Follicular Dendritic Cell Sarcoma Annie Wu, MD; Sheeja Pullarkat, MD
Follicular dendritic cell sarcoma is an uncommon neoplastic proliferation of spindled to ovoid cells with morphologic and immunophenotypic features similar to normal follicular dendritic cells. While most follicular dendritic cell sarcomas arise from lymph nodes, at least one-third occur in extranodal sites. A broad differential diagnosis can be developed—as this tumor has morphologic features similar to other tumors, hence creating a diagnostic pitfall—but its immunophenotypic profile is quite specific and is diagnostically crucial. Herein, we review the pathogenesis; histologic morphology; and immunohistochemical, electron microscopy, and clinical features, including treatment and prognosis, of follicular dendritic cell sarcomas. We will briefly describe the role of molecular studies including utility of BRAF mutations in diagnosing this tumor. (Arch Pathol Lab Med. 2016;140:186–190; doi: 10.5858/ arpa.2014-0374-RS)
F
ollicular dendritic cell sarcoma (FDCS) was first described in 1986 by Monda et al,1 in a series of 4 cases with initial presentation of unilateral cervical adenopathy, as a nonlymphomatous primary lymph node malignancy with features suggesting dendritic reticulum cell origin. Follicular dendritic cell sarcoma is a neoplastic proliferation of spindled to ovoid cells with morphologic and immunophenotypic features similar to those of normal follicular dendritic cells and is classified under histiocytic and dendritic cell neoplasms by the World Health Organization Classification of Tumours.2 Follicular dendritic cells are normally present in both nodal and extranodal lymphoid follicles and serve as antigenpresenting cells to B-cell lymphocytes, serving an important role in B-cell migration, proliferation, and differentiation.3 In addition to storing antigens as cell surface immune complexes for long periods of time, follicular dendritic cells are a nonmigrating population likely derived from the stroma that assist in the architectural support of the lymphoid follicles via cellto-cell attachments and desmosomes.4,5 Accepted for publication November 24, 2014. From the Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Annie Wu, MD, Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Room 13-145G, Los Angeles, CA 90095-1732 (e-mail: [email protected]). 186 Arch Pathol Lab Med—Vol 140, February 2016
EPIDEMIOLOGY AND PATHOGENESIS There is a wide age range associated with FDCS, mostly affecting young to middle-aged adults (mean age, 44 years; median age in the fifth decade) of both sexes, although there is a female predilection for the inflammatory pseudotumorlike variant of FDCS, an uncommon and distinct variant of FDCS.2 There is also the possibility that FDCS may occur more among certain ethnicities or in certain geographic locations because many cases have been reported from East Asia.6 Most cases do not have a known etiology. Human herpesvirus 8 is not associated with FDCS.7 The inflammatory pseudotumor-like variant of FDCS is an uncommon tumor that is consistently associated with the Epstein-Barr virus. It has selective involvement to the liver and spleen and is characterized by marked female predominance and frequent presence of systemic symptoms.8 Epstein-Barr virus–encoded RNA is found in almost all neoplastic cells, and Southern blot studies have shown that the virus has a monoclonal episomal form.2 Approximately 10% to 20% of FDCS cases are associated with antecedent or concurrent Castleman disease, a benign lymphoproliferative disorder, mostly the hyaline vascular variant (Figure 1). Some cases of antecedent Castleman disease demonstrate areas of follicular dendritic cell proliferation, and FDCS is hypothesized to arise in these areas.9 Additionally, a shared feature of Castleman disease and FDCS is expression of epidermal growth factor receptor (EGFR).10 CLINICAL FEATURES Most patients generally present with an asymptomatic, slow-growing, painless cervical lymphadenopathy. Approximately one-third of FDCS cases occur in extranodal sites, including skin, mediastinum, tonsil, gastrointestinal tract, and soft tissue.11,12 Most cases are asymptomatic, although patients with abdominal disease may present with abdominal pain, and systemic symptoms can include fatigue, fever, and night sweats. Additionally, there may be an association between FDCS and autoimmune disease: paraneoplastic pemphigus and myasthenia gravis. Paraneoplastic pemphigus has been seen in patients with FDCS, either with or without evidence of previous Castleman disease.13,14 There have also been at least 6 reports of FDCS in patients with concurrent diagnoses of myasthenia gravis. Their tumors show aggregates of small lymphocytes composed of predominantly immature T cells, which are uncharacteristic of FDCS. This suggests another paraneoplastic manifestation of FDCS.6,15 Follicular Dendritic Cell Sarcoma—Wu & Pullarkat
GROSS PATHOLOGY Follicular dendritic cell sarcomas are characteristically well circumscribed or even encapsulated, bosselated masses that are solid with pink or white to tan-grey cut surfaces. The size has been reported to range from 1 to 15 cm, largely dependent on the tumor location, with a median size of approximately 5 cm.9,16 The average size of extranodal tumors is 7.4 cm with a range from 1 to 20 cm.17 Larger tumors may show necrosis or gross hemorrhage.
