Genetic analysis of primary lung interdigitating dendritic cell sarcomas

Interdigitating dendritic cell sarcomas (IDCSs) are rare tumors that commonly arise in the hematopoietic system and rarely outside. The genetic drivers of IDCS carcinogenesis are unknown; therefore, therapeutic options are limited. We investigated somatic gene mutations and copy-number alterations (CNAs) in nine IDCSs arising in the lung by whole-exome sequencing (WES) paired with shallow whole-genome sequencing (sWGS). Using a panel of immunohistochemical markers, follicular dendritic sarcomas and Langerhans cell sarcomas were excluded, and inflammatory myofibroblastic tumors were excluded based on morphology. The Ki-67 score was used to stratify the tumors into low-grade (≤ 20%) and high-grade (> 20%) tumors. The main question addressed by the study was whether genetic aberrations can be identified in IDCSs and whether these are druggable. High-grade IDCSs showed a higher fraction of genome altered by CNA (48.42%) than low-grade IDCSs (18.15%) and tended to have greater tumor mutation burden (7.56 versus 0.88 mut/Mb; not significant). Heterogeneous gains on chromosome 17 were characteristic of almost all IDCS cases (eight of nine cases, 89%), independent of grade. CNA in cancer-actionable genes was independent of clinicopathological characteristics and included amplifications in EGFR, MYC, MDM4, ERBB2, CCNE1, and BRAF and losses in MTAP, CDKN2A, CDKN2B, MLH1, and VHL, as well as homozygous losses in SMAD2/4, ATM, and TP53. Somatic gene mutations in cancer-related genes were identified in seven of nine IDCSs. No common driver mutations were identified. The heterogeneous genetic landscape suggests a mixed etiology of IDCS carcinogenesis and genomic instability in high-grade tumors. Distinct druggable biomarkers have been identified in almost all tumors, providing novel therapeutic options. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.