- Throughout the American Thyroid Association (ATA) 2025 Thyroid Cancer Guidelines:
- The 5th edition of the WHO Classification of Thyroid Tumors has been utilized for descriptions of the types of non-anaplastic follicular cell-derived thyroid carcinomas and NIFTP
- Approximately 90% of thyroid cancer cases are well differentiated and are classified based on the predominant histomorphology:
- However, they now also can be categorized based on their molecular profiles
- Four main types of DTC include:
- Follicular thyroid carcinoma (FTC)
- Invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC)
- Papillary thyroid carcinoma (PTC)
- Oncocytic thyroid carcinoma (OTC)
- PTC is the most common type of DTC:
- PTC is typically indolent and associated with excellent long-term survival:
- 96% at 5 years
- 93% at 10 years
- Greater than 90% at 20 years
- Overall, mortality rates for PTC are:
- 1% to 6.5%
- Overall recurrence rate of 15% to 35%:
- Tumor recurrence typically occurs in the:
- Tumor bed
- Cervical lymph nodes
- Distant sites (rarely)
- Tumor recurrence typically occurs in the:
- PTCs have characteristic nuclear features:
- Core elements fall into three buckets (per WHO 5th ed. framework and modern scoring systems):
- Size / shape/ crowding:
- Nuclear enlargement
- Elongation / ovality
- Overlapping / crowding
- Pseudostratification at the papillary edges
- These are low-power cues to look closer
- Membrane irregularities:
- Nuclear grooves (longitudinal folds)
- Intranuclear cytoplasmic pseudoinclusions (INCIs):
- Round, sharply circumscribed, eosinophilic inclusions:
- Caused by cytoplasmic invagination
- Round, sharply circumscribed, eosinophilic inclusions:
- Irregular nuclear contours / notches
- Notes for practice:
- Grooves are sensitive but not specific
- INCIs are more specific for PTC when true (focus and multiple planes help)
- Chromatin changes:
- Chromatin clearing with peripheral margination:
- The classic “Orphan Annie-eye” look
- Fine (“powdery”) chromatin with micronucleoli
- Apparent thickened nuclear membrane on H&E
- Clearing can be mimicked by Hashimoto thyroiditis or fixation artifact:
- So it needs to be interpreted with the full nuclear constellation
- Chromatin clearing with peripheral margination:
- Size / shape/ crowding:
- How pathologists operationalize this:
- In follicular-patterned lesions (e.g., NIFTP vs infiltrative FV-PTC), a 3-category nuclear score is applied:
- Size / shape
- Membrane irregularities
- Chromatin features
- A score ≥ 2 supports PTC-type nuclear features
- NIFTP requires papillary-type nuclei (score ≥ 2) and strict architectura l/ invasion criteria
- In follicular-patterned lesions (e.g., NIFTP vs infiltrative FV-PTC), a 3-category nuclear score is applied:
- WHO 2022 emphasizes first deciding whether PTC-type nuclei are present before subtyping;
- This step drives nomenclature:
- Low-risk neoplasm vs malignancy
- This step drives nomenclature:
- Molecular correlations you’ll see in reports:
- BRAF V600E–driven tumors (classic / tall-cell subtypes):
- Tend to show florid nuclear features:
- Grooves (longitudinal folds)
- INCIs
- Glassy nuclei
- Tend to show florid nuclear features:
- RAS-mutated follicular-patterned tumors:
- Often have subtler nuclei
- BRAF V600E–driven tumors (classic / tall-cell subtypes):
- Papillary thyroid carcinomas (PTC) can present as:
- Infiltrative and encapsulated tumors
- Molecular studies have shown that most PTCs (90%) develop by:
- The activation of a Mitogen-Activated Protein Kinase (MAPK) pathway-event:
- This activation occurs via mutually exclusive mutations in:
- BRAF or RAS oncogenes
- This activation occurs via mutually exclusive mutations in:
- A subset of PTCs is acquired by gene fusions involving:
- Rearranged during transfection (RET) or (less commonly) other receptor tyrosine kinases
- Oncogenic mutations at BRAFV600E:
- Are the most common in PTC
- A minority can show non-V600E mutations:
- Such as BRAFK601E or BRAF fusions
- The IEFVPTC is an encapsulated and invasive follicular-patterned tumor:
- Based on its tendency for vascular invasion, distant metastasis, and molecular profile:
- It can behave similarly to FTC
- Based on its tendency for vascular invasion, distant metastasis, and molecular profile:
- The activation of a Mitogen-Activated Protein Kinase (MAPK) pathway-event:
- Core elements fall into three buckets (per WHO 5th ed. framework and modern scoring systems):
- PTC is typically indolent and associated with excellent long-term survival:
- Histologically, FTCs are encapsulated follicular patterned tumors:
- Without the nuclear features of PTC
- They are characterized by the presence of:
- Vascular:
- Limited or extensive
- Capsular invasion:
- Vascular invasion involving vessels within the tumor capsule
- Widely invasive:
- Extensive invasion of the thyroid parenchyma beyond the tumor capsule
