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• W3049273385 abstract "Extranodal inflammatory pseudotumour-like follicular dendritic cell (FDC)/fibroblastic reticular cell (FRC) sarcoma is a rare neoplasm with morphological and immunophenotypical features of FDCs/FRCs. It is a subset of FDC sarcoma (FDCS), the distinguishing features being the consistent association with Epstein–Barr virus (EBV) and accompanying rich lymphoplasmacytic infiltrate. EBV-positive inflammatory FDCS (EBV+ iFDCS) was recently included in the 2019 WHO Classification of Digestive System Tumours.1WHO Classification of Tumours Editorial BoardWHO Classification of Tumours.Digestive System Tumours. 5th ed. IARC, Lyon2019Google Scholar There are <50 reported cases, and almost all involve the liver and spleen, one in the pancreas,2Mograbi M. Stump M.S. Luyimbazi D.T. Shakhatreh M.H. Grider D.J. Pancreatic inflammatory pseudotumor-like follicular dendritic cell tumor.Case Rep Pathol. 2019; 2019: 2648123PubMed Google Scholar and two described in the colon.3Pan S.T. Cheng C.Y. Lee N.S. Liang P.I. Chuang S.S. 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,4Gong S. Auer I. Duggal R. Pittaluga S. Raffeld M. Jaffe E.S. Epstein-Barr virus- associated inflammatory pseudotumor presenting as a colonic mass.Hum Pathol. 2015; 46: 1956-1961Crossref PubMed Scopus (21) Google Scholar Given its rarity in the colon and inflammatory cell-rich infiltrate predominating over the inconspicuous EBV+ spindle cells, recognition of this lesion presents a diagnostic challenge, especially in biopsies. We report a rare case of EBV+ iFDCS presenting as a colonic polyp and discuss the diagnostic pitfalls for inflammatory cell-rich colonic polyps. A 46-year-old woman was admitted for symptomatic anaemia (Hb 6.4 g/dL). Computed tomography (CT) of the abdomen and pelvis showed colo-colic intussusception. Colonoscopy revealed a hepatic flexure polyp. Haematoxylin and eosin (H&E) of the biopsy with extensive immunohistochemistry (IHC) disclosed vague fascicles of EBV+ spindle cells which were variably immunoreactive for CD21, CD23, CD35, SMA, D2-40 and clusterin, accompanied by a dense mixed inflammatory infiltrate of CD20/CD79/PAX5+ B cells, CD3/CD5/CD2/CD7/CD43+ T-cells, CD138+ plasma cells and CD68/CD163+ macrophages. EBV+ iFDCS was suspected. She opted for surgery over endoscopic resection. Her right hemicolectomy specimen (Fig. 1A) confirmed a 4 cm hepatic flexure polypoid tumour and several enlarged lymph nodes. Histology of the polyp revealed lamina propria expansion by B- and T-lymphocytes, macrophages, eosinophils and a predominance of plasma cells. The lesional EBV+ spindle cells were vastly outnumbered by inflammatory cells (Fig. 1B). They demonstrated oval vesicular nuclei, fine chromatin and poorly defined cell borders. Some manifested paired nuclei, reminiscent of FDCS. Nuclear atypia varied from minimal to moderate. Submucosal extension was not identified. Immunohistochemically, the EBV+ spindle cells displayed patchy expression of various FDC markers: CD21, CD23, clusterin, CD35, D2-40 (in decreasing order of immunoreactivity), diffuse SMA and focal MSA/HHF35 expression (Fig. 1C). S100, CD34, ALK, desmin, CD117, CD10, CD68, CD163 were negative. A few reactive follicles with CD20/CD79a/PAX5+, CD10+, BCL2–, high Ki-67 germinal centres were present. CD3, CD5 highlighted numerous non-atypical small to medium sized interfollicular T-cells, which were EBER and CD56 negative. Double immunolabelling with EBER and SMA, HHF35/MSA, CD21, CD23, CD68, CD163, CD3, CD20 confirmed co-expression of EBER/SMA (Fig. 1D), EBER/MSA, EBER/CD21 (Fig. 1E), EBER/CD23 in the spindle cells; no co-expression was observed for EBER/CD68, EBER/CD163, EBER/CD20, EBER/CD3. Kappa and lambda in situ hybridisation (ISH) revealed polyclonal plasma cells (4:1 ratio). There was a marked increase in IgG4+ cells (240/HPF), and an elevated