Recurrent PTBP1::MAML2 fusions in composite hemangioendothelioma with neuroendocrine differentiation: A report of two cases involving neck lymph nodes.

Composite hemangioendothelioma (CHE) displaying neuroendocrine differentiation is a rare histologic variant that is often mistaken for angiosarcoma, having a predilection for visceral locations and being associated with an aggressive clinical course. Their pathogenesis is still evolving, with only two cases to date from separate studies reporting a recurrent PTBP1-MAML2 fusion. Herein, we report two new cases of neuroendocrine CHE harboring PTBP1-MAML2 fusions occurring in two elderly patients (70-year-old male and 71-year-old female), both involving neck lymph nodes. The first case presented with multifocal cervical lymphadenopathy, while the second case occurred unifocally in an enlarged neck lymph node. Histologically, the tumors displayed heterogenous architectural patterns with areas reminiscent of benign cavernous hemangioma, retiform hemangioendothelioma, epithelioid hemangioendothelioma, and angiosarcoma. Cytologically, the cells were monotonous with round to ovoid nuclei, open to fine chromatin, scant to moderate cytoplasm, and frequent vacuolization. In addition, the first case showed focal solid areas of large epithelioid cells with severe nuclear atypia, enlarged nuclei and prominent nucleoli, resembling epithelioid angiosarcoma. Tumor cells were diffusely positive for vascular markers and focally positive for synaptophysin. In both cases, a next-generation sequencing fusion panel confirmed an in-frame fusion between PTBP1 exon 10 and MAML2 exon 2. One case with clinical follow-up showed stable recurrent disease and metastatic lung deposits following treatment. Both patients were alive at 3 months and 1 year following initial diagnosis. Our findings lend further support to classifying CHE with PTBP1-MAML2 fusions as a distinct variant of CHE with unique clinicopathologic features, including neuroendocrine features.