Papillary Thyroid Cancer Histology: Variants and Markers

Papillary thyroid cancer (PTC) is the most common thyroid malignancy, making up the majority of differentiated thyroid carcinoma cases. It generally has a favorable prognosis, but certain histological variants and molecular markers affect its behavior and clinical management. Recognizing its distinct pathological features is essential for accurate diagnosis and treatment planning.

Cellular Architecture And Nuclear Features

PTC is identified by its characteristic cellular organization and nuclear features, which are essential for histopathological diagnosis. The tumor forms branching papillae lined by neoplastic follicular cells supported by a fibrovascular core. These papillae vary in size and shape, sometimes appearing compact or irregularly fused. In some cases, the tumor exhibits a microfollicular or solid growth pattern, complicating differentiation from other thyroid neoplasms.

The defining nuclear features of PTC are among its most diagnostic aspects. A hallmark characteristic is nuclear enlargement with overlapping, irregular contours and a ground-glass or “Orphan Annie eye” appearance due to chromatin clearing. This optical clarity results from chromatin dispersion along the nuclear membrane. Nuclear grooves, appearing as linear indentations along the nuclear membrane, are common and often accompanied by intranuclear cytoplasmic pseudoinclusions—eosinophilic structures representing cytoplasmic invaginations into the nucleus. While not exclusive to PTC, these features strongly suggest the diagnosis when observed together.

The nuclear alterations in PTC are linked to its molecular pathogenesis. BRAF mutations, particularly BRAF V600E, are strongly associated with the classic nuclear morphology of PTC. This mutation activates the MAPK signaling pathway, driving tumorigenesis and influencing nuclear architecture. Tumors with BRAF mutations tend to exhibit more pronounced nuclear irregularities compared to those with RAS mutations, which are more common in the follicular variant. The correlation between genetic alterations and nuclear morphology highlights the connection between molecular and histological features in thyroid cancer.

Subtypes

PTC has several histological subtypes, each with distinct morphological and clinical characteristics. These variants influence tumor behavior, prognosis, and treatment decisions.

Follicular Variant

The follicular variant of PTC (FVPTC) has a predominantly follicular growth pattern while retaining PTC’s nuclear features. Unlike classic PTC, which forms papillary structures, FVPTC consists of neoplastic cells arranged in small follicles, often resembling benign thyroid nodules or follicular neoplasms. This similarity can make diagnosis challenging, especially when nuclear features are subtle. The encapsulated form of FVPTC generally has an indolent course, while the infiltrative variant, which lacks a well-defined capsule and invades surrounding tissue, carries a higher risk of recurrence and metastasis.

FVPTC is more frequently associated with RAS mutations rather than BRAF V600E, setting it apart from classic PTC. The 2022 WHO classification of thyroid tumors refines FVPTC diagnostic criteria, emphasizing strict nuclear feature assessment to differentiate it from non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), a low-risk entity with minimal malignant potential.

Tall Cell Variant

The tall cell variant (TCV) consists of tumor cells at least twice as tall as they are wide, with abundant eosinophilic cytoplasm and prominent nuclear features. This variant is linked to more aggressive behavior, including higher rates of extrathyroidal extension, lymph node metastasis, and distant spread. Histologically, TCV exhibits elongated cells arranged in papillary structures, often with dense fibrotic stroma.

For classification, TCV features must be present in more than 30% of the tumor, as smaller proportions may not significantly impact prognosis. BRAF V600E mutations are highly prevalent in TCV, contributing to its aggressive nature through sustained MAPK pathway activation. Studies indicate that TCV is associated with lower disease-free survival compared to classic PTC, highlighting the need for more intensive management, including total thyroidectomy and radioactive iodine therapy in many cases.

Columnar Cell Variant

The columnar cell variant (CCV) is a rare but aggressive subtype characterized by tall, columnar cells with hyperchromatic nuclei and stratified architecture. Unlike TCV, CCV cells have a more basophilic appearance and often form pseudostratified layers, resembling endometrial or colonic epithelium. This variant is associated with rapid tumor progression, higher rates of distant metastasis, and resistance to conventional therapies.

