Thyroid & parathyroid
Benign thyroid neoplasms
Solitary thyroid nodule
Editorial Board Member: Marc Pusztaszeri, M.D.
Last staff update: 31 March 2025 (update in progress)
Copyright: 2014-2025, PathologyOutlines.com, Inc.
PubMed Search: Solitary thyroid nodule
Table of Contents
Definition / general | Essential features | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Electron microscopy description | Molecular / cytogenetics description | Videos | Sample pathology report | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Iqbal M, Conway S, Zhou J. Solitary thyroid nodule. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/thyroidsolitary.html. Accessed April 3rd, 2025.
Definition / general
- Lump in the thyroid gland caused by abnormal cell proliferation, identified by manual examination or detected on imaging tests as an incidentaloma
Essential features
- Discrete lesion within the thyroid gland due to the aberrant proliferation of thyroid cells, resulting in the formation of a lump either detected by manual examination or through imaging studies only as an incidentaloma (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
- ~5 - 7% in adults during a physical exam, 70% during imaging studies and 50% reported during autopsy (Int J Gen Med 2024;17:135)
- 90% are benign, 4 - 6.5% are malignant (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
ICD coding
- ICD-10
- C73 - malignant neoplasm of thyroid gland
- D17.0 - benign lipomatous neoplasm of skin and subcutaneous tissue of head, face and neck
- D21.9 - benign neoplasm of connective and other soft tissue, unspecified
- D34 - benign neoplasm of thyroid gland
- D44.0 - neoplasm of uncertain behavior of thyroid gland
- Q89.2 - congenital malformations of other endocrine glands
Epidemiology
- Risk increases with age and exceeds 50% by seventh decade of life, F > M, radiation exposure, iodine deficiency (benign lesion) (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
Sites
- Thyroid gland
Pathophysiology
- Differs among individual lesions
- Benign (Endocr Pathol 2022;33:27)
- Toxic adenoma: activating mutations in the TSH receptor proteins, making them independent of thyroid stimulating hormones and 33% of cases have enhancer of zeste, homolog 1 (EZH1) mutation that functions as an epigenetic regulator of gene expression
- Follicular adenoma: BRAF K601E, EIF1AX, EZH1, DICER1, PTEN or TSHR, PAX8::PPARG has < 10% mutational changes
- BRAF, RET, NTRK or ALK fusions are not observed
- Borderline lesions
- Low malignant potential
- BRAF K601E, EIF1AX, EZH1, DICER1, PTEN, TSHR or RAS < 10% mutation
- PAX8::PPARG and THADA fusions up to 30%
- Malignant
- BRAF p.V600E, RAS, RET, NTRK, ALK, NTRK1 - NTRK3, TERT promotor mutations are the most common genetic alterations
Etiology
- Factors leading to benign causes (Front Endocrinol (Lausanne) 2023;14:1113977)
- Iodine deficiency
- Increase goitrogenic food intake
- Smoking
- Medications
- Genetic alterations such as DICER1 syndrome, Cowden disease, Carney complex
- Factors leading to malignant causes (J Clin Endocrinol Metab 2020;105:2869)
- Obesity
- Iodine deficiency and excess
- Ionizing radiation exposure including 131 iodine
- Thyroid adenoma
- Multinodular goiter
- Hashimoto thyroiditis
- Graves disease
- Genetic mutations such as MEN2A, MEN2B, FMTC, familial adenopolyposis syndrome, Carney complex, Werner syndrome, DICER1 syndrome, etc.