- Vascular:
- These tumors are mostly driven by activating mutations in:
- RAS oncogenes (NRAS > HRAS > KRAS), PAX8::PPARγ fusions, EIF1AX mutations, PIK3CA mutations, or loss of PTEN expression:
- BRAFV600E and RET fusions typically are not seen in FTC
- Expression of PAX8::PPARγ fusions oncoprotein:
- Occur in 25% of FTC:
- In which the thyroid transcription factor PAX8 drives the expression of PPARγ:
- A receptor involved in adipocyte biology
- In which the thyroid transcription factor PAX8 drives the expression of PPARγ:
- Occur in 25% of FTC:
- Mutations in DICER1:
- Which encodes a ribonuclease in the processing of microRNA precursors:
- Occur in RAS-like thyroid neoplasms and are prevalent in FTC
- DICER1 mutations can also be seen in subsets of PTC, differentiated high-grade thyroid carcinoma (DHGTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC)
- Which encodes a ribonuclease in the processing of microRNA precursors:
- RAS oncogenes (NRAS > HRAS > KRAS), PAX8::PPARγ fusions, EIF1AX mutations, PIK3CA mutations, or loss of PTEN expression:
- With greater recognition of the unique genomic features of OTC (previously known as Hürthle cell carcinoma) and different clinical behavior from classical forms of FTC:
- These tumors are now considered a third form of DTC:
- Rather than a subtype of FTC in the current WHO classification:
- They account for ∼ 3% of all DTC
- Rather than a subtype of FTC in the current WHO classification:
- An “oncocyte” is an enlarged polygonal cell with an abundant granular eosinophilic cytoplasm, round nuclei with even chromatin pattern, and prominent nucleoli:
- As defined by WHO:
- Oncocytic neoplasms are usually encapsulated and composed of ≥ 75% oncocytic cells
- Oncocytic features can be identified in some PTC or FTC cells at lower frequencies
- As defined by WHO:
- Most of these tumors are larger in size; however, smaller tumors can be identified
- Like FTC, the presence of invasive characteristics:
- Tumor capsule and / or vascular invasion:
- In an encapsulated oncocytic neoplasm:
- Is diagnostic of OTC
- In an encapsulated oncocytic neoplasm:
- OTCs can be classified as:
- Minimally invasive
- Encapsulated angio-invasive
- Widely invasive
- Tumor capsule and / or vascular invasion:
- Genomically, OTCs are characterized typically by:
- A near-haploid genome
- Mitochondrial DNA mutations:
- Commonly involving genes encoding Complex 1 of the mitochondrial respiratory chain
- Mutations in DAXX and ATRX:
- Involved in telomere length
- OTCs can also have mutations that activate:
- Mammalian target of rapamycin (mTOR) and MAPK signaling
- Like PTC and FTC:
- More aggressive OTCs can have mutations in the:
- TERTpromoter or TP53
- More aggressive OTCs can have mutations in the:
- Clinically, some studies have shown that OTCs have a greater tendency toward lymph node metastases while retaining a predilection for distant metastases, and unlike FTC:
- OTCs often are not radioiodine-avid despite retaining other differentiated features:
- Such as Tg secretion and TSH receptor expression
- OTCs often are not radioiodine-avid despite retaining other differentiated features:
- These tumors are now considered a third form of DTC:
- The 5th edition of the WHO Classification of Thyroid Tumors:
- Also introduces a new category of high-grade follicular cell derived, non-anaplastic carcinoma that includes:
- PDTC and DHGTC.
- By molecular analysis, poorly differentiated thyroid cancer and DHGTC:
- Harbor driver mutations in BRAF (BRAFV600E) and RAS genes:
- In some cases may show gene fusions:
- Often RET and NTRK3
- In some cases may show gene fusions:
- Additional mutations in the:
- TERT promoter, PIK3CA, and TP53 are commonly identified
- Harbor driver mutations in BRAF (BRAFV600E) and RAS genes:
- DHGTC has been defined by certain authors as a:
- “Thyroid malignancy” that is recognized as DTC but in which certain histological and cytopathologic features are present that justify the lesion being classified as “high-grade”
- The DHGTCs are invasive, high-grade carcinomas:
- That show one of the following two histological features:
- Mitotic count ≥ 5 per 2 mm2
- Tumor necrosis
- That show one of the following two histological features:
- By contrast, thyroid carcinomas classified as PDTC are follicular cell-derived tumors that show a minor component of DTC (papillary, follicular, oncocytic):
- Show solid and / or insular growth pattern with presence of either:
- Necrosis or ≥ mitotic count of 3 per 2 mm2, and lack the usual histological characteristics and aggressiveness of ATC
- Show solid and / or insular growth pattern with presence of either:
- In both cases, clinical behavior is considered:
- Intermediate between DTC and ATC
- Also introduces a new category of high-grade follicular cell derived, non-anaplastic carcinoma that includes:
Rodrigo Arrangoiz MS, MD, FACS, FSSO 