor cells
- Polygonal oncocytic cells
- Abundant dense cytoplasm, well defined cell margins
- Eccentric or centrally placed nuclei
- Well developed nuclear features of PTC
- Inconspicuous nucleoli
Background
- Lymphocytes, plasma cells, histiocytes
- Multinucleated giant cells
Usually Bethesda VI or V (Int J Endocrinol 2015;2015:456027, J Pathol Transl Med 2018;52:105, Diagn Cytopathol 2017;45:837)
- Rarely misdiagnosed as thyroiditis (Diagn Cytopathol 2017;45:837)
Liquid based cytology (Korean J Pathol 2014;48:170)
- Easily visualized tumor cells
- Minimal / absent lymphocytic background

Cytology images

Contributed by Shipra Agarwal, M.D.

Inflammatory background

Lymphocytic permeation

Oncocytic cells

Images hosted on other servers:

Liquid based cytology and conventional smear

Positive stains

Usually not needed; diagnosis is made on histology
Thyroid specific: TTF1, PAX8, thyroglobulin
Cytokeratins: AE1 / AE3, CK7, CK19
Galectin3 (Arch Pathol Lab Med 2002;126:710)
HBME1 (Pathol Oncol Res 2015;21:735)
MIB1 index 2 - 5% (Histopathology 2001;39:17)
Papillary cores: CD45, CD20, CD3 in lymphocytes; S100 dendritic / Langerhans cells (Histopathology 2001;39:17)

Negative stains

CK20
Calcitonin and neuroendocrine markers (synaptophysin, chromogranin)

Molecular / cytogenetics description

BRAF^V600E mutation in 65 - 75% (Int J Endocrinol 2015;2015:456027, Virchows Arch 2005;446:589)
RET / PTC fusion based on limited evidence (Histopathology 2000;36:493)

Sample pathology report

Thyroid, total thyroidectomy:
- Papillary thyroid carcinoma, Warthin-like variant, left lobe, 2.5 cm (see synoptic report)

Differential diagnosis

Oncocytic variant of PTC:
- Lacks lymphoplasmacytic infiltrate in the papillary stalks
Tall cell variant of PTC:
- Tumor cells have a height 2 to 3 times their width and constitute at least 30% of all tumor cells
- Papillary stalks lack the lymphocyte rich stroma
Classic type PTC with focal oncocytic change:
- Absent lymphoid stroma
- Only focal oncocytic change
Classic type PTC associated with lymphocytic / Hashimoto thyroiditis:
- Tumor cells lack oncocytic change
- Absent lymphoplasmacytic infiltrate in papillary cores
- May contain small areas of Warthin-like architecture (papillary cores stuffed with lymphoplasmacytic infiltrate), which is not sufficient to qualify the whole tumor as Warthin-like variant
Follicular neoplasm with oncocytic change:
- Lacks well developed nuclear features of PTC; round nuclei, prominent nucleoli and rare intranuclear inclusions
- Usually lacks papillae
- Absent stromal lymphoplasmacytic infiltrate in stalks of papillae
Hashimoto thyroiditis:
- Lacks papillae
- Oncocytic cells of Hashimoto thyroiditis have round nuclei with a prominent single nucleolus and lack well developed nuclear features of PTC
Cytology:
- Hürthle cell neoplasm:
  - Lacks papillary fragments, nuclear features of PTC and a lymphocytic background, except if associated lymphocytic thyroiditis
- Oncocytic PTC:
  - Usually lacks lymphocytic background, except if associated with lymphocytic thyroiditis
  - Cannot be differentiated on liquid based cytology
- Classic type PTC:
  - Lacks diffuse oncocytic change
  - Usually lacks lymphocytic background except if associated with lymphocytic thyroiditis
- Tall cell variant of PTC:
  - Tall columnar cells with cytoplasmic tails
- Hashimoto thyroiditis:
  - Lacks well developed nuclear features of PTC and papillary fragments

Board review style question #1

This thyroid tumor is named after which of the following salivary gland tumors?

Lymphadenoma
Oncocytic carcinoma
Oncocytoma
Sialadenoma papilliferum
Warthin tumor

Board review style answer #1

E. Warthin tumor. Warthin-like variant of papillary thyroid carcinoma is characterized on histomorphology by papillae lined by oncocytic cells and a dense lymphoplasmacytic infiltrate within the papillary cores, closely mimicking Warthin tumor of salivary gland. The latter shows oncocytic columnar cells with underlying basal cells, resting on a dense lymphoid stroma.

Comment Here

Reference: Warthin-like variant

Board review style question #2

Which of the following is typically associated with Warthin-like variant of papillary thyroid carcinoma?

