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PA31.{4,6} | Thyroid Tumors & Parathyroid Disease — SDL Guide (Part 2)

Follicular Thyroid Carcinoma: When Invasion Defines Malignancy

Follicular thyroid carcinoma (FTC) accounts for 10–15% of thyroid carcinomas. The critical teaching point: you cannot diagnose follicular carcinoma on cytology alone — the diagnosis requires histologic demonstration of invasion.

Why? Follicular carcinoma and follicular adenoma look identical on cytology (both show follicular cells, may show microfollicular pattern). The only features that prove malignancy are:

1. Capsular invasion — tumor cells penetrating through the fibrous capsule (must be full-thickness breach, not just pushing up against it)
2. Vascular invasion — tumor thrombi within capsular blood vessels lined by endothelium

Classification by invasion extent:

Type	Invasive Features	Metastatic Risk
Minimally invasive	Limited capsular ± vascular invasion	Low (<5% metastasis)
Widely invasive	Broad fronts of capsular breach, extensive vascular invasion	High (30–50% distant metastasis)

Gross pathology:
• Solitary, encapsulated mass — indistinguishable from adenoma grossly unless invasion is evident
• Widely invasive forms may infiltrate thyroid parenchyma extensively

Molecular: RAS mutations (30–45%) and PAX8-PPARG translocation (30–35%) are characteristic. BRAF mutations are absent (helps distinguish from PTC follicular variant).

Spread: Hematogenous — metastases to lungs and bones are characteristic ("cannon ball" lung mets, lytic/sclerotic bone mets). Lymph node metastasis is much less common than in PTC.

Prognosis: Worse than PTC for widely invasive forms. Minimally invasive FTC has an excellent prognosis similar to adenoma after resection.

Capsular Invasion in Follicular Thyroid Carcinoma vs. Intact Capsule in Follicular Adenoma (H&E, Medium Power)

Vascular Invasion in Follicular Thyroid Carcinoma: Diagnostic Histology

Medullary Thyroid Carcinoma: The Calcitonin-Secreting Tumor

Medullary thyroid carcinoma (MTC) arises from parafollicular C cells — the calcitonin-secreting cells scattered between thyroid follicles. It accounts for 5–10% of thyroid carcinomas but is clinically distinct and critically important because of its hereditary associations.

Two forms:

Feature	Sporadic MTC	Hereditary MTC
Frequency	~75%	~25%
Age	40–60s	Younger (childhood–30s)
Laterality	Usually unilateral	Often bilateral and multifocal
Precursor	—	C-cell hyperplasia → MTC
Mutation	Somatic RET	Germline RET point mutation

Hereditary MTC occurs in three settings:
1. MEN2A (Sipple syndrome) — MTC + bilateral pheochromocytoma + parathyroid hyperplasia
2. MEN2B — MTC + pheochromocytoma + mucosal neuromas + marfanoid habitus
3. Familial MTC — MTC alone, no other endocrine tumors

All hereditary MTC is caused by germline RET proto-oncogene point mutations. Genetic testing of family members is mandatory.

Gross pathology:
• Firm, gray-white mass; often bilateral in hereditary forms

Microscopic features:
1. Sheets, nests, or trabeculae of uniform polygonal to spindle cells (no follicle formation — remember, C cells don't make thyroid hormone)
2. Amyloid stroma — the hallmark. Amyloid here consists of polymerized calcitonin precursor peptides (calcitonin amyloid, stained with Congo red, shows apple-green birefringence under polarized light)
3. Fine stippled ("salt-and-pepper") chromatin — a neuroendocrine pattern
4. May show carcinoid-like architecture

Biochemical marker: Serum calcitonin — elevated in virtually all cases; used for diagnosis, staging, and post-operative follow-up. Carcinoembryonic antigen (CEA) is also elevated and correlates with prognosis.

Prognosis: Intermediate — better than anaplastic, worse than PTC. 10-year survival ~60–80% for localized disease, but poor with distant metastases.

Medullary Thyroid Carcinoma — H&E Histology and Amyloid Confirmation

Congo Red Stain: Amyloid in Medullary Thyroid Carcinoma — Bright Field vs. Polarized Light

Anaplastic Thyroid Carcinoma: The Most Aggressive Thyroid Tumor

Anaplastic (undifferentiated) thyroid carcinoma is rare (~1–2% of thyroid carcinomas) but constitutes one of the most lethal human malignancies. It does not respond to radioiodine or TSH suppression.

Key features:

• Age: Almost exclusively in patients >65 years of age — a thyroid carcinoma in an elderly patient that is rapidly enlarging must raise this diagnosis
• Pathogenesis: Often arises by dedifferentiation from pre-existing well-differentiated thyroid carcinoma (PTC or FTC), with acquisition of additional mutations (TP53, BRAF, CTNNB1)
• Presentation: Rapidly enlarging neck mass, dysphagia, dyspnea, stridor from tracheal compression, and hoarseness (recurrent laryngeal nerve invasion)

Gross: Large, infiltrative mass replacing much of the thyroid; frequently extends into adjacent soft tissues, trachea, esophagus

Microscopic features:
• Markedly pleomorphic, high-grade cells in three possible patterns:
1. Giant cell — bizarre, multinucleated giant cells with atypical mitoses
2. Spindle cell — sarcomatoid appearance
3. Squamoid — focal squamous differentiation
• Abundant mitoses and necrosis
• Complete loss of thyroid follicular differentiation (negative for thyroglobulin on IHC)

Prognosis: Uniformly fatal. Median survival is 3–6 months from diagnosis. No effective systemic therapy exists, though BRAF-targeted therapy (dabrafenib + trametinib) shows modest benefit in BRAF V600E-mutant cases.

Anaplastic Thyroid Carcinoma — H&E Histology (Medium and High Power)