Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity.

• Klíčová slova
• GATA3, Hand2, Neuroendocrine tumors, Paraganglioma, Phox2B, dHand,
• MeSH
• imunohistochemie MeSH
• lidé MeSH
• neuroendokrinní karcinom * patologie   MeSH
• neuroendokrinní nádory * patologie   MeSH
• paragangliom * diagnóza   patologie   MeSH
• transkripční faktory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• transkripční faktory MeSH

Phox2B is a transcription factor responsible for chromaffin cell phenotype. Although it is used routinely for diagnosis of neuroblastoma, previous reports concerning its utility in the diagnosis of neuroendocrine neoplasms have been conflicting. We assessed Phox2b immunoreactivity in different neuroendocrine neoplasms. Tissue microarrays or whole sections of 36 paragangliomas (PGs), 91 well-differentiated neuroendocrine tumours of different organs (WDNETs), 31 neuroendocrine carcinomas (NECs), and 6 olfactory neuroblastomas (ONBs) were stained with Phox2B antibody (EP312) and GATA3. The percentage of positive cells and intensity was analysed using H-score. Phox2B immunoreactivity was seen in 97.2% (35/36) PGs, 11% (10/91) WDNETs, 9.7% (3/31) NECs, and 16.7% (1/6) ONBs. PGs were significantly more often positive (p < 0.001, χ2) than other neuroendocrine tumours, showing highest H-score (mean 144.9, SD ± 75.1) and percentage of positive cells (median 81.3%, IQR 62.5-92.5%). Compared to Phox2B-positive WDNETs, PGs showed significantly higher H-score (median 145 vs 7.5, p < 0.001) and percentage of positive cells (median 82.5% vs 4.5%, p < 0.001). Phox2B positivity was 97.2% sensitive and 89% specific for the diagnosis of PG. GATA3 was 100% sensitive and 88% specific for the diagnosis of PG. When combined, any Phox2B/GATA3 coexpression was 97.1% sensitive and 99.1% specific for the diagnosis of paraganglioma. Widespread Phox2B immunoreactivity is a highly characteristic feature of PGs and it can be used as an additional marker in differential diagnosis of neuroendocrine tumours.

• Klíčová slova
• Chromaffin cell, GATA3, Neuroendocrine neoplasms, Olfactory neuroblastoma, Paraganglioma, Phox2B, Well differentiated neuroendocrine tumours,
• MeSH
• imunohistochemie MeSH
• lidé MeSH
• nádorové biomarkery analýza   MeSH
• neuroendokrinní karcinom * MeSH
• neuroendokrinní nádory * diagnóza   patologie   MeSH
• paragangliom * diagnóza   MeSH
• transkripční faktory analýza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• nádorové biomarkery MeSH
• transkripční faktory MeSH

Cauda equina neuroendocrine tumors (CENETs) are neoplasms of uncertain histogenesis with overlapping features between those of paragangliomas (PGs) and visceral neuroendocrine tumors (NETs). We have explored their biological relationship to both subsets of neuroendocrine neoplasms. The clinical and radiological features of a cohort of 23 CENETs were analyzed. A total of 21 cases were included in tissue microarrays, along with a control group of 38 PGs and 83 NETs. An extensive panel of antibodies was used to assess epithelial phenotype (cytokeratins, E-cadherin, EpCAM, Claudin-4, EMA, CD138), neuronal and neuroendocrine features (synaptophysin, chromogranin A, INSM1, neurofilaments, NeuN, internexin-α, calretinin), chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase), and possible histogenesis (Sox2, T-brachyury, Oct3/4, Sox10). The cohort included 5 women (22%) and 18 men (78%). The average age at the time of surgery was 48.3 years (range from 21 to 80 years). The average diameter of the tumors was 39.27 mm, and invasion of surrounding structures was observed in 6/21 (29%) tumors. Follow-up was available in 16 patients (median 46.5 months). One tumor recurred after 19 months. No metastatic behavior and no endocrine activity were observed. Compared to control groups, CENETs lacked expression of epithelial adhesion molecules (EpCAM, CD138, E-cadherin, Claudin-4), and at the same time, they lacked features of chromaffin differentiation (GATA3, Phox2b, tyrosine hydroxylase). We observed no loss of SDHB. Cytokeratin expression was present in all CENETs. All the CENETs showed variable cytoplasmic expression of T-brachyury and limited nuclear expression of Sox2. These findings support the unique nature of the neoplasm with respect to NETs and PGs.

• Klíčová slova
• Cauda equina, Immunohistochemistry, Neuroendocrine tumors, Paragangliomas, Sox2,
• MeSH
• adhezní molekula epiteliálních buněk MeSH
• cauda equina * metabolismus   patologie   chirurgie   MeSH
• claudin-4 MeSH
• lidé MeSH
• lokální recidiva nádoru patologie   MeSH
• nádory centrálního nervového systému * patologie   MeSH
• neuroendokrinní nádory * patologie   MeSH
• paragangliom * MeSH
• represorové proteiny MeSH
• transkripční faktory MeSH
• tyrosin-3-monooxygenasa MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adhezní molekula epiteliálních buněk MeSH
• claudin-4 MeSH
• INSM1 protein, human MeSH Prohlížeč
• represorové proteiny MeSH
• transkripční faktory MeSH
• tyrosin-3-monooxygenasa MeSH