Figure 1. Castleman disease hyaline vascular variant demonstrating regressed follicles with penetrating vessel and vascular proliferation (hematoxylin-eosin, original magnification 3200). Figure 2. Follicular dendritic cell sarcoma, with highly cellular areas showing varied fascicular, whorled, and storiform architecture, low- and high-power (inset) views (hematoxylin-eosin, original magnifications 340 and 3200 [inset]). Figure 3. High-grade features in a follicular dendritic cell sarcoma with cellular atypia including irregular nuclear membranes and large hyperchromatic nuclei (hematoxylin-eosin, original magnification with oil 31000). Arch Pathol Lab Med—Vol 140, February 2016
HISTOPATHOLOGY Most FDCSs are considered low-grade sarcomas. Histologic sections demonstrate a spindle cell proliferation with a varied architectural pattern in storiform (most common) or whorled (meningioma-like) bundles, fascicles, trabecular, or diffuse sheets (Figure 2).18 Several growth patterns can often be seen in the same tumor. Prominent lymphocytes can be spread throughout the tumor in between tumor cells and in perivascular spaces, with some cases predominantly B-cell lymphocytes and other cases predominantly T-cell lymphocytes. Scattered multinucleated cells, although in small numbers, can be seen and can resemble Warthin-Finkeldey giant cells.9 The cell borders are generally indistinct, imparting a syncytial appearance, and the cytoplasm is moderately abundant, lightly eosinophilic, and can have a fibrillary quality. The tumor cells have elongated or ovoid nuclei with a thin nuclear membrane, vesicular or granular chromatin, and small nucleoli. Nuclear pseudoinclusions can occasionally be seen, with frequency increased after radiation therapy.19 Mitotic rate is usually low with 0 to 10 mitoses per 10 highpower fields and necrosis is not commonly seen. Most cases are relatively bland and uniform but cytologic atypia may be seen in some cases with pleomorphic cells (Figure 3). High-grade histologic features may include significant cellular atypia (irregular nuclear membranes and large hyperchromatic nuclei), high mitotic count (reported cases of 11 to 35 mitoses per 10 high-power fields), and extensive necrosis.16 High-grade features are associated with deep-seated lesions and recurrent or metastatic lesions.9 The inflammatory pseudotumor-like follicular dendritic cell tumor is a variant of FDCS with distinct histologic features. This variant shows a loose fascicular and sheetlike growth pattern of spindle or ovoid cells with vesicular nuclei in a background of abundant lymphocytes and plasma cells.8 Nuclear atypia can be variable with some nuclei resembling Reed-Sternberg cells. Cytomorphology of FDCS is characteristic but may be difficult to recognize, and often requires further confirmation with immunohistochemical studies. Aspiration cytology of a lesion will show large, spindle to ovoid epithelioid cells singly, in small clusters, and in syncytial sheets; moderate to abundant cytoplasm; indistinct cell borders; irregular nuclear membranes; fine to vesicular chromatin; and conspicuous nucleoli.20 IMMUNOHISTOCHEMISTRY Immunohistochemical studies are essential in the diagnosis of FDCS (Figure 4, a through c). Nodal and extranodal FDCSs have similar immunophenotypes. Follicular dendritic cell sarcomas generally demonstrate the immunophenotype Follicular Dendritic Cell Sarcoma—Wu & Pullarkat 187
Figure 4. Immunohistochemical profile of follicular dendritic cell sarcoma including (a) CD23þ cells, (b) variable CD68 staining, and (c) epidermal growth factor receptor staining (original magnification 3200 [a through c]). Figure 5. Electron micrograph of follicular dendritic cell sarcoma shows well-developed, long interdigitating cytoplasmic processes and desmosome-like junctions; no Birbeck granules are seen (original magnification 320 000).
of nonneoplastic follicular dendritic cells and are usually positive for dendritic cell markers CD21 (C3b complement receptor), CD23, and/or CD35 (C3d complement receptor), exhibiting cell membrane staining, although cytoplasmic staining can also be seen.9,18,21 Clusterin is a glycoprotein associated with many cellular functions, including apoptosis, and shows strong positivity in follicular dendritic cell tumors with weak to no expression in other dendritic cell tumors.22 Strong diffuse clusterin staining has high specificity and sensitivity for FDCS.23 Podoplanin (D2-40) is another marker shown to have high sensitivity for FDCS with strong membranous staining.24 c-Synuclein is a relatively recent marker shown to strongly stain follicular dendritic cell meshwork and may also be considered helpful in identifying FDCS.25 Additionally, the tumor is usually positive for vimentin, fascin, desmoplakin, EGFR, and human leukocyte antigen– DR. It is variably positive for epithelial membrane antigen, S100, and CD68, which can present diagnostic pitfalls. Staining for CD1a, lysozyme, myeloperoxidase, CD34, CD3, CD79a, CD30, HMB-45, desmin, and high-molecular188 Arch Pathol Lab Med—Vol 140, February 2016
weight cytokeratins is negative. Ki-67 labeling ranges from 1% to 25%.2,9 ELECTRON MICROSCOPY Diagnostic ultrastructural features of FDCS include long, slender, interdigitating cytoplasmic processes, sometimes producing a labyrinth-like pattern and desmosome-like junctions (Figure 5).18 The cytoplasm often contains few organelles. Birbeck granules and lysosomes are not seen. GENETICS Follicular dendritic cell sarcoma has no B-cell or T-cell gene rearrangements and only isolated cases of cytogenetic abnormalities have been reported. Based on the literature, it seems that FDCS is frequently associated with complex cytogenetic abnormalities, although consistent or specific aberration has not been established to date in this entity. Recently, a multicenter study performed by Go et al26 examined the BRAF pathway and its contribution to the pathogenesis of histiocytic and dendritic cell neoplasms, including FDCS. Through direct Sanger sequencing, as well as peptide nucleic acid clamp quantitative polymerase chain Follicular Dendritic Cell Sarcoma—Wu & Pullarkat
