John P Lee, Yin P Hung, Thomas M O'Dorisio, James R Howe, Jason L Hornick, Andrew M Bellizzi

Paired-like homeobox 2b (PHOX2B) is a transcription factor with expression outside of the central nervous system restricted to neurons and chromaffin cells of the autonomic nervous system. Germline mutations cause congenital central hypoventilation syndrome and predispose to neuroblastoma and Hirschsprung disease. Among pediatric small round cell tumors, PHOX2B is neuroblastoma-specific. Two studies of adult autonomic nervous system tumors (n=62) produced conflicting results (all tumors stained in one; expression was restricted to 40% of paragangliomas in the other). We examined PHOX2B expression in a large cohort of pheochromocytomas and paragangliomas, as well as well-differentiated neuroendocrine tumors (WDNET) and poorly differentiated neuroendocrine carcinomas (PDNEC). Tissue microarrays were constructed from 609 tumors: 111 pheochromocytomas, 146 paragangliomas, 250 WDNETs, and 102 PDNECs. PHOX2B immunohistochemistry was scored for extent (%) and intensity (0-3+), with an H-score (extent*intensity) calculated. PHOX2B expression was seen in 32% of pheochromocytomas and 47% of paragangliomas. Mean/median H-scores for these tumors were in the 30-55 range (i.e., weak to moderate staining). No WDNETs and only 7% of PDNECs stained, the latter often strongly so. In a representative cohort of corresponding whole sections (n=55), results in WDNETs and PDNECs were unchanged, while half of pheochromocytomas/paragangliomas negative on TMA became focally, weakly positive. We found frequent, weak to moderate PHOX2B expression in pheochromocytomas/paragangliomas and no expression in WDNETs, which could be diagnostically useful in the distinction of these tumors. Expression in a minority of PDNECs likely reflects the transcription factor lineage infidelity characteristic of this tumor class. This article is protected by copyright. All rights reserved.