Favorable clinical outcome
Frequent dedifferentiation
Mitochondrial DNA mutations
Multiple (soap bubble-like) intranuclear inclusions
Tumor cells have height 2 to 3 times the width

Board review style answer #2

A. Favorable clinical outcome. Warthin-like variant of papillary thyroid carcinoma (PTC) has a favorable clinical outcome and dedifferentiation is unusual. It harbours BRAF^V600E mutation in 65 - 75% cases. Mitochondrial DNA mutations are characteristic of oncocytic variant of PTC. Tumor cells having height 2 to 3 times the width is a diagnostic feature of tall cell variant of PTC. Multiple soap bubble-like intranuclear inclusions are typically described in tall cell variant of PTC but can be seen in other variants like hobnail variant also.

Comment Here

Reference: Warthin-like variant

WDT-UMP

Table of Contents

Definition / general

Follicular neoplasm with equivocal nuclear features of papillary thyroid carcinoma and questionable capsular or vascular invasion
Most cases behave in an indolent manner (Arch Pathol Lab Med 2006;130:984)
Diagnosis is based on morphologic criteria; immunostains are not reliable
Terminology was proposed by Chernobyl pathologists to avoid unnecessary aggressive treatment (Int J Surg Pathol 2000;8:181, Arch Pathol Lab Med 2006;130:984)

Essential features

Follicular neoplasm with equivocal nuclear features of papillary thyroid carcinoma and questionable capsular or vascular invasion

Diagrams / tables

Images hosted on other servers:

Schematic drawing for capsular invasion

Schematic drawing for vascular invasion

Prognostic factors

Excellent prognosis with lobectomy

Gross description

Well circumscribed or encapsulated solid nodule

Microscopic (histologic) description

Well circumscribed or encapsulated follicular neoplasm with equivocal nuclear features of papillary thyroid carcinoma and questionable capsular or vascular invasion

Microscopic (histologic) images

Contributed by Shuanzeng Wei, M.D., Ph.D.

Questionable nuclear features of papillary carcinoma

Cytology description

Can have subtle nuclear grooves, but no nuclear pseudoinclusion (Endocr J 2012;59:483)

Cytology images

Images hosted on other servers:

Cytological features of WDT-UMP

Positive stains

Can be positive for HBME1 (Mod Pathol 2005;18:541)

Differential diagnosis

Follicular tumor of uncertain malignant potential (FT-UMP): encapsulated follicular neoplasm with equivocal vascular or capsular invasion, without nuclear features of papillary carcinoma (Endocr Pathol 2005;16:279)
Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): encapsulated follicular neoplasm with nuclear features of papillary carcinoma, without vascular or capsular invasion (JAMA Oncol 2016;2:1023)

Additional references

Cancer Sci 2011;102:288, Virchows Arch 2009;455:21, Pathol Res Pract 2015;211:320, J Egypt Natl Canc Inst 2015;27:59, Rom J Morphol Embryol 2014;55:49

WHO classification

Table of Contents

WHO (2017) - Thyroid gland | WHO (2017) - Parathyroid gland | Diagrams / tables | Major Updates | Additional references

WHO (2017) - Thyroid gland

Tumours of the thyroid gland ICD 0 codes
- Follicular adenoma 8330/0
- Hyalinizing trabecular tumour 8336/1
- Other encapsulated follicular patterned thyroid tumours
  - Follicular tumours of uncertain malignant potential 8335/1
  - Well differentiated tumour of uncertain malignant potential8348/1
  - Noninvasive follicular thyroid neoplasm with papillary-like nuclear features 8349/1
- Papillary thyroid carcinoma
  - Papillary carcinoma8260/3
  - Follicular variant of PTC8340/3
  - Encapsulated variant of PTC8343/3
  - Papillary microcarcinoma8341/3
  - Columnar cell variant of PTC8344/3
  - Oncocytic variant of PTC8342/3
- Follicular thyroid carcinoma (FTC), NOS8330/3
  - FTC, minimally invasive8335/3
  - FTC, encapsulated angioinvasive8339/3
  - FTC, widely invasive8330/3
- Hürthle (oncocytic) cell tumours
  - Hürthle cell adenoma8290/0
  - Hürthle cell carcinoma8290/3
- Poorly differentiated thyroid carcinoma 8337/3
- Anaplastic thyroid carcinoma 8020/3
- Squamous cell carcinoma 8070/3
- Medullary thyroid carcinoma 8345/3
- Mixed medullary and follicular thyroid carcinoma 8346/3
- Mucoepidermoid carcinoma 8430/3
- Sclerosing mucoepidermoid carcinoma with eosinophilia 8430/3
- Mucinous carcinoma 8480/3
- Ectopic thymoma 8580/3
- Spindle epithelial tumour with thymus-like differentiation 8588/3
- Intrathyroid thymic carcinoma 8589/3
- Paraganglioma and mesenchymal / stromal tumours
  - Paraganglioma 8693/3
  - Peripheral nerve sheath tumours (PNSTs)
    - Schwannoma9560/0
    - Malignant PNST9540/3
  - Benign vascular tumours
    - Haemangioma9120/0
    - Cavernous haemangioma9121/0
    - Lymphangioma9170/0
  - Angiosarcoma 9120/3
  - Smooth muscle tumours
    - Leiomyoma8890/0
    - Leiomyosarcoma8890/3
  - Solitary fibrous tumour 8815/1
- Hematolymphoid tumours
  - Langerhans cell histiocytosis 9751/3
  - Rosai-Dorfman disease
  - Follicular dendritic cell sarcoma 9758/3
  - Primary thyroid lymphoma
- Germ cell tumours
  - Benign teratoma9080/0
  - 9080/1 Immature teratoma9080/1
  - 9080/3 Malignant teratoma9080/3
- Secondary tumours