reaction, the authors found that the BRAFV600E mutation was positive in 18.5% (5 of 27) of FDCS cases, and in both conventional as well as inflammatory pseudotumor-like types. Notably, BRAFV600E was found in 40% (2 of 5) of inflammatory pseudotumor-like subtypes. The authors note that BRAF mutations could potentially help differentiate inflammatory pseudotumor-like FDCS from inflammatory myofibroblastic tumor.26 DIFFERENTIAL DIAGNOSES Follicular dendritic cell sarcoma can often be misdiagnosed, with reports of 30% to 58% misdiagnosed cases, especially when arising from extranodal sites.11,17 Differential diagnoses of FDCS include interdigitating dendritic cell sarcoma, thymoma, spindle cell carcinoma, metastatic undifferentiated carcinomas, malignant melanoma, and gastrointestinal stromal tumor (GIST). Interdigitating dendritic cell sarcomas are rare entities and usually arise from lymph nodes or the spleen, and thus may be considered a differential diagnosis for FDCS when a lesion arises from those sites. Interdigitating dendritic cell sarcomas have a paracortical distribution in lymph nodes and lack the storiform and whorled patterns of FDCS.27 Unlike FDCS, interdigitating dendritic cell sarcomas are diffusely positive for S100, negative for dendritic cell markers (CD21, CD35), and lack desmosomes on electron microscopy. When arising from the mediastinum, a FDCS can be confused with a thymoma because of similar histomorphology, but thymomas stain for cytokeratins and p63 and do not express follicular dendritic cell markers. A helpful morphologic distinguishing feature is the presence of Hassall corpuscles in thymomas. Spindle cell carcinomas also express cytokeratin positivity. Follicular dendritic cell sarcoma with epithelial membrane antigen expression may be mistaken for metastatic undifferentiated or sarcomatoid carcinomas; however, FDCSs are usually negative for cytokeratins.27 Malignant melanomas are positive for HMB-45 and Melan-A. Follicular dendritic cell sarcomas arising in the gastrointestinal tract may be mistaken for KIT-negative GIST but dense lymphocytic infiltrates are uncommon in GIST; GIST is also negative for CD21 and CD35, whereas FDCS is negative for CD34 and DOG1.27 Other entities that should be considered in the list of differential diagnoses include sarcomas such as malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, histiocytic sarcoma, and carcinomas, particularly lymphoepithelioma-like carcinomas. The inflammatory pseudotumor-like variant of FDCS that arises in the liver and spleen can resemble inflammatory myofibroblastic tumor. It is positive for Epstein-Barr virus– encoded RNA. The location of the tumor is helpful in diagnosis. Also, unlike FDCS, inflammatory myofibroblastic tumor is positive for smooth muscle actin, may express desmin, and 50% are positive for ALK, with ALK gene arrangements.27 In the right context, a high index of suspicion is required in the diagnosis of FDCS and should be seriously considered when there is an unusual-appearing cytokeratin-negative neoplasm, thymoma-like tumor presenting outside the mediastinum, meningioma-like tumor outside the dura, and GIST rich in lymphoid cells.18 It is important to remember that FDCS has a distinctive immunophenotype, and the absence of cytokeratin staining can rule out many Arch Pathol Lab Med—Vol 140, February 2016
carcinoma entities. Also, expression of dendritic cell markers is very specific. CURRENT TREATMENT AND PROGNOSIS Follicular dendritic cell sarcoma has a variable clinical course and there is no uniform treatment strategy at present. Follicular dendritic cell sarcoma was traditionally considered to act like a low-grade neoplasm. However, further studies with longer follow-up periods, and the recognition of increased cytologic atypia, have indicated that FDCS is a more high-grade lesion, or at the very least an intermediategrade lesion characterized by local recurrences and occasional distant metastases. While the role of radiation therapy and chemotherapy is not well defined, complete surgical resection appears to be the treatment of choice for both primary and recurrent lesions.6,16 For FDCSs with the BRAFV600E mutation, there is potential for vemurafenib, a BRAF enzyme inhibitor, as a targeted therapy as it was shown to exhibit dramatic effects in other dendritic and histiocytic neoplasms such as ErdheimChester disease and Langerhans cell histiocytosis.28 Another potential class of therapeutic agents is EGFR inhibitors, particularly in cases with moderate to strong expression of EGFR.10 Local recurrences are common, occurring in approximately 40% to 50% of cases. Tumors arising in lymph nodes are often indolent, with low rate of metastases (approximately 10%), whereas extranodal tumors, especially abdominal tumors, have higher metastatic potential (.20%). Common metastatic sites include liver, lung, and lymph nodes. Unfavorable prognostic factors include intra-abdominal location, large tumor size (greater than 6 cm), coagulative necrosis, mitotic count greater than 5 mitoses per 10 highpower fields, and significant cellular atypia, with intraabdominal location the single most important unfavorable prognostic factor.2,16,17,19,27 Although for many patients the disease responds to treatment, the relapse rate can be as high as 80%.21 The mortality rate is approximately 20%, usually after a protracted course. References 1. Monda L, 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. Chan J, Pileri S, Delsol G, Fletcher C, Weiss L, Grogg K. Follicular dendritic cell sarcoma. In: Swerdlow S, Campo E, Harris N, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:363–364. World Health Organization Classification of Tumours; vol 2. 3. Imal Y, Yamakawa M. Morphology, function and pathology of follicular dendritic cells. Pathol Int. 1996;46(11):807–833. 4. Jaffe R, Pileri S, Facchetti F, Jones D, Jaffe E. Histiocytic and dendritic cell neoplasms, Introduction. In: Swerdlow S, Campo E, Harris N, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:354–355. World Health Organization Classification of Tumours; vol 2. 5. van Nierop K, de Groot C. Human follicular dendritic cells: function, origin and development. Semin Immunol. 2002;14(4):251–257. 6. Saygin C, Uzunaslan D, Ozguroglu M, Senocak M, Tuzuner N. Dendritic cell sarcoma: a pooled analysis including 462 cases with presentation of our case series. Crit Rev Oncol Hematol. 2013;88(2):253–271. 7. Nayler SJ, Taylor L, Cooper K. HHV-8 is not associated with follicular dendritic cell tumours. Mol Pathol. 1998;51(3):168–170. 8. Cheuk W, Chan JK, Shek TW, 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. 9. Chang K, Weiss L. Other histiocytic and dendritic cell neoplasms. In: Jaffe E, Harris N, Vardiman J, Campo E, Arber D, eds. Hematopathology. 1st ed. Philadelphia, PA: Saunders/Elsevier; 2011:829–833. 10. Sun X, Chang KC, Abruzzo LV, Lai R, Younes A, Jones D. Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman’s disease. Hum Pathol. 2003; 34(9):835–840.
