Integrated genomic and immunophenotypic profiling of histiocytic disorders reveals therapeutic implications of differential BCL2 expression

Abstract

Abstract Background Histiocytic disorders, including Langerhans Cell Histiocytosis (LCH), Erdheim-Chester Disease (ECD), and Rosai-Dorfman Disease (RDD), are rare clonal proliferations of myeloid lineage with frequent MAPK pathway alterations. While the role of BCL2-mediated apoptosis resistance is well recognized in LCH, its expression and potential significance in ECD and RDD remain poorly defined. Characterizing BCL2 expressions in these entities may uncover new therapeutic opportunities. Methods We conducted a retrospective review of patients with histologically confirmed LCH, ECD, or RDD managed at two tertiary centers, in Saudi Arabia. Clinical data, including demographics, organ involvement, and history of treatment were abstracted from medical records. Immunohistochemical analysis included assessment of BCL2 expressions on the histiocytes, while molecular testing targeted recurrent MAPK pathway mutations using next-generation sequencing where tissue was available. Treatment details and response assessments by PET/CT were evaluated. Statistical analyses examined associations between BCL2 expression, mutational status, disease subtype, and clinical outcomes. Results A total of 43 patients were included, comprising 20 with LCH (46.5%), 7 with ECD (16.3%), and 16 with RDD (37.2%). The median age at diagnosis was 34 years (range, 14–67), and 56% were male. Skeletal involvement was the most frequent disease site overall, while ECD patients commonly exhibited multi-organized disease including cardiovascular and renal sites, and RDD primarily involved lymph nodes and soft tissue. MAPK pathway alterations were present in 39.5% of cases. BCL2 expression varied significantly between subtypes (p<0.001), being present in 8 of 20 LCH cases (40%), 1 of 7 ECD cases (14%), and 11 of 16 RDD cases (69%). First-line therapy included corticosteroids (30.2%), surgery (27.9%), cladribine (16.3%), rituximab (16.3%), and targeted therapy in 7.0% (BRAF inhibitor in 4.7%, MEK inhibitor in 2.3%). Response assessment following initial therapy demonstrated remission in 62.4%, regression in 9.4%, stable disease in 17.6%, and progression in 7.1%. BCL2 expression did not correlate with early imaging response but was strongly enriched in RDD, supporting a role for anti-apoptotic signaling in disease persistence. Conclusions This integrated clinical and molecular analysis highlights marked heterogeneity of BCL2 expression across histiocytic disorders, with RDD showing the highest prevalence. These findings suggest a potential role for BCL2-mediated survival signaling in RDD and provide a rationale for evaluating BCL2-directed therapies, such as venetoclax, in selected histiocytic neoplasms.