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Follicular Dendritic Cell Sarcoma.

Follicular dendritic cell sarcoma (FDCS), a neoplasm with follicular dendritic cell differentiation, was first characterized by Monda et al1 in 1986. Although FDCS is a rare tumor, it generally occurs in lymph nodes--most commonly, the cervical, mediastinal, or axillary lymph nodes. In fewer than one-third of cases, FDCS can also be found in extranodal sites, including the tonsils, nasopharynx, pancreas, liver, and peripancreatic and peritoneal tissues. (1,2) Follicular dendritic cell sarcoma occurs at a mean age of 44, has a roughly equal male-to-female ratio, with the exception of the inflammatory pseudotumor-like variant having a higher predilection for women, and typically presents as a painless slow-growing mass with no associated symptoms. (3-5) If present, symptoms are more common among patients with liver or abdominal FDCS. Follicular dendritic cell sarcoma is associated with paraneoplastic pemphigus (6,7) and Castleman disease. Some reports suggest that FDCS may evolve from Castleman disease, (8-10) possibly through a mechanism involving the epidermal growth factor receptor (11); however, most FDCS cases occur sporadically. (12) Despite its rarity, it is important to maintain a high index of suspicion for FDCS and include it in the differential diagnosis of a spindle cell neoplasm, when appropriate, to avoid a potential misdiagnosis.


Upon gross examination, FDCS is a relatively well-circumscribed tumor with a tan, solid-appearing cut surface with pushing borders (2) and variable areas of hemorrhage and necrosis (Figure 1).


Histologically, FDCS is composed of uniform, spindle and ovoid cells, with eosinophilic cytoplasm and nuclei with a vesicular chromatin pattern, nuclear pseudoinclusions, and distinct nucleoli (Figure 2). The neoplastic cells are usually arranged in fascicular, somewhat syncytial sheets, with whorled or storiform patterns in some areas, sometimes reminiscent of meningioma, (2,5) often with intermixed, small lymphocytes (4) (Figure 3). The mitotic rate is typically low, but pleomorphic cases can have higher mitotic rates.

Follicular dendritic cell sarcoma is frequently misdiagnosed, primarily because it is rare and often not considered in the differential diagnosis of a spindle cell neoplasm. Depending on location and presentation, the differential diagnosis of FDCS can include inflammatory myofibroblasts tumor, inflammatory pseudotumor, interdigitating dendritic cell sarcoma, Langerhans cell histiocytosis, sarcomatoid carcinoma, undifferentiated pleomorphic sarcoma, thymoma, lymphoma, Schwannoma, and gastrointestinal stromal tumor.

Immunohistochemical markers assist in arriving at the diagnosis of FDCS if the appropriate immunohistochemical markers specific for follicular dendritic cell differentiation/FDCS are applied. The neoplastic spindle cells of FDCS are typically immunohistochemically positive for CD21 (Figure 4), CD35 (Figure 5), and CD23. Clusterin is also highly sensitive and specific for FDCS when strongly and diffusely positive. (13,14) Although the neoplastic cells of FDCS cells can have variable immunohistochemical expression of vimentin (positive in several soft tissue tumors), CD68 (typically positive in undifferentiated pleomorphic sarcoma and Langerhans cell histiocytosis), and S100 (typically positive in Schwannoma), none of these markers are specific for FDCS. Because of the lack of specificity of these markers for FDCS, a misdiagnosis can occur if FDCS is not considered in the differential diagnosis, and dendritic cell immunohistochemical markers described above are not applied. The neoplastic cells of FDCS are consistently negative for cytokeratins, CD31, CD34, and CD1a, making sarcomatoid carcinoma, angiosarcoma, and Langerhans cell histiocytosis less likely.


An inflammatory pseudotumor-like variant of FDCS has been described, with areas that are histologically similar to conventional inflammatory pseudotumors, differentiating it from conventional FDCS. (3) The inflammatory pseudotumorlike variant of FDCS occurs most commonly in the liver and spleen. Aside from the differences in histology and location from conventional FDCS, the 2 entities also differ in clinical presentation (15); the inflammatory pseudotumor variant of FDCS has a marked female predominance (15-17) and often presents with systemic symptoms. The inflammatory pseudotumor-like variant of FDCS is associated with Epstein-Barr virus (EBV), with Epstein-Barr virus-encoded RNA found in most cases. (16,18) Ge et al (19) found Epstein-Barr virus-encoded RNA in situ hybridization was positive in 92.1% of the neoplastic spindle cells. Most cases also expressed conventional FDCS markers, including CD21, CD35, CD23, and clusterin. In addition to the differential diagnosis for conventional FDCS, the differential diagnosis of the inflammatory pseudotumor-like variant could also include Hodgkin lymphoma because the inflammatory pseudotumor-like variant of FDCS can occasionally show Reed-Sternberg-like cells in a background of predominantly spindle cell morphology. (20)


Several recent studies have evaluated molecular and cytogenetic abnormalities that may be linked to FDCS. Griffin et al (21) found recurrent loss-of-function alterations in nuclear factor [kappa]B regulatory genes NFKBIA and CYLD, cell cycle progression genes (CDKN2A and RBI), and genes involved in immune evasion, including CD274 and PDCD1LG2, which resulted in the activation of the nuclear factor [kappa]B genes. Go et al (22) showed BRAF mutations were present in 18.5% of FDCS and 40% of inflammatory pseudotumor-like variants of FDCS cases. Increased knowledge about the molecular genetic profile of FDCS can potentially translate to targeted therapy in the future.