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11. Duan GJ, Wu F, Zhu J, et al. Extranodal follicular dendritic cell sarcoma of the pharyngeal region: a potential diagnostic pitfall, with literature review. Am J Clin Pathol. 2010;133(1):49–58. 12. Perez-Ordonez B, Rosai J. Follicular dendritic cell tumor: review of the ˜ entity. Semin Diagn Pathol. 1998;15(2):144–154. 13. Lee IJ, Kim SC, Kim HS, et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma arising from Castleman’s tumor. J Am Acad Dermatol. 1999;40(2, pt 2):294–297. 14. Meijs M, Mekkes J, van Noesel C, et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma without Castleman’s disease; treatment with rituximab. Int J Dermatol. 2008;47(6):632–634. 15. Hsu C, Vega F, Grimes LM, Hunt KK. Follicular dendritic cell sarcoma and associated myasthenia gravis: true, true, related? J Clin Oncol. 2011;29(13):e369– e371. 16. Perez-Ordonez B, Erlandson RA, Rosai J. Follicular dendritic cell tumor: report of 13 additional cases of a distinctive entity. Am J Surg Pathol. 1996;20(8): 944–955. 17. Shia J, Chen W, Tang LH, et al. Extranodal follicular dendritic cell sarcoma: clinical, pathologic, and histogenetic characteristics of an underrecognized disease entity. Virchows Arch. 2006;449(2):148–158. 18. Chan JK. Proliferative lesions of follicular dendritic cells: an overview, including a detailed account of follicular dendritic cell sarcoma, a neoplasm with many faces and uncommon etiologic associations. Adv Anat Pathol. 1997;4(6): 387–411. 19. 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. 20. Wang XI, Zhang S, Thomas JO, Adegboyega PA. Cytomorphology, ultrastructural, and cytogenetic findings in follicular dendritic cell sarcoma: a case report. Acta Cytol. 2010;54(5 suppl):759–763.
21. 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. 22. Grogg KL, Lae ME, Kurtin PJ, Macon WR. 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 dendritic cell tumors. Am J Surg Pathol. 2004;28(8):988–998. 23. Grogg KL, Macon WR, Kurtin PJ, Nascimento AG. 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. 24. Yu H, Gibson JA, Pinkus GS, Hornick JL. Podoplanin (D2-40) is a novel marker for follicular dendritic cell tumors. Am J Clin Pathol. 2007;128(5):776– 782. 25. Zhang H, Maitta RW, Bhattacharyya PK, et al. c-Synuclein is a promising new marker for staining reactive follicular dendritic cells, follicular dendritic cell sarcoma, Kaposi sarcoma, and benign and malignant vascular tumors. Am J Surg Pathol. 2011;35(12):1857–1865. 26. Go H, Jeon YK, Huh J, et al. Frequent detection of BRAF(V) (600E) mutations in histiocytic and dendritic cell neoplasms. Histopathology. 2014; 65(2):261–272. 27. Hornick JL. Soft tissue tumors with prominent inflammatory cells. In: Hornick J, ed. Practical Soft Tissue Pathology: A Diagnostic Approach. Philadelphia, PA: Elsevier Saunders; 2013:257–261. 28. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013; 121(9):1495–1500.
CAP16 Abstract Program Submission Dates Announced Abstract and case study submissions to the College of American Pathologists (CAP) 2016 Abstract Program will be accepted beginning on Friday, January 8 through 5 p.m. Central time Friday, March 11, 2016. Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine Web site as a Web-only supplement to the September 2016 issue. The CAP16 meeting will be held from September 25 to 28 in Las Vegas, Nevada. Visit the CAP16 Web site (www.cap.org/cap16) for additional abstract program information as it becomes available.
