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Acute / infectious thyroiditis
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
Diagnosis
  • Usually based on serologic tests
Case reports
Treatment
  • Drainage, antibiotics, fistulectomy
Gross description
  • Normal or slightly enlarged thyroid gland
  • May have suppurative areas
Gross images

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Aspergillus septic foci

Microscopic (histologic) description
  • Neutrophils, possibly microabscesses and tissue necrosis
  • Fungi are associated with necrosis, acute inflammation and granulomas
Cytology images

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Aspergillus

Nocardia

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

Adequacy
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



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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?

  1. 3 groups with 10 follicular cells
  2. Abundant thick colloid only
  3. Air dried specimen without any atypical cells
  4. Foamy histiocytes only
  5. 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
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):
  1. Age cutoff used for staging was increased from 45 to 55 years at diagnosis
  2. 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
  3. 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
  4. T3a is a new category for tumors > 4 cm confined to the thyroid gland
  5. T3b is a new category for tumors of any size demonstrating gross extrathyroidal extension into strap muscles (sternohyoid, sternothyroid, thyrohyoid or omohyoid muscles)
  6. 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
  7. 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):
  1. 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
  2. Intrathyroidal disease is stage IVA, gross extrathyroidal extension or cervical lymph node metastases are stage IVB and distant metastases are stage IVC
Diagrams / tables

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

AJCC / TNM charts



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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?

  1. Stage I
  2. Stage II
  3. Stage III
  4. Stage IVA
  5. 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?

  1. pT1N0
  2. pT1aN1a
  3. pT1bN1a
  4. pT2N1a
  5. 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

Amiodarone induced hyperthyroidism
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
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:
  • 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
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:
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



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Missing Image

Amiodarone induced thyrotoxicosis

Electron microscopy description

Amyloid goiter
Definition / general
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
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



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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



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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
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?

  1. Can be seen in renal transplant patients on dialysis
  2. Commonly seen in males
  3. Is associated with medullary thyroid carcinoma
  4. Microscopically shows diffuse deposition of amyloid
  5. 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
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
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
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

Molecular landscape

Treatment of stage IVA - B

Treatment of stage IVA - B

Treatment of stage IVC

Treatment of stage IVC

Clinical features
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
  • Computed tomography scan
Radiology images

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Neck CT, FDG PET scan, sonography

Neck CT, FDG PET scan, sonography

Neck CT Neck CT

Neck CT

Neck CT

Neck CT

CT for staging

CT for staging

FDG PET before / after therapy

FDG PET before / after therapy

Prognostic factors
Case reports
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

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

Variegated, fleshy

Large, tan, fleshy mass with hemorrhage

Large, tan, fleshy mass with hemorrhage

Metastases to stomach with ulcerated center

Metastases to stomach with ulcerated center



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Diffusely infiltrative, fleshy

Diffusely infiltrative, fleshy

Gray-white, 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
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

Malignant spindle cells

Nuclear hyperchromasia and pleomorphism

Nuclear hyperchromasia and pleomorphism

Squamoid cells

Squamoid cells

Tumor giant cells

Tumor giant cells

Angiomatoid pattern

Angiomatoid pattern

Neck muscle infiltration

Neck muscle infiltration


Angioinvasion

Angioinvasion

Associated papillary thyroid carcinoma

Associated papillary thyroid carcinoma

Anaplastic carcinoma and adjacent papillary thyroid carcinoma Anaplastic carcinoma and adjacent papillary thyroid carcinoma

Anaplastic carcinoma and adjacent papillary thyroid carcinoma

Anaplastic carcinoma with necrosis and inflammation Anaplastic carcinoma with necrosis and inflammation

Anaplastic carcinoma with necrosis and inflammation


Malignant spindle cells Malignant spindle cells

Malignant spindle cells

AE1 / AE3 AE1 / AE3

AE1 / AE3

CK903 CK903

CK903


Keratin stains many mesenchymal-like tumor cells

Keratin stains many mesenchymal-like tumor cells

Thyroglobulin stain

Thyroglobulin stain

Virtual slides

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Epithelioid pattern, ATC

Epithelioid pattern, ATC

Sarcomatoid 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

Necroinflammatory
background

Atypical mitoses

Atypical mitoses

Epithelioid pattern

Epithelioid pattern

Sarcomatoid variant

Sarcomatoid variant

Differentiated thyroid carcinoma component

Differentiated thyroid carcinoma component

Pleomorphism

Pleomorphism

Positive stains
Negative stains
Molecular / cytogenetics description
Molecular / cytogenetics images

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Hierarchical clustering

Hierarchical clustering

Genetic alterations

Genetic alterations

Involved molecular pathways

Involved molecular pathways

Recurrent MSK-IMPACT derived copy number alterations

Recurrent MSK-IMPACT derived copy number alterations

Increased mutation burden

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
Board review style question #1

    A 72 year old woman presented with a hoarse voice and rapid enlargement of neck mass of 3 months' duration. Radiology revealed lumbar vertebral metastases. Cytological examination from the low anterior neck mass showed a tumor composed of mitotically active pleomorphic polygonal and spindle cells in a necrotic and inflammatory background. Incisional biopsy revealed a malignant spindle cell tumor. What is the most likely diagnosis?

  1. Anaplastic thyroid carcinoma
  2. Follicular thyroid carcinoma
  3. Metastatic carcinoma to thyroid gland
  4. Papillary thyroid carcinoma
  5. 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
    Which of the following immunohistochemical profiles best defines anaplastic thyroid carcinoma?

  1. TTF1 negative, thyroglobulin negative, CD5 positive, CD117 positive
  2. TTF1 negative, thyroglobulin negative, PAX8 positive, cytokeratin positive
  3. TTF1 negative, thyroglobulin negative, S100 positive, HMB45 positive
  4. TTF1 positive, thyroglobulin negative, PAX8 negative, calcitonin positive
  5. 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
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
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
Gross images

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Surgical specimen

Levator glandulae thyroideae

Microscopic (histologic) images

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

Pyramidal lobe

Videos

Thyroid anatomy


Anatomy & histology-parathyroid
Definition / general
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
  • 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

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Embryological pathway of parathyroid migration

Anatomy

Anatomy

Laboratory
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

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
  • 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 Normal parathyroid gland

Normal parathyroid gland

Chief cells Chief cells

Chief cells


Oxyphils cells Oxyphils cells

Oxyphil cells

Transitional cells

Transitional cells

Water clear cells

Water clear cells

Colloid type material, without oxalate crystals

Colloid type material, without oxalate crystals

Virtual slides

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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
Negative stains
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?

  1. Chief cell
  2. Oxyphil cell
  3. Transitional cell
  4. 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?

  1. Ectopic glands
  2. Fetal glands
  3. Normal adult glands
  4. 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
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
Case reports
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
Negative stains
Differential diagnosis

Aplasia / hypoplasia
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)
  • 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
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:
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:
Hypoplasia
Hemiagenesis
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
Microscopic (histologic) images

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Hashimoto thyroiditis in
thyroid hemiagenesis

Cytology description
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
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

AUS
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
Diagnosis
Case reports
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.
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Cytologic atypia

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Architectural atypia

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Hürthle cell atypia

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Atypical lymphocytes



Images hosted on other servers:
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Cytologic atypia


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Atypical cyst lining cells

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Architectural atypia

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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 (< 20 cells) with enlarged, often overlapping, nuclei, pale chromatin, irregular nuclear outlines and nuclear grooves
    • 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
      Which case belongs to architectural atypia?

    1. A sparsely cellular aspirate comprised of Hürthle cells with minimal colloid
    2. Atypical lymphoid cells
    3. Focally prominent microfollicles with minimal nuclear atypia
    4. Most of the aspirate appears benign but rare cells have irregular nuclear contours
    5. 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

      A 70 year old man underwent FNA for the nodule of the thyroid right lobe. A cytological image of the lesion is shown. Which marker would most likely show positive staining?

    1. PAX8
    2. Calcitonin
    3. GATA3
    4. Thyroglobulin
    5. 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
    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
    Clinical features
    • May be due to disturbance in suppressor T cells

    Benign
    Definition / general
    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
    Prognostic factors
    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
    • 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
    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
    Board review style question #1
    What risk of malignancy is associated with benign thyroid cytology?

    1. 0 - 3%
    2. 5 - 10%
    3. 12 - 15%
    4. 20 - 30%
    5. 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
    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
    • 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 2017

    TBS metrics

    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:
    • 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

    Board review style question #1

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

    1. Atypia of undermined significance / follicular lesion of undetermined significance
    2. Benign
    3. Follicular neoplasm / suspicious for a follicular neoplasm
    4. Malignant
    5. 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?

    1. Follow up
    2. Molecular testing
    3. Reaspiration
    4. Thyroid lobectomy
    5. 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
    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
    Pathophysiology
    Clinical features
    Diagnosis
    Case reports
    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
    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
    Negative stains
    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

    Branchial pouch / cleft anomalies
    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
    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:
    Missing Image

    Branchial apparatus

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    Branchial cleft anomalies location

    Missing Image

    Anatomical relations

    Clinical features
    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:
    Missing Image

    Cystic lesion in left parotid gland

    Missing Image

    CT fistulogram

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    CT fistulogram

    Missing Image

    Infrahyoid cyst

    Prognostic factors
    Case reports
    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:
    Missing Image

    Fistula opening (1st branchial cleft anomaly)

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    First branchial cleft fistula opening

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    Bilateral fistula opening

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    Saliva coming out, third branchial fistula


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    Fistula opening above sternocleidomastoid muscle

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    Sinus originating from pyriform sinus

    Missing Image

    With cervical abscess

    Missing Image

    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:
    Missing Image

    Fistula tract

    Missing Image

    Fistula tract ending in parotid gland

    Missing Image

    Collaural fistula

    Missing Image

    Third branchial fistula

    Missing Image

    Fistula tract exiting pharynx

    Missing Image

    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:
    Missing Image

    Cyst lined by stratified squamous epithelium

    Missing Image

    Sinus tract in parotid gland

    Missing Image

    Cyst wall with chronic inflammation

    Missing Image

    Fibrotic wall of a cyst

    Missing Image

    Lymphoid aggregates in cyst wall

    Missing Image

    Ciliated pseudostratified columnar epithelium

    Virtual slides

    Images hosted on other servers:
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    Case 10, right neck node

    Cytology description
    Cytology images

    Images hosted on other servers:
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    Squamous cells, keratin debris

    Missing Image

    High power

    Missing Image

    Pap stain

    Missing Image

    Inflammation

    Missing Image

    Cholesterol crystals

    Videos

    Pharyngeal pouches

    Differential diagnosis

    C cell hyperplasia
    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
    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
    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
    Negative stains
    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
    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)
    Board review style question #1
      Which of the following statements are not true of C cell hyperplasia?