IgG4:IgG ratio (70%) (Fig. 1G,H). Other features of IgG4-related disease such as obliterative phlebitis and storiform fibrosis were absent. Increased IgG4+ cells and IgG4:IgG ratio were also observed in the enlarged lymph nodes (Fig. 1F), which demonstrated foci of Castleman disease-like regressive follicular changes such as lymphocyte depleted germinal centres containing hyalinised material penetrated by hyalinised vessels. There was no atypical EBV+ FDC proliferation in the lymph nodes. The FDC meshworks were not expanded and EBER-ISH highlighted rare EBV+ small lymphocytes in the interfollicular region. The patient's anaemia resolved post-colectomy. Her post-operative serum IgG4 was raised (2.08 g/L, reference range 0.04–1.57). However, there were no clinico-radiological findings to suggest IgG4-related disease. She remains well, without disease recurrence 5 months post-operatively. The clinical and pathological characteristics of colonic EBV+ iFDCS, including the current case, are summarised in Table 1. All occurred in women and were right-sided polypoid mucosal limited lesions. Unlike liver and spleen cases, necrosis and granulomas were absent. EBV+ spindle cells were SMA+ in all three cases, while two were variably immunoreactive with a panel of FDC markers. The colonic lesions pursued an indolent course following polypectomy or resection. No recurrences were reported, although evidently a longer follow-up is required. Liver and spleen cases have a reported recurrence rate of ∼10%.5Chen Y. Shi H. Li H. Zhen T. Han A. Clinicopathological features of inflammatory pseudotumour-like follicular dendritic cell tumour of the abdomen.Histopathology. 2016; 68: 858-865Crossref PubMed Scopus (31) Google ScholarTable 1Clinical and pathological characteristics of colonic EBV+ inflammatory follicular dendritic cell sarcomaPan et al.,3Pan S.T. Cheng C.Y. Lee N.S. Liang P.I. Chuang S.S. 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 2014Gong et al.,4Gong S. Auer I. Duggal R. Pittaluga S. Raffeld M. Jaffe E.S. Epstein-Barr virus- associated inflammatory pseudotumor presenting as a colonic mass.Hum Pathol. 2015; 46: 1956-1961Crossref PubMed Scopus (21) Google Scholar 2016Current caseAge, gender78, female42, female46, femaleClinical presentationAbdominal discomfort, bloody stool; mild anaemia Hb 10 g/dLIncidental colonoscopy finding following appendicectomySymptomatic anaemia (Hb 6.4 g/dL, dizziness, breathlessness, lethargy); colo-colic intussusceptionColonoscopy findings3 cm pedunculated polyp in transverse colon4.5 cm broadly pedunculated polyp in ascending colon4 cm broadly pedunculated polyp at hepatic flexureTreatmentPolypectomyPolypectomyBiopsy, followed by right hemicolectomyH&E findings: Epithelioid granulomasNoneNoneNone NecrosisNoneNoneNoneIHC: FDC markersCD21+, CD23+, CD35+, D2-40+CD21–, CD23–, CD35–CD21+, CD23+, CD35+, D2-40+, clusterin+ FRC markersSMA+SMA+SMA+, MSA/HHF35+IgG4+ plasma cells and IgG4:IgG ratioNot mentionedNot increasedIncreasedRegional lymph nodes––Castleman disease-likeFollow-upDisease free after 5 monthsDisease free after undisclosed periodDisease free after 5 monthsFDC, follicular dendritic cell; FRC, fibroblastic reticulum cell; H&E, haematoxylin and eosin; Ig, immunoglobulin; IHC, immunohistochemistry; MSA, muscle specific actin; SMA, smooth muscle actin. Open table in a new tab FDC, follicular dendritic cell; FRC, fibroblastic reticulum cell; H&E, haematoxylin and eosin; Ig, immunoglobulin; IHC, immunohistochemistry; MSA, muscle specific actin; SMA, smooth muscle actin. Its rarity in the colon and predominance of inflammatory cells over inconspicuous EBV+ lesional cells make EBV+ iFDCS a diagnostic challenge, especially in biopsies. This is compounded by the patchy, variable expression of lesional cells for FDC and/or FRC markers. As such, application of a panel of FDC (CD21, CD23, CD35, clusterin, D2-40, CXCL13, CAN.42) and FRC (SMA, MSA/HHF35) markers, together with EBER is necessary. Double immunolabelling of EBER with FDC/FRC, B- and T-cell markers will also be helpful in delineating the lesional EBV+ population. The term ‘inflammatory pseudotumour’ is non-specific and encompasses lesions as diverse as inflammatory myofibroblastic tumour (IMT), inflammatory fibroid polyp (IFP), IgG4-related disease to tumefactive lesions associated with infections, trauma, autoimmunity, to the rare EBV+ iFDCS. Morphologically, the dense lymphoplasmacytic infiltrate raised concern for lymphoproliferative diseases in which EBV+ cells can be found such as immunodeficiency associated lymphoproliferations, lymphomatoid granulomatosis, angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma. These were excluded by double immunolabelling of EBER with various FDC, B- and T-cell markers, the lack of atypia and immunophenotypic aberrancy in B- and T-cell populations. IMT, a clonal neoplasm comprising lesional spindle cells with a rich admixture of lymphocytes and plasma cells, presents a morphological mimic of EBV+ iFDCS. In 35–60% of cases, the lesional cells are ALK IHC+ and 50% manifest the ALK translocation. Immunophenotypically, spindle cells of IMTs express SMA, but not FDC markers, and are usually EBER negative. IFP, another morphological mimic, is often centred in the submucosa.1WHO Classification of Tumours Editorial BoardWHO Classification of Tumours.Digestive System Tumours. 5th ed. IARC, Lyon2019Google Scholar The spindle cells are immunoreactive with CD34 and platelet derived growth factor receptor alpha (PDGFRA), occasionally with SMA, and typically negative for FDC markers and EBER. Eosinophils are the predominant inflammatory cells. It may feature small to intermediate sized blood vessels with concentric onion skin fibrosis, which is absent in EBV+ iFDCS. EBV+ iFDCS with less dense inflammatory cell accompaniment and a more prominent spindle cell component may raise consideration for spindle cell gastrointestinal tract tumours such as gastrointestinal stromal tumours (GIST), smooth muscle tumours (including EBV related smooth muscle tumour), neural tumours, perineurioma, inflammatory myoglandular polyp,6Grech P. Schofield J.B. Spindle cell proliferations of the sigmoid colon, rectum and anus: a review with emphasis on perineurioma.Histopathology. 2020; 76: 342-353Crossref PubMed Scopus (2) Google Scholar the discussion of which is beyond this review. Other less common differentials include interdigitating dendritic cell sarcoma (IDCS) and conventional FDCS (cFDCS). The lymphoplasmacytic inflammatory infiltrate in these is typically sparse and spindle cells tend to predominate. Both are usually not associated with EBV. The spindle cells in IDCS are S100-positive and FDC antigen-negative. The distinction between cFDCS and EBV+ iFDCS is important, as intra-abdominal cFDCS exhibits more aggressive behaviour,5Chen Y. Shi H. Li H. Zhen T. Han A. Clinicopathological features of inflammatory pseudotumour-like follicular dendritic cell tumour of the abdomen.Histopathology. 2016; 68: 858-865Crossref PubMed Scopus (31) Google Scholar,7Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. IARC, Lyon2017: 585Google Scholar is capable of metastases (4/18 patients, 22%) and local recurrence (6/18 patients, 33%) within 1–84 months post-surgery.8Agaimy 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 Given the plasma cell-rich infiltrate of EBV+ iFDCS, IgG4-related disease presents a differential diagnosis. Literature pertaining to gastrointestinal tract IgG4-related disease mostly describes pancreatohepatobiliary lesions, and ‘reported cases with disease in the tubular gut are generally met with a healthy dose of skepticism’.9Deshpande V. Igg4-related disease of the gastrointestinal tract: a 21st century chameleon.Arch Pathol Lab Med. 2015; 139: 742-749Crossref PubMed Scopus (29) Google Scholar Interestingly, our