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Follicular Dendritic Cell Sarcoma

Written2016-11Jahanbanoo Shahryari, Robert S. Ohgami
Department of Pathology, Stanford University, Stanford, CA, USA;

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

Keywords Follicular Dendritic Cell Sarcoma; BRAF; CYLD; NFKBIA; CDKN2A; RB1; CD274; PDCD1LG2

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ICD-Topo C420,C421,C424
ICD-Morpho 9758/3 Follicular dendritic cell sarcoma
Atlas_Id 1719

Clinics and Pathology

Disease 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 / cell stem 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).
Etiology The etiology is unknown. Rare cases have been described in association with the hyaline vascular type of Castleman disease (Youens et al., 2008).
Epidemiology 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.
Clinics 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.
Pathology 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.
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.
Treatment 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.
Prognosis 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 NameBRAF (v-raf murine sarcoma viral oncogene homolog B1)
Location 7q34
Protein 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 NameCYLD (cylindromatosis (turban tumor syndrome))
Location 16q12.1
Protein 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 NameNFKBIA (NFKB inhibitor alpha)
Location 14q13.2
Protein 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 NameCDKN2A (cyclin dependent kinase 2a / p16)
Location 9p21.3
Protein 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 NameRB1 (retinoblastoma)
Location 13q14.2
Protein 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 NameCD274 (CD274 molecule)
Location 9p24.1
Protein 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 NamePDCD1LG2 (programmed cell death 1 ligand 2)
Location 9p24.1
Protein 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.


Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms
Go H, Jeon YK, Huh J, Choi SJ, Choi YD, Cha HJ, Kim HJ, Park G, Min S, Kim JE
Histopathology 2014 Aug;65(2):261-72
PMID 24720374
Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-κB regulatory genes
Griffin GK, Sholl LM, Lindeman NI, Fletcher CD, Hornick JL
Mod Pathol 2016 Jan;29(1):67-74
PMID 26564005
Indolent T-lymphoblastic proliferation (iT-LBP): a review of clinical and pathologic features and distinction from malignant T-lymphoblastic lymphoma
Ohgami RS, Arber DA, Zehnder JL, Natkunam Y, Warnke RA
Adv Anat Pathol 2013 May;20(3):137-40
PMID 23574769
Indolent T-lymphoblastic proliferation with disseminated multinodal involvement and partial CD33 expression
Ohgami RS, Sendamarai AK, Atwater SK, Liedtke M, Fleming MD, Natkunam Y, Warnke RA
Am J Surg Pathol 2014 Sep;38(9):1298-304
PMID 24618611
TdT+ 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, Zhao S, Ohgami JK, Leavitt MO, Zehnder JL, West RB, Arber DA, Natkunam Y, Warnke RA
Am J Surg Pathol 2012 Nov;36(11):1619-28
PMID 23060347
Cytogenetic abnormalities in follicular dendritic cell sarcoma: report of two cases and literature review
Perry AM, Nelson M, Sanger WG, Bridge JA, Greiner TC
In Vivo 2013 Mar-Apr;27(2):211-4
PMID 23422480
Follicular Dendritic Cell Sarcoma: Cytogenetics and pathological findings
Udayakumar AM, Al-Bahri M, Burney IA, Al-Haddabi I
Sultan Qaboos Univ Med J 2015 Aug;15(3):e411-4
PMID 26355964
Paraneoplastic pemphigus and myasthenia gravis, associated with inflammatory pseudotumor-like follicular dendritic cell sarcoma: response to rituximab
Wang L, Deng H, Mao M
Clin Case Rep 2016 Jul 15;4(8):797-9
PMID 27525088
Follicular Dendritic Cell Sarcoma
Wu A, Pullarkat S
Arch Pathol Lab Med 2016 Feb;140(2):186-90
PMID 26910224
Extranodal follicular dendritic cell sarcoma
Youens KE, Waugh MS
Arch Pathol Lab Med 2008 Oct;132(10):1683-7
PMID 18834231


This paper should be referenced as such :
Jahanbanoo Shahryari, Robert S Ohgami
Follicular Dendritic Cell Sarcoma
Atlas Genet Cytogenet Oncol Haematol. 2017;21(9):324-326.
Free journal version : [ pdf ]   [ DOI ]
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