Follicular Dendritic Cell Sarcoma

2016-11-01   Robert S. Ohgami , Jahanbanoo Shahryari 

1.Department of Pathology, Stanford University, Stanford, CA, USA;


Review on Follicular Dendritic Cell Sarcoma, with data on clinics, and the genes involved.

Clinics and Pathology


Follicular dendritic cell sarcoma (FDCS) is an extremely rare mesenchymal neoplasm. This tumor was first reported in 1986 by Monda et al. and is classified by the World Health Organization (WHO) under histiocytic and dendritic cell neoplasms.

Phenotype stem cell origin

The cell of origin is the antigen presenting follicular dendritic cell. Normal (Non-neoplastic) follicular dendritic cells process antigen antibody complexes, and present them to B-cells in lymphoid follicles (Wu et al., 2016).


The etiology is unknown. Rare cases have been described in association with the hyaline vascular type of Castleman disease (Youens et al., 2008).


Follicular dendritic cell sarcomas are extremely rare. The number of reported cases are fewer than 100. Patients as young as 9 up to 82 years old have been described, though it occurs predominantly in adults. Mean and median age of disease are in the fifth decade of life. Both sexes are equally affected.


Most cases of follicular dendritic cell sarcoma present with asymptomatic lymphadenopathy. Cervical and axillary lymph nodes are commonly affected. Extra nodal sites that can be involved include spleen, liver, gastrointestinal tract, skin, lung, mediastinum, pharynx, tonsils and soft tissue. Patients with intra-abdominal tumors may suffer from abdominal pain. Other systemic presentations include fever, night sweats and fatigue. Rarely paraneoplastic myasthenia gravis and pemphigus has been reported in FDCS (Wang et al., 2016). Abnormal levels of alkaline phosphatase as well as anemia are reported with hepatic involvement by FDCS.


The tumor shows various histologic patterns of spindle cells in storiform (the most common form), meningioma -like (whorled), fascicles, bundles or diffuse sheets; heterogenicity in growth patterns can also be seen. Tumor cells are plump with indistinct cell borders (syncytial appearance) and show fibrillary slightly eosinophilic cytoplasm. Tumor cells have vesicular nuclei with fine chromatin, sometimes intranuclear pseudoinclusions, and nucleoli; binucleate cells are present. Perivascular B or T lymphocytes can be seen. In some cases TdT+ T-lymphoblasts can be associated with these tumors (Ohgami et al., 2012, 2013, 2014).
Tumor necrosis is unusual and the mitotic rate can vary from 0 to 10 per 10 high power fields. High mitotic rates are more common in cases with cytologic atypia and clinically aggressive behavior.
Atlas Image
Figure 1: Histopathologic features of a follicular dendritic cell sarcoma (FDCS). Numerous spindled shaped elongated cells are seen with finer nuclear chromatin and frequently prominent nucleoli, some binucleate (red arrows) cells are clearly seen which is typical of FDCS.

Other features

Immunohistochemistry: Cells show membranous reaction for CD21, CD23, CD35 (C3d complement receptor). Clusterin is the most sensitive marker which shows diffuse strong cytoplasmic positivity in FDCS. This marker is not positive in other dendritic cell tumors. Podoplanin (D2-40) is another highly sensitive marker that shows a strong membranous reaction. c-Synuclein is another new helpful marker strongly stains follicular dendritic cells and may be useful in diagnosis FDCS. Other markers which are usually positive in the tumor are vimentin, EGFR, fascin, and HLA-DR. MIB-1/Ki-67 index ranges from 1% to 25%. Staining for CD1a, lysozyme, myeloperoxidase, CD34, CD3, CD79a, CD30, HMB-45, desmin, and high-molecular weight cytokeratins are negative on the tumor cells.


Complete surgical excision is the treatment of choice for both primary and recurrent cases. The benefits and advantages of radiotherapy and chemotherapy are not established yet. In cases with a BRAF V600 mutation, a BRAF enzyme inhibitor such as vemurafenib can be a potential choice. Another therapeutic agent are EGFR inhibitors, especially in cases which express moderate to strong EGFR.


Extranodal tumors have a higher risk of metastases than nodal counterparts. Local recurrences are common. Liver, lung and lymph nodes are common metastatic sites. Tumors with larger size (>6cm) significant cellular atypia, coagulative necrosis, intra-abdominal location and high mitotic rate (greater than 5 mitoses in 10 hpf) have unfavorable prognosis.