patient had elevated IgG4+ cells and IgG4:IgG ratio on histology which met the recommended thresholds of ≥10 IgG4+ plasma cells/HPF and IgG4:IgG ratio of ≥40% in both the colonic lesion and regional lymph nodes, and elevated serum IgG4. However, there was no obliterative phlebitis, storiform fibrosis and no clinico-radiological evidence of IgG4-related disease. A case series on splenic EBV+ iFDCS documented increased IgG4+ plasma cells (6/6 cases, 100%), increased IgG4:IgG ratio (4/6, 66.7%), with obliterative vasculitis (3/6, 50%) and sclerosis (4/6, 66.7%), suggesting a possible association between EBV+ iFDCS and IgG4-related disease.10Choe J.Y. Go H. Jeon Y.K. et al.Inflammatory pseudotumor-like follicular dendritic cell sarcoma of the spleen: a report of six cases with increased IgG4-positive plasma cells.Pathol Int. 2013; 63: 245-251Crossref PubMed Scopus (49) Google Scholar Serum IgG4 was not able to be checked in that series and the patients lacked other evidence of IgG4-related disease. IgG4+ cells were not increased in one of the two previously reported cases of colonic EBV+ iFDCS4Gong S. Auer I. Duggal R. Pittaluga S. Raffeld M. Jaffe E.S. Epstein-Barr virus- associated inflammatory pseudotumor presenting as a colonic mass.Hum Pathol. 2015; 46: 1956-1961Crossref PubMed Scopus (21) Google Scholar and unknown in the other case.3Pan S.T. Cheng C.Y. Lee N.S. Liang P.I. Chuang S.S. 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 Hence, it would appear that EBV+ iFDCS is another lesion that may be associated with increased IgG4+ plasma cells and increased IgG4:IgG ratio. A relationship with IgG4-related disease remains to be proven. EBV, rather than FDCs, may be the link driving increased IgG4 production, as proposed in a study investigating EBV reactivation in Graves' disease and IgG4 production.11Nagata K. Hara S. Nakayama Y. et al.Epstein-Barr virus lytic reactivation induces IgG4 production by host B lymphocytes in Graves' disease patients and controls: a subset of Graves' disease is an IgG4-related disease-like condition.Viral Immunol. 2018; 31: 540-547Crossref PubMed Scopus (10) Google Scholar Lymphocytes in Graves' disease patients and controls were cultured and subjected to EBV reactivation. EBV reactivated cells were found to express surface IgG4, and IgG4:IgG ratio in culture fluids of both Graves' patients and controls were higher than normal serum levels. This suggests EBV contributes to IgG4 production both in local thyroid tissue (7/11 resected thyroids for Graves' disease fulfilled histological criteria of increased IgG4+ cells and/or IgG4:IgG ratio) and in circulation (increased IgG4 levels in culture medium post-EBV reactivation). In conclusion, this is the third reported case of colonic EBV+ iFDCS. Its diagnosis hinges on the demonstration of FDC and/or FRC markers in EBV+ spindle cells and an awareness that such lesions are not limited to the liver and spleen. Given the patchy, variable expression of the lesional cells for FDC and/or FRC markers, a panel of these markers should be applied together with EBER, and double immunolabelling of EBER with FDC/FRC, B- and T-cell markers may help in delineating the EBV+ population. So far, all three cases have occurred in the right colon, in women, and followed an indolent course. Further studies are required to investigate its possible association (if any) with IgG4-related disease. Currently, no association has been found and the increase in tissue IgG4+ plasma cells and IgG4:IgG ratio, and elevated serum IgG4 levels, may be related to EBV-induced IgG4 production." @default.
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• W3049273385 title "Beware the inflammatory cell-rich colonic polyp: a rare case of EBV-positive inflammatory pseudotumour-like follicular dendritic cell sarcoma with increased IgG4-positive plasma cells" @default.
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