    1. C cells are found along the entire longitudinal axis of the thyroid lobe
    2. Neoplastic C cell hyperplasia can be detected in H&E stains
    3. Patients with a thyroid mass and hypercalcinemia may have something other than MTC
    4. Reactive and neoplastic C cell hyperplasia are biologically and morphologically distinct
    5. 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
    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
    Case reports
    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
    Differential diagnosis

    Children
    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
    Clinical features
    • Regional nodal metastases occur in 60 - 80%, distant metastases in 10 - 20% at diagnosis, often lung
    Prognostic factors
    Case reports
    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)


    Clear cell
    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
    Clinical features
    • Neck mass
    • May have obstructive symptoms
    Diagnosis
    • Neck ultrasound
    • Fine needle aspiration
    • Hemithyroidectomy versus complete thyroidectomy
    Prognostic factors
    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
    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
    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
    Board review style question #1

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

    1. Clear cell papillary thyroid carcinoma
    2. Columnar papillary thyroid carcinoma
    3. Hobnail papillary thyroid carcinoma
    4. Solid papillary thyroid carcinoma
    5. 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
    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
    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
    Electron microscopy images

    AFIP images

    Signet ring follicular adenoma

    Marked dilation of cisternae

    Differential diagnosis

    Columnar cell
    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
    Sites
    • Lateral lobes or isthmus of thyroid gland
    Clinical features
    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
    Radiology images

    Images hosted on other servers:

    Ultrasound

    Prognostic factors
    Case reports
    Treatment
    Gross description
    Gross images

    Images hosted on other servers:

    Circumscribed and infiltrative

    Microscopic (histologic) description
    Microscopic (histologic) images

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

    Papillary pattern

    Pseudostratification

    Tightly packed

    Invasive

    High Ki67

    Cytology description
    Cytology images

    Contributed by Ayana Suzuki, C.T.

    Papillary fragments

    Nuclear features

    Positive stains
    Negative stains
    Molecular / cytogenetics description
    Sample pathology report
    • Thyroid, total thyroidectomy:
      • Papillary thyroid carcinoma, columnar cell variant, right lobe, 5.5 cm (see synoptic report)
    Differential diagnosis
    Board review style question #1

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

    1. TTF1+, PAX8+, CDX2+
    2. TTF1+, PAX8+, CDX2-
    3. TTF1+, PAX8-, CDX2+
    4. TTF1-, PAX8+, CDX2-
    5. 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?

    1. An indolent clinical course
    2. Abundant oncocytic cytoplasm
    3. Multiple intranuclear pseudoinclusions
    4. One of the most common variants of papillary thyroid carcinoma
    5. 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
    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
    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
    Diagnosis
    Laboratory
    Radiology description
    Case reports
    Treatment
    Gross description
    Microscopic (histologic) description
    Cytology description
    Differential diagnosis
    Additional references

    Cribriform-morular thyroid carcinoma
    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
    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
    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
    Diagnosis
    • Diagnosis may be done or suggested either preoperatively using thyroid FNA or (more commonly) postoperatively with histologic evaluation and immunohistochemical confirmation
    Laboratory
    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
    Case reports
    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
    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


    Squamoid morules

    Hallmark feature

    19 year old woman with right sided neck swelling

    Papillary and cribriform architecture

    Papillary and cribriform architecture


    Scattered squamous morules

    Scattered squamous morules

    Scattered mitotic figures

    Scattered mitotic figures

    Multifocal tumor necrosis

    Multifocal tumor necrosis

    CK5/6

    TTF1


    TTF1

    TTF1

    PAX8

    PAX8

    Thyroglobulin

    Thyroglobulin

    Beta catenin


    Beta catenin

    Beta catenin

    Estrogen receptor

    Estrogen receptor

    CD10

    CD10

    CDX2

    CDX2

    Virtual slides

    Images hosted on other servers:

    Cribriform-morular thyroid carcinoma

    Cytology description
    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

    Electron microscopy description
    Molecular / cytogenetics description
    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: < 1 mm
        • 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
    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?

    1. Cardiac myxoma
    2. Colorectal carcinoma
    3. Pheochromocytoma
    4. Pleuropulmonary blastoma
    5. 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).

    Comment Here

    Reference: Cribriform-morular thyroid carcinoma
    Board review style question #2
    What is the beta catenin immunohistochemical staining pattern in cribriform-morular thyroid carcinoma (CMTC)?

    1. Diffuse cytoplasmic and nuclear positivity
    2. Loss of nuclear staining
    3. Membranous, cytoplasmic and Golgi staining
    4. Stippled nuclear staining
    5. 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.

    Comment Here

    Reference: Cribriform-morular thyroid carcinoma
    Board review style question #3
    Which of the following statements about cribriform-morular thyroid carcinoma is true?

    1. It does not occur in a familial setting
    2. It is a subtype (variant) of papillary thyroid carcinoma
    3. It typically is negative for thyroglobulin and PAX8
    4. 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.

    Comment Here

    Reference: Cribriform-morular thyroid carcinoma

    Crystals
    Definition / general
    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
    Pathophysiology
    Diagnosis
    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
    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
    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
    Board review style question #1
    How are calcium oxalate crystals useful in frozen sections from thyroid and parathyroid?

    1. Differentiate cancer from benign tissue
    2. Distinguishing thyroid from parathyroid tissue
    3. Helps to locate psammoma bodies
    4. Identify age of patient
    5. 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.

    Comment Here

    Reference: Crystals

    Differentiated high grade thyroid carcinomas (pending)
    Definition / general
    Essential features
    Differential diagnosis

    Diffuse follicular
    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

    Diffuse sclerosing
    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
    Sites
    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
    Clinical features
    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
    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 of DSV PTC Ultrasonographic features of DSV PTC Ultrasonographic features of DSV PTC

    Ultrasonographic features

    Prognostic factors
    Case reports
    Treatment
    Gross description
    Gross images

    AFIP images
    Diffuse growth and fibrosis

    Diffuse growth and fibrosis



    Images hosted on other servers:
    Fibrotic cut surface

    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
    Microscopic (histologic) images

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

    Lymphocytic infiltrate

    Papillary pattern

    Papillary pattern

    Dense fibrosis

    Dense fibrosis

    Dense sclerosing fibrosis

    Dense sclerosing fibrosis


    Infiltrative growth

    Infiltrative growth

    Nuclear features

    Nuclear features

    Psammoma bodies and sclerosis Psammoma bodies and sclerosis

    Psammoma bodies and sclerosis

    Solid pattern

    Solid pattern


    Squamous morule Squamous morule

    Squamous morule

    Lymphovascular invasion

    Lymphovascular invasion

    Lymph node metastasis Lymph node metastasis

    Lymph node metastasis



    Contributed by Andrey Bychkov, M.D., Ph.D.
    Multiple tumor nodules

    Multiple tumor nodules

    Fibrosis and lymphocytic infiltration

    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

    3D ball-like clusters

    Protruding hobnail cells

    Protruding hobnail cells

    Squamous metaplasia

    Squamous metaplasia

    Cytological atypia

    Cytological atypia

    3D ball-like clusters

    3D ball-like clusters

    Psammoma body

    Psammoma body


    Cytological and architectural atypia

    Cytological and architectural atypia

    Cytological atypia

    Cytological atypia

    Cytological and architectural atypia

    Cytological and architectural atypia

    Psammoma bodies and lymphocytes

    Psammoma bodies and lymphocytes

    Nuclear features

    Nuclear features

    Psammoma bodies and lymphocytes

    Psammoma bodies and lymphocytes

    Positive stains
    Molecular / cytogenetics description
    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)?

    1. Extrathyroidal extension and lymph node metastasis are usually not detected
    2. Not considered an aggressive type of papillary thyroid carcinoma
    3. Patients are usually older than those with classical papillary thyroid carcinoma
    4. Presents as a solitary thyroid nodule in which calcifications are infrequent
    5. 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?

    1. ALK translocation
    2. BRAF V600E mutation
    3. ETV6 / NTRK rearrangement
    4. RAS mutation
    5. 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
    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
    Radiology images

    Images hosted on other servers:

    Absent thymus on CT

    Subglottic stenosis on CT

    Basal ganglia and periventricular calcification

    Case reports
    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
    Microscopic (histologic) description
    Microscopic (histologic) images

    Images hosted on other servers:

    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):

    Dyshormonogenetic goiter
    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
    Epidemiology
    • Rare inherited disorder with incidence of 1 per 30 - 50K live births in Europe and North America
    • 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

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    Ultrasound of fetal goiter

    Ultrasound of 26 year old man

    Various defects
    on scintigraphy
    (NIS, TPO and PDS)

    Scintigraphy

    Case reports

    Cancers in dyshormonogenetic goiter
    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

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    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

    Scroll to see all images:


    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
    Positive stains
    Negative stains
    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+
    Board review style question #1
    Dyshormonogenetic goiter is characterized by all of the following except:

    1. Decreased T3, T4 and increased TSH
    2. Family history of hypothyroidism or goiter in 20% cases
    3. Highly atypical pleomorphic and hyperchromatic nuclei in internodular areas
    4. Increased T3, T4 and decreased TSH
    5. 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?

    1. Capsular invasion of the nodules
    2. Highly atypical pleomorphic and hyperchromatic (bizarre) nuclei
    3. Large areas of necrosis
    4. Orphan Annie nuclei
    5. 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
    Definition / general
    Sites
    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



    Images hosted on other servers:

    Thymic tissue contains a mass of parathyroid cells


    Ectopic thyroid tissue
    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:
    • 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

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    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
    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

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    Neck CT


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    Radionuclide scan

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    Abdominal MRI


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    Head MRI

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    Chest CT

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    Intracardiac thyroid

    Prognostic factors
    • Prognosis is good: there is a very low chance of recurrence after surgical excision
    Case reports
    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
    Gross images

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    Submental mass

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    Ectopic thyroid, lateral neck

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    Intratracheal thyroid tissue, hyperplasia

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    Mediastinal mass

    Missing Image

    Cystic mass, adrenal gland

    Microscopic (histologic) description
    Microscopic (histologic) images

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

    Perithyroid thyroid follicles



    Images hosted on other servers:
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    Benign conditions

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    Ectopic vs. orthotopic thyroid

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    Posterior mediastinal mass

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    Adrenal mass


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    Adrenal mass, IHC

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    Adenoma, ectopic thyroid


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    PTC arising in ectopic thyroid

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    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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    Missing Image

    Follicular cells

    Positive stains
    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
    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
    • 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
    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)
      • 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
    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
    Developmental abnormalities
    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

    Board review style question #1
    Which of the following are the main genes involved in regulation of thyroid development?