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Follicular Dendritic Cell Sarcoma—Wu & Pullarkat
Follicular dendritic cell sarcoma is an uncommon neoplastic proliferation of spindled to ovoid cells with morphologic and immunophenotypic features similar to normal follicular dendritic cells. While most follicular dendritic cell sarcomas arise from lymph nodes, at least one-third occur in extranodal sites. A broad differential diagnosis can be developed—as this tumor has morphologic features similar to other tumors, hence creating a diagnostic pitfall—but its immunophenotypic profile is quite specific and is diagnostically crucial. Herein, we review the pathogenesis; histologic morphology; and immunohistochemical, electron microscopy, and clinical features, including treatment and prognosis, of follicular dendritic cell sarcomas. We will briefly describe the role of molecular studies including utility of BRAF mutations in diagnosing this tumor. (Arch Pathol Lab Med. 2016;140:186–190; doi: 10.5858/ arpa.2014-0374-RS)
F
ollicular dendritic cell sarcoma (FDCS) was first described in 1986 by Monda et al,1 in a series of 4 cases with initial presentation of unilateral cervical adenopathy, as a nonlymphomatous primary lymph node malignancy with features suggesting dendritic reticulum cell origin. Follicular dendritic cell sarcoma is a neoplastic proliferation of spindled to ovoid cells with morphologic and immunophenotypic features similar to those of normal follicular dendritic cells and is classified under histiocytic and dendritic cell neoplasms by the World Health Organization Classification of Tumours.2 Follicular dendritic cells are normally present in both nodal and extranodal lymphoid follicles and serve as antigenpresenting cells to B-cell lymphocytes, serving an important role in B-cell migration, proliferation, and differentiation.3 In addition to storing antigens as cell surface immune complexes for long periods of time, follicular dendritic cells are a nonmigrating population likely derived from the stroma that assist in the architectural support of the lymphoid follicles via cellto-cell attachments and desmosomes.4,5 Accepted for publication November 24, 2014. From the Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California. The authors have no relevant financial interest in the products or companies described in this article. Reprints: Annie Wu, MD, Department of Pathology & Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Room 13-145G, Los Angeles, CA 90095-1732 (e-mail: [email protected]). 186 Arch Pathol Lab Med—Vol 140, February 2016
EPIDEMIOLOGY AND PATHOGENESIS There is a wide age range associated with FDCS, mostly affecting young to middle-aged adults (mean age, 44 years; median age in the fifth decade) of both sexes, although there is a female predilection for the inflammatory pseudotumorlike variant of FDCS, an uncommon and distinct variant of FDCS.2 There is also the possibility that FDCS may occur more among certain ethnicities or in certain geographic locations because many cases have been reported from East Asia.6 Most cases do not have a known etiology. Human herpesvirus 8 is not associated with FDCS.7 The inflammatory pseudotumor-like variant of FDCS is an uncommon tumor that is consistently associated with the Epstein-Barr virus. It has selective involvement to the liver and spleen and is characterized by marked female predominance and frequent presence of systemic symptoms.8 Epstein-Barr virus–encoded RNA is found in almost all neoplastic cells, and Southern blot studies have shown that the virus has a monoclonal episomal form.2 Approximately 10% to 20% of FDCS cases are associated with antecedent or concurrent Castleman disease, a benign lymphoproliferative disorder, mostly the hyaline vascular variant (Figure 1). Some cases of antecedent Castleman disease demonstrate areas of follicular dendritic cell proliferation, and FDCS is hypothesized to arise in these areas.9 Additionally, a shared feature of Castleman disease and FDCS is expression of epidermal growth factor receptor (EGFR).10 CLINICAL FEATURES Most patients generally present with an asymptomatic, slow-growing, painless cervical lymphadenopathy. Approximately one-third of FDCS cases occur in extranodal sites, including skin, mediastinum, tonsil, gastrointestinal tract, and soft tissue.11,12 Most cases are asymptomatic, although patients with abdominal disease may present with abdominal pain, and systemic symptoms can include fatigue, fever, and night sweats. Additionally, there may be an association between FDCS and autoimmune disease: paraneoplastic pemphigus and myasthenia gravis. Paraneoplastic pemphigus has been seen in patients with FDCS, either with or without evidence of previous Castleman disease.13,14 There have also been at least 6 reports of FDCS in patients with concurrent diagnoses of myasthenia gravis. Their tumors show aggregates of small lymphocytes composed of predominantly immature T cells, which are uncharacteristic of FDCS. This suggests another paraneoplastic manifestation of FDCS.6,15 Follicular Dendritic Cell Sarcoma—Wu & Pullarkat
GROSS PATHOLOGY Follicular dendritic cell sarcomas are characteristically well circumscribed or even encapsulated, bosselated masses that are solid with pink or white to tan-grey cut surfaces. The size has been reported to range from 1 to 15 cm, largely dependent on the tumor location, with a median size of approximately 5 cm.9,16 The average size of extranodal tumors is 7.4 cm with a range from 1 to 20 cm.17 Larger tumors may show necrosis or gross hemorrhage.
