Classification of Papillary and Follicular Thyroid Cancers
Main Histologic Framework
Papillary and follicular thyroid cancers are both differentiated thyroid carcinomas but represent distinct entities with different molecular profiles, clinical behaviors, and classification systems that should not be grouped together for staging purposes. 1, 2
Three-Tier Histologic Classification
Thyroid carcinomas are divided into three main histologic categories 3:
- Differentiated carcinomas (including papillary, follicular, and Hürthle cell)
- Medullary carcinoma (from parafollicular C cells)
- Anaplastic carcinoma (aggressive undifferentiated tumor)
Among differentiated thyroid carcinomas, papillary accounts for approximately 80-89% of cases, follicular 8-11%, and Hürthle cell 3% 3, 4, 5.
Papillary Thyroid Carcinoma (PTC) Classification
Molecular Classification
PTC is characterized by BRAF-predominant molecular signatures, distinguishing it from follicular carcinomas 1, 6. Key molecular alterations include:
- BRAF mutations (most common)
- RET/PTC fusions
- NTRK fusions
- ALK fusions 1
Morphologic Subtypes
The 2022 WHO Classification requires detailed subtyping of all papillary carcinomas, including microcarcinomas, rather than designating size-based categories 6. Important subtypes include:
- Classical variant PTC - characterized by papillae and clear nuclei 1
- Tall cell variant - criteria have been revisited in recent classifications 6
- Follicular variant PTC - when invasive and encapsulated, represents RAS-like malignancies 6
- Oncocytic variant - must have characteristic PTC nuclear features 6
Papillary thyroid microcarcinoma (PTMC) is no longer considered a unique PTC subtype; classification should be based on morphology rather than tumor size alone 3.
Clinical Characteristics
PTC demonstrates distinct presentation patterns 1, 2:
- Multifocal disease with bilateral involvement is common
- High rates of lymph node metastases compared to follicular carcinoma
- Generally excellent prognosis with 5-year survival rates of 98% 4
Follicular Thyroid Carcinoma (FTC) Classification
WHO Three-Category System
FTC is classified into three categories based on invasion pattern, which directly impacts prognosis 1, 7:
- Minimally invasive FTC - limited capsular invasion
- Angioinvasive FTC - vascular invasion present
- Widely invasive FTC - extensive invasion 1, 7
This classification system is critical because it determines treatment intensity and surveillance protocols 7.
Molecular Classification
FTC demonstrates RAS-predominant molecular signatures, contrasting with PTC 1, 6. Key alterations include:
- RAS mutations (most common)
- PAX8/PPARγ fusions
- EIF1AX mutations
- THADA fusions 1
Diagnostic Requirements
FTC cannot be diagnosed by fine-needle aspiration cytology alone - this is a critical diagnostic pitfall 1, 7. Definitive diagnosis requires:
- Surgical excision with complete histological examination
- Histological evidence of capsular and/or vascular invasion
- Assessment of invasion extent to determine WHO category 1, 7
FTC is typically classified as "indeterminate" on cytology reporting schemes 7.
Clinical Characteristics
FTC presents with distinct features 1, 7:
- Typically unifocal (not multifocal) at presentation
- Lower rates of lymph node metastases compared to PTC
- Demonstrates follicular architecture without papillary features
- Incidence rates have remained stable over 30 years, unlike rising PTC rates 1, 7
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 1. The term "Hürthle cell" is discouraged as a misnomer; "oncocytic carcinoma" is preferred 6.
Oncocytic carcinoma refers to neoplasms composed of >75% oncocytic cells that:
- Lack characteristic PTC nuclear features
- Lack high-grade features (necrosis and ≥5 mitoses per 2 mm²) 6
Risk Stratification Systems
American Thyroid Association Classification
The ATA risk stratification system classifies differentiated thyroid cancers as low-, intermediate-, or high-risk based on postoperative characteristics 3, 1. Critical caveats:
- This system is specific to differentiated thyroid carcinoma only (not medullary)
- "Risk" refers to probability of recurrence after treatment, not initial aggressiveness
- Classification requires postoperative data including TNM staging, histological features, and imaging
- Cannot be applied preoperatively 3
High-Grade Follicular Cell-Derived Malignancies
The classification now includes 6:
- Poorly differentiated thyroid carcinoma - defined by mitosis and necrosis
- High-grade differentiated thyroid carcinomas - characterized by increased mitotic activity (≥5 mitoses per 2 mm²) and tumor necrosis without anaplastic histology
- Both behave similarly and require aggressive management 6
Key Clinical Distinctions Between PTC and FTC
Despite similar overall survival rates, PTC and FTC possess fundamentally different prognostic factors and should be staged separately 2. Major differences include:
| Feature | Papillary (PTC) | Follicular (FTC) |
|---|---|---|
| Molecular profile | BRAF-predominant [1] | RAS-predominant [1] |
| Presentation | Multifocal, bilateral [1] | Unifocal [1,7] |
| Lymph node metastases | High rates [1] | Lower rates [1] |
| FNA diagnosis | Readily diagnosed [1] | Cannot be diagnosed [1,7] |
| Histology | Papillae, clear nuclei [1] | Capsular/vascular invasion [1] |
Important Clinical Pitfalls
Do not perform FNA on non-subcapsular thyroid nodules classified as cT1a cN0 (measuring <1 cm), even if considered high-risk by TIRADS criteria 3.
Do not group PTC and FTC together for staging purposes - each requires its own independent prognostic assessment and staging system 2.
Do not diagnose FTC based on cytology alone - surgical excision with complete histological examination is mandatory 1, 7.