    1. BRAF, TP53, TERT
    2. HRas, NRAS, KRAS
    3. NKX2-1, FOXE1, PAX8, HHEX
    4. PAX6, ASPM, KATNB1, TUBB5
    5. 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. 1 lateral and 2 medial anlagen
    2. 1 medial, 1 lateral and 2 intermediate anlagen
    3. 1 medial and 1 lateral anlagen
    4. 1 medial and 2 lateral anlagen
    5. 2 lateral anlagen only
    Board review style answer #2
    D. 1 medial and 2 lateral anlagen

    Comment Here

    Reference: Embryology

    Encapsulated
    Definition / general
    • Papillary carcinoma totally surrounded by a capsule
    • 8 - 13% of papillary carcinomas
    Prognostic factors
    Case reports
    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

    Encapsulated follicular
    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
    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
    Epidemiology
    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

    Board review style question #1
    Which statement regarding endemic goiter is false?

    1. Increases risk for follicular neoplasm
    2. Increases risk for papillary neoplasm
    3. May cause tracheal compression
    4. 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
    Definition / general
    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
    • Angioinvasion (vascular invasion)
      • Present
      • Absent
      • Cannot be determined
      • CAP note: extent of invasion can be optionally reported as focal (< 4 vessels) or extensive (≥ 4 foci)
      • 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:
    • Size of the largest metastatic deposit, in centimeters
      • Comment: micrometastases (< 2 mm and less than 5 involved nodes) likely do not increase risk of locoregional recurrence
    • 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

    Diagrams / tables

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

    AJCC / TNM charts

    Missing Image

    ATA initial stratification

    Missing Image

    WHO classification



    Images hosted on other servers:
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    Levels of the cervical lymph nodes

    Pattern of nodal metasatasis

    Missing Image

    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

    Missing Image

    Vascular invasion


    Vascular invasion

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    Psammoma bodies

    Missing Image

    Microscopically positive margin

    Missing Image

    Extrathyroidal extension


    Extrathyroidal extension

    Missing Image

    Extrathyroidal extension


    Extrathyroidal extension

    Missing Image

    Extranodal extension

    Videos

    Extrathyroidal extension by J. Hernandez-Prera (2020)

    Sample of case summary
      Thyroid, total thyroidectomy:
    • 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)
    Board review style question #1
      Which histopathologic feature is not mandatory to report according to the CAP thyroid protocol?

    1. Extranodal extension
    2. Histologic type
    3. Lymphatic invasion
    4. Perineural invasion
    5. 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
    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
    ICD coding
    • ICD-O: 8260/3 - Papillary carcinoma of thyroid
    • ICD-10: C73 - Malignant neoplasm of thyroid gland
    Epidemiology
    Sites
    • Either lobe or isthmus of thyroid gland
    Pathophysiology
    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
    Case reports
    Treatment
    Gross description
    Gross images

    Images hosted on other servers:

    Well demarcated, solid

    Fibrotic nodule

    Frozen section description
    Microscopic (histologic) description
    • Mixed epithelial-mesenchymal tumor
    • Epithelial component:
    • 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

    Stromal fragment

    Positive stains
    Negative stains
    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
    Board review style question #1

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

    1. BRAF V600E mutation in epithelial component
    2. EWSR1 fusions
    3. CTNNB1 (beta catenin) mutation in mesenchymal component
    4. HRAS mutation in epithelial component
    5. 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?

    1. Aggressive clinical course
    2. Fibromatosis may recur postthyroidectomy
    3. Only the epithelial component can metastasize
    4. Membranous expression of beta catenin in both epithelial and mesenchymal elements
    5. 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
    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

    Ultrasound FNA techniques



    Images hosted on other servers:
    Risk based on appearance and nodule characteristics

    Risk based on appearance and nodule characteristics

    Technique

    Technique

    Short, rapid strokes with only slight changes in direction

    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
    Radiology description
    Radiology images
    Case reports
    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
    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 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
    • 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
    Microscopic (histologic) description
    Microscopic (histologic) images

    Contributed by Andrey Bychkov, M.D., Ph.D. and AFIP
    FNA induced alterations in thyroid nodule

    FNA induced alterations in thyroid nodule

    Pseudo angiosarcomatous pattern

    Pseudo angiosarcomatous pattern

    Fine needle induced changes in follicular adenoma

    Fine needle
    induced changes
    in follicular
    adenoma

    Molecular / cytogenetics description
    Molecular / cytogenetics images
    Videos

    FNA biopsy techniques

    Thyroid FNA and smearing techniques

    Superficial FNA technique

    Board review style question #1
    What type of sample is evaluated during a rapid on site evaluation of a thyroid fine needle aspiration?

    1. Air dried stained slide
    2. Cell block material
    3. Core biopsy slide
    4. SurePath slide
    5. 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?

    1. First biopsy of the specific lesion in question
    2. Patient referred specifically for fine needle aspiration with rapid on site evaluation
    3. Predominantly solid nodule
    4. Superficial thyroid nodule > 1 cm
    5. 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
    Definition / general
    • Focal lymphocytes in thyroid gland
    • Usually an incidental finding
    Epidemiology
    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
    Electron microscopy images

    Images hosted on other servers:

    Coarsely
    condensed
    chromatin at
    nuclear periphery


    Follicular adenoma
    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
    Sites
    • Either thyroid lobe, isthmus, ectopic thyroid tissue
    Etiology
    Diagrams / tables

    Images hosted on other servers:
    Diagnostic

    Diagnostic capsular invasions

    Incomplete (questionable) capsular invasions in uncertain malignant potential

    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
    Radiology images

    Images hosted on other servers:
    Ultrasound Ultrasound

    Ultrasound

    Ultrasound

    Ultrasound

    Color doppler sonogram Color doppler sonogram

    Color Doppler sonogram


    Color doppler sonogram Color doppler sonogram Color doppler sonogram

    Color Doppler sonogram

    Prognostic factors
    • Benign tumor
    Case reports
    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

    Capsule & compressed thyroid

    Mixed micro and normofollicular pattern

    Mixed micro and normofollicular pattern

    Hyperchromatic, small round nuclei

    Hyperchromatic, small round nuclei

    Abundant crystals of calcium oxalate

    Abundant crystals of calcium oxalate

    Calcium oxalate crystals

    Calcium oxalate crystals


    Processing artifact with distorted nuclei

    Processing artifact with distorted nuclei

    Distorted nuclei due to technical / processing artifact

    Distorted nuclei due to technical / processing artifact

    Tissue degeneration

    Tissue degeneration

    Circumscribed thyroid nodule

    Cellular follicular adenoma

    Cellular follicular adenoma


    Cellular follicular adenoma

    Cellular follicular adenoma

    Trabecular type Trabecular type

    Trabecular type

    Trabecular type Trabecular type

    Trabecular type


    Thin and uniform fibrous capsule

    Thin and uniform fibrous capsule

    Marked fibrosis and stromal hyalinization

    Marked fibrosis and stromal hyalinization

    Marked hyaline thickening of vessel walls

    Marked hyaline thickening of vessel walls

    Marked fibrosis, hyalinization and calcium deposition

    Marked fibrosis, hyalinization and calcium deposition

    Marked vascularization

    Marked vascularization

    Capsular vessel with smooth muscle cells

    Capsular vessel with smooth muscle cells


    Bizarre nuclei

    Bizarre nuclei

    Large, extremely irregular nuclei

    Large, extremely irregular nuclei

    With papillary hyperplasia With papillary hyperplasia

    With papillary hyperplasia

    With papillary hyperplasia and adipose metaplasia

    With papillary hyperplasia and adipose metaplasia

    Cartilaginous metaplasia (adenochondroma)

    Cartilaginous metaplasia (adenochondroma)


    Prominent, clear cell change

    Prominent, clear cell change

    Squamous metaplasia

    Squamous metaplasia

    Mucin production

    Mucin production

    Thyroglobulin+

    Thyroglobulin+

    Alcian blue+

    Alcian blue+



    Patterns:
    Solid, trabecular, microfollicular, macrofollicular patterns

    Solid, trabecular, microfollicular, macrofollicular patterns

    Left: macrofollicular, right: solid pattern

    Left: macrofollicular, right: solid pattern

    Signet ring

    Signet ring

    Atypical adenomas:
    Markedly cellular with irregular growth

    Markedly cellular with irregular growth

    Well formed follicles merge with solid pattern

    Well formed follicles merge with solid pattern

    Spindle cells mix with round cells

    Spindle cells mix with round cells



    Not invasion:
    Fine needle induced changes resemble 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

    Cellular aspirate

    Microfollicles and small round nuclei

    Microfollicles and small round nuclei

    Microfollicles

    Microfollicles



    Images hosted on other servers:
    Microfollicular Microfollicular

    Microfollicular

    Microfollicular Microfollicular

    Microfollicular

    Microfollicular

    Microfollicular


    FNA

    FNA

    Round hyperchromatic nuclei

    Round hyperchromatic nuclei

    FNAC

    FNAC

    Thyroid neoplasms

    Thyroid neoplasms

    Positive stains
    Negative stains
    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
    Molecular / cytogenetics images

    Images hosted on other servers:
    Gene expression analysis

    Gene expression analysis

    CNV landscape of thyroid tumors

    CNV landscape of thyroid tumors

    Driver mutations in thyroid tumors

    Driver mutations in thyroid tumors

    Driver mutations and pathway analyses

    Driver mutations and pathway analyses

    Microarray and qRT PCR

    Microarray and qRT PCR


    Expression ratios of CRABP1, FABP4 and HMGA2

    Expression ratios of CRABP1, FABP4 and HMGA2

    Clinicopathological features and mutation spectrum

    Clinicopathological features and mutation spectrum

    Hierarchical clustering Hierarchical clustering Hierarchical clustering

    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
    Board review style question #1

    Which of the following best describes this thyroid tumor?

    1. Benign, completely encapsulated, lacks nuclear features of papillary thyroid carcinoma, absent capsular and vascular invasion
    2. Benign, partially encapsulated, lacks nuclear features of papillary thyroid carcinoma, absent capsular and vascular invasion
    3. Malignant, encapsulated, lacks nuclear features of papillary thyroid carcinoma, capsular invasion present
    4. Uncertain malignant potential, completely encapsulated, lacks nuclear features of papillary thyroid carcinoma, questionable capsular invasion
    5. 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?

    1. Galectin3+, HBME-1+, CITED1+
    2. PAX8-, calcitonin+, chromogranin+
    3. TTF1+, CD56+, PAX8+
    4. TTF1+, CK19+, HBME-1+
    5. 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
    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
    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
    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
    1. Dx / category: follicular neoplasm
      • Cellular aspirate of follicular cells with a predominantly microfollicular architecture, scattered isolated cells and scant colloid.
    2. 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.
    3. 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
    Board review style question #1
    Which lesion is not included in follicular neoplasm / suspicious for a follicular neoplasm category?

    1. Conventional papillary carcinoma
    2. Follicular carcinoma
    3. Invasive follicular variant of papillary carcinoma
    4. Nodular goiter
    5. 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?

