Perifollicular granulomatous inflammation in reactive lymph nodes: a possible morphologic marker for IgG4 plasmacytosis

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1 J Hematopathol (2011) 4: DOI /s ORIGINAL ARTICLE Perifollicular granulomatous inflammation in reactive lymph nodes: a possible morphologic marker for IgG4 plasmacytosis Imran N. Siddiqi & Russell K. Brynes & Kate Grimm & Dennis P. O Malley & Endi Wang Received: 19 July 2011 / Accepted: 19 September 2011 / Published online: 12 October 2011 # Springer-Verlag 2011 Abstract IgG4-related sclerosing disease is a steroidresponsive syndrome of possible autoimmune origin that can manifest with mass-like lesions in a variety of organ sites. Lymph node involvement may clinically mimic malignant lymphoma, Castleman disease, or infectious lymphadenitis; consequently, accurate diagnosis is necessary to exclude other processes and to initiate steroid therapy appropriately. Histologically, a number of relatively nonspecific features have been associated with IgG4-related lymphadenopathy, mainly increased plasma cells in an interfollicular or intra-germinal center pattern. We describe seven lymph node cases with distinctive perifollicular granulomas, in a concentric or crescent-like arrangement, partially or completely encircling lymphoid follicles. This finding was specifically associated with a marked intragerminal center increase in IgG4-positive plasma cells, as compared to other patterns of nodal granulomas in a series of control cases. We discuss the clinicopathologic features of these cases, including an unusual presentation in a pediatric patient. This study adds to the morphologic spectrum of IgG4-related lymphadenopathy. I. N. Siddiqi (*) : R. K. Brynes Department of Pathology, University of Southern California Keck School of Medicine, 2011 Zonal Ave., HMR 209, Los Angeles, CA 90033, USA isiddiqi@usc.edu K. Grimm : D. P. O Malley Clarient Inc./GE Healthcare, Aliso Viejo, CA, USA E. Wang Department of Pathology, Duke University Medical Center, Durham, NC, USA Keywords IgG4 plasmacytosis. Plasma cell. Lymphadenopathy. Mikulicz s disease. Antinuclear antibodies Introduction IgG4-related sclerosing disease is a relatively recently described systemic syndrome characterized by organ infiltration by IgG4-positive plasma cells, often accompanied by fibrosis and elevated serum IgG4 levels [1]. This condition was first associated with autoimmune pancreatitis [2] but subsequently expanded to encompass pathologic conditions seen in a variety of organ sites, including bile ducts (sclerosing cholangitis), soft tissue (retroperitoneal fibrosis), salivary glands (Mikulicz s disease), ocular adnexa (sclerosing dacryoadenitis), lung, breast, prostate, kidney, and the pituitary gland (lymphocytic hypophysitis) [1, 3, 4]. Indeed, the list of affected organ sites and associated conditions continues to expand, encompassing many previously described idiopathic and inflammatory conditions. The pathogenesis of IgG4-related sclerosing disease has not yet been fully elucidated, but it is thought to have an autoimmune basis. IgG4 is a rare subclass of IgG, normally accounting for 3% to 6% of total serum IgG [2]. Increase in serum IgG4 levels (>135 mg/dl) is typically associated with a pathologic process, though serum elevation is not independently specific for IgG4-related systemic disease [5], nor do all patients with IgG4-related disease demonstrate increased serum IgG4 [3]. Elevated IgG4 is often accompanied by other markers, such as increased serum IgE and the presence of antinuclear antibodies. Lymphadenopathy frequently occurs in IgG4-related disease, either in combination with other organ manifestations or as an isolated finding. Lymphadenopathy can be