Figure 1. Castleman disease hyaline vascular variant demonstrating regressed follicles with penetrating vessel and vascular proliferation (hematoxylin-eosin, original magnification 3200). Figure 2. Follicular dendritic cell sarcoma, with highly cellular areas showing varied fascicular, whorled, and storiform architecture, low- and high-power (inset) views (hematoxylin-eosin, original magnifications 340 and 3200 [inset]). Figure 3. High-grade features in a follicular dendritic cell sarcoma with cellular atypia including irregular nuclear membranes and large hyperchromatic nuclei (hematoxylin-eosin, original magnification with oil 31000). Arch Pathol Lab Med—Vol 140, February 2016
HISTOPATHOLOGY Most FDCSs are considered low-grade sarcomas. Histologic sections demonstrate a spindle cell proliferation with a varied architectural pattern in storiform (most common) or whorled (meningioma-like) bundles, fascicles, trabecular, or diffuse sheets (Figure 2).18 Several growth patterns can often be seen in the same tumor. Prominent lymphocytes can be spread throughout the tumor in between tumor cells and in perivascular spaces, with some cases predominantly B-cell lymphocytes and other cases predominantly T-cell lymphocytes. Scattered multinucleated cells, although in small numbers, can be seen and can resemble Warthin-Finkeldey giant cells.9 The cell borders are generally indistinct, imparting a syncytial appearance, and the cytoplasm is moderately abundant, lightly eosinophilic, and can have a fibrillary quality. The tumor cells have elongated or ovoid nuclei with a thin nuclear membrane, vesicular or granular chromatin, and small nucleoli. Nuclear pseudoinclusions can occasionally be seen, with frequency increased after radiation therapy.19 Mitotic rate is usually low with 0 to 10 mitoses per 10 highpower fields and necrosis is not commonly seen. Most cases are relatively bland and uniform but cytologic atypia may be seen in some cases with pleomorphic cells (Figure 3). High-grade histologic features may include significant cellular atypia (irregular nuclear membranes and large hyperchromatic nuclei), high mitotic count (reported cases of 11 to 35 mitoses per 10 high-power fields), and extensive necrosis.16 High-grade features are associated with deep-seated lesions and recurrent or metastatic lesions.9 The inflammatory pseudotumor-like follicular dendritic cell tumor is a variant of FDCS with distinct histologic features. This variant shows a loose fascicular and sheetlike growth pattern of spindle or ovoid cells with vesicular nuclei in a background of abundant lymphocytes and plasma cells.8 Nuclear atypia can be variable with some nuclei resembling Reed-Sternberg cells. Cytomorphology of FDCS is characteristic but may be difficult to recognize, and often requires further confirmation with immunohistochemical studies. Aspiration cytology of a lesion will show large, spindle to ovoid epithelioid cells singly, in small clusters, and in syncytial sheets; moderate to abundant cytoplasm; indistinct cell borders; irregular nuclear membranes; fine to vesicular chromatin; and conspicuous nucleoli.20 IMMUNOHISTOCHEMISTRY Immunohistochemical studies are essential in the diagnosis of FDCS (Figure 4, a through c). Nodal and extranodal FDCSs have similar immunophenotypes. Follicular dendritic cell sarcomas generally demonstrate the immunophenotype Follicular Dendritic Cell Sarcoma—Wu & Pullarkat 187
Figure 4. Immunohistochemical profile of follicular dendritic cell sarcoma including (a) CD23þ cells, (b) variable CD68 staining, and (c) epidermal growth factor receptor staining (original magnification 3200 [a through c]). Figure 5. Electron micrograph of follicular dendritic cell sarcoma shows well-developed, long interdigitating cytoplasmic processes and desmosome-like junctions; no Birbeck granules are seen (original magnification 320 000).
of nonneoplastic follicular dendritic cells and are usually positive for dendritic cell markers CD21 (C3b complement receptor), CD23, and/or CD35 (C3d complement receptor), exhibiting cell membrane staining, although cytoplasmic staining can also be seen.9,18,21 Clusterin is a glycoprotein associated with many cellular functions, including apoptosis, and shows strong positivity in follicular dendritic cell tumors with weak to no expression in other dendritic cell tumors.22 Strong diffuse clusterin staining has high specificity and sensitivity for FDCS.23 Podoplanin (D2-40) is another marker shown to have high sensitivity for FDCS with strong membranous staining.24 c-Synuclein is a relatively recent marker shown to strongly stain follicular dendritic cell meshwork and may also be considered helpful in identifying FDCS.25 Additionally, the tumor is usually positive for vimentin, fascin, desmoplakin, EGFR, and human leukocyte antigen– DR. It is variably positive for epithelial membrane antigen, S100, and CD68, which can present diagnostic pitfalls. Staining for CD1a, lysozyme, myeloperoxidase, CD34, CD3, CD79a, CD30, HMB-45, desmin, and high-molecular188 Arch Pathol Lab Med—Vol 140, February 2016
weight cytokeratins is negative. Ki-67 labeling ranges from 1% to 25%.2,9 ELECTRON MICROSCOPY Diagnostic ultrastructural features of FDCS include long, slender, interdigitating cytoplasmic processes, sometimes producing a labyrinth-like pattern and desmosome-like junctions (Figure 5).18 The cytoplasm often contains few organelles. Birbeck granules and lysosomes are not seen. GENETICS Follicular dendritic cell sarcoma has no B-cell or T-cell gene rearrangements and only isolated cases of cytogenetic abnormalities have been reported. Based on the literature, it seems that FDCS is frequently associated with complex cytogenetic abnormalities, although consistent or specific aberration has not been established to date in this entity. Recently, a multicenter study performed by Go et al26 examined the BRAF pathway and its contribution to the pathogenesis of histiocytic and dendritic cell neoplasms, including FDCS. Through direct Sanger sequencing, as well as peptide nucleic acid clamp quantitative polymerase chain Follicular Dendritic Cell Sarcoma—Wu & Pullarkat