    1. Conventional papillary carcinoma
    2. Follicular adenoma or follicular carcinoma
    3. Invasive follicular variant of papillary carcinoma or noninvasive follicular thyroid neoplasm with papillary-like nuclear features
    4. Nodular goiter
    5. 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
    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:
    Missing Image

    Schematic drawing for capsular invasion

    Missing Image

    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
    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
    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
    Board review style question #1
      Which statement for thyroid follicular carcinoma is false?

    1. Cannot have necrosis or increased mitotic figures (≥ 3/10 HPF)
    2. Commonly metastases to bone, lung, not lymph node
    3. Detecting RAS mutations and PPAX8-PPAR gamma rearrangements can be used to distinguish follicular carcinoma from adenoma
    4. Nuclear atypia does not indicate malignancy
    5. 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
    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
    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 (< 10%) due to certain biological differences and historically higher diagnostic threshold for PTC nuclei (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)
    • 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
    Etiology
    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
    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
    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

    Encapsulated follicular variant

    Infiltrative 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 Follicular architecture & nuclear features

    Follicular architecture & nuclear features

    Infiltrative follicular variant Infiltrative follicular variant

    Infiltrative follicular variant


    Encapsulated follicular variant

    Encapsulated follicular variant

    Ossification

    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

    Hypercellular aspirate

    Microfollicular and trabecular pattern

    Microfollicular and trabecular pattern

    Microfollicles

    Microfollicles

    Irregular nuclei

    Irregular nuclei

    Nuclear inclusions

    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
    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
    Board review style question #1
    What is the most common molecular alteration seen in follicular variant of papillary thyroid carcinoma?

    1. BRAF V600E mutation
    2. RAS mutation
    3. RET / PTC fusion
    4. 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?

    1. Adenomatoid nodule
    2. Follicular adenoma
    3. Follicular carcinoma
    4. Papillary thyroid carcinoma, follicular variant
    Board review style answer #2
    D. Papillary thyroid carcinoma, follicular variant

    Comment Here

    Reference: Follicular variant

    Frozen section
    Definition / general
    • 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:

    • 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

    Frozen section-parathyroid
    Definition / general
    • 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

    FT-UMP (pending)
    [Pending]

    Graves disease
    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
    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
    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.
    Missing Image

    Benign thyroid follicles

    Radiation changes with stromal fibrosis

    Various images

    Active tall epithelium with light vacuolated cytoplasm

    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:
    Missing Image

    Graves disease: flame cells

    Positive stains
    Negative stains
    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
    Board review style question #1
    All of the following statements are true about Graves disease except:

    1. Graves disease is caused by anti-TPO autoantibodies
    2. Associated with HLA-DR
    3. Caused due to anti-thyrotropin antibodies
    4. 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
    Surgical procedures
    • Note operation records of surgeon and clinical history; this will help guide dissection
    • 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
    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:
    • 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):
    • 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


    Hashimoto thyroiditis
    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
    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: < 18 years of age, (mean age of 11 years); usually asymptomatic thyroid swelling
    • 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
    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
    Radiology images

    Contributed by Ayana Suzuki, C.T.

    Isoechoic nodule



    Images hosted on other servers:

    Ultrasound

    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
    Treatment
    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

    Oncocytic cell nodule

    Virtual slides

    Images hosted on other servers:
    Fibrous variant of Hashimoto thyroiditis

    Fibrous variant of Hashimoto thyroiditis

    Lymphoid follicles and oncocytic metaplasia

    Lymphoid follicles and oncocytic metaplasia

    Dense infiltrate and atrophied follicles

    Dense infiltrate and atrophied follicles

    Oncocytic metaplasia

    Oncocytic metaplasia


    Fibrous variant with squamous metaplasia

    Fibrous variant with squamous metaplasia

    Oncocytic and adenomatous nodules

    Oncocytic and adenomatous nodules

    Oncocytic nodule

    Oncocytic nodule

    Cytology description
    • Moderately or highly cellular aspirate
    • Inflammatory infiltrate
    • 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

    Lymphocytes and oncocytes

    Follicular destruction by lymphocytes follicular destruction by lymphocytes

    Follicular destruction by lymphocytes

    Crushed cells

    Crushed cells

    Grade 1, 2 and 3 thyroiditis

    Electron microscopy description
    • Oncocytic cells have numerous large mitochondria
    Molecular / cytogenetics description
    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:
    Board review style question #1

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

    1. Fibrosis extends into perithyroidal soft tissues
    2. Increased risk of follicular thyroid carcinoma
    3. Increased risk of medullary thyroid carcinoma
    4. Increased risk of primary thyroid lymphoma
    5. 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?

    1. Common in iodine deficient areas
    2. Mononuclear cell infiltration of the thyroid parenchyma
    3. More common in males
    4. Not a familial disease
    5. 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
    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

    Histology
    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
    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
    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
    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)
    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
    Pathophysiology
    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
    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
    Treatment
    • Total thyroidectomy with neck lymph node dissection followed by TSH suppression therapy and radioactive iodine treatment (Thyroid 2018;28:96)
    Gross description
    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:
    Missing Image Missing Image

    PTC hobnail variant on different magnifications


    Missing Image Missing Image Missing Image

    Group 2 papillary carcinoma of the thyroid

    Missing Image

    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:
    Missing Image

    Conventional smear

    Missing Image

    LBP

    Positive stains
    Electron microscopy description
    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
    Board review style question #1
    Which statement is incorrect about hobnail PTC?

    1. Rare variant of papillary thyroid carcinoma
    2. Relatively aggressive clinical behavior
    3. Microscopically characterized by hobnail cells and micropapillary pattern
    4. Common BRAF V600E, TP53 and TERT promoter mutations
    5. 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?

    1. 5%
    2. 10%
    3. 25%
    4. 30%
    5. 50%
    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?

    1. I (non-diagnostic)
    2. III (AUS/FLUS)
    3. IV (FN/SFN)
    4. V (suspicious for malignancy)
    5. 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
    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
    Laboratory
    • Thyroid function tests are usually within normal limits; no specific preoperative test is definitive
    Prognostic factors
    Case reports
    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
    Microscopic (histologic) images

    Contributed by Virginia A. Livolsi, M.D.
    HTT thinly encapsulated

    HTT thinly encapsulated

    Solid trabecular growth

    Solid trabecular growth

    Trabecular pattern noted

    Trabecular pattern noted

    Elongated nuclei

    Elongated nuclei

    Prominent intranuclear inclusion

    Prominent intranuclear inclusion

    Nuclear clearing and grooves

    Nuclear clearing and grooves


    Yellow bodies

    Yellow bodies

    Calcification in tumor stroma

    Calcification in tumor stroma

    Thyroglobulin stain variable

    Thyroglobulin stain variable

    TTF1 decorates nuclei

    TTF1 decorates nuclei

    Ki67 decorates membranes

    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
    Negative stains
    Electron microscopy description
    • Giant lysosomes are found in the cytoplasm
    Molecular / cytogenetics description
    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
    Board review style question #1

    This solitary thyroid nodule represents

    1. Hyalinizing trabecular tumor
    2. Medullary thyroid carcinoma
    3. Papillary thyroid carcinoma, trabecular variant
    4. 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

    1. BRAF K601 mutation
    2. BRAF V600E mutation
    3. GLIS rearrangement
    4. NRAS mutation
    Board review style answer #2
    C. GLIS rearrangement

    Comment Here

    Reference: Hyalinizing trabecular tumor

    Hyperparathyroidism
    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
    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
    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

    Hyperthyroidism
    Definition / general
    Epidemiology
    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:
    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
    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
    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:
    Missing Image

    Diffuse hyperplasia of thyroid gland

    Videos

    Histopathology Thyroid - Graves Disease


    Hypothyroidism
    Definition / general
    Essential features
    Epidemiology
    Sites
    Pathophysiology
    • Secretion of thyroid hormones are regulated by the hypothalamic pituitary thyroid axis
    • In primary hypothyroidism, the following changes occur:
    • 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
    Clinical features
    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
    Radiology description
    • Primary hypothyroidism:
    • 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
    Treatment
    Gross description
    Microscopic (histologic) description
    Positive stains
    Electron microscopy description
    Videos

    Endocrinology overview


    Intrathyroidal thymic carcinoma
    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)
    • 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
    Sites
    • Commonly involves the lower pole of thyroid lobes or attached to the thyroid (WHO 5th edition)
    Etiology
    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
    Case reports
    Treatment
    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
    Microscopic (histologic) images

    Contributed by Shuanzeng Wei, M.D., Ph.D. and Andrey Bychkov, M.D., Ph.D.
    Tumor nests and fibrosis Tumor nests and fibrosis Tumor nests and fibrosis

    Tumor nests and fibrosis

    Central necrosis

    Central necrosis


    Tumor and thyroid tissue

    Tumor and thyroid tissue

    Fibrous bands

    Fibrous bands

    Squamoid cells

    Squamoid cells

    Invasive growth

    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
    Electron microscopy description
    Molecular / cytogenetics description
    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
    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?

    1. Follicular carcinoma
    2. Intrathyroidal thymic carcinoma
    3. Medullary carcinoma
    4. Papillary carcinoma
    5. 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?

    1. CD5 in intrathyroidal thymic carcinoma only highlights the lymphocytes
    2. Most commonly located in upper pole of thyroid
    3. Most patients have a poor prognosis and die from this tumor
    4. Nests of squamoid cells with lymphocyte infiltrate is the key microscopic feature
    5. 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
    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
    Sites
    • Thyroid
    Pathophysiology
    Etiology
    Clinical features
    • May be found incidentally on imaging or present as a visible or palpable tumor in the thyroid
    Diagnosis
    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
    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

    Vesicular nuclei with irregular membranes

    Evident major and minor diagnostic features

    Evident major and minor diagnostic features

    Dark colloid with frequent scalloping and clefting

    Dark colloid with frequent scalloping and clefting

    Free floating of small tumor fragment in vascular lumen

    Free floating of small tumor fragment in vascular lumen

    Small piece of tumor floats 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

    Tumor plug is associated with thrombus

    Overlapping, elongation and a single mitotic figure

    Overlapping, elongation and a single mitotic figure

    Irregular nuclear contours, grooves, pseudoinclusions

    Irregular nuclear contours, grooves, pseudoinclusions

    Clear chromatin with margination

    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

    Microfollicles and nuclear enlargement

    Negative stains
    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
    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?

    1. Capsular invasion
    2. Lymph node metastasis
    3. Microfollicular growth pattern
    4. Mitotic figures
    5. 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?