- Benign
- Thyroglossal duct cyst (Diseases 2022;10:7)
- Thyroid follicular adenoma (Semin Cancer Biol 2022;79:180)
- Follicular thyroid adenoma with papillary architecture (Front Endocrinol (Lausanne) 2018;9:737)
- Oncocytic adenoma (Endocr Pathol 2022;33:27)
- Lipoma (Medicine (Baltimore) 2020;99:e20392)
- Hemangioma (Ann Ital Chir 2023;94:557)
- Angiolipoma (Head Neck Pathol 2023;17:246)
- Lymphangioma (J Craniofac Surg 2021;32:1417)
- Leiomyoma (Indian J Otolaryngol Head Neck Surg 2024;76:1998)
- Schwannoma (Medicina (Kaunas) 2022;58:1345)
- Granular cell tumor (Endocrine 2022;76:395)
- Solitary fibrous tumor (Arch Clin Cases 2021;8:97)
- Low risk neoplasms (Endocr Pathol 2022;33:27)
- Noninvasive follicular thyroid neoplasm with papillary nuclear-like features
- Hyalinizing trabecular tumor
- Thyroid tumor of uncertain malignant potential
- Malignant (Endocr Pathol 2022;33:27)
- Follicular thyroid carcinoma
- Invasive encapsulated follicular variant of papillary thyroid carcinoma
- Papillary thyroid carcinoma
- Oncocytic carcinoma
- High grade follicular cell derived nonanaplastic thyroid carcinoma
- Anaplastic thyroid carcinoma
- Medullary thyroid carcinoma
- Mixed medullary and follicular cell derived thyroid carcinoma
- Mucoepidermoid carcinoma
- Secretory carcinoma
- Metastatic (Head Neck Pathol 2023;17:447)
- Melanoma, breast, kidney, lung
Clinical features
- Hypo and hyperthyroidism symptoms (heat and cold intolerance, change in bowel habits, weight change, generalized swelling, mood change, etc.) (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
- Radiation exposure, family history of thyroid cancers, symptoms associated with multiple endocrine neoplasia 2a or 2b, Cowden disease (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
- Local symptoms (dysphonia, stridor, cough, dysphagia and odynophagia), pain (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
- Lump could be cystic to firm in consistency, mobile to fixed to adjacent structures (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
Diagnosis
- Workup (S D Med 2022;75:569)
- If nodule is > 1 cm, proceed with thyroid stimulating hormone (TSH) levels
- If TSH levels are low, which indicates a hyperfunctioning nodule (low probability of cancer), no need for fine needle aspiration (FNA), proceed with T3, T4 levels and scintigraphy / radionucleotide iodine 123 scan
- If TSH levels are normal to high, which indicates a hypofunctioning cold nodule (high probability of cancer), proceed with ultrasound
- Thyroid imaging reporting and data systems (TIRADS) 1 and TIRADS 2, FNA is not indicated
- TIRADS 3 with 1.5 - 2.4 cm nodule, TIRADS 4 with 1 - 1.4 cm nodule and TIRADS 5 with nodule 0.5 - 0.9 cm, proceed with follow up
- TIRADS 3 with ≥ 2.5 cm nodule, TIRADS 4 with ≥ 1.5 cm nodule and TIRADS 5 with ≥ 1 cm nodule, proceed with FNA
- On cytology (S D Med 2022;75:569)
- Thyroid Bethesda System (TBS) 1: repeat FNA
- TBS 2: follow up
- TBS 3: repeat FNA or molecular testing
- TBS 4: molecular testing or lobectomy
- TBS 5: lobectomy or total thyroidectomy
- TBS 6: total thyroidectomy
- Molecular studies (Endocr Pathol 2022;33:27)
- BRAF, HRAS, KRAS, NRAS, RET, PTEN, TP53, TERT, PAX8::PPARG, GNAS, AKT1, EIF1AX, CD274 (PDL1) (Endocrinol Diabetes Metab 2021;4:e00241)
Laboratory
- Thyroid function test (TSH, T3 and T4), could show hyper, hypo and euthyroid state depending upon the lesion
- Molecular studies (see Diagnosis)
Radiology description
- Ultrasound (thyroid imaging reporting and data systems [TIRADS], lesion composition, echogenicity, shape, margin and echogenic foci observed) (S D Med 2022;75:569)
- TIRADS 1 (0 points, benign, no FNA)
- TIRADS 2 (2 points, not suspicious, no FNA)
- TIRADS 3 (3 points, mildly suspicious, if ≥ 2.5 cm, then FNA and if ≥ 1.5 cm, then follow up)
- TIRADS 4 (4 - 6 points, moderately suspicious, if ≥ 1.5 cm, then FNA and if ≥ 1 cm, then follow up)
- TIRADS 5 (7+ points, highly suspicious, if ≥ 1 cm, then FNA and if ≥ 0.5 cm, then follow up)
- Thyroid scintigraphy / radionucleotide iodine 123 scan (hot nodule is most likely benign and cold nodule could be benign and malignant)
- Computed tomography (CT) and magnetic resonance imaging (MRI) for the evaluation of the extent of the lesion
Radiology images
Images hosted on other servers:
Multiple hypoechoic lesions
Prognostic factors
- Variation differs from one lesion to another
- Benign lesions most common (~90%), malignant lesions 4 - 6.5% (StatPearls: Thyroid Nodule [Accessed 17 October 2024])
Case reports
- 24 year old woman with thyroid vein hemangioma in the left lobe (J Int Med Res 2020;48:300060520954718)
- 51 year old woman with undifferentiated sarcoma in the right thyroid lobe (Asian J Surg 2023;46:5058)
- 65 year old woman with primary extraskeletal osteosarcoma, osteoblastic type in the right thyroid lobe (ORL J Otorhinolaryngol Relat Spec 2023;85:52)
Treatment
- Varies from lesion to lesion, including observation, thyroid lobectomy or total thyroidectomy
Gross description
- Varies depending upon the lesion
- Follicular adenoma: solid homogeneous, grayish white, tan or brown cut surface with thick capsule (see Follicular adenoma)
- Follicular carcinoma: solid and tan-gray cut surface (see Follicular thyroid carcinoma)
- Papillary thyroid cancer: firm and white in color to variegated in appearance (see Papillary thyroid carcinoma overview)
Gross images
Contributed by Sara Conway, M.D. and Momin Iqbal, M.D., M.B.B.S.
