Inflammatory pseudotumour-like follicular dendritic cell tumour of the colon with plasmacytosis mimicking EBV-positive lymphoproliferative disorder

Follicular dendritic cell (FDC) sarcoma, a neoplasm with follicular dendritic cell differentiation, is rare and divided morphologically into conventional type and inflammatory pseudotumour (IPT)-like variant. The former, occurring in both nodal and extranodal sites, shows sarcomatous appearance composed of short spindle or ovoid cells arranged characteristically in a fascicular, whorl or storiform pattern intermixed with sprinkled lymphocytes. In contrast, the IPT-like variant, affecting almost always the liver and spleen, features a small amount of spindle or ovoid cells against an inflammatory background rich in lymphoplasmacytic infiltrates. Interestingly, the tumour cells invariantly carry Epstein–Barr virus (EBV) infection. Because the IPT-like variant occurs only rarely in an extrahepatosplenic location, the morphology of dense lymphoplasmacytic infiltrate with EBV positivity in the colon may be easily misdiagnosed as an EBV-positive lymphoproliferative disorder (LPD) or other lymphoma.1Agaimy A. Wunsch P.H. Follicular dendritic cell tumor of the gastrointestinal tract: report of a rare neoplasm and literature review.Pathol Res Pract. 2006; 202: 541-548Crossref PubMed Scopus (20) Google Scholar,2Chen Y. Shi H. Li H. et al.Clinicopathological features of inflammatory pseudotumour-like follicular dendritic cell tumour of the abdomen.Histopathology. 2016; 68: 858-865Crossref PubMed Scopus (31) Google Scholar Here, we report two such cases presenting as a colonic polyp. To the best of our knowledge, these are the second and third cases of primary colonic EBV-positive IPT-like FDC tumour (sarcoma) reported in the literature. We corroborated EBV present in the FDCs by double staining of immunohistochemistry and EBER in situ hybridisation (ISH). Case 1 was a 54-year-old man who presented to the department of colorectal surgery with a colon mass, which had been found in another hospital. The fecal occult blood test was positive, but no abdominal pain, bowel habit change, body weight loss, or fever was noted. Physical examination revealed no evidence of lymphadenopathy. Laboratory data including CEA, CA19-9, haemoglobin, renal function and liver function tests were all within normal limits. A computed-tomography scan of the abdomen showed a 2.8 cm tumour in the splenic flexure of colon with an enlarged lymph node 1.2 cm along the common hepatic artery. Colonoscopic examination revealed a 2.4 cm pedunculated polyp at the splenic flexure of the colon, 70 cm from the anal verge (Fig. 1A). Endoscopic polypectomy was performed. Microscopically, the excised polypoid mass showed effacement of colonic structure by a polymorphic infiltrate (Fig. 1B), composed predominantly of plasma cells intermixed with small lymphocytes, immunoblasts, and histiocyte-like cells (Fig. 1C). The latter possessed scant cytoplasm and large ovoid to spindled nuclei with vesicular chromatin and small to large recognisable nucleoli (naked nuclei, Fig. 1C inset). Hyalinised blood vessels and focal ulceration were noted, but no eosinophilic infiltration or granuloma formation was identified. The differential diagnosis was broad, including inflammatory myofibroblastic tumour, lymphoproliferative disorder, and inflammatory pseudotumour-like FDC sarcoma (tumour). Immunohistochemical analysis showed that the large ovoid to spindled cells were positive for CD21 (Fig. 1D), CD23 (Fig. 1E), D2-40 and fascin, but negative for CD35, CD30 and CD15. The background lymphocytes were composed of a mixed population positive for CD3, CD20, CD5 and MNDA. CD10 highlighted some residual germinal centres. The dense infiltrate of plasma cells was demonstrated by CD138 staining but was negative for light chain restriction (kappa:lambda = 2–3:1). B-cell clonality testing by immunoglobulin genes rearrangement was also negative. Interestingly, EBER-ISH showed positive signals on the large ovoid to spindled cells with occasionally binucleation (Fig. 1F). Double staining with immunohistochemistry and ISH revealed the EBV-infected cells were positive for CD21, consistent with follicular dendritic cells (FDCs) in origin (Fig. 1F inset). Case 2 was a 68-year-old male, with a past history of benign prostate hypertrophy (BPH) and old cerebral vascular accident (CVA), who had a positive fecal occult blood test during a recent health examination. No body weight loss or bowel habit change was noted. The laboratory test and digital examination were normal. A colonoscopy showed a 2.0 cm polyp in the transverse colon, 130 cm above the anal verge (Fig. 2A). Endoscopic polypectomy was performed. The pathological features were similar to those of Case 1 and showed predominantly lymphoplasmacytic infiltration with formation of several lymphoid follicles (Fig. 2B). In the dense infiltrate, there were scattered ovoid or spindle