reaction, the authors found that the BRAFV600E mutation was positive in 18.5% (5 of 27) of FDCS cases, and in both conventional as well as inflammatory pseudotumor-like types. Notably, BRAFV600E was found in 40% (2 of 5) of inflammatory pseudotumor-like subtypes. The authors note that BRAF mutations could potentially help differentiate inflammatory pseudotumor-like FDCS from inflammatory myofibroblastic tumor.26 DIFFERENTIAL DIAGNOSES Follicular dendritic cell sarcoma can often be misdiagnosed, with reports of 30% to 58% misdiagnosed cases, especially when arising from extranodal sites.11,17 Differential diagnoses of FDCS include interdigitating dendritic cell sarcoma, thymoma, spindle cell carcinoma, metastatic undifferentiated carcinomas, malignant melanoma, and gastrointestinal stromal tumor (GIST). Interdigitating dendritic cell sarcomas are rare entities and usually arise from lymph nodes or the spleen, and thus may be considered a differential diagnosis for FDCS when a lesion arises from those sites. Interdigitating dendritic cell sarcomas have a paracortical distribution in lymph nodes and lack the storiform and whorled patterns of FDCS.27 Unlike FDCS, interdigitating dendritic cell sarcomas are diffusely positive for S100, negative for dendritic cell markers (CD21, CD35), and lack desmosomes on electron microscopy. When arising from the mediastinum, a FDCS can be confused with a thymoma because of similar histomorphology, but thymomas stain for cytokeratins and p63 and do not express follicular dendritic cell markers. A helpful morphologic distinguishing feature is the presence of Hassall corpuscles in thymomas. Spindle cell carcinomas also express cytokeratin positivity. Follicular dendritic cell sarcoma with epithelial membrane antigen expression may be mistaken for metastatic undifferentiated or sarcomatoid carcinomas; however, FDCSs are usually negative for cytokeratins.27 Malignant melanomas are positive for HMB-45 and Melan-A. Follicular dendritic cell sarcomas arising in the gastrointestinal tract may be mistaken for KIT-negative GIST but dense lymphocytic infiltrates are uncommon in GIST; GIST is also negative for CD21 and CD35, whereas FDCS is negative for CD34 and DOG1.27 Other entities that should be considered in the list of differential diagnoses include sarcomas such as malignant fibrous histiocytoma, malignant peripheral nerve sheath tumors, histiocytic sarcoma, and carcinomas, particularly lymphoepithelioma-like carcinomas. The inflammatory pseudotumor-like variant of FDCS that arises in the liver and spleen can resemble inflammatory myofibroblastic tumor. It is positive for Epstein-Barr virus– encoded RNA. The location of the tumor is helpful in diagnosis. Also, unlike FDCS, inflammatory myofibroblastic tumor is positive for smooth muscle actin, may express desmin, and 50% are positive for ALK, with ALK gene arrangements.27 In the right context, a high index of suspicion is required in the diagnosis of FDCS and should be seriously considered when there is an unusual-appearing cytokeratin-negative neoplasm, thymoma-like tumor presenting outside the mediastinum, meningioma-like tumor outside the dura, and GIST rich in lymphoid cells.18 It is important to remember that FDCS has a distinctive immunophenotype, and the absence of cytokeratin staining can rule out many Arch Pathol Lab Med—Vol 140, February 2016
carcinoma entities. Also, expression of dendritic cell markers is very specific. CURRENT TREATMENT AND PROGNOSIS Follicular dendritic cell sarcoma has a variable clinical course and there is no uniform treatment strategy at present. Follicular dendritic cell sarcoma was traditionally considered to act like a low-grade neoplasm. However, further studies with longer follow-up periods, and the recognition of increased cytologic atypia, have indicated that FDCS is a more high-grade lesion, or at the very least an intermediategrade lesion characterized by local recurrences and occasional distant metastases. While the role of radiation therapy and chemotherapy is not well defined, complete surgical resection appears to be the treatment of choice for both primary and recurrent lesions.6,16 For FDCSs with the BRAFV600E mutation, there is potential for vemurafenib, a BRAF enzyme inhibitor, as a targeted therapy as it was shown to exhibit dramatic effects in other dendritic and histiocytic neoplasms such as ErdheimChester disease and Langerhans cell histiocytosis.28 Another potential class of therapeutic agents is EGFR inhibitors, particularly in cases with moderate to strong expression of EGFR.10 Local recurrences are common, occurring in approximately 40% to 50% of cases. Tumors arising in lymph nodes are often indolent, with low rate of metastases (approximately 10%), whereas extranodal tumors, especially abdominal tumors, have higher metastatic potential (.20%). Common metastatic sites include liver, lung, and lymph nodes. Unfavorable prognostic factors include intra-abdominal location, large tumor size (greater than 6 cm), coagulative necrosis, mitotic count greater than 5 mitoses per 10 highpower fields, and significant cellular atypia, with intraabdominal location the single most important unfavorable prognostic factor.2,16,17,19,27 Although for many patients the disease responds to treatment, the relapse rate can be as high as 80%.21 The mortality rate is approximately 20%, usually after a protracted course. References 1. Monda L, 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. Chan J, Pileri S, Delsol G, Fletcher C, Weiss L, Grogg K. Follicular dendritic cell sarcoma. In: Swerdlow S, Campo E, Harris N, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:363–364. World Health Organization Classification of Tumours; vol 2. 3. Imal Y, Yamakawa M. Morphology, function and pathology of follicular dendritic cells. Pathol Int. 1996;46(11):807–833. 4. Jaffe R, Pileri S, Facchetti F, Jones D, Jaffe E. Histiocytic and dendritic cell neoplasms, Introduction. In: Swerdlow S, Campo E, Harris N, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008:354–355. World Health Organization Classification of Tumours; vol 2. 5. van Nierop K, de Groot C. Human follicular dendritic cells: function, origin and development. Semin Immunol. 2002;14(4):251–257. 6. Saygin C, Uzunaslan D, Ozguroglu M, Senocak M, Tuzuner N. Dendritic cell sarcoma: a pooled analysis including 462 cases with presentation of our case series. Crit Rev Oncol Hematol. 2013;88(2):253–271. 7. Nayler SJ, Taylor L, Cooper K. HHV-8 is not associated with follicular dendritic cell tumours. Mol Pathol. 1998;51(3):168–170. 8. Cheuk W, Chan JK, Shek TW, 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. 9. Chang K, Weiss L. Other histiocytic and dendritic cell neoplasms. In: Jaffe E, Harris N, Vardiman J, Campo E, Arber D, eds. Hematopathology. 1st ed. Philadelphia, PA: Saunders/Elsevier; 2011:829–833. 10. Sun X, Chang KC, Abruzzo LV, Lai R, Younes A, Jones D. Epidermal growth factor receptor expression in follicular dendritic cells: a shared feature of follicular dendritic cell sarcoma and Castleman’s disease. Hum Pathol. 2003; 34(9):835–840.