    1. Bosselation on inner aspect of capsule
    2. Follicles aligned parallel to capsule
    3. Follicles aligned perpendicular to capsule
    4. Tumor bud invading into but not through capsule
    5. 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
    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
    Pathophysiology
    Etiology
    Diagrams / tables

    Images hosted on other servers:
    Risk factor model Risk factor model

    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
    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

    Ultrasound

    MRI

    MRI

    FDG-PET

    Prognostic factors
    Case reports
    Treatment
    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

    Discrete nodule

    Eosinophils

    Eosinophils

    Follicular stuffing

    Follicular stuffing

    LCH cells

    LCH cells

    LCH cells and eosinophils

    LCH cells and eosinophils


    Langerin

    Langerin

    CD1a

    CD1a

    Thyroglobulin

    Thyroglobulin

    Virtual slides

    Images hosted on other servers:
    Thyroid LCH

    Thyroid LCH

    Cytology description
    Cytology images

    Images hosted on other servers:
    FNA smear FNA smear

    FNA smear

    S100 and CD1a

    S100 and CD1a

    Positive stains
    Negative stains
    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 Birbeck granules

    Birbeck granules

    Molecular / cytogenetics description
    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

    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-
    Board review style question #1

    What is a widely used IHC marker for Langerhans cell histiocytosis?

    1. CD1a
    2. CD20
    3. Cytokeratin
    4. Thyroglobulin
    5. TTF1
    Board review style answer #1
    Board review style question #2
    What is the most common molecular alteration in Langerhans cell histiocytosis?

    1. BRAF V600E mutation
    2. EGFR mutation
    3. RAS family mutations
    4. TERT promoter mutation
    5. 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
    Definition / general

    Lymphoepithelial cyst
    Definition / general
    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
    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)
    • 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
    Diagnosis
    Radiology description
    Case reports
    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:
    Missing Image

    H&E, p63, Ki67

    Cytology description
    Cytology images

    Images hosted on other servers:
    Missing Image

    FNA

    Differential diagnosis

    Lymphoma
    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:
    • Hodgkin lymphoma: very rare, favorable prognosis, female predominance (Neuroimaging Clin N Am 2003;13:371)
    Epidemiology
    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
    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
    Missing Image

    Diffuse large cell lymphoma: fish flesh cut surface

    Missing Image

    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.
    Missing Image

    Large cell type, reticulin stain



    AFIP images

    Diffuse large B cell lymphoma:
    Missing Image

    Tumor cells

    Missing Image

    Follicle in lower right

    Missing Image

    Fibrous bands

    Missing Image

    Tumor cells are CD45 (LCA)+

    Missing Image

    Keratin, thyroglobulin



    Hodgkin lymphoma:
    Missing Image Missing Image

    Nodular sclerosing subtype


    Follicular lymphoma:
    Missing Image

    Residual thyroid follicles



    Images hosted on other servers:
    Missing Image

    Large pleomorphic cells

    Missing Image

    Hodgkin lymphoma: nodular sclerosis type

    Missing Image

    Hodgkin lymphoma: CD30+

    Missing Image

    Follicular lymphoma: morphology

    Missing Image

    Follicular lymphoma: negative for bcl2 and IGH-BCL2

    Missing Image

    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

    Missing Image

    Large cell type



    Images hosted on other servers:
    Missing Image

    Intermediate grade lymphoma

    Missing Image

    MALT lymphoma

    Missing Image

    Hodgkin lymphoma: Reed-Sternberg cell


    Diffuse large B cell lymphoma:
    Missing Image

    Large and irregular lymphoid cells

    Missing Image

    Misdiagnosed as anaplastic carcinoma

    Missing Image

    High grade lymphoma

    Missing Image

    CD45 / LCA+, CD20+, keratin-

    Positive stains
    Molecular / cytogenetics description
    Differential diagnosis
    Additional references

    Lysosomal storage diseases
    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
    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
    Diagnosis
    Laboratory
    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
    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
    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:
    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

    Images hosted on other servers:

    Gaucher cell in bone marrow

    Peripheral smear description
    Positive stains
    Negative stains
    • CD107b helps to differentiate cardiomyopathy due to Danon disease
    Electron microscopy description
    Electron microscopy images

    Images hosted on other servers:

    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)


    Macrofollicular
    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

    Nodal metastasis, macrofollicular variant PTC

    Cytology description
    Differential diagnosis

    Malakoplakia
    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
    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
    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

    Malignant
    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
    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
    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:
    • 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 Papillary thyroid carcinoma Papillary thyroid carcinoma

    Papillary thyroid carcinoma


    Medullary thyroid carcinoma

    Medullary thyroid carcinoma

    Poorly differentiated thyroid carcinoma

    Poorly differentiated thyroid carcinoma

    Anaplastic thyroid carcinoma

    Anaplastic thyroid carcinoma

    Primary thyroid lymphoma

    Primary thyroid lymphoma

    Videos

    Thyroid cytopathology

    Sample pathology report
    1. Dx / category: malignant
      • Papillary thyroid carcinoma, favor tall cell variant
    2. Dx / category: malignant
      • Medullary thyroid carcinoma
      • The malignant cells are positive for calcitonin.
    3. 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
    Board review style question #1

      What is the most likely histological diagnosis of this thyroid aspirate?

    1. Anaplastic thyroid carcinoma
    2. Follicular carcinoma
    3. Medullary thyroid carcinoma
    4. Papillary thyroid carcinoma
    5. 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
      Which thyroid malignancy is included in the malignant category of the Bethesda system for reporting thyroid cytopathology?

    1. Chronic thyroiditis
    2. Follicular carcinoma
    3. Hyalinizing trabecular tumor
    4. Nodular goiter
    5. 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
    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
    Epidemiology
    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
    Case reports
    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:

    Variants (important for differential diagnosis, most are of no prognostic importance):
    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


    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

    Diff-Quik

    Pap Pap

    Pap

    Cell block

    Cell block

    Calcitonin

    Calcitonin

    TTF1

    TTF1

    Positive stains
    Negative stains
    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
    Board review style question #1
    Which statement is not true for medullary thyroid carcinoma (MTC)?

    1. Majority of MTC have translocation involving RET proto-oncogene
    2. MTC can be monitored for recurrence with serum CEA levels
    3. MTC has a wide variety of morphology, can mimic any other thyroid malignancies
    4. MTC is most commonly found at the junction of the upper and mid portions of the thyroid lobes
    5. 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
    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
    Sites
    • Thyroid
    • Exceedingly rare at other sites (see Case reports below)
    Pathophysiology
    Etiology
    Diagrams / tables

    Images hosted on other servers:

    Incidence and prognosis

    Clinical features
    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)
    • 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 (< 45 years), tumor multifocality and lymph node metastasis at presentation, whereas no association with gender, tumor size and extrathyroidal extension was found (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
    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 < 2 mm

    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
    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
    Negative stains
    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
    Board review style question #1

    Which of the following statements about papillary thyroid microcarcinoma (shown in the image) is correct?

    1. Can always be diagnosed on cytology alone
    2. Can contain tall cell features
    3. More likely to show a pure papillary rather than follicular architecture
    4. Must be incidental and measure ≤ 1 cm
    5. 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?

    1. BRAF V600E
    2. CK19
    3. Galectin3
    4. HBME
    5. 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
    Definition / general
    • Aggressive
    Case reports
    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
    Differential diagnosis
    • Entrapping of thyroid follicles by medullary carcinoma
    • Medullary carcinoma with glandular growth pattern

    Molecular pathology basics
    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

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    Molecular pathways in thyroid cancer development


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    Stepwise mechanism of thyroid neoplasia

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    Progress in identifying
    mutational markers
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    MAPK pathway

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    PI3K-AKT pathway

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    Genomic landscape of PTC


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    Gene mutations in thyroid tumors

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    Gene fusions in PTC

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    BRAF vs. RAS in PTC

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    BRAF V600E and tumor recurrence


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    BRAF mutation and iodine uptake

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    TERT mutations

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    miRNAs in thyroid cancer

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    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

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    ALK fusions

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    β-catenin (nuclear) in cribriform-morular PTC associated with FAP syndrome

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    BRAF V600E (sequencing)

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    BRAF V600E (MALDI-TOF)


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    BRAF K601E

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    BRAF V600E / VE1

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    KRAS mutations

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    NRAS mutations (sequencing)

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    NRAS mutations (pyrosequencing)

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    PPARγ IHC in FTC (A)


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    PTEN IHC (A - C)

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    PTEN loss in Cowden syndrome

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    PTEN evaluation (breast cancer)

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    RET / PTC rearrangements

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    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

    MAPK pathway


    PI3K-AKT pathway

    PI3K-AKT pathway

    PI3K-AKT pathway


    Molecular pathology-practical
    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:
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    Progress in identifying
    mutational markers
    in thyroid cancer

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    Gene mutations in thyroid tumors

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    Genomic landscape of PTC

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    Gene fusions in PTC


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    BRAF mutation and iodine uptake

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    BRAF V600E and tumor recurrence

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    TERT mutations

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    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:
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    ALK fusions

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    β-catenin (nuclear) in cribriform-morular PTC associated with FAP syndrome

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    BRAF V600E (sequencing)

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    BRAF V600E (MALDI-TOF)


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    BRAF K601E

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    BRAF V600E / VE1

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    KRAS mutations

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    NRAS mutations (sequencing)

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    NRAS mutations (pyrosequencing)

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    PPARγ IHC in FTC (A)


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    PTEN IHC (A - C)

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    PTEN loss in Cowden syndrome

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    PTEN evaluation (breast cancer)

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    RET / PTC rearrangements

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    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)


    Molecular testing in FNA
    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

    Overview of platforms and workflow

    Proposed clinical algorithm

    Proposed clinical algorithm

    NPV and PPV of ThyroSeq v2.1

    NPV and PPV of ThyroSeq v2.1

    Genetics of thyroid tumors

    Genetics of thyroid tumors

    Diagnostic performance

    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)
    • 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?

    1. Benign (II)
    2. Follicular neoplasm / suspicious for follicular neoplasm (IV)
    3. Malignant (VI)
    4. Nondiagnostic (I)
    5. 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)?

    1. BRAF
    2. NTRK1
    3. P53
    4. RAS
    5. RET
    Board review style answer #2

    Mucoepidermoid carcinoma
    Definition / general
    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
    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
    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
    Negative stains
    Molecular / cytogenetics description
    Differential diagnosis
    Board review style question #1
    Which statement is not true for mucoepidermoid carcinoma of thyroid?

