TY  - JOUR
T1  - 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 
AU  - Helenius, Mari
AU  - Kalfert, David
AU  - Maleki, Zahra
AU  - Barkan, Güliz A.
AU  - Rossi, Esther Diana
AU  - Cai, Guoping
AU  - Kholová, Ivana
JF  - Journal of Clinical and Translational Pathology
VL  - 
IS  - 000
SN  - 2771-165X
SP  - 
EP  - 
Y1  - 2026-06-16
DO  - 10.14218/JCTP.2026.00011
UR  - https://www.xiahepublishing.com/2771-165X/JCTP-2026-00011
AB  - Background and objectives 
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.
Methods
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.
Results
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.
Conclusions
There were no significant differences in PITX2 expression between primary and secondary MTC samples. PITX2 did not show reliable utility in distinguishing MTC from thyroid carcinomas of follicular origin. PHOX2B and HAND2 were negative in all samples. These results suggest that these new markers do not offer diagnostic value for MTC as stand-alone markers or as additions to the diagnostic workup panel.