Abstract Background Histiocytic sarcoma (HS) is an aggressive, rare malignant neoplasm of cells with histiocytic differentiation. It can occur de novo or develop in the context of other malignant disorders. HS can present as disseminated or localized lesions in the skin, lymphatics, gastrointestinal tract, central nervous system, or other organs. Little is known about factors that impact HS clinical outcomes. We conducted this pooled database analysis to delineate key clinicopathological characteristics, prognostic indicators, and treatment modalities that affect survival in this rare histiocytic entity. Methods To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 146 cases of HS. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS). Results A total of 146 patients with confirmed HS were identified. The median age was 52, with bimodal peaks between 14-28 and 56-70 years. There was a male preponderance with M:F of 1.3. Primary sites of involvement were CNS (21%), GI(16%), soft tissues (12%), H&N and bones (9% each), skin (8%), liver (7%), spleen (5%), lung (4%), and breast (1%). Lymphadenopathy and bone marrow (BM) were involved in 21% and 42%, respectively. Constitutional symptoms were present in 6%. The median size of the HS tumor was 4.45cm. The median OS of the whole group was 16 months. Age younger than 55 had better median OS (NR vs. 6 months, p=0.038). The primary site of involvement also impacted the median OS, where soft tissues and visceral disease had longer OS than those with CNS and spleno-lymphatic disease (60 vs. 7 vs. 6 months, p=0.03). Stage 1 disease had better median OS than stages 2-4 (p=0.06). Furthermore, unifocal had better median OS than multifocal/multicentric disease (60 vs. 9 months, p=0.007). The presence of inflammatory background positively impacted OS (p=0.01). Compared to no treatment, localized therapies such as surgery (S) and radiation therapy (RT), and systemic combination chemotherapy (CT) were statistically superior, with a median OS of 1, 204, and 21 months, respectively (p=0.003). With HS not amenable to complete resection, CT and CT+S were superior to RT+S (15 vs. 60 vs. 7 months, p=0.008). While BM involvement and size >10 cm were associated with worse OS, the latter did not reach statistical significance. There was no difference in median OS with respect to sex. Conclusion This study presents updated clinicopathologic data from a pooled cohort of patients with HS. It identifies age, the primary site of the disease, stage and extent of the disease, the inflammatory background status, and treatment approach as key determinants of OS. Citation Format: Dinesh Keerty, Philip A. Haddad. Histiocytic sarcoma descriptors and clinicopathologic determinants of survival: Analysis of a pooled database. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6749.