    1. Comedo necrosis and psammoma bodies may be seen
    2. Foci of associated papillary thyroid carcinoma are often seen
    3. Lymph nodes metastases, extrathyroidal invasion are common
    4. Mucoepidermoid carcinoma of thyroid is associated with lymphocytic thyroiditis
    5. 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
    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
    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.
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    Mutations in various types of thyroid tumors

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    Putative molecular pathogenesis of thyroid tumors

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    Indeterminate cytological diagnosis



    Images hosted on other servers:
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    NIFTP incidence

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    Diagnostic algorithm

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    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 BRAFV600E 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:
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    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
    Treatment
    Gross description
    Gross images

    Images hosted on other servers:
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    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


    Clear circumscription of the encapsulated lesion with a predominantly follicular growth pattern

    Nuclear features of PTC



    Images hosted on other servers:
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    Noninvasive follicular thyroid neoplasm

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    Low power

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    Medium power

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    5.6 cm NIFTP


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    High power

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    NIFTP vs HCC


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    NIFTP vs PDTC

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    NIFTP vs FTC

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    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:
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    Microfollicular pattern, nuclear enlargement

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    Microfolliclar pattern

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    Microfollicles, nuclear grooves

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    Enlarged nuclei

    Molecular / cytogenetics description
    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)

    Board review style question #1
      Which of the following mutations is most commonly associated with NIFTP?

    1. BRAFV600E
    2. PAX8 / PPAR gamma rearrangement
    3. PIK3CA
    4. RAS family
    5. 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
      Which of the following features differentiates a PTC from a NIFTP?

    1. Follicular growth pattern
    2. Nuclear elongation
    3. Nuclear grooves
    4. Thick colloid
    5. 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
    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
    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
    Diagnosis
    • Preoperative fine needle aspiration cytology
    • Histopathological examination of tumor post resection
    Radiology description
    Radiology images

    Images hosted on other servers:

    Ultrasound

    Prognostic factors
    Case reports
    Treatment
    Gross description
    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
    Negative stains
    Electron microscopy description
    Molecular / cytogenetics description
    Sample pathology report
    • Thyroid, total thyroidectomy:
      • Papillary thyroid carcinoma, oncocytic variant, left lobe, 1.5 cm (see synoptic report)
    Differential diagnosis
    Board review style question #1

      Which of the following is a typical finding on ultrastructural examination of this thyroid tumor?

    1. Abnormal mitochondria
    2. Filament-ribosomal complexes
    3. Membrane bound crystals
    4. Neurosecretory granules
    5. 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
      Oncocytic variant of papillary thyroid carcinoma is typically associated with which of the following molecular alterations?

    1. BRAFV600E mutation
    2. Mitochondrial DNA mutations
    3. PAX8/PPARγ translocation
    4. RAS mutations
    5. TERT promoter mutations
    Board review style answer #2
    B. Mitochondrial DNA mutations. Oncocytic papillary thyroid carcinomas show accumulation of mitochondrial DNA mutations. BRAFV600E 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
    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
    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
    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

    Hürthle cell adenoma

    Adenoma with atypia


    Hürthle cell carcinoma

    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
    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
    Board review style question #1
    Which statement is not true for oncocytic carcinoma?

    1. More aggressive compared to conventional follicular carcinoma
    2. More resistant to radioactive iodine compared to conventional follicular carcinoma
    3. Not only metastases to bone or lung; can also spread to lymph node
    4. Oncocytic appearance is due to accumulation of dysfunctional mitochondria
    5. 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
    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
    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:
    Case reports
    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

    Hürthle cell adenoma, Pap stain

    Treatment
    Sample cytology report
    1. Dx / category: follicular neoplasm, Hürthle cell (oncocytic) type
      • Cellular aspirate consisting of abundant isolated oncocytes in the absence of colloid
    2. 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
    3. 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
    Board review style question #1
    Which finding is not helpful in distinguishing medullary carcinoma from a Hürthle cell neoplasm?

    1. Salt and pepper chromatin
    2. Metachromasia in Romanowsky stain
    3. Calcitonin measurement using needle washout fluid
    4. PTH value measurement using needle washout fluid
    5. 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?

    1. Chronic thyroiditis
    2. Adenomatous nodule
    3. Hürthle cell neoplasm
    4. Medullary carcinoma
    5. 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
    Definition / general
    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
    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
    Negative stains

    Palpation thyroiditis
    Definition / general
    • Common (85%+ of surgically resected thyroids) but clinically insignificant
    Terminology
    • Also called multifocal granulomatous thyroiditis
    Clinical features
    Case reports
    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

    Papillary thyroid carcinoma - classic
    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
    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

    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
    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

    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

    Papillary projections

    Nuclear features

    Nuclear features

    Psammoma body Psammoma body

    Psammoma body


    Cystic change with BRAF V600E Cystic change with BRAF V600E Cystic change with BRAF V600E

    Cystic change with BRAF V600E

    Osseous metaplasia

    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 Papanicolaou stain

    Papanicolaou stain

    Positive stains
    Negative stains
    Molecular / cytogenetics description
    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?

    1. BRAF V600E mutation
    2. HRAS Q61R mutation
    3. NRAS Q61R mutation
    4. 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?

    1. Composed entirely of follicles
    2. Nuclei of the lesional cells are small and round without nuclear membrane irregularity
    3. Contains well formed papillae with a fibrovascular core
    4. 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
    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
    • BRAFV600E 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
    Sites
    Etiology
    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:
    Missing Image

    Invasion of trachea

    Missing Image

    Enhancing nodular lesion

    Missing Image

    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 < 3 cm in greatest dimension, microscopic extrathyroidal extension (perithyroidal fibroadipose tissue)
      • 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
    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:
    Missing Image

    Cystic neck mass

    Missing Image

    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.
    Missing Image

    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
      • 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


    BRAFV600E

    TTF1

    PAX8

    Virtual slides

    Images hosted on other servers:
    Missing Image

    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
    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

    Tall cuboidal cells

    Surface microvilli

    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 BRAFV600E, 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:
    Missing Image

    TCGA

    Missing Image

    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

      What is the most common molecular alteration of this thyroid tumor?

    1. BRAFV600E mutation
    2. EGFR mutation
    3. HRAS mutation
    4. TERT promoter mutation
    5. TP53 mutation
    Board review style answer #1
    A. BRAFV600E mutation

    Comment Here

    Reference: Papillary thyroid carcinoma
    Board review style question #2
      Which of the following variants of papillary thyroid carcinoma is considered as an aggressive variant?

    1. Follicular variant
    2. Oncocytic variant
    3. Papillary microcarcinoma
    4. Tall cell variant
    5. 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
    Definition / general
    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
    Radiology images

    Images hosted on other servers:
    Missing Image

    Neck ultrasonography

    Missing Image

    Color flow Doppler

    Missing Image

    Tracer uptake, lateral neck

    Missing Image Missing Image Missing Image

    Radiography of mediastinal mass

    Case reports
    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
    Missing Image

    Nodular hyperplasia



    Images hosted on other servers:
    Missing Image

    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

    Missing Image Missing Image

    Patient with Hashimoto

    Missing Image

    Hyperplastic nodule



    Images hosted on other servers:
    Missing Image

    Parasitic nodule vs lymph node

    Missing Image

    Thyroid follicles

    Missing Image

    TTF1, Thyroglobulin

    Cytology description
    Negative stains
    Molecular / cytogenetics description
    Differential diagnosis

    Parathyroid adenoma
    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
    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
    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
    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
    Treatment
    • Parathyroidectomy
    Clinical images

    Images hosted on other servers:

    Giant parathyroid adenoma (intraoperative)

    Gross description
    Gross images

    Contributed by Mona Kandil, M.D and @Andrew_Fltv on Twitter
    Parathyroid adenoma (black arrow) and thyroid Parathyroid adenoma (black arrow) and thyroid

    Parathyroid adenoma (black arrow) and thyroid

    Parathyroid adenoma Parathyroid adenoma

    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

    Chief cells

    Oxyphil adenoma

    Oxyphil adenoma

    Oxyphil cells

    Oxyphil cells

    Atypical adenoma and thyroid

    Atypical adenoma and thyroid

    Atypical adenoma fibrous bands

    Atypical adenoma fibrous bands


    Parathyroid adenoma Parathyroid adenoma

    Parathyroid adenoma

    Parathyroid adenoma Parathyroid adenoma

    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

    Electron microscopy description
    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
    Board review style question #1

    What is the best diagnosis for this neck mass?

    1. Parathyroid adenoma, oxyphil type
    2. Oncocytoma
    3. Hurthle cell adenoma
    4. 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?

    1. Adherence to adjacent thyroid
    2. Nuclear atypia
    3. Necrosis
    4. Perineural invasion
    Board review style answer #2
    D. Perineural invasion

    Comment Here

    Reference: Parathyroid adenoma

    Parathyroid carcinoma
    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
    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
    Radiology description
    Radiology images

    Images hosted on other servers:
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    Xray lytic lesion

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    Sestamibi scan

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    Bone scan

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    Tc MIBI scintigraphy and CT

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    Tc MIBI SPECT / CT

    Missing Image

    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
    Treatment
    Clinical images

    Images hosted on other servers:
    Missing Image

    Intraoperative dissection

    Gross description
    Gross images

    Images hosted on other servers:
    Missing Image

    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.
    Missing Image

    Solid and nodular growth

    Missing Image

    Skeletal muscle invasion

    Missing Image

    Uniform cytomorphology

    Missing Image

    Numerous mitoses

    Missing Image

    Prominent nucleoli


    Missing Image

    PTH

    Missing Image

    GATA3

    Missing Image

    Thyroglobulin

    Missing Image

    TTF1

    Missing Image

    Ki67

    Virtual slides

    Images hosted on other servers:
    Missing Image Missing Image

    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.
    Missing Image Missing Image

    Cohesive clusters and sheets of cells

    Positive stains
    Negative stains
    Molecular / cytogenetics description
    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
    Board review style question #1

      Which of the following is diagnostic for parathyroid carcinoma in a parathyroid lesion?

    1. Broad fibrous bands
    2. Increased mitotic activity (> 5/10 mm2)
    3. Parafibromin loss
    4. Perineural invasion
    5. 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
      Which of the following markers is recommended for atypical parathyroid tumors and parathyroid carcinoma in routine practice and may also be associated with the risk of tumor recurrence?

