Aberrant expression of neuroendocrine markers is extremely rare in endothelial neoplasms, with only a single report describing three cases. Although originally classified as conventional angiosarcoma, further assessment of these tumors revealed a strikingly composite morphology composed of retiform and epithelioid elements reminiscent of composite hemangioendothelioma, a rare subtype of hemangioendothelioma. To further investigate these findings, available materials from 11 morphologically distinctive endothelial tumors showing neuroendocrine marker expression were retrieved from our archives. Immunohistochemistry for CD31, CD34, FLI-1, synaptophysin, chromogranin, D2-40, ERG, keratin (OSCAR), and CAMTA1 was performed. Total RNA from five cases were extracted and subjected to whole transcriptome sequencing. Clinical follow-up was obtained. These tumors were found to arise in five males and six females in patients from 9 to 55 years in age (median 47 years). They arose both in superficial (wrist, ankle, scalp, hip, and foot) and deep (periaortic tissues, C5 vertebra, pulmonary vein, and liver) locations. All contained elongated, retiform vascular channels lined by hyperchromatic 'hobnail' endothelial cells and a solid growth of uniform epithelioid cells reminiscent of epithelioid hemangioendothelioma. Hemangioma-like foci also lined by hobnail endothelial cells were frequently present. Mitotic activity was typically <1/10 HPF, and necrosis or areas of conventional angiosarcoma was absent. The results of immunohistochemistry were: CD31 (10/10), FLI-1 (10/10), ERG (9/9), CD34 (5/10), D2-40 (7/10), synaptophysin (11/11), chromogranin A (1/11), CD56 (5/11), keratin (0/11), and CAMTA1 (0/6). Sequencing analysis showed one case with PTBP1-MAML2 and one case with EPC1-PHC2 fusion transcripts; fusion transcripts were not identified in the remaining cases. Follow-up (8 cases) revealed local recurrence in one patient and metastatic spread in four individuals (bone, lung, liver, and brain). One person died of disease. Although the morphological features of these tumors are characteristic of composite hemangioendothelioma, this distinctive subset with neuroendocrine differentiation more often involves deep locations and displays more aggressive behavior than typically described in other cases of composite hemangioendothelioma.
