Simple SummaryEpithelioid hemangioendothelioma (EHE) is a very rare malignant vascular neoplasm with unpredictable clinical course due to its remarkable heterogeneity. Large cohort studies with molecularly/immunohistochemically confirmed EHE are scarce, and what determines survival has been controversial. This retrospective nationwide cohort study addresses EHE epidemiology and aims to identify clinical and histopathological parameters with prognostic significance, thereby providing useful insights into the clinical behavior of this rare cancer. Our findings emphasize the aggressive behavior of EHE, demonstrated by lower 1- and 5-year overall survival rates compared to those in the current literature. Moreover, we confirmed the usefulness of the risk stratification model by Shibayama for unifocal disease and showed that multifocal and metastatic disease have no survival differences, indicating that multifocality is early metastatic disease. Tumors in the head and neck area have a higher propensity for lymph node metastases, entailing consideration of lymphadenectomy.AbstractEpithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma with variable aggressive clinical behavior. In this retrospective study, we aimed to investigate prognostic factors based on clinicopathologic findings in a molecularly/immunohistochemically confirmed nationwide multicenter cohort of 57 EHE cases. Patients had unifocal disease (n= 29), multifocal disease (n= 5), lymph node metastasis (n= 8) and/or distant metastasis (n= 15) at the time of diagnosis. The overall survival rate was 71.4% at 1 year and 50.7% at 5 years. Survival did not correlate with sex, age or histopathological parameters. No survival differences were observed between multifocal and metastatic disease, suggesting that multifocality represents early metastases and treatment options are limited in comparison to unifocal disease. In unifocal tumors, survival could be predicted using the risk stratification model of Shibayama et al., dividing the cases into low- (n= 4), intermediate- (n= 15) and high- (n= 3) risk groups. No clinical or histopathological parameters were associated with progressive unifocal disease course. Lymph node metastases at the time of diagnosis occurred in 14.0% of the cases and were mainly associated with tumor localization in the head and neck area, proposing lymph node dissection. In conclusion, our results demonstrate the aggressive behavior of EHE, emphasize the prognostic value of a previously described risk stratification model and may provide new insights regarding tumor focality, therapeutic strategies and prognosis.