    1. Isocitrate dehydrogenase 1 (IDH1)
    2. Menin
    3. Parafibromin
    4. SMARCB1 / INI1
    5. 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
    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
    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
    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
    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
    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
    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:
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    Sonogram

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    Intrathyroidal PT adenoma

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    MIBI scan

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    Technetium sestamibi scan


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    Parathyroid carcinoma

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    Parathyroid glands

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    Coronal oblique slices

    Missing Image

    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

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    Excised tissue

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    Resected thyroid

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    Parathyroid adenoma

    Missing Image

    Thyroid lobe


    Missing Image Missing Image

    Intrathyroidal PT adenoma

    Missing Image

    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:
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    Ectopic thymus and PT within thyroid

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    Surrounded by thyroid parenchyma

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    PT hyperplasia

    Missing Image Missing Image

    Intrathyroidal PT cystic adenoma


    Missing Image Missing Image Missing Image Missing Image

    Intrathyroidal PT adenoma

    Missing Image

    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:
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    Common and uncommon FNA features

    Missing Image

    FNA

    Positive stains
    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
    • 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
    • Water clear-cell intrathyroidal PT adenoma
      • Thyroid clear cell adenoma

    Plasma cell granuloma
    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
    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
    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
    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

    Images hosted on other servers:

    Plasma cells, lymphocytes and fibrous tissue

    Clumps of plasma cells

    Plasma cells around follicular epithelium

    CD79a

    Kappa and lambda light chains

    Positive stains
    Negative stains
    • ALK1 for spindle cells (no positive cases reported so far)
    Molecular / cytogenetics description
    • No monoclonality by PCR

    Plasmacytoma
    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
    Gross images

    Images hosted on other servers:
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    Gray, firm, fleshy

    Missing Image

    Thyroidectomy specimen

    Microscopic (histologic) description
    Microscopic (histologic) images

    Case #394

    10×

    20×

    40×


    CD79a

    CD138

    Kappa

    Lambda



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    Mature and immature plasma cells

    Missing Image Missing Image

    H&E, CD138+

    Missing Image

    (A) Kappa light chain+
    (B) Lambda light chain-

    Cytology description
    Cytology images

    Images hosted on other servers:
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    Intranuclear inclusion

    Missing Image

    Congo red+

    Positive stains
    Negative stains
    Differential diagnosis

    Poorly differentiated thyroid carcinoma
    Definition / general
    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
    Case reports
    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:
        • Prototypical type insular carcinoma: solid nests (may contain microfollicules) composed of small uniform cell with round hyperchromatic nuclei or convoluted nuclei, increased mitotic figures, necrosis (Am J Surg Pathol 1984;8:655)
        • Others tumors: solid nests composed of larger more pleomorphic tumor cells; may have oncocytic cells, clear cells, signet ring cells or rhabdoid cells
        • Component of well differentiated tumor (papillary or follicular carcinoma) may also be present
        • As few as 10% of poorly differentiated carcinomas (in otherwise well differentiated carcinomas) may be associated with unfavorable prognosis (Am J Surg Pathol 2011;35:1866)
        • May have peritheliomatous pattern (tumor cells around blood vessels with necrosis of tumor cells further away from vessels), vascular and capsular invasion (Lloyd: WHO Classification of Tumours of Endocrine Organs, 4th Edition, 2017)
    Microscopic (histologic) images

    Contributed by Shuanzeng Wei, M.D., Ph.D., Andrey Bychkov, M.D., Ph.D.
    Nests of tumor with necrosis Nests of tumor with necrosis

    Nests of tumor with necrosis

    Follicular carcinoma with high grade progression Follicular carcinoma with high grade progression 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

    Negative stains
    Molecular / cytogenetics description
    Videos

    Poorly differentiated thyroid carcinoma by M. Brandwein (2020)

    Differential diagnosis
    Board review style question #1
    Which of the following features are not required for the diagnosis of poorly differentiated thyroid carcinoma?

    1. Absence of conventional nuclear features of papillary thyroid carcinoma
    2. Necrosis / convoluted nuclei / increased mitotic activity
    3. Solid, trabecular or insular growth
    4. 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
    Definition / general
    Clinical features
    • Thyroid mass
    • History of surgery or FNA
    Radiology description
    Case reports
    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
    Electron microscopy description
    • Characteristic myofibroblastic features
    Differential diagnosis

    Radiation thyroiditis
    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
    Main references recommended by editor

    Recommended thyroid books
    First choice:

    Chapters in general pathology books:

    Endocrine/Head-Neck volumes:

    FNA:

    Related:

    Clinical:

    Professional societies
    Pathology:

    Clinical:

    Media
    Virtual slides (main):

    Virtual slides (more):

    Images:

    YouTube channels:

    Guidelines
    Pathology:

    Clinical:

    Online resources
    Literature from 2020
    Literature from 2019
    Literature from 2018
    Literature from 2016

    Riedel thyroiditis
    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
    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
    Treatment
    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
    Differential diagnosis
    Additional references

    Sarcoidosis
    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
    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

    Isolated sarcoidosis of the thyroid:
    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
    Negative 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)

    Sarcoma
    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
    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
    Negative stains
    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

    Sclerosing mucoepidermoid carcinoma with eosinophilia
    Definition / general
    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
    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


    Missing Image

    Small irregular strands of tumor cells



    Images hosted on other servers:
    Missing Image Missing Image

    Various images

    Cytology description
    Cytology images

    Images hosted on other servers:
    Missing Image

    Epithelial pearl-like structure

    Missing Image

    Cell block

    Missing Image

    Cell block, p40

    Positive stains
    Negative stains
    Differential diagnosis
    Board review style question #1
    Which item is correct regarding sclerosing mucoepidermoid carcinoma with eosinophilia?

    1. Sclerosing mucoepidermoid carcinoma with eosinophilia is not associated with Hashimoto thyroiditis
    2. Lymph nodes metastases, extracapsular spread, vascular invasion and perineural invasion are common
    3. Death due to sclerosing mucoepidermoid carcinoma with eosinophilia is common
    4. Eosinophil infiltration is common, and no keratin pearls and keratin debris are seen
    5. 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
    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
    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
    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
    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
    Negative stains
    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
    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
    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
    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
    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
    Laboratory
    • Elevated T3 / T4, low radioactive iodine uptake
    Case reports
    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
    Definition / general
    • 50 - 70% or more solid growth pattern with papillary cytologic features, without necrosis
    • Rare in adults (3% of all papillary carcinomas)
    • In children, solid / trabecular variant is very common, has higher risk of relapse (Am J Surg Pathol 2006;30:1420)
    • Also seen in post-Chernobyl cases associated with RET / PTC3 rearrangement (J Clin Endocrinol Metab 1999;84:4232)
    Prognostic factors
    • Associated with slightly poorer prognosis and slightly more distant metastases than classic papillary carcinoma but better prognosis than poorly differentiated carcinoma (Am J Surg Pathol 2001;25:1478)
    Case reports
    Microscopic (histologic) description
    • Unencapsulated with invasive borders
    • Composed of round solid nests resembling filled up follicles, surrounded by fibrous / hyaline stroma
    • May have vague papillary or follicular formations
    • Nuclear features of papillary carcinoma are present
    Microscopic (histologic) images

    Images hosted on other servers:

    Solid architecture
    traversed by
    delicate fibrous
    septa

    Classic nuclear features of papillary thyroid carcinoma

    Fig 3D: RET staining

    Cytology images

    Images hosted on other servers:

    Solid aggregates of epithelial follicular cells

    Monolayered epithelial cellular sheets

    Enlarged nuclei
    with fine chromatin,
    occasional nuclear
    grooves

    Electron microscopy description

    Solid cell nests / ultimobranchial body remnants
    Definition / general
    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
    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
    Diagnosis
    • Usually an incidental microscopic finding
    Case reports
    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

    Missing Image

    Type 1 and 2 solid cell nests



    Images hosted on other servers:
    Missing Image

    Admixture of main and C cell

    Missing Image

    High mag of solid cell nests

    Missing Image

    Various stains

    Missing Image

    Galectin 3, CEA

    Missing Image

    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
    Negative stains
    Electron microscopy description
    Molecular / cytogenetics description
    Differential diagnosis

    Solitary fibrous tumor
    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
    • < 10% cases of SFT of thyroid may show malignant histological features
    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
    Sites
    • Entire thyroid
    Etiology
    Diagrams / tables

    Images hosted on other servers:

    4 variable risk stratification

    Clinical features
    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
    Radiology images

    Images hosted on other servers:

    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
    Treatment
    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

    Well defined border

    Entrapped thyroid follicles

    Entrapped thyroid follicles

    Patternless proliferation of spindled cells Patternless proliferation of spindled cells

    Patternless proliferation of spindled cells


    Staghorn-like vessels Staghorn-like vessels

    Staghorn-like vessels

    Collagenous stroma

    Collagenous stroma

    STAT6

    STAT6

    CD34

    CD34

    Virtual slides

    Images hosted on other servers:

    Solitary fibrous tumor of thyroid

    Cytology description
    Cytology images

    Images hosted on other servers:
    Scattered spindle-like cells with fusiform nuclei

    Scattered spindle-like cells with fusiform nuclei

    Positive stains
    Negative stains
    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
    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?

    1. Medullary carcinoma
    2. Riedel thyroiditis
    3. Solitary fibrous tumor
    4. Spindle epithelial tumor with thymus-like differentiation
    5. 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?

    1. CD34
    2. Cytokeratin CAM 5.2
    3. STAT6
    4. Thyroglobulin
    5. 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
    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
    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
    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

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    Hemangioma

    Metastatic squamous cell carcinoma

    Cytology description
    Positive stains
    Videos

    Thyroid cytology: colloid nodule

    Solitary thyroid nodule

    Thyroid: compare and contrast


    Squamous cell carcinoma
    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
    Treatment
    • Radical resection and radiation (often radioresistant)
    Clinical images

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    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
    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
    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
    Board review style question #1
    A patient presented with a parathyroid carcinoma directly invading thyroid and adjacent fibroadipose tissue. What is the pT category?

    1. pTis
    2. pT1
    3. pT2
    4. pT3
    5. pT4
    Board review style answer #1
    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?

    1. Stage I
    2. Stage II
    3. Stage III
    4. Stage IV
    5. 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
    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
    Sites
    Etiology
    Diagrams / tables

    Images hosted on other servers:

    Thyroid function

    Clinical features
    Diagnosis
    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
    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
    Case reports
    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
    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
    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
    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?

    1. Abscesses
    2. Clear nuclei and psamomma bodies
    3. Clustered epithelioid cells and giant cells
    4. Lymphocyte and oncocytic change
    5. 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?

    1. Enlarged cells with large intranuclear inclusions
    2. Foreign material
    3. Granulomas with giant cells and epithelioid histiocytes
    4. Markedly atypical cells
    5. 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
    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 < 5%, resection rate 70%, risk of malignancy 80% (NIFTP = malignant), 45 - 60% (NIFTP ≠ malignant)
    • Most common histological diagnosis is papillary thyroid carcinoma (PTC) (Acta Cytol 2014;58:15)
    Clinical features
    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:
    Missing Image Missing Image

    Suspicious for lymphoma

    Missing Image Missing Image

    Suspicious for medullary thyroid carcinoma


    Missing Image

    Suspicious for papillary thyroid carcinoma

    Missing Image Missing Image Missing Image

    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
    • For suspicious for lymphoma
    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
    Board review style question #1

      What is the most likely histological diagnosis of this thyroid aspirate consistent with suspicious for malignancy diagnostic category?

    1. Classic papillary thyroid carcinoma
    2. Follicular adenoma
    3. Follicular variant of papillary thyroid carcinoma
    4. Medullary thyroid carcinoma
    5. 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
      What is the most common histological equivalent of suspicious for malignancy aspirate of thyroid?