Histopathologically, CCV can be mistaken for poorly differentiated thyroid carcinoma due to its architectural complexity and high mitotic activity. Molecular profiling shows that CCV often harbors BRAF V600E and TERT promoter mutations, both linked to aggressive thyroid cancers. Studies indicate that CCV patients tend to present with larger tumors and more advanced disease at diagnosis, necessitating early and aggressive intervention, including consideration of targeted therapies in refractory cases.

Diffuse Sclerosing Variant

The diffuse sclerosing variant (DSV) is characterized by extensive stromal fibrosis, lymphocytic infiltration, and numerous psammoma bodies. It often presents with diffuse thyroid involvement, mimicking Hashimoto’s thyroiditis both clinically and histologically. The tumor cells retain PTC’s nuclear features but are interspersed within a dense sclerotic stroma, often accompanied by squamous metaplasia.

DSV is more common in younger patients and has a higher propensity for lymph node metastasis at presentation. Despite its aggressive histological appearance, long-term outcomes are generally favorable with appropriate treatment. Molecularly, DSV frequently exhibits RET/PTC rearrangements rather than BRAF mutations, distinguishing it from other aggressive PTC variants. While DSV has a higher recurrence rate than classic PTC, overall survival remains comparable, particularly in patients receiving comprehensive surgical and radioactive iodine therapy.

Psammoma Bodies And Stromal Patterns

PTC frequently exhibits psammoma bodies—microscopic, concentrically laminated calcifications within the tumor stroma. These structures arise from progressive dystrophic calcification of necrotic tumor cells and apoptotic debris, forming dense, eosinophilic spheroids visible under light microscopy. Their presence is considered a hallmark feature when observed alongside the characteristic nuclear alterations. Psammoma bodies contribute to the gritty texture often noted during surgical resection and can be detected on fine-needle aspiration cytology. A higher density of psammoma bodies has been associated with increased lymph node metastasis, suggesting their potential as a marker of disease dissemination.

The stromal environment in PTC varies, reflecting the tumor’s biological diversity. Fibrosis is common, particularly in more aggressive variants, where dense collagen deposition creates a desmoplastic reaction encasing tumor nests. This fibrotic response is especially pronounced in tumors with extensive psammoma body formation, contributing to a firmer, more sclerotic consistency. In some cases, stromal hyalinization occurs, producing a glassy, eosinophilic appearance under histological staining. These stromal modifications may influence tumor rigidity and invasiveness, affecting surgical resectability and histological interpretation.

Angioinvasion and stromal vascularity also shape PTC’s histological landscape. Some tumors exhibit a well-vascularized stroma with prominent capillary networks supporting neoplastic cell proliferation, while others present with relatively avascular, hyalinized regions. Increased vascularization facilitates nutrient and oxygen supply, potentially accelerating tumor expansion, while excessive fibrosis may restrict perfusion, leading to localized hypoxia that can drive tumor persistence. This interplay between stromal remodeling and tumor biology underscores the complexity of PTC histopathology and highlights the need for careful stromal assessment in diagnostic evaluation.

Immunohistochemical Markers

Immunohistochemistry is central to PTC diagnosis, aiding differentiation from other thyroid neoplasms and providing insights into tumor biology. Thyroid transcription factor-1 (TTF-1) and paired box gene 8 (PAX8) confirm thyroid origin, as they are expressed in nearly all PTC cases. While not specific to PTC alone, these markers help distinguish thyroid carcinomas from metastatic malignancies.

Galectin-3, a β-galactoside-binding protein linked to cell adhesion and apoptosis regulation, is frequently overexpressed in PTC and helps differentiate malignant from benign thyroid lesions, particularly in cases with indeterminate cytology.

Cytokeratin 19 (CK19) is another highly sensitive marker, displaying strong diffuse immunoreactivity in PTC compared to follicular-patterned thyroid neoplasms. It helps differentiate PTC from follicular thyroid carcinoma, which typically exhibits weaker or absent CK19 staining. Hector Battifora mesothelial antigen-1 (HBME-1) further enhances diagnostic accuracy when used alongside CK19 and galectin-3, as it demonstrates membranous and cytoplasmic staining in most PTCs. Combining these markers in a panel increases specificity, reducing the likelihood of misdiagnosis in challenging cases.