Follicular dendritic cell sarcoma

Abstract

Summary 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.

A Cytological Review of Follicular Dendritic Cell-Derived Tumors with Emphasis on Follicular Dendritic Cell Sarcoma and Unicentric Castleman Disease

“…They locate in B follicles and are specialized in the capture of immunocomplexes that can remain for long periods in the cell surface and be presented to surrounding B-lymphocytes. This function is facilitated by the numerous cytoplasmic prolongations and interdigitations that form an intricate network connected through desmosomes [ 1 , 2 , 3 , 10 ]. In collaboration with macrophages, FDCs control the removal of apoptotic germinal center B cells.…”

“…Their nuclei are round to ovoid with a small eosinophilic nucleolus and finely dispersed chromatin. Vey often they are binucleated showing overlapping or molding (“kissing” pattern) [ 10 ]. The most common markers used in diagnostic immunohistochemistry are CD21, CD23 and CD35.…”

“…The most common markers used in diagnostic immunohistochemistry are CD21, CD23 and CD35. They also express desmoplakins, epidermal growth factor receptor (EGFR), claudin 4 and podoplanins [ 6 , 10 , 11 ]. On fine needle aspiration (FNA) cytology, FDCs are relatively easy to recognize.…”

“…One of the two patients reported had a history of HV-CD with histologic evidence of dysplastic FDCs. Some authors consider that the association of CD and FDCS may be underestimated, since FDCS overgrowth may prevent the histologic recognition of residual HV-CD [ 10 ]. In addition to other markers, FDCs of CD and FDCS share an intense expression of EGFR that is rarely seen in normal or reactive FDCs [ 19 ].…”

“…Similarly, they can have a common miRNA profile [ 20 ]. Although there are few molecular studies, a remarkable coincidence was the detection of the PDGFRB N666S mutation, that often occurs in HV-CD, in a case of FDCS with a previous history of CD [ 10 ]. These findings further strengthen the relationship between these two entities.…”