2 208 J Hematopathol (2011) 4: diffuse and may clinically mimic lymphoma. IgG4-related lymphadenopathy is characterized by interfollicular and/or intra-germinal center plasmacytosis. Based on a limited number of studies, these features are typically present in the context of five main histologic patterns: follicular hyperplasia, progressive transformation of germinal centers (PTGC), interfollicular expansion, immunoblastic hyperplasia, and/or inflammatory pseudotumor-like changes [3, 6 8]. Interfollicular plasmacytosis can be subtle or profound, raising the possibility of plasma cell variant of Castleman disease, rheumatoid arthritis-associated or syphilis-associated (luetic) lymphadenopathy. Intragerminal center plasma cells are most often seen in a background of marked follicular hyperplasia, often with PTGC; the plasma cells in these cases can often be overlooked. Additional histologic features, including capsular and interfollicular fibrosis, eosinophilia, and increased paracortical vascularity may also be seen. As in other organs, pathologic diagnosis of IgG4-related disease in lymph nodes relies on recognition of these vaguely defined histologic features, followed by immunohistochemical staining for IgG4 and IgG, and exclusion of other processes [9]. Increased IgG4-positive plasma cells, defined as an IgG4/IgG ratio above 40% and greater than 50 cells per high-power-field, have been used as diagnostic criteria for this syndrome [3] and should generally be followed up by serum IgG4 studies and a trial of steroids. Given the steroid-responsiveness of this syndrome, accurate and timely recognition is important particularly as the masslike lesions often mimic neoplastic processes. Nonetheless, without well-defined criteria, the relatively nonspecific histologic features make it difficult to determine when IgG4 immunohistochemical staining is indicated. We report seven cases of lymphadenopathy with increased IgG4-positive plasma cells that exhibit distinctive concentric or crescent-like perifollicular granulomas, often in the absence of well-developed features typically associated with IgG4-related lymphadenopathy. Our findings expand the list of morphologic features that should raise suspicion for IgG4-related lymphadenopathy. Materials and methods Case selection The index case (case 1, Table 1) was identified after immunohistochemical staining for IgG4 based on recognition of follicular hyperplasia, capsular fibrosis, and increased interfollicular and intra-germinal center plasma cells, features previously associated with IgG4 lymphadenopathy. This case additionally demonstrated a distinctive morphologic finding of perifollicular granulomas. We therefore performed a retrospective search for lymph nodes with potential perifollicular granulomatous or histiocytic infiltrates (cases 2, 4) as well as prospective identification of cases with this finding (cases 3, 6, 7). To determine the specificity of this histologic feature in predicting IgG4 plasmacytosis, additional cases of granulomatous lymphadenitis were randomly selected and analyzed for the presence of perifollicular granulomatous inflammation and increased IgG4-positive plasma cells. Cases with reactive follicles, architectural preservation, and peri- or interfollicular granulomas were included, while lymph nodes with extensive granulomatous inflammation or coalescent noncaseating granulomas (e.g., sarcoidosis) were excluded from this analysis, as these would not cause diagnostic confusion with IgG4-related lymphadenopathy. Of the additional 15 cases identified in this fashion, one (case 5) was identified as having IgG4 plasmacytosis, while the remaining 14 cases lacked increased IgG4-positive plasma cells and thus served as control cases. Cases 2, 4, and 5 were previously diagnosed as florid reactive follicular hyperplasia with nonnecrotizing granulomas. Cases were retrieved from the pathology files at the University of Southern California, Duke University Medical Center, and Clarient Inc./GE Healthcare (Aliso Viejo, CA). The research was performed in accordance with institutional research protocols. Histologic and immunohistochemical studies Lymph nodes and other tissues were fixed in formalin or B-5. All specimens were then processed routinely, embedded in paraffin, sectioned, and stained with hematoxylin and eosin (H&E). We immunostained 4-μm sections from paraffinembedded blocks with CD138 (DAKO), κ light chain (polyclonal antibody, DAKO), λ light chain (polyclonal antibody, DAKO), IgG (rabbit polyclonal, DAKO), and IgG4 (Invitrogen, Carlsbad, CA), using the streptavidin biotin complex method. All cases were stained with acid fast and GMS to exclude the presence of microorgansims. Case 1 was also immunostained for spirochetes (Treponema pallidum, polyclonal; BioCare). The corresponding positive and negative control slides for each antibody stain were carefully examined for quality assurance purposes. The numbers of IgG4-positive plasma cells and IgG4/ IgG ratios were determined in areas with the highest density of positive cells, using five separate high-power fields, similar to methodology described by Sato et al. [7]. Results Seven lymph nodes in total were identified that demonstrated increased IgG4-positive plasma cells and perifollicular granulomatous inflammation (Table 1). One of these

3 J Hematopathol (2011) 4: Table 1 Clinicopathologic features of lymph node cases with perifollicular granulomas and increased IgG4 plasma cells Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Clinical features Age/sex 47/M 63/M 50/F 34/M 12/M 58/M 83/M Medical history DM Colon cancer 10 years ago, CAD Lymph node site and duration (if known) Allergies Unknown Asthma Hodgkin lymphoma 18 years ago Unknown Cervical 3 months Axillary Cervical 2 years Cervical Cervical 7 years Unknown Axillary Extent of lymphadenopathy Bilateral cervical Diffuse (axillary, inguinal, pelvic) Bilateral cervical Unknown Single site Unknown Unknown Histologic features Fibrosis Marked None Mild None None None Mild Follicular hyperplasia Marked Marked Marked Marked Marked Marked Marked Interfollicular hyperplasia Moderate Mild Marked Mild Mild Moderate Marked Immunoblastic proliferation Mild Mild Moderate Mild Moderate Mild Mild Vascular proliferation Moderate Mild