Pain in Epithelioid Hemangioendothelioma: Development of Disease-Specific Pain Assessment Criteria (PAC-E)

Objective Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma with heterogeneous behavior. Tumor-related pain is a clinically relevant symptom in advanced disease. We report the first prospective evaluation of pain in EHE, its incidence and prognostic significance, and the development of EHE-tailored Pain Assessment Criteria (PAC-E) framework. Methods From March 2021, patients with molecularly confirmed EHE were enrolled in the POEM study, a prospective, multicentric, international observational study (NCT06680401). Tumor-related pain was assessed using a numerical rating scale (NRS), with worst pain intensity (WPI) used for analysis. Clinically relevant pain was defined as WPI >4. Pain characteristics, serosal involvement, analgesic response, and overall survival (OS) were evaluated. PAC-E were developed by integrating longitudinal pain changes and analgesic use, based on POEM data and a targeted literature review. Results Among 54 patients with advanced EHE enrolled by June 2025, 15 (27.8%) experienced tumor-related pain and 13 (24%) had WPI>4. Pain was predominantly nociceptive and associated with pleural involvement (n=7). High-potency NSAIDs were effective in patients with pleural pain and limited opioid response. WPI>4 was associated with shorter OS compared with WPI≤4 (p<0.001). PAC-E was derived from these observations. Conclusions Moderate-to-severe tumor-related pain affected approximately one quarter of patients with advanced EHE and was associated with poorer survival. Its predominance as nociceptive pain and association with serosal involvement support its role as a clinically relevant marker of disease aggressiveness. PAC-E provides disease-specific criteria for standardized pain assessment, pending validation in larger cohorts.