cells with violaceous nuclear membrane, vesicular chromatin and distinct nucleoli but indistinct cell borders (Fig. 2C). These stromal cells showed mild nuclear atypia with focal binucleation (Fig. 2C inset). These spindled cells were immunoreactive for CD21, CD23, fascin (Fig. 2D) and D2-40 (Fig. 2E), but negative for CD35, CD30 and CD15. EBER-ISH also showed positive signals on the large ovoid to spindled cells (Fig. 2F). Double staining showed co-labelling of CD21 and EBER-ISH in the ovoid or spindle cells (Fig. 2F inset). The follow-up was uneventful in both cases. FDC sarcoma, a neoplasm of FDC origin, is rare and classified morphologically as conventional type and IPT-like variant. After a thorough search of the English literature, we enrolled convincing cases of IPT-like FDC sarcoma with EBV positivity (n=52). The relevant clinical and pathological comparison between conventional and IPT-like variants is summarised in Table 1. Extranodal FDC sarcomas occurring in gastrointestinal tract are rare and almost all cases are of the conventional type.1Agaimy A. Wunsch P.H. Follicular dendritic cell tumor of the gastrointestinal tract: report of a rare neoplasm and literature review.Pathol Res Pract. 2006; 202: 541-548Crossref PubMed Scopus (20) Google Scholar,3Chang K.C. Jin Y.T. Chen F.F. et al.Follicular dendritic cell sarcoma of the colon mimicking stromal tumour.Histopathology. 2001; 38: 25-29Crossref PubMed Scopus (44) Google Scholar In the English literature only three EBV-positive cases, including the two presented here, are reported: all are in the colon, polypoid, and IPT-like variant.4Pan S.T. Cheng C.Y. Lee N.S. et al.Follicular dendritic cell sarcoma of the inflammatory pseudotumor-like variant presenting as a colonic polyp.Korean J Pathol. 2014; 48: 140-145Crossref PubMed Scopus (28) Google Scholar Another similar case has been reported but classified as genuine EBV-positive IPT, given that the spindle cells lacked expression of ALK-1 and FDC markers but were instead co-labelled by smooth muscle actin and EBER-ISH.5Gong S. Auer I. Duggal R. et al.Epstein-Barr virus-associated inflammatory pseudotumor presenting as a colonic mass.Hum Pathol. 2015; 46: 1956-1961Crossref PubMed Scopus (21) Google ScholarTable 1Clinicopathological features of conventional versus IPT-like FDC sarcomaTypeConventional typeIPT-like variantIncidenceLess than 400 case reports11Saygin C. Uzunaslan D. Ozguroglu M. et al.Dendritic cell sarcoma: a pooled analysis including 462 cases with presentation of our case series.Crit Rev Oncol Hematol. 2013; 88: 253-271Crossref PubMed Scopus (144) Google Scholar52 case reports2Chen Y. Shi H. Li H. et al.Clinicopathological features of inflammatory pseudotumour-like follicular dendritic cell tumour of the abdomen.Histopathology. 2016; 68: 858-865Crossref PubMed Scopus (31) Google Scholar,4Pan S.T. Cheng C.Y. Lee N.S. et al.Follicular dendritic cell sarcoma of the inflammatory pseudotumor-like variant presenting as a colonic polyp.Korean J Pathol. 2014; 48: 140-145Crossref PubMed Scopus (28) Google Scholar,9Kazemimood R. Saei Hamedani F. Sharif A. et al.A rare case of Epstein-Barr virus negative inflammatory pseudotumor-like follicular dendritic cell sarcoma presenting as a solitary colonic mass in a 53-year-old woman; case report and review of literature.Appl Immunohistochem Mol Morphol. 2017; 25: e30-e33Crossref PubMed Scopus (12) Google Scholar,12Ge R. Liu C. Yin X. et al.Clinicopathologic characteristics of inflammatory pseudotumor-like follicular dendritic cell sarcoma.Int J Clin Exp Pathol. 2014; 7: 2421-2429PubMed Google ScholarAgeMiddle age (median 50 years)Middle age (median 54 years)SexMale = femaleSlight female predominance (M:F = 21:31)LocationLymph node 32%; extra-nodal site 58%; both nodal and extranodal 10%Almost exclusively in liver and spleen; extrahepatosplenic site: one peri-pancreatic and three colonic casesSystemic symptomsRare (10%)Frequent (41%)Paraneoplastic pemphigusRare (18 case reports)None (0%)MorphologyFDCs arrange in fascicular or syncytial sheets with a sprinkling of inflammatory cellsFDCs dispersed in a background rich in lymphoplasmacytic infiltratesEBV association4%100%BehaviourIntermediate-grade sarcomaIndolentRecurrence rate28%10%Metastasis27%0%Mortality21%4%EBV, Epstein–Barr virus; FDC, follicular dendritic cell; IPT, inflammatory pseudotumour. Open table in a new tab EBV, Epstein–Barr virus; FDC, follicular dendritic cell; IPT, inflammatory pseudotumour. Regarding the differential diagnosis, the main consideration of conventional type FDC sarcoma is gastrointestinal stromal tumour in which prominently storiform and whorled growth patterns of tumour cells are unusual and immunohistochemically the tumour cells are positive for CD117, DOG-1 and CD34, but negative for FDC markers.1Agaimy A. Wunsch P.H. Follicular dendritic cell tumor of the gastrointestinal tract: report of a rare neoplasm and literature review.Pathol Res Pract. 