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Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets.

ABSTRACT: Epithelioid hemangioendothelioma is a low-grade malignant vascular tumor with an intermediate clinical behavior between benign hemangiomas and high-grade angiosarcomas. Pathologic or molecular factors to predict this clinical heterogeneity are not well defined. A WWTR1-CAMTA1 fusion is present in most classic epithelioid hemangioendothelioma, regardless of their clinical behavior, suggesting that additional genetic abnormalities might be responsible in driving a more aggressive biology. A small subset of cases show distinct morphology and are characterized genetically by a YAP1-TFE3 fusion. Two histologic grades have been described in classic epithelioid hemangioendothelioma of the soft tissue. However, proposed criteria do not apply to other clinical presentations and have not been assessed in the YAP1-TFE3 positive tumors. Furthermore, no previous studies have compared the survival of these two molecular subsets. In this study we investigate the clinicopathologic and molecular findings of a large cohort of 93 translocation-positive epithelioid hemangioendothelioma managed at our institution. Patient characteristics, histologic features, treatment outcomes, and genetic abnormalities were investigated and these factors were correlated with overall survival. In 18 patients (15 with WWTR1-CAMTA1 and 3 with YAP1-TFE3) Memorial Sloan Kettering-IMPACT targeted DNA sequencing was performed to identify secondary genetic alterations showing more than half of tumors had a genetic alteration beyond the disease-defining gene fusion. Patients with conventional epithelioid hemangioendothelioma with WWTR1-CAMTA1 fusion had a less favorable outcome compared with the YAP1-TFE3 subset, the 5-year overall survival being 59% versus 86%, respectively. Soft tissue epithelioid hemangioendothelioma were frequently solitary, followed an uneventful clinical course being often managed with curative surgery. Multifocality, pleural involvement, lymph node or distant metastases had a significantly worse outcome. Patients with pleural disease or lymph node metastases had an aggressive clinical course akin to high-grade sarcomas, with 22% and 30%, respectively, alive at 5 years, compared with >70% survival rate in patients lacking these two adverse factors.

SUBMITTER: Rosenbaum E

PROVIDER: S-EPMC7228463 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets.

Rosenbaum Evan E Jadeja Bhumika B Xu Bin B Zhang Lei L Agaram Narasimhan P NP Travis William W Singer Samuel S Tap William D WD Antonescu Cristina R CR

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20190919 4

Epithelioid hemangioendothelioma is a low-grade malignant vascular tumor with an intermediate clinical behavior between benign hemangiomas and high-grade angiosarcomas. Pathologic or molecular factors to predict this clinical heterogeneity are not well defined. A WWTR1-CAMTA1 fusion is present in most classic epithelioid hemangioendothelioma, regardless of their clinical behavior, suggesting that additional genetic abnormalities might be responsible in driving a more aggressive biology. A small ...[more]

PMID: 31537895

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Project description:ImportanceEpithelioid hemangioendothelioma (EHE) is a rare, malignant vascular sarcoma characterized in most cases by a WWTR1-CAMTA1 fusion. The clinical course of EHE exhibits a dual nature. The condition is often indolent but can rapidly grow and metastasize unpredictably. No biomarkers to date are available to predict this phenotype. The hypothesis of this study was that better defining the genomic landscape of EHE using next-generation sequencing could offer additional therapies and insight into clinical outcomes.ObjectiveTo characterize secondary EHE genomic alterations and their association with clinical outcomes.Design, setting, and participantsMulticenter, cross-sectional, retrospective study of next-generation sequencing results collected from participants diagnosed with EHE. Data were abstracted between May 1, 2013, and May 31, 2019. This analysis was conducted from January through June 2019. Summary genomic data were provided by commercial genomic testing companies.Main outcomes and measuresPresence or absence of secondary pathogenic genomic variants and their association with disease stage and clinical features.ResultsA total of 49 participants with EHE were assessed for the presence or absence of secondary genomic variants. Of these, 32 (65.3%) were female; the mean (SD) age at diagnosis was 49.9 (18.3) years (range, 11-81 years). In all, 46 participants (93.9%) had confirmed WWTR1-CAMTA1 fusion; 26 participants (57.1%) exhibited a pathogenic genomic variant secondary to the WWTR1-CAMTA1 fusion; and 9 participants (18.4%) exhibited potentially targetable genomic variants. Commonly altered genes included CDKN2A/B, RB1, APC, and FANCA. Participants older than 45 years at diagnosis had an increased prevalence of secondary genomic variants that was not statistically significant (65.6% vs 38.5%; difference, 27.1%; 95% CI, -3.5% to 58.0%; P?=?.16) and were more likely to have a clinically targetable variant (28.1% vs 0%; difference, 28.1%; 95% CI, 11.2%-40.2%; P?=?.03). In 14 participants with clinical data available, those with stage III/IV EHE were more likely to exhibit a secondary pathogenic genomic variant (80% vs 0%; difference, 80%; 95% CI, 55.2%-100%; P?=?.006). Participants with stage III/IV EHE were diagnosed at an older age (mean [SD] age, 54.6 [14.1] years vs 31.7 [16.0] years; P?=?.05) and had elevated WWTR1-CAMTA1 fusion expression that was not statistically significant (mean [SD] expression, 677 [706] copies vs 231 [213] copies; P?=?.20).Conclusions and relevanceAlthough EHE exhibits few secondary genomic variants, presence of key secondary variants may be prognostic for aggressive EHE. Further research is needed to confirm this finding and determine whether more intensive upfront treatment is necessary for these patients.

Dataset Information

Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets.

Publications

Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets.

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