Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma

Abstract

Background. Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. Methods. Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes. Results. Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/ Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance. Conclusion. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors.

Follicular dendritic cell sarcoma

“…Notably, the PDGFRB N666S mutation often occurring in HV-CD 92 , 93 , was detected in a case of FDCS with history of Castleman disease 82 , further strengthening the biological relationship between these two diseases.…”

“…Despite the common expression of PD-L1 in FDCS 63 , 90 , 96 a low mutational burden (< 6 mutations/megabase) was detected in the majority of cases in a large series (41/44) 82 thus questioning the potential efficacy of an immunotherapy-based treatment for this neoplasm.…”

“…Five different translocations leading to fusion proteins were identified in four cases TYK2-ATPAF2, MAP3K1-GCOM1, NTRK1-PDIA3, BPTF-WDR72 and HDGRFP3-SHC4) 80 , 82 . Future studies are required to evaluate whether these translocations are recurrent and retain diagnostic specificity for FDCS; notably, some may represent molecular targets for treatment 80 , 82 .…”

“…In summary, FDCS is characterized by alterations on genes belonging to the NF-κB regulatory pathway (34/61 patients, 56%) 82-85 , including copy number loss or missense mutations of NFKBIA 82 , 83 , 85 , CYLD 83 , TRAF3 82 , 85 , SOCS3 82 and TNFAIP3 82 , 85 . Additionally, in line with the hypothesis of a tumor-suppressor driven biology, mutated cell-cycle regulators have been found in more than one study, and included the oncosuppressor genes TP53 80 , 82 , 83 , 85-87 , RB1 and CDKN2A 82 , 83 as well as the related genes CDK4 and MDM2 83 . Notably, in a few additional cases, copy number gains or amplifications of the oncogenes MYC and CCND2 were also reported 83 , 87 .…”

“…While the mitogen activated protein kinase (MAPK) pathway has been shown to be pivotal in the pathogenesis of hematopoietic-derived histiocytic and dendritic cells tumors 63 , 88 , FDCS typically lacks mutations of genes such as KRAS, NRAS and MAP2K1 82 . Data on BRAF are more controversial, since BRAF V600E mutation was found in 5 of 27 cases in a single study 89 , BRAF copy number loss reported in one additional case 84 , but no anomalies on this gene were detected in at least 95 FDCS collected from different studies 24 , 63 , 82 , 83 , 90 , 91 .…”