2006; 202: 541-548Crossref PubMed Scopus (20) Google Scholar For IPT-like variant, the differential diagnoses may be broader. Inflammatory fibroid polyp is composed typically of bland spindle cells, inflammatory cells with prominent eosinophils, and a rich vascular network in a myxoedematous background. Both spindle cells and eosinophils may concentrate around the blood vessels. The spindle cells frequently express CD34 and PDGFR, and frequently (∼70% of cases) harbour gain-of-function mutations in the PDGFRA gene.6Schildhaus H.U. Cavlar T. Binot E. et al.Inflammatory fibroid polyps harbour mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene.J Pathol. 2008; 216: 176-182Crossref PubMed Scopus (120) Google Scholar Inflammatory myofibroblastic tumour occurs more commonly in children. Pathologically, it shows spindle or rarely epithelioid tumour cells with abundant amphophilic cytoplasm and variably prominent nucleoli in a myxoid or fibrotic background rich in lymphoplasmacytic infiltrates with polyclonal plasma cells. The tumour cells are variably positive of ALK-1 staining and negative for FDC markers and EBER-ISH. ALK mutations are found in approximately half of cases.7Coffin C.M. Patel A. Perkins S. et al.ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor.Mod Pathol. 2001; 14: 569-576Crossref PubMed Scopus (491) Google Scholar The finding of many EBV-positive cells in a plasmacytic-rich inflammatory background may raise the possibility of classic Hodgkin lymphoma (cHL) or EBV-positive B-lymphoproliferative disorders (EBV-LPD) such as those in immunocompromised hosts. For cHL, it is essential to demonstrate CD30-positive and/or CD15-positive Reed–Sternberg cells dispersed in an inflammatory background with or without fibrosis. For EBV-LPD, there are typically large B cells expressing CD20, CD79a and PAX-5 with mostly monotypic plasma cells. Most importantly, the EBV-positive cells in cHL and EBV-LPD are typically round and single in appearance in contrast to those in IPT-like FDC tumour, which show oval to spindle nuclei with occasional binucleation. The ancillary double staining, such as CD20/EBER and CD21/EBER, helps confirm the nature of EBV-positive cells, as in our cases. Finally, deserving of mention is the genuine EBV-associated IPT of the colon reported by Gong et al.5Gong S. Auer I. Duggal R. et al.Epstein-Barr virus-associated inflammatory pseudotumor presenting as a colonic mass.Hum Pathol. 2015; 46: 1956-1961Crossref PubMed Scopus (21) Google Scholar The lesion is composed of bland spindle cells associated with a dense lymphoplasmacytic infiltrate containing lymphoid follicles. Immunohistochemically, the spindle cells are positive for smooth muscle actin but negative for ALK-1 and all conventional FDC markers tested (CD21, CD23 and CD35), and are co-labelled by smooth muscle actin and EBER-ISH. Although the spindle cells in a subset of EBV-positive IPT-like FDC tumours are negative for conventional FDC markers (CD21, CD23, and CD35), they may be labelled with novel markers for FDC such as D2-40, clusterin and fascin.8Denning K.L. Olson P.R. Maley R.H. Jr. et al.Primary pulmonary follicular dendritic cell neoplasm: a case report and review of the literature.Arch Pathol Lab Med. 2009; 133: 643-647PubMed Google Scholar,9Kazemimood R. Saei Hamedani F. Sharif A. et al.A rare case of Epstein-Barr virus negative inflammatory pseudotumor-like follicular dendritic cell sarcoma presenting as a solitary colonic mass in a 53-year-old woman; case report and review of literature.Appl Immunohistochem Mol Morphol. 2017; 25: e30-e33Crossref PubMed Scopus (12) Google Scholar Thus, we concur with the idea proposed by Kiryu et al. that EBV-positive IPT and IPT-like FDC tumours are probably of the same disease entity.10Kiryu S. Takeuchi K. Shibahara J. et al.Epstein-Barr virus-positive inflammatory pseudotumour and inflammatory pseudotumour-like follicular dendritic cell tumour.Br J Radiol. 2009; 82: e67-e71Crossref PubMed Scopus (26) Google Scholar We also suggest that EBV infection might down-regulate the expression of conventional FDC markers in some cases of IPT-like FDC tumours. More studies are warranted to clarify this concept. In conclusion, we reported a rare case of EBV-positive IPT-like FDC tumour presenting as a colonic polyp, which mimicked EBV-LPD due to dense plasmacytic infiltration and inconspicuous FDCs. IPT-like lesions may encompass several disease entities such as mycobacterial pseudotumour, resolved abscess, inflammatory myofibroblastic tumour, and IPT-like FDC tumour. A high index of suspicion is the key to reach the right diagnosis and so is the appreciation that IPT-like FDC tumour is not restricted to the liver and spleen. In addition to the characteristic naked/bilobed nuclei, FDC markers and EBER-ISH, and double staining to confirm the nature of EBV-positive cells also helps establish a correct diagnosis. The authors state that there are no conflicts of interest to disclose.