Follicular dendritic cell sarcoma

Abstract

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.

Keywords: diagnosis; follicular dendritic cell sarcoma; mutations; personalized medicine.

Figure 1.

Follicular dendritic cell (FDC) functions in the germinal center. FDC plays a crucial role in the recruitment of B and T cells in B follicles, especially by secreting CXCL13(1) and interacting with B cells by integrins and cognate receptors (2). FDC cell membrane is lined by immunocomplexes which are “exposed” to germinal center B-cells (2, 3). FDC promotes B-cell survival and maturation through secretion of various B-cell growth factors, especially BAFF (4). During the germinal center reaction, B-cells with low-affinity B-cell receptor undergo apoptosis and are phagocytized by tingible body macrophages, a process mediated by Mfge8 secreted by FDC (5). FDC can modulate the adaptive response by sensing, via TLR4, environmental innate stimuli (e.g. microbial lipopolysaccharides) resulting into TLR signaling that induces production of factors (CXCL13, TGFβ1 and BAFF), which contribute to recruitment, class-switch recombination and survival of B cells (6). For details see paragraph (Origin and functions of FDC). BAFF, B activating factor; BAFF-R, BAFF receptor; BCR, B-cell receptor; C4Bp, Complement component 4 binding protein; CD40L, CD40 Ligand; CR, Complement receptor; CXCL13, C-X-C motif chemokine ligand 13; CXCR5, C-X-C motif chemokine receptor 5; FcR, Fc receptor; FoB, Follicular B-cell; GCB, Germinal center B-cell; ICAM1, Intercellular adhesion molecule 1; IC, Immunocomplex; ITGA1, Integrin subunit alpha 1; ITGAV:ITGB3, Integrin subunit alpha V: beta 3; ITGB2, Integrin subunit beta 2; LPS, Lipopolysaccharide; Mfge8, Milk fat globule-EGF factor 8; TBM, Tingible body macrophage; TGFβ1, Transforming growth factor beta 1; T_FH, T follicular helper cells; TLR4, Toll-like receptor 4; VCAM1, Vascular cell adhesion molecule 1.

Figure 2.

Follicular dendritic cells in a reactive germinal center are typically recognizable by their medium-sized nuclei, showing well demarcated membranes and single small nucleoli; paired nuclei often show membrane molding (arrows).

Figure 3.

Variability of FDCS architectural growth patterns: whorled (A), diffuse (B), reticular and lymphocyte-rich mimicking a thymoma (C); this pattern, highlighted by immunostains as CD23 (D), is often observed in FDCS occurring in hyaline-vascular Castleman disease. An unusual “angiomatoid” pattern simulating angiosarcoma is shown in E, with strong immunoreactivity of tumor cells for CD21 (F).

Figure 4.

FDCS cytological details in three cases composed of epitheliod tumor cells (A, B, C). Note the delicate nuclear membrane and the single eosinophilic nucleolus, especially obvious in A, where tumor cells are associated with a rich lymphocytic infiltrate and rare eosinophils. B shows FDCS composed of mono- bi- and multinucleated cells, showing round nuclei with delicate membrane, small eosinophilic nucleoli and nuclear molding. C illustrates the tendency of clustering and uneven distribution of nuclei, as well as nuclear pseudoinclusions. In D, FDCS cytological details on fine needle aspiration (Papanicolau stain) is shown. Two examples of FDCS with atypical mitoses, significant pleomorphism and atypia (E and F), including Hodgkin-Sternberg-like cells (F).

Figure 5.

Inflammatory pseudotumor-like FDCS: tumor cells are hardly recognizable among the predominant inflammatory component mostly represented by lymphocytes and plasma cells (A). In situ hybridization for EBV prompts identification of the positive tumor cells (B).

Figure 6.

FDCS expression of classical and novel markers. A (CD21), B (CD23) and C (Clusterin) are from the same tumor and are heterogeneously expressed, particularly with partial loss of CD23. D and E are from the same FDCS case illustrated in Fig. 4A: note the peculiar Golgi-dot pattern of positivity for CXCL13 (D) and the delicate cell membrane expression of podoplanin (E). The novel FDC markers FDC secreted protein (FDCSP)(left) and Serglycin (right) are shown in F.

Figure 7.

Plot of the most commonly affected genes in FDCS. The colors of the bars identify different types of alterations, and numbers refer to cases reported in the literature. Data obtained from references ^,,. SNV, single nucleotide variation.