A study by Perry et al (23) demonstrated cytogenetic abnormalities of a near diploid clone with loss of chromosomes 3 and 14 in one FDCS case and a hypodiploid clone with loss of chromosomes 5, 6, 9, 14, 16, and 22 in another FDCS case. However, FDCS is often associated with a complex karyotype.


Although FDCS typically has an indolent course, local recurrence is very common, with a recurrence rate of 40% to 50%, and an aggressive clinical course, including metastases to lung, liver, or lymph nodes, is possible. (15) Overall, FDCS should be considered at least an intermediate-grade tumor. (5) Poor prognostic factors for FDCS include a size of 6 cm or larger, an intra-abdominal location, coagulative necrosis, 5 mitoses/10 high-power fields or more, and prominent nuclear atypia/pleomorphism. (5) The inflammatory pseudotumor-like variant of FDCS is thought to have a more indolent clinical course when compared with conventional FDCS. (20,24)

Prospective data, comparing treatment regimens for FDCS, are not available, likely because of the low incidence of FDCS; therefore, optimal treatment recommendations for these patients are not well-defined. For localized FDCS, most cases are treated by surgical resection, with or without adjuvant chemotherapy and/or radiation. Although Gounder and colleagues (12) reported no significant difference in 5-year survival rates between those who received adjuvant or neoadjuvant therapy (n = 11) and those who underwent surgical resection alone (n = 12), Soriano et al (25) found longer disease-free survival in patients with FDCS who received a combination of surgery, chemotherapy, and radiation. For patients with more-widespread FDCS or those in whom surgical resection is otherwise not possible, lymphoma-type regimens or sarcoma regimens may be used.


Follicular dendritic cell sarcoma is a rare neoplasm with follicular dendritic cell differentiation, which typically has an indolent course, but should be considered at least an intermediate-grade tumor given its metastatic potential. The histologic appearance and typical immunohistochemical staining pattern are often sufficiently sensitive and specific to help make the diagnosis. However, it can easily be misdiagnosed in clinical practice if not considered in the differential diagnosis; therefore, a high level of clinical suspicion is needed in appropriate cases.


(1.) Monda I, Warnke R, Rosai J. A primary lymph node malignancy with features suggestive of dendritic reticulum cell differentiation, a report of 4 cases. Am J Pathol. 1986;122(3):562-572.

(2.) Biddle D, Ro J, Yoon G, Yong YW, Ayala A, Ordonez N. Extranodal follicular dendritic cell sarcoma of the head and neck region: three new cases, with a review of the literature. Mod Pathol. 2002;15(1):50-58.

(3.) De Pas T, Spitaleri G, Pruneri G, et al. Dendritic cell sarcoma: an analytic overview of the literature and presentation of original five cases. Crit Rev Oncol Hematol. 2008;65(1):1-7.

(4.) Cheuk W, Walford N, Lou J, et al. Primary histiocytic lymphoma of the central nervous system: a neoplasm frequently overshadowed by a prominent inflammatory component. Am J Surg Pathol. 2001;25(11):1372-1379.

(5.) Chan JK, Fletcher CD, Nayler SJ, Cooper K. Follicular dendritic cell sarcoma: clinicopathologic analysis of 17 cases suggesting a malignant potential higher than currently recognized. Cancer. 1997;79(2):294-313.

(6.) Su Z, Liu G, Fang T, et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma: report of a case and review of literature. Int J Clin Exp Pathol. 2015;8(10):11983-11994.

(7.) Chow SC, Yeung EC, Ng CS, Wong R, To KF, Wan I. Mediastinal follicular dendritic cell sarcoma with paraneoplastic pemphigus. Asian Cardiovasc Thorac Ann. 2015;23(6):732-734.

(8.) Hwang SO, Lee TH, Bae SH, et al. Transformation of Castleman disease into follicular dendritic cell sarcoma presenting as an asymptomatic abdominal mass. Korean J Gastroenterol. 2013;62(2):131-134.

(9.) Lee BE, Korst RJ, Taskin M. Right pneumonectomy for resection of a posterior mediastinal follicular dendritic cell sarcoma arising from Castleman disease. Ann Thorac Surg. 2014;97(4):e101-e103.

(10.) Cakir E, Aydin NE, Samdanci E, Karadag N, Sayin S, Kizilay A. Follicular dendritic cell sarcoma associated with hyaline-vascular Castleman disease. J Pak Med Assoc. 2013;63(3):393-395.

