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 2nd, 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
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
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
Virtual slides
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
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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