Prognostic stratification of clinical and molecular epithelioid hemangioendothelioma subsets

Mod Pathol. 2020 Apr;33(4):591-602. doi: 10.1038/s41379-019-0368-8. Epub 2019 Sep 19.


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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Biomarkers, Tumor / genetics*
  • Calcium-Binding Proteins / genetics
  • Female
  • Gene Fusion*
  • Genetic Predisposition to Disease
  • Hemangioendothelioma, Epithelioid / genetics*
  • Hemangioendothelioma, Epithelioid / mortality
  • Hemangioendothelioma, Epithelioid / pathology*
  • Hemangioendothelioma, Epithelioid / therapy
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Phenotype
  • Retrospective Studies
  • Time Factors
  • Trans-Activators / genetics
  • Transcription Factors / genetics
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • YAP-Signaling Proteins
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Biomarkers, Tumor
  • CAMTA1 protein, human
  • Calcium-Binding Proteins
  • TFE3 protein, human
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • YAP-Signaling Proteins
  • YAP1 protein, human