J Pathol Transl Med.  2024 Nov;58(6):265-282. 10.4132/jptm.2024.10.11.

Cytologic hallmarks and differential diagnosis of papillary thyroid carcinoma subtypes

• Harahap AS
• Jung CK

• KMID: 2560668
• DOI: http://doi.org/10.4132/jptm.2024.10.11

Abstract

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, characterized by a range of subtypes that differ in their cytologic features, clinical behavior, and prognosis. Accurate cytologic evaluation of PTC using fine-needle aspiration is essential but can be challenging due to the morphologic diversity among subtypes. This review focuses on the distinct cytologic characteristics of various PTC subtypes, including the classic type, follicular variant, tall cell, columnar cell, hobnail, diffuse sclerosing, Warthin-like, solid/trabecular, and oncocytic PTCs. Each subtype demonstrates unique nuclear features, architectural patterns, and background elements essential for diagnosis and differentiation from other thyroid lesions. Recognizing these distinct cytologic patterns is essential for identifying aggressive subtypes like tall cell, hobnail, and columnar cell PTCs, which have a higher risk of recurrence, metastasis, and poorer clinical outcomes. Additionally, rare subtypes such as diffuse sclerosing and Warthin-like PTCs present unique cytologic profiles that must be carefully interpreted to avoid diagnostic errors. The review also highlights the cytologic indicators of lymph node metastasis and high-grade features, such as differentiated high-grade thyroid carcinoma. The integration of molecular testing can further refine subtype diagnosis by identifying specific genetic mutations. A thorough understanding of these subtype-specific cytologic features and molecular profiles is vital for accurate diagnosis, risk stratification, and personalized management of PTC patients. Future improvements in diagnostic techniques and standardization are needed to enhance cytologic evaluation and clinical decision-making in thyroid cancer.

Keyword

Thyroid neoplasms; Thyroid cancer, papillary; Biopsy, fine-needle; Lymphatic metastasis; Prognosis; Clinical decision-making; Diagnostic errors; Reference standards; Risk assessment

Figure

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  Fig. 1. Cytological features of classic papillary thyroid carcinoma show a monolayer sheet of cells with a syncytial-like appearance observed on liquid-based cytology (ThinPrep).

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  Fig. 2. Cellular swirls (arrows), identified by flat, two-dimensional, concentrically organized aggregates of tumor cells devoid of colloid, are specific features of papillary thyroid carcinoma (A & B, ThinPrep).

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  Fig. 3. (A) Classic papillary thyroid carcinoma demonstrating typical nuclear features, including enlarged nuclei, glassy chromatin, prominent nucleoli, and intranuclear pseudoinclusions on conventional smear. (B) Liquid-based cytology smear showing a monolayer syncytial-like sheet of tumor cells with marked nuclear irregularities (ThinPrep).

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  Fig. 4. (A) Various sizes of intranuclear pseudoinclusions are visible with well-defined borders and coloration similar to the cell cytoplasm (Thin-Prep). (B) Nonspecific pseudoinclusion (arrow) lacks a clear nuclear border and may resemble bubbles, making them less distinct (ThinPrep).

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  Fig. 5. Nuclear grooves are observed as nuclear longitudinal folds. While not entirely specific, the presence of grooves in at least onethird of the tumor cell clusters, often forming branching patterns or parallel lines (insets), indicates papillary thyroid carcinoma.

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  Fig. 6. Psammoma bodies, identified as concentric calcified structures (arrows), are typically found within the papillary stalk of papillary thyroid carcinoma cells. These bodies may be absent in liquid-based cytology specimens. (A, ThinPrep; B, SurePath).

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  Fig. 7. Infiltrative follicular variant of papillary thyroid carcinoma. Tumor cells are arranged in a microfollicular pattern (A) with irregular nuclear membranes, fine chromatin, and prominent nucleoli (B) (ThinPrep).

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  Fig. 8. (A) Papillary thyroid carcinoma with cystic degeneration demonstrating ball-like clusters, characterized by tight, round aggregates of tumor cells with typical nuclear features such as nuclear grooves (ThinPrep). (B) Thyroid spherules, distinct from the carcinoma clusters and microfollicles, are observed as well-circumscribed round structures often surrounded by follicular cells, representing a diagnostic feature distinguishing benign follicular nodules from malignant lesions and follicular neoplasms (ThinPrep).

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  Fig. 9. Liquid-based cytology specimen of tall cell subtype of papillary thyroid carcinoma shows parallel, elongated tumor cells with characteristic nuclear features and abundant granular cytoplasm (A, B, ThinPrep).

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  Fig. 10. Hobnail subtype of papillary thyroid carcinoma. (A) Conventional smear shows papillary clusters of tumor cells with nuclei protruding toward the apical surface, dense chromatin, and eosinophilic cytoplasm. (B) Liquid-based cytology smear displays discohesive tumor cells with comet-like morphology (ThinPrep).

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  Fig. 11. Diffuse sclerosing subtype of papillary thyroid carcinoma. (A) Cell block preparation shows tumor cells with squamous metaplasia and numerous psammoma bodies. (B) Squamous metaplasia is observed in a liquid-based cytology smear (ThinPrep).

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  Fig. 12. (A) Papillary thyroid carcinoma with cystic degeneration shows numerous foamy histiocytes (ThinPrep). (B) Careful examination of tumor cell clusters with characteristic nuclear features is essential for accurate diagnosis (ThinPrep).

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  Fig. 13. Metastasis of papillary thyroid carcinoma to the lymph node often presents with atypical histiocytoid cells resembling discohesive histiocytes with vesicular nuclei and abundant cytoplasm (A, ThinPrep), along with multinucleated giant cells (B, smear).

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  Fig. 14. Poorly differentiated thyroid carcinoma. (A) The tumor shows high cellularity with a trabecular architecture (ThinPrep). (B) The tumor is composed of monomorphic cells characterized by a high nuclear-to-cytoplasmic ratio, coarse chromatin, and scant cytoplasm (ThinPrep).

Reference

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