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11. Duan GJ, Wu F, Zhu J, et al. Extranodal follicular dendritic cell sarcoma of the pharyngeal region: a potential diagnostic pitfall, with literature review. Am J Clin Pathol. 2010;133(1):49–58. 12. Perez-Ordonez B, Rosai J. Follicular dendritic cell tumor: review of the ˜ entity. Semin Diagn Pathol. 1998;15(2):144–154. 13. Lee IJ, Kim SC, Kim HS, et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma arising from Castleman’s tumor. J Am Acad Dermatol. 1999;40(2, pt 2):294–297. 14. Meijs M, Mekkes J, van Noesel C, et al. Paraneoplastic pemphigus associated with follicular dendritic cell sarcoma without Castleman’s disease; treatment with rituximab. Int J Dermatol. 2008;47(6):632–634. 15. Hsu C, Vega F, Grimes LM, Hunt KK. Follicular dendritic cell sarcoma and associated myasthenia gravis: true, true, related? J Clin Oncol. 2011;29(13):e369– e371. 16. Perez-Ordonez B, Erlandson RA, Rosai J. Follicular dendritic cell tumor: report of 13 additional cases of a distinctive entity. Am J Surg Pathol. 1996;20(8): 944–955. 17. Shia J, Chen W, Tang LH, et al. Extranodal follicular dendritic cell sarcoma: clinical, pathologic, and histogenetic characteristics of an underrecognized disease entity. Virchows Arch. 2006;449(2):148–158. 18. Chan JK. Proliferative lesions of follicular dendritic cells: an overview, including a detailed account of follicular dendritic cell sarcoma, a neoplasm with many faces and uncommon etiologic associations. Adv Anat Pathol. 1997;4(6): 387–411. 19. 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. 20. Wang XI, Zhang S, Thomas JO, Adegboyega PA. Cytomorphology, ultrastructural, and cytogenetic findings in follicular dendritic cell sarcoma: a case report. Acta Cytol. 2010;54(5 suppl):759–763.
21. 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. 22. Grogg KL, Lae ME, Kurtin PJ, Macon WR. 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 dendritic cell tumors. Am J Surg Pathol. 2004;28(8):988–998. 23. Grogg KL, Macon WR, Kurtin PJ, Nascimento AG. 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. 24. Yu H, Gibson JA, Pinkus GS, Hornick JL. Podoplanin (D2-40) is a novel marker for follicular dendritic cell tumors. Am J Clin Pathol. 2007;128(5):776– 782. 25. Zhang H, Maitta RW, Bhattacharyya PK, et al. c-Synuclein is a promising new marker for staining reactive follicular dendritic cells, follicular dendritic cell sarcoma, Kaposi sarcoma, and benign and malignant vascular tumors. Am J Surg Pathol. 2011;35(12):1857–1865. 26. Go H, Jeon YK, Huh J, et al. Frequent detection of BRAF(V) (600E) mutations in histiocytic and dendritic cell neoplasms. Histopathology. 2014; 65(2):261–272. 27. Hornick JL. Soft tissue tumors with prominent inflammatory cells. In: Hornick J, ed. Practical Soft Tissue Pathology: A Diagnostic Approach. Philadelphia, PA: Elsevier Saunders; 2013:257–261. 28. Haroche J, Cohen-Aubart F, Emile JF, et al. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013; 121(9):1495–1500.
CAP16 Abstract Program Submission Dates Announced Abstract and case study submissions to the College of American Pathologists (CAP) 2016 Abstract Program will be accepted beginning on Friday, January 8 through 5 p.m. Central time Friday, March 11, 2016. Accepted submissions will appear on the Archives of Pathology & Laboratory Medicine Web site as a Web-only supplement to the September 2016 issue. The CAP16 meeting will be held from September 25 to 28 in Las Vegas, Nevada. Visit the CAP16 Web site (www.cap.org/cap16) for additional abstract program information as it becomes available.
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