Follicular thyroid lesion
Oncocytic tumor
Papillary thyroid cancer
Microscopic (histologic) description
- Varies from lesion to lesion
- Papillary thyroid cancer (PTC) (Adv Ther 2020;37:3112)
- Papillary architecture with thin fibrovascular core, the cells can have overcrowded nuclei
- Nuclei have distinct features with elongated to oval nuclei, open chromatin, nuclear grooves and intranuclear cytoplasmic pseudoinclusions
- Follicular thyroid cancer: follicular thyroid cancer histologically is very similar to thyroid adenoma except for invasion of capsule or vessels (Endocr Pathol 2022;33:27)
- Oncocytic / Hürthle cell tumor: encapsulated lesion with predominantly oncocytic / Hürthle cells with intensely eosinophilic granular cytoplasm (Endocr Pathol 2022;33:27)
Microscopic (histologic) images
Contributed by Momin Iqbal, M.D., M.B.B.S. and Sara Conway, M.D.
Papillary thyroid carcinoma
Mushroom-like capsular invasion
Tall cell variant of PTC
Thyroid oncocytic / Hürthle cell tumor
Angioinvasive Hürthle cell tumor
Follicular thyroid adenoma
Follicular thyroid adenoma
Virtual slides
Images hosted on other servers:
Primary thyroid hemangioma
PTC fine needle aspiration
Medullary thyroid carcinoma
Cytology description
- Features that are pertinent to assess include cellularity, colloid, nuclear features, Hürthle cells, atypical cells, oncocytic cells, inflammatory cells
- Reported as TBS classification
- TBS 1: nondiagnostic or unsatisfactory (see Thyroid & parathyroid-Unsatisfactory)
- TBS 2: benign (see Thyroid & parathyroid-Benign)
- TBS 3: atypia of undetermined significance (see Thyroid & parathyroid-AUS)
- TBS 4: follicular neoplasm or suspicious for a follicular neoplasm (see Thyroid & parathyroid-Follicular neoplasm)
- TBS 5: suspicious for malignancy (see Thyroid & parathyroid-Suspicious for malignancy)
- TBS 6: positive for malignancy (see Thyroid & parathyroid-Malignant)
Electron microscopy description
- Similar to normal thyroid gland and hyperplastic nodules
- Hyperfunctioning follicular adenomas: organelle rich cytoplasm, especially rough endoplasmic reticulum; numerous, long microvilli on surface (Am J Clin Pathol 1982;78:299)
- Clear cell follicular adenomas: cytoplasmic vesicles of variable size; these may be dilated cisternae of the rough endoplasmic reticulum or mitochondria, lysosomes or endocytic vesicles (Virchows Arch A Pathol Anat Histol 1978;380:205)
- Hürthle cell tumor: cytoplasm packed with mitochondria (Endocr Pathol 2022;33:27)
Molecular / cytogenetics description
- Molecular studies (Endocr Pathol 2022;33:27)
- BRAF: papillary thyroid carcinoma, anaplastic thyroid carcinoma, follicular thyroid carcinoma, thyroid follicular adenoma
- HRAS: follicular thyroid carcinoma, follicular thyroid adenoma, anaplastic thyroid carcinoma
- KRAS: papillary thyroid carcinoma, follicular thyroid carcinoma, follicular thyroid adenoma, anaplastic thyroid carcinoma
- NRAS: papillary thyroid carcinoma, follicular thyroid carcinoma, follicular thyroid adenoma, anaplastic thyroid carcinoma
- RET: medullary thyroid carcinoma, papillary thyroid carcinoma, follicular thyroid carcinoma
- PTEN: follicular thyroid carcinoma, papillary thyroid carcinoma