(11.) Sun X, Chang KC, Abruzzo LV, Lai R, Younes A, Jones D. Epidermal growth factor receptor in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman disease. Hum Pathol. 2003;34(9):835-840.

(12.) Gounder M, Desai V, Kuk D, et al. Impact of surgery, radiation and systemic therapy on the outcomes of patients with dendritic cell and histiocytic sarcomas. Eur J Cancer. 2015;51(16):2413-2422.

(13.) Grogg KL, Lae ME, Kurtin PJ, William M. Clusterin expression distinguishes follicular dendritic cell tumors from other dendritic cell neoplasms: report of a novel follicular dendritic cell marker and clinicopathologic data on 12 additional follicular dendritic cell tumors and 6 additional interdigitating cell tumors. Am J Surg Pathol. 2004;28(8):988-998.

(14.) Grogg KL, Macon WR, Kurtin PJ, Nascimento A. A survey of clusterin and fascin expression in sarcomas and spindle cell neoplasms: strong clusterin immunostaining is highly specific for follicular dendritic cell tumor. Mod Pathol. 2005;18(2):260-266.

(15.) Cheuk W, Chan J, Shek T, et al. Inflammatory pseudotumor-like follicular dendritic cell tumor. A distinctive low-grade malignant intra-abdominal neoplasm with consistent Epstein-Barr virus association. Am J Surg Pathol. 2001;25(6):721-731.

(16.) Arber DA, Weiss LM, Chang KL. Detection of EBV in inflammatory pseudotumor. Semin Diagn Pathol. 1998;15(2):155-160.

(17.) Caillard S, Lelong C, Pessione F, Moulin B; French PTLD Working Group. Post-transplant lymphoproliferative disorders occurring after renal transplantation in adults: report of 230 cases from the French registry. Am J Transplant. 2006; 6(11):2735-2742.

(18.) Li XQ, Cheuk W, Lam PW, et al. Inflammatory pseudotumor-like follicular dendritic cell tumor of liver and spleen: granulomatous and eosinophil-rich variants mimicking inflammatory or infective lesions. Am J Surg Pathol. 2014; 38(5):646-653.

(19.) Ge R, Liu C, Yin X, et al. Clinicopathologic characteristics of inflammatory pseudotumor-like follicular dendritic cell sarcoma. Int J Clin Exp Pathol. 2014; 7(5):2421-2429.

(20.) Selves J, Meggetto F, Brousset P, et al. Inflammatory pseudotumor of the liver: evidence of follicular dendritic reticulum cell proliferation associated with clonal EBV. Am J Surg Pathol. 1996;20(6):747-753.

(21.) Griffin GK, Sholl LM, Lindeman NI, Fletcher C, Hornick JL. Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-[kappa]B regulatory genes. Mod. Pathol. 2016;29(1):67-74.

(22.) Go H, Jeon YK, Huh J, et al. Frequent detection of BRAFV600E mutations in histiocytic and dendritic cell neoplasms. Histopathology. 2014;65(2):261-272.

(23.) Perry AM, Nelson M, Sanger WG, Bridge JA, Greiner TC. Cytogenetic abnormalities in follicular dendritic cell sarcoma: report of two cases and literature review. In Vivo. 2013;27(2):211-214.

(24.) Yoon S, Ko H, Kim BH, Kwon GY, Jeon KY, Kim CW. Epstein-Barr virus-associated inflammatory pseudotumor-like follicular dendritic cell tumor in the spleen of a patient with diffuse large B cell lymphoma: a case report and review of the literature. The Korean Journal of Pathology 2007;41 (3):198-202.

(25.) Soriano AO, Thompson MA, Admirand JH, et al. Follicular dendritic cell sarcoma: a report of 14 cases and a review of the literature. Am J Hematol. 2007; 82(8):725-728.

Please Note: Illustration(s) are not available due to copyright restrictions

Caption: Figure 1. Abdominal, extranodal follicular dendritic cell sarcoma with smooth, tan cut surface and relatively well-circumscribed border.

Caption: Figure 2. Follicular dendritic cell sarcoma composed of uniform spindle and oval cells with eosinophilic cytoplasm, nuclei with a vesicular chromatin pattern, occasional intracellular inclusions, distinct nucleoli, and admixed chronic inflammatory cells (hematoxylin-eosin, original magnification X40).

Caption: Figure 3. Follicular dendritic cell sarcoma with spindle cells arranged in fascicular sheets with whorled/storiform pattern and admixed chronic inflammatory cells (hematoxylin-eosin, original magnification X10).

Caption: Figure 4. CD21 immunohistochemical stain highlighting follicular dendritic cell sarcoma spindle cells (original magnification X20).

Caption: Figure 5. CD35 immunohistochemical stain highlighting follicular dendritic cell sarcoma spindle cells (original magnification X20).
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Title Annotation:Resident Short Reviews
Author:Chen, Tiffany; Gopal, Purva
Publication:Archives of Pathology & Laboratory Medicine
Date:Apr 1, 2017
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