RESUMEN
Standardized treatment options are lacking for patients with unresectable or multifocal follicular dendritic cell sarcoma (FDCS) and disease-related mortality is as high as 20%. Applying whole genome sequencing (WGS) in one case and whole exome sequencing (WES) in additional twelve, this study adds information on the molecular landscape of FDCS, expanding knowledge on pathobiological mechanisms and identifying novel markers of potential theragnostic significance. Massive parallel sequencing showed high frequency of mutations on oncosuppressor genes, particularly in RB1, CARS and BRCA2 and unveiled alterations on homologous recombination DNA damage repair related genes in 70% (9/13) of cases. This indicates that patients with high stage FDCS may be eligible for poly ADP ribose polymerase inhibition protocols. Low tumor mutational burden was confirmed in this study despite common PDL1 expression in FDCS arguing on the efficacy of immune checkpoint inhibitors. CDKN2A deletion, detected by WGS and confirmed by FISH in 41% of cases (9/22) indicates that impairment of cell cycle regulation may sustain oncogenesis in FDCS. Absence of mutations in the RAS/RAF/MAPK pathway and lack of clonal hematopoiesis related mutations in FDCS sanction its differences from dendritic cell-derived neoplasms of haematopoietic derivation. WGS and WES in FDCS provides additional information on the molecular landscape of this rare tumor, proposing novel candidate genes for innovative therapeutical approaches to improve survival of patients with multifocal disease.
RESUMEN
Follicular dendritic cells (FDC) are mesenchymal-derived dendritic cells located in B-follicles where they play a pivotal role in triggering and maintaining B-cell adaptive immune response. In 1986 Dr. Juan Rosai first reported a series of neoplasms showing features of FDC and defined it as Follicular Dendritic Cell Tumor, subsequently renamed as "sarcoma" (FDCS). In its seminal and subsequent articles Rosai and colleagues highlighted the heterogeneous microscopic appearance of FDCS and its immunohistochemical and ultrastructural features.FDCS mostly occurs in extranodal sites (79.4% of cases) and lymph nodes (15.1%); in about 7%-10% of cases it is associated with hyaline-vascular Castleman disease. Given its significant growth pattern and cytological variability, FDCS can be confused with various neoplasms and even inflammatory processes. The diagnosis requires the use of a broad spectrum of FDC markers (e.g. CD21, CD23, CD35, clusterin, CXCL13, podoplanin), particularly considering that tumor antigen-loss is frequent. The inflammatory-pseudotumor-like (IPT-like) variant of FDCS, in addition to its peculiar histopathological and clinical features, is characterized by positivity of tumor cells for Epstein-Barr virus, representing a diagnostic requisite.No distinctive genetic and molecular anomalies have been identified in FDCS. It often carries an aberrant clonal karyotype and chromosomal structural alterations, frequently involving onco-suppressor genes. Direct or next generation sequencing showed alterations on genes belonging to the NF-κB regulatory pathway and cell-cycle regulators. In contrast to hematopoietic-derived histiocytic and dendritic cells tumors, FDCS typically lacks mutations in genes related to the MAPK pathway.FDCS recurs locally in 28% and metastasizes in 27% of cases. Extent of the disease, surgical resectability and histopathological features are significantly associated with the outcome. IPT-like FDCS behaves as an indolent tumor, even if it often recurs locally over years.Complete surgical excision is the gold standard of treatment. Data on targeted therapies (e.g.: tyrosine kinase inhibitors) or immune checkpoint inhibitors are very limited and responses are variable. A better understanding of the molecular drivers of this tumor may lead to potential new therapeutic strategies.