- TP53: papillary thyroid carcinoma, follicular thyroid carcinoma, anaplastic thyroid carcinoma
- TERT: papillary thyroid carcinoma, follicular thyroid carcinoma, anaplastic thyroid carcinoma
- PAX8::PPARG: follicular thyroid carcinoma, follicular thyroid adenoma
- GNAS: noninvasive follicular thyroid neoplasm with papillary nuclear-like features, follicular thyroid adenoma
- AKT1: papillary thyroid carcinoma, follicular thyroid carcinoma, follicular thyroid adenoma
- EIF1AX: follicular adenoma, follicular thyroid carcinoma, anaplastic thyroid carcinoma, poorly differentiated thyroid carcinoma (Cancers (Basel) 2022;14:6097)
- CD274 (PDL1): medullary thyroid carcinoma, follicular thyroid carcinoma, papillary thyroid carcinoma (Endocrinol Diabetes Metab 2021;4:e00241, Theranostics 2021;11:1310)
Videos
Solitary thyroid nodule
Thyroid carcinoma I: pathology evaluation
Sample pathology report
- Thyroid, total thyroidectomy:
- Follicular thyroid carcinoma (4.8 cm), minimally invasive with capsular invasion (A27, A28, A11), isthmus (see comment)
- Surgical resection margins, negative for tumor; no vascular invasion identified
- Nonneoplastic thyroid showing thyroid follicular nodular disease with adenomatous nodules and chronic lymphocytic (Hashimoto) thyroiditis
- 5 lymph nodes (0/5), negative for malignancy
- AJCC tumor stage: pT3N0a
- Comment: Immunohistochemical stains are performed.
Slide Immunohistochemical stain Result A112 CK19 Focally positive A113 BRAF V600E Negative A182 CD31 Negative
Board review style question #1
What is the most commonly associated genetic abnormality identified in papillary thyroid carcinoma?
- BRAF mutation
- E1F1AX mutation
- PTEN mutation
- RAS mutation
Board review style answer #1
A. BRAF mutation. BRAF mutations are frequently linked to papillary thyroid carcinoma. The prevalence of papillary thyroid carcinoma in adults is 80 - 95% of all thyroid cancers and 90% in the pediatric population. Answer D is incorrect because RAS mutation is found in 20 - 30% of follicular adenomas. Answer B is incorrect because E1F1AX mutation is seen in 10 - 20% of follicular adenomas. Answer C is incorrect because PTEN mutation occurs in 10 - 15% of follicular adenomas.
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Board review style question #2
For a patient with thyroid imaging reporting and data systems (TIRADS) 4 thyroid nodule, what is the cut off size for subsequent FNA evaluation?
- ≥ 1 cm
- ≥ 1.5 cm
- ≥ 2.0 cm
- ≥ 2.5 cm
Board review style answer #2
B. ≥ 1.5 cm. For a TIRADS 4 thyroid lesion, it is recommended for ultrasound guided FNA if the lesion is ≥ 1.5 cm. Ultrasound TIRADS is based on the lesion composition, echogenicity, shape, margin and echogenic foci observed; based on the scores, the thyroid lesion is categorized as TIRADS 1 (0 points, benign, no FNA), TIRADS 2 (2 points, not suspicious, no FNA), TIRADS 3 (3 points, mildly suspicious, if ≥ 2.5 cm, then FNA and if ≥ 1.5 cm, then follow up); TIRADS 4 (4 - 6 points, moderately suspicious, if ≥ 1.5 cm, then FNA and if ≥ 1 cm, then follow up); and TIRADS 5 (7+ points, highly suspicious, if ≥ 1 cm, then FNA and if ≥ 0.5 cm, then follow up).
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