Cytogenetics morphological

No specific chromosomal aberration has been established in FDCS. Non-recurrent types of complex cytogenetic abnormalities have been documented (Udayakumar et al., 2015; Perry et al., 2013).

Cytogenetics molecular

The genetic alterations that drive tumorogenesis are not well understood in FDCS. One recent study that assessed the genetic basis of FDCS reported BRAF V600 mutations in a subset of cases (Go et al., 2014). Another study analyzing somatic alterations, showed loss of function alterations in tumor suppressor genes (NF-kB regulatory genes), including bi-allelic loss of CYLD and frameshift mutations in NFKBIA. Alterations in genes that regulate cell cycle include bi-allelic loss of CDKN2A and RB-1. Finally, focal copy-number gains on chromosome 9p24, a well described mechanism of immune evasion, have been observed in the regions containing CD274 (PD-L1) and PDCD1LG2 (PD-L2) (Griffin et al., 2016).

Genes Involved and Proteins

Gene name
BRAF (v-raf murine sarcoma viral oncogene homolog B1)
Protein description
This gene belongs to the RAF/MIL family of serine/threonine kinases. The protein product affects cell division, secretion and differentiation through its regulating role in the MAP kinase/ERK signaling pathway. Mutations have been associated with cancers including malignant melanoma, colorectal cancer, non-Hodgkin lymphoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.
Gene name
CYLD (cylindromatosis (turban tumor syndrome))
Protein description
The product of this gene is a cytoplasmic protein. The role of this gene in FDCS is purportedly through negative regulation of NF-kB activation by bi-allelic loss of CYLD gene.
Gene name
NFKBIA (NFKB inhibitor alpha)
Protein description
NFKBIA is a member of the NF-kappa-B inhibitor family and involved in inflammatory responses. The alteration in FDCS is a frameshift mutation or deletion in NFKBI resulting in altered cytoplasmic sequestration of NF-kB complex.
Gene name
CDKN2A (cyclin dependent kinase 2a / p16)
Protein description
This gene generates several transcripts differing in their first exon. At least three spliced variants encode distinct proteins. The most well-known proteins are p16 (INK4a) and p14 (ARF) which both have tumor suppressor activity.
Gene name
RB1 (retinoblastoma)
Protein description
This gene encodes a protein which is a negative regulator of the cell cycle. Bi-allelic losses of RB1 are seen, as well as nonsense mutations in FDCS.
Gene name
CD274 (CD274 molecule)
Protein description
The protein product of PD-L1 is involved in T-cell proliferation, activation and the production of cytokines like IL-10 and IFN-gamma. It is considered to be prognostic in various types of malignancies, including renal cell carcinoma and colon cancer.
Gene name
PDCD1LG2 (programmed cell death 1 ligand 2)
Protein description
PD-L2 is involved in T-cell proliferation and INF-gamma production. In some cases of FDCS, a copy number gain on chromosome 9p24 in the location of these genes was observed, and believed to contribute to immune system evasion.


Pubmed IDLast YearTitleAuthors
247203742014Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms.Go H et al
265640052016Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-κB regulatory genes.Griffin GK et al
235747692013Indolent T-lymphoblastic proliferation (iT-LBP): a review of clinical and pathologic features and distinction from malignant T-lymphoblastic lymphoma.Ohgami RS et al
246186112014Indolent T-lymphoblastic proliferation with disseminated multinodal involvement and partial CD33 expression.Ohgami RS et al
230603472012TdT+ T-lymphoblastic populations are increased in Castleman disease, in Castleman disease in association with follicular dendritic cell tumors, and in angioimmunoblastic T-cell lymphoma.Ohgami RS et al
234224802013Cytogenetic abnormalities in follicular dendritic cell sarcoma: report of two cases and literature review.Perry AM et al
263559642015Follicular Dendritic Cell Sarcoma: Cytogenetics and pathological findings.Udayakumar AM et al
275250882016Paraneoplastic pemphigus and myasthenia gravis, associated with inflammatory pseudotumor-like follicular dendritic cell sarcoma: response to rituximab.Wang L et al
269102242016Follicular Dendritic Cell Sarcoma.Wu A et al
188342312008Extranodal follicular dendritic cell sarcoma.Youens KE et al


Robert S. Ohgami ; Jahanbanoo Shahryari

Follicular Dendritic Cell Sarcoma

Atlas Genet Cytogenet Oncol Haematol. 2016-11-01

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