What is the anatomy of the thyroid gland, which cells are most vulnerable to mutations, and how are thyroid tumors classified?

Thyroid Gland Anatomy and Cellular Vulnerability to Mutations

Anatomical Structure

The thyroid gland is composed of two lateral lobes connected by an isthmus, located in the anterolateral region of the second to fourth tracheal cartilages. 1

• The gland contains two primary cell types with distinct functions and malignant potential 2
• Follicular cells constitute the majority of thyroid tissue and store thyroid hormones within thyroglobulin molecules 3
• Parafollicular C cells are scattered throughout the gland and produce calcitonin 2
• Anatomical variations are common, including rare cases of isthmus agenesis or ectopic thyroid tissue 1

Most Vulnerable Cells to Malignant Transformation

Follicular cells are by far the most vulnerable to malignant transformation, accounting for approximately 95% of all thyroid carcinomas. 4

Follicular Cell Vulnerability

• Follicular cells give rise to differentiated thyroid carcinomas (papillary, follicular, and Hürthle cell types) 2, 4
• Papillary thyroid carcinoma alone represents the vast majority of cases, arising from follicular cells 4
• These cells are susceptible to specific mutations including BRAF V600E (occurring in ~45% of papillary carcinomas), RET/PTC, RAS, and PAX8/PPARγ 2
• Anaplastic carcinoma, the most aggressive form, arises from follicular cells that have undergone additional mutational events, particularly p53 mutations 2

Parafollicular C Cell Vulnerability

• C cells account for a much smaller proportion of thyroid malignancies 2
• These cells give rise to medullary thyroid carcinoma (MTC), which represents approximately 2-3% of thyroid cancers 2
• C cells are particularly vulnerable when RET proto-oncogene mutations are present, especially codon 918 mutations (>95% of MEN 2B cases) 2
• Unlike follicular cells, C cells lack TSH receptors and do not concentrate radioactive iodine 2

Classification of Thyroid Tumors

Follicular Cell-Derived Neoplasms (Most Common)

The 2022 WHO classification divides follicular cell-derived tumors into benign, low-risk, and malignant categories based on molecular profiles and biological behavior. 5

Benign Tumors

• Follicular adenoma (including variants with papillary architecture and oncocytic adenomas) 5
• Thyroid follicular nodular disease (multifocal hyperplastic/neoplastic lesions in multinodular goiter) 5

Low-Risk Neoplasms

• Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) 5
• Thyroid tumors of uncertain malignant potential 5
• Hyalinizing trabecular tumor 5

Malignant Tumors - BRAF-like Profile

• Papillary thyroid carcinoma (PTC) and its multiple morphological subtypes represent BRAF-like malignancies with excellent prognosis (10-year survival 99%) 2, 5
• The BRAF V600E mutation is the most common mutation in papillary carcinomas 2
• Cribriform-morular thyroid carcinoma is no longer classified as a PTC subtype 5

Malignant Tumors - RAS-like Profile

• Invasive encapsulated follicular variant PTC 5
• Follicular thyroid carcinoma (10-year survival 95%) 2, 5

Oncocytic (Hürthle Cell) Carcinoma

• Now classified as a distinct entity by WHO, not a follicular variant 6, 7, 5
• Represents approximately 3% of thyroid carcinomas with 10-year survival of 76% 6
• Defined as neoplasms composed of >75% oncocytic cells without PTC nuclear features or high-grade features 5
• Requires total thyroidectomy, not lobectomy, due to more aggressive behavior 6
• Molecular diagnostics perform poorly for Hürthle cell neoplasms with high false-positive rates 2, 6

High-Grade Follicular Cell-Derived Malignancies

• Poorly differentiated carcinoma (5-year survival 60-85%) 2, 5
• High-grade differentiated thyroid carcinomas (characterized by ≥5 mitoses per 2mm² and tumor necrosis) 5

Anaplastic Thyroid Carcinoma

• The most aggressive thyroid tumor and one of the most aggressive human cancers 2
• Represents <2% of thyroid tumors with mean survival <6 months 2
• Arises from follicular cells but retains no biological features (no iodine uptake or thyroglobulin synthesis) 2
• Develops from pre-existing well-differentiated tumors after additional p53 mutations 2
• All ATCs are classified as stage IV regardless of size 2
• Squamous cell carcinoma of the thyroid is now considered a subtype of anaplastic carcinoma 5

C Cell-Derived Neoplasms

Medullary thyroid carcinoma (MTC) arises from parafollicular C cells 2

• More aggressive than differentiated carcinomas with 10-year survival of 82% 2
• Associated with RET proto-oncogene mutations (>95% of MEN 2B have codon 918 mutations) 2
• Does not concentrate radioactive iodine and responds poorly to conventional chemotherapy 2
• A new grading system based on mitotic count, tumor necrosis, and Ki67 labeling index has been introduced 5

Other Tumor Categories

Salivary gland-type carcinomas (mucoepidermoid and secretory carcinoma) 5

Thymic tumors within the thyroid (thymomas, thymic carcinomas, spindle epithelial tumor with thymus-like elements) 5

Tumors of unclear lineage (sclerosing mucoepidermoid carcinoma with eosinophilia, cribriform-morular thyroid carcinoma) 5

Thyroblastoma (embryonal tumor associated with DICER1 mutations) 5

Secondary tumors (metastases from lung, kidney, breast) 8

Hematolymphoid neoplasms (malignant lymphoma) 8, 5

Key Clinical Pitfalls

• Do not treat Hürthle cell carcinoma with lobectomy alone—this leads to inadequate management of a potentially aggressive cancer requiring total thyroidectomy 6
• Molecular diagnostics should not be routinely used for Hürthle cell neoplasms due to 86% false-positive rates leading to unnecessary surgery 6
• Always exclude pheochromocytoma before thyroid surgery in MTC patients to avoid hypertensive crisis 2
• TSH suppression is inappropriate for MTC since C cells lack TSH receptors; maintain TSH in normal range 2