What are the different types of thyroid malignancy and their characteristics?

Types of Thyroid Malignancy and Their Characteristics

Overview of Thyroid Cancer Classification

Thyroid carcinomas are divided into three main histologic categories: differentiated carcinomas (papillary and follicular), medullary carcinoma, and anaplastic carcinoma, with differentiated carcinomas accounting for approximately 95% of all cases. 1, 2

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Differentiated Thyroid Carcinomas (DTCs)

Papillary Thyroid Carcinoma (PTC)

PTC represents 84% of all thyroid malignancies and has an excellent prognosis with a 10-year survival rate of 99%. 1

Key Characteristics:

• Molecular Profile: BRAF-predominant molecular signatures, including BRAF V600E mutations, RET/PTC fusions, NTRK fusions, and ALK fusions 1, 2
• Presentation Pattern: Multifocal disease with bilateral involvement and high rates of lymph node metastases 2
• Cytologic Features: Papillae with clear nuclei (ground-glass appearance) that can be readily diagnosed on fine-needle aspiration (FNA) 1, 2
• Histologic Variants: Classical variant, follicular variant, tall cell variant, columnar cell variant, hobnail variant, diffuse sclerosing variant, and oncocytic variant 1, 2

Aggressive Variants:

• Tall Cell Variant: Associated with higher tumor stages and lymph node metastases at diagnosis 3
• Hobnail Variant: Moderately differentiated subtype with aggressive clinical behavior, significant mortality, and strong propensity for disease progression 3
• Columnar Cell Variant: Considered high-risk with poorer clinical outcomes 3

Follicular Thyroid Carcinoma (FTC)

FTC represents 11% of all thyroid malignancies with a 10-year survival rate of 95%, and is classified into three categories based on invasion pattern: minimally invasive, angioinvasive, and widely invasive. 1, 4, 2

Key Characteristics:

• Molecular Profile: RAS-predominant molecular signatures, including RAS mutations, PAX8/PPARγ fusions, EIF1AX mutations, and THADA fusions 1, 2
• Presentation Pattern: Typically unifocal (not multifocal) with lower rates of lymph node metastases compared to PTC 4, 2
• Diagnostic Challenge: Cannot be diagnosed by FNA alone—requires histological evidence of capsular and/or vascular invasion after surgical excision 4, 2
• Histologic Features: Follicular architecture without papillary features; diagnosis depends on demonstrating capsular or vascular invasion 1, 2

Classification by Invasion:

• Minimally Invasive FTC: Capsular invasion only; best prognosis 4, 3
• Angioinvasive FTC: Vascular invasion involving <4 blood vessels; intermediate risk 3
• Widely Invasive FTC: Neoplastic emboli involving ≥4 blood vessels; considered high-risk 3

Hürthle Cell (Oncocytic) Carcinoma

Hürthle cell carcinomas are no longer classified as follicular tumors and should be managed as distinct high-risk carcinomas when associated with extensive vascular and/or capsular invasion, with recurrence risk of 30-55%. 1, 3

Key Characteristics:

• Definition: "Pure" Hürthle cell carcinomas have >75% Hürthle cell component 1, 3
• Molecular Profile: Distinct molecular abnormalities from conventional follicular carcinomas, including RAS mutations, EIF1AX mutations, PTEN mutations, TP53 mutations, and mitochondrial DNA alterations 1, 3
• Clinical Behavior: More aggressive than conventional follicular carcinomas when extensive vascular/capsular invasion is present 3

Poorly Differentiated Carcinoma

Poorly differentiated carcinomas are defined as invasive tumors with solid/trabecular/insular growth pattern plus at least one of the following: mitotic index ≥3 per 10 high-power fields, necrosis, or convoluted nuclei. 1, 3

Key Characteristics:

• Molecular Features: RAS mutations, BRAF K601E, TERT promoter mutations, TP53 mutations, PIK3CA mutations, and alterations in histone methyltransferases 1
• Clinical Behavior: Aggressive while maintaining some degree of functional differentiation (e.g., thyroglobulin production) 1
• Prognosis: Intermediate between differentiated and anaplastic carcinomas 1

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Medullary Thyroid Carcinoma (MTC)

MTC arises from parafollicular C-cells and represents approximately 5% of thyroid malignancies, with a 10-year survival rate of approximately 75-82%. 1

Key Characteristics:

• Cell of Origin: Parafollicular C-cells (not follicular epithelial cells) 1
• Clinical Associations: Associated with MEN 2A, MEN 2B, hyperparathyroidism, pheochromocytoma, marfanoid habitus, and mucosal neuromas 1
• Diagnostic Features: Calcitonin immunohistochemistry confirms diagnosis; can be identified through pathologic diagnosis or prospective genetic screening 1
• Prognosis: More aggressive than differentiated thyroid carcinomas but better than anaplastic carcinoma 1

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Anaplastic Thyroid Carcinoma (ATC)

ATC is an aggressive undifferentiated tumor with a 10-year survival of only 8%, median survival of approximately 5 months, and is almost uniformly fatal. 1

Key Characteristics:

• Presentation: Rapidly enlarging neck mass, dyspnea, dysphagia, neck pain, Horner's syndrome, stroke, and hoarseness due to vocal cord paralysis 1
• Staging: All ATCs are considered stage IV (A, B, or C) at diagnosis 1
• Distant Metastases: Present at initial diagnosis in 15-50% of patients; lungs and pleura are most common sites (≤90% of patients with distant disease) 1
• Morphology: Most common morphology is biphasic spindle and giant cell tumor; many have mixed morphologies 1
• Prognosis: 1-year relative survival rate is approximately 18%; death often attributable to upper airway obstruction and suffocation in 50% of patients 1
• Treatment: No curative therapy exists; treatment does not significantly impact survival 1

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Rare Thyroid Malignancies

Primary thyroid lymphoma, sarcoma, and metastases to the thyroid are rare, comprising less than 5% of thyroid malignancies. 1, 5

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Critical Diagnostic Pitfalls to Avoid

• Do not confuse minimally invasive FTC with widely invasive disease: Only widely invasive FTC (≥4 vessels involved) qualifies as high-risk histology 3
• Do not mistake Hürthle cell neoplasms for MTC: They can mimic MTC cytologically and on frozen section; calcitonin immunohistochemistry distinguishes them 1
• Do not overlook metastatic disease: Metastatic renal carcinoma can mimic follicular neoplasm, melanoma can mimic MTC, and metastatic lung cancer can mimic ATC 1
• Recognize non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): This has <1% recurrence risk and should not be confused with high-risk disease 3