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Recurrent YAP1 and MAML2 Gene Rearrangements in Retiform and Composite Hemangioendothelioma.

ABSTRACT: Retiform and composite hemangioendotheliomas (CHEs) are both locally aggressive, rarely metastasizing vascular neoplasms characterized by arborizing vascular channels lined by endothelial cells with a hobnail morphology. CHE displays additional cytologic and architectural components, including often vacuolated epithelioid cells, solid areas, or features reminiscent of well-differentiated angiosarcoma. Triggered by an index case of a soft tissue retiform hemangioendothelioma (RHE) which revealed a YAP1-MAML2 gene fusion by targeted RNA sequencing, we sought to investigate additional cases in this morphologic spectrum for this genetic abnormality. A total of 24 cases, 13 RHE and 11 CHE involving skin and soft tissue were tested by fluorescence in situ hybridization using custom BAC probes for rearrangements involving these genes. An additional visceral CHE with neuroendocrine differentiation was tested by targeted RNA sequencing. Among the soft tissue cohort, 5/13 (38%) RHE and 3/11 (27%) CHE showed YAP1 gene rearrangements, with 5 cases showing a YAP1-MAML2 fusion, including all 3 CHE. The single neuroendocrine CHE showed the presence of a PTBP1-MAML2 fusion. All YAP1-positive CHE lesions occurred in female children at acral sites, compared with fusion-negative cases which occurred in adults, with a wide anatomic distribution. YAP1-positive RHE occurred preferentially in males and lower limb, compared with negative cases. These results suggest that RHE and CHE represent a morphologic continuum, sharing abnormalities in YAP1 and MAML2 genes. In contrast, the neuroendocrine CHE occurring in a 37-year-old male harbored a distinct PTBP1-MAML2 fusion and showed aggressive clinical behavior (pancreatic mass with multiple liver and lung metastases). These preliminary findings raise the possibility that neuroendocrine CHE may be genetically distinct from the conventional RHE/CHE spectrum. Further studies are needed to investigate the pathogenetic relationship of fusion-negative cases with this subset and, less likely, with other members of the HE family of tumors.

SUBMITTER: Antonescu CR

PROVIDER: S-EPMC7773139 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma, characterized by a distinctive epithelioid phenotype in a densely sclerotic collagenous stroma, that shows frequent MUC4 immunoreactivity and recurrent gene fusions, often involving EWSR1 gene. A pathogenetic link with low-grade fibromyxoid sarcoma (LGFMS) has been suggested, due to cases with hybrid morphology as well as overlapping genetic signature. However, a small subset of SEF is negative for MUC4 and lacks the canonical EWSR1/FUS gene rearrangements. Triggered by the identification of recurrent YAP1-KMT2A gene fusions by RNA sequencing in 3 index cases of MUC4-negative, EWSR1/FUS fusion-negative SEF, we further investigated a cohort of 14 similar SEF cases (MUC4-negative, EWSR1/FUS fusion-negative) by fluorescence in situ hybridization (FISH), reverse transcription-polymerase chain reaction, and/or DNA-based massively parallel sequencing (MSK-IMPACT) for abnormalities in these genes. Three additional SEFs with KMT2A gene rearrangements and one additional case with YAP1 gene rearrangements were identified by FISH. In addition, one case with YAP1-KMT2A and one with KMT2A-YAP1 fusion were detected by reverse transcription-polymerase chain reaction and MSK-IMPACT, respectively. As a control group, 24 fibromyxoid spindle cell tumors, diagnosed or suspected as fusion-negative LGFMS, were also tested for YAP1 and KMT2A abnormalities by FISH, but none were positive. The YAP1/KMT2A-rearranged SEF group affected patients ranging from 10 to 86 years old (average and median: 45) of both sexes (4 females, 5 males). The tumors involved somatic soft tissues with a wide distribution, including extremities, trunk, neck, and dura. Histologically, the tumors showed variable cellularity, with monotonous ovoid to epithelioid tumor cells and hyalinized collagenous background typical of SEF. More than half of the cases showed infiltrative borders, within fat or skeletal muscle. No LGFMS component was identified. All tumors were negative for MUC4 and had an otherwise nonspecific immunophenotype. Of the 6 cases with available follow-up information, 2 had local recurrences, and 2 developed soft tissue and/or bone metastases, including 1 of them died of the disease.

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Recurrent YAP1 and MAML2 Gene Rearrangements in Retiform and Composite Hemangioendothelioma.

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