    1. Anaplastic thyroid carcinoma
    2. Follicular carcinoma
    3. Medullary thyroid carcinoma
    4. Papillary thyroid carcinoma
    5. 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
    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 < 30%, the tumor should be designated as PTC with tall cell features (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
    Sites
    • Thyroid
    • Exceedingly rare at other sites, e.g. ectopic thyroid tissue in thyroglossal duct (see case reports below)
    Pathophysiology
    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
    Radiology description
    Radiology images

    Images hosted on other servers:

    Tall cell variant in 19 year old woman

    Prognostic factors
    Case reports
    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
    Electron microscopy description
    Molecular / cytogenetics description
    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
    Board review style question #1

    Which of the following statements concerning the tall cell variant of papillary thyroid carcinoma is correct?

    1. It usually has an indolent clinical course
    2. Most cases are associated with a RAS mutation
    3. Patients are usually older adults
    4. The tumor is positive for TTF1, synaptophysin and calcitonin
    5. 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?

    1. A dense lymphocytic infiltration of tumor stroma
    2. Cells with granular eosinophilic cytoplasm and nuclei with a soap bubble appearance on cytology
    3. Focal positivity for GATA3
    4. Infrequent nuclear grooves and pseudoinclusions
    5. 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
    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
    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
    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
    Definition / general
    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:
    Missing Image

    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:
    • 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
    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:
    Missing Image

    Ectopic thymic tissue

    Missing Image

    Sonographic images

    Missing Image

    Intrathyroidal ectopic thymic tissue

    Missing Image Missing Image

    Longitudinal US images


    Missing Image

    Hyperechoic nodule

    Missing Image Missing Image

    CT scan

    Missing Image Missing Image

    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
    Missing Image

    Intrathyroidal thymus gland



    Images hosted on other servers:
    Missing Image

    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:
    Missing Image Missing Image

    Intrathyroidal thymic tissue

    Missing Image Missing Image

    Degenerated Hassall corpuscle

    Missing Image

    Ectopic thymus and parathyroid


    Missing Image

    Subcapsular intrathyroidal thymus (E)

    Missing Image Missing Image

    Subcapsular intrathyroid thymus, rats

    Missing Image

    Ectopic intrathyroidal thymoma

    Cytology description
    Cytology images

    Images hosted on other servers:
    Missing Image

    Hassall corpuscle (D)

    Missing Image

    CK+ epithelial cells

    Missing Image

    Lymphocytes

    Positive stains
    Negative stains
    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

    Thyroblastoma (pending)
    [Pending]

    Thyroglossal duct carcinoma
    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:
    • 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)
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    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
    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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    Intraoperative

    Gross description
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    Thyroidectomy

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    Total resection

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    Modified neck dissection

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    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

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    Squamous epithelium


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    PTC tall cell variant

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    TTF1, thyroglobulin

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    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

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    Papillary carcinoma in TGD cyst aspirate

    Positive stains
    Molecular / cytogenetics description
    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
    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
    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)
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    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



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    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
    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
    • Incision / draining or sclerotherapy is strictly discouraged
    Clinical images

    Contributed by Ayana Suzuki, C.T.

    Flocculated appearance



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    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

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    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:
    • 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
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    Denuded TGD, perihoid location

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    Variable epithelial lining

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    Thyroid follicles of various size

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    Thyroid follicles embedded within skeletal muscles

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    Rupture of the cyst wall

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    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.
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    Benign squamous cell

    Histiocytes and squame

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    Negative stains
    Videos

    Sistrunks Procedure for Thyroglossal Duct Cyst

    Differential diagnosis
    • Cystic lesions
    • 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

    Thyroid cancer-general
    Definition / general
    Epidemiology
    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
    Negative stains
    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

    Thyroid follicular nodular disease (multinodular goiter)
    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:
    • 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
    Treatment
    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 Adipose metaplasia

    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
    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
    Negative stains
    • Loss of PTEN protein in patient with PTEN hamartoma syndrome
    Molecular / cytogenetics description
    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
    Board review style question #1

    Which of the histological features is seen in nodular goiter?

    1. Nodules with distinct thick capsule
    2. Papillary projections of the epithelium with nuclear features of papillary thyroid carcinoma
    3. Variably sized follicles with flattened hyperplastic epithelium, cysts, hemorrhage, granulomatous response, fibrosis, calcification or osseous metaplasia
    4. 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
    Multinodular goiter Multinodular goiter


    These images from a thyroid nodule belong in what category of The Bethesda System for Reporting Thyroid Cytopathology?

    1. Category I
    2. Category II
    3. Category III
    4. Category IV
    5. 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
    Definition / general
    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
    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
    Diagrams / tables

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

    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
    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
    Missing Image

    Ectopic thyroid follicles



    Images hosted on other servers:
    Missing Image

    Subcapsular nodal thyroid inclusion

    Missing Image

    Lymph node with metastatic papillary thyroid carcinoma

    Missing Image Missing Image

    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
    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

    Thyroid metastases
    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
    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)
    • 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
    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)
    • 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
    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
    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

    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

    HCA capsule

    Interface between components

    Interface between components

    Pigmented component

    Pigmented component

    Hürthle cell component

    Hürthle cell component

    Melanoma in OFA interface

    Melanoma in OFA interface

    Melanoma in OFA SOX10

    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
    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
    Differential diagnosis
    Board review style question #1
    Which statement is false regarding metastatic clear cell renal cell carcinoma to the thyroid?

    1. Metastasis from renal cell carcinoma is generally a solitary mass
    2. Metastatic clear cell renal cell carcinoma can have a very long latency after nephrectomy
    3. Metastatic clear cell renal cell carcinoma can have a spurious thyroglobulin stain
    4. TTF1 and PAX8 can be used to differentiate tumors of renal and thyroid origins
    5. 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?

    1. Metastases to the thyroid are a common finding
    2. Most patients with thyroid metastases have no known primary
    3. Melanoma is a common primary that metastasizes to the thyroid
    4. 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?

    1. Carcinomas of the breast are among the most common "donor" tumors
    2. Melanoma is the most common "recipient" tumor
    3. Most "recipient" tumors are benign
    4. Sarcomas are the most common "donor" tumor
    5. 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
    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
    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
    Additional references

    Ultrasound
    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 < 1 mm slice
      • 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

    Ultrasound FNA techniques



    Images hosted on other servers:
    Risk of thyroid cancer

    Risk of thyroid cancer

    ATA algorithm for patients with thyroid nodules

    ATA algorithm for
    patients with
    thyroid nodules

    ATA association

    ATA association

    ACR TI-RADS chart

    ACR TI-RADS chart

    Comparison of systems

    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 (< 1 cm)
      • 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:
    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)
    • 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
    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:
    • 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 images

    Images hosted on other servers:
    Calcified nodule

    Calcified nodule

    Complex cystic thyroid nodule

    Complex cystic thyroid nodule

    Multinodular goiter

    Multinodular goiter

    17 year old girl with Graves disease

    17 year old girl with Graves disease

    35 year old woman with diffuse Hashimoto thyroiditis

    35 year old woman
    with diffuse
    Hashimoto
    thyroiditis


    50 year old woman with colloid multinodular goiter

    50 year old woman
    with colloid
    multinodular
    goiter

    Hypoechoic nodule

    Hypoechoic nodule

    Microcalcifications in a thyroid nodule

    Microcalcifications in a thyroid nodule

    Intranodular vascularity in thyroid nodule

    Intranodular vascularity in thyroid nodule

    Oval shaped thyroid nodule

    Oval shaped thyroid nodule

    Case reports
    Videos

    Fine needle aspiration (FNA) biopsy techniques - Dr. Britt Marie Ljung playlist

    Neck ultrasonography basics

    Thyroid ultrasound course

    Board review style question #1

    Which of the following sonographic features of a thyroid nodule would increase suspicion for malignancy?

    1. Cystic change accounting for > 50% of nodule
    2. Fluid filled
    3. Honeycomb morphology
    4. Hyperechoic
    5. 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?

    1. Abscess or infected linear tract in the thyroid
    2. Enlarged, heterogeneous with lobular margins; hypoechoic and micronodular, septal lines
    3. Enlarged, mildly hypoechoic, heterogeneous
    4. Large, ill defined, markedly hypoechoic nodules or masses
    5. 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
    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
    Case reports
    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
    1. Diagnosis / category: nondiagnostic
      • Nondiagnostic specimen due to insufficient cellularity
      • Note: a repeat FNA should be considered
    2. Diagnosis / category: nondiagnostic
      • Unsatisfactory aspirate due to poor fixation and preservation
      • Note: a repeat FNA should be considered
    3. 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
    4. 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?

    1. ≥ 6 groups of well visualized follicular cells
    2. Abundant thick colloid
    3. A few cells with cytological atypia
    4. Foamy histiocytes only
    5. 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
    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
    Sites
    • Either lobe or isthmus of thyroid gland
    Clinical features
    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)
      • Color Doppler ultrasound: little or no internal vascularity
      • Thyroid parenchyma: heterogeneous echogenicity, indicative of diffuse thyroiditis
    Radiology images

    Images hosted on other servers:
    Ultrasound Ultrasound

    Ultrasound

    Prognostic factors
    Case reports
    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

    Solid, gray-white

    Microscopic (histologic) description
    Microscopic (histologic) images

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

    Enlarged papillae

    Lymphoid follicle

    Lymphoid follicle

    Oncocytic epithelium

    Oncocytic epithelium

    Background thyroiditis

    Background thyroiditis

    Ki67

    Ki67

    Cytology description
    Cytology images

    Contributed by Shipra Agarwal, M.D.
    Inflammatory background

    Inflammatory background

    Lymphocytic permeation

    Lymphocytic permeation

    Oncocytic cells

    Oncocytic cells



    Images hosted on other servers:
    Liquid based cytology and conventional smear

    Liquid based cytology and conventional smear

    Positive stains
    Negative stains
    Molecular / cytogenetics description
    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
    Board review style question #1

    This thyroid tumor is named after which of the following salivary gland tumors?

    1. Lymphadenoma
    2. Oncocytic carcinoma
    3. Oncocytoma
    4. Sialadenoma papilliferum
    5. 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?

    1. Favorable clinical outcome
    2. Frequent dedifferentiation
    3. Mitochondrial DNA mutations
    4. Multiple (soap bubble-like) intranuclear inclusions
    5. 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 BRAFV600E 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
    Definition / general
    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:
    Missing Image

    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.
    Missing Image

    Questionable nuclear features of papillary carcinoma

    Cytology description
    Cytology images

    Images hosted on other servers:

    Cytological features of WDT-UMP

    Positive stains
    Differential diagnosis

    WHO classification
    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
    Diagrams / tables

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

    WHO classification: thyroid tumors

    Major Updates
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    Recent Thyroid & parathyroid Pathology books

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