ICD 0 note: the first four digits indicate the specific histological term; the fifth digit after the slash (/) is the behavior code, including /0 for benign tumors, /1 for unspecified, borderline or uncertain behavior, /2 for carcinoma in situ and grade III intraepithelial neoplasia (not used for adrenal tumors), and /3 for malignant tumors

WHO (2017) - Parathyroid gland

Tumours of the parathyroid glands ICD 0 codes
- Parathyroid carcinoma 8140/3
- Parathyroid adenoma 8140/0
- Secondary, mesenchymal and other tumours

ICD 0 note: the first four digits indicate the specific histological term; the fifth digit after the slash (/) is the behavior code, including /0 for benign tumors, /1 for unspecified, borderline or uncertain behavior, /2 for carcinoma in situ and grade III intraepithelial neoplasia (not used for adrenal tumors), and /3 for malignant tumors
References: Lloyd: WHO Classification of Tumours of Endocrine Organs (IARC WHO Classification of Tumours), Fourth Edition, 2017

Diagrams / tables

Contributed by Andrey Bychkov, M.D., Ph.D.

WHO classification: thyroid tumors

Major Updates

A group of borderline thyroid tumors has been introduced for the first time:
1. FT - UMP (follicular tumor of uncertain malignant potential)
2. WDT - UMP (well differentiated tumor of uncertain malignant potential)
3. NIFTP (noninvasive follicular thyroid neoplasm with papillary nuclear features)
Borderline tumors ("not cancer yet") are equivalent to carcinoma in situ in other organs; they are placed between follicular adenoma and follicular carcinoma or follicular variant of papillary carcinoma
Papillary thyroid carcinoma (PTC) variants:
1. Conventional / classic variant
2. Papillary microcarcinoma
3. Encapsulated PTC – applicable to fully encapsulated classic PTC
4. Follicular variant – PTC with an exclusively or almost exclusively follicular pattern, and no developed papillae
5. Diffuse sclerosing variant
6. Tall cell variant
7. Columnar cell variant
8. Cribriform-morular variant
9. Hobnail variant – new entity
10. PTC with fibromatosis/fascitiis-like stroma
11. Solid/trabecular variant
12. Oncocytic variant
13. Spindle cell variant
14. Clear cell variant
15. Warthin like variant
Follicular thyroid carcinoma (FTC) groups:
1. Minimally invasive FTC – capsular invasion only
2. Angioinvasive FTC
3. Widely invasive FTC – grossly invasive
Hürthle cell (oncocytic) tumors as a separate entity:
- include Hürthle cell adenoma and Hürthle cell carcinoma
- previously classified as oncocytic variant of follicular adenoma and FTC
- term "Hürthle" is favored over "oncocytic"
Poorly differentiated thyroid carcinoma:
- Turin criteria were adopted
Anaplastic thyroid carcinoma:
- "anaplastic" is favored over "undifferentiated"

Additional references

Recent Thyroid & parathyroid Pathology books

Adeniran: 2016

Ali: 2023

Boerner: 2016

Braverman: 2020

Duick: 2018

Gill: 2022

Gnepp: 2020

IARC: 2017

Jiang: 2023

Kakudo: 2024

Kini: 2015

Mete: 2016

Mody: 2022

Nikiforov: 2019

Nosé: 2022

Rosai: 2015

Stelow: 2020

Thompson: 2022

Wartofsky: 2016

Wenig: 2024

Find related Pathology books: cytopathology, head & neck/endocrine, GU/adrenal, GI

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