Medullary thyroid carcinoma (MTC) is a neuroendocrine malignancy arising from parafollicular C-cells with known variations in cytomorphologic and immunophenotypic features. New neuroendocrine markers pituitary homeobox 2 (PITX2), paired-like homeobox 2B (PHOX2B), and heart and neural crest derivatives expressed 2 (HAND2) have recently been introduced, but studies using these markers in MTC are limited. The aim of this study was to evaluate the expression and potential diagnostic utility of PITX2, PHOX2B, and HAND2 in primary and secondary MTCs and to compare their expression with chromogranin A, synaptophysin, insulinoma-associated protein 1 (INSM1), and calcitonin.
A total of 34 histologically confirmed cases of MTC with available cell blocks were included. Sixteen MTC samples were fine-needle aspirates from primary thyroid lesions, and eighteen were from secondary metastatic lesions. Twelve samples from thyroid carcinomas of follicular origin were included as controls.
PITX2 positivity was observed in 17 (50.0%) MTC samples and in 4 (33.3%) control samples ( P = 0.502). PITX2 positivity was found in 43.8% of primary thyroid MTC lesions and in 55.6% of secondary MTC lesions ( P = 0.366). Co-expression of PITX2 with chromogranin A, synaptophysin, INSM1, and calcitonin was observed. PHOX2B and HAND2 were negative in all MTC and control samples.
None of the studied neuroendocrine markers, PITX2, PHOX2B, or HAND2, demonstrated sufficient diagnostic utility for the cytological evaluation of MTC. However, the complete negativity of PHOX2B and HAND2 in MTCs is a notable finding that highlights the need for further research into emerging neuroendocrine markers, which may improve the accuracy and reliability of routine diagnostic protocols, particularly in calcitonin-negative MTCs and in cases with variable neuroendocrine marker expression.
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https://www.xiahepublishing.com/2771-165X/JCTP-2026-00011
The study was recently published in the Journal of Clinical and Translational Pathology .
Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.
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Journal of Clinical and Translational Pathology
New Neuroendocrine Markers PITX2, PHOX2B, and HAND2 Do Not Offer Diagnostic Utility in Fine-needle Aspiration Biopsies of Primary and Secondary Medullary Thyroid Carcinomas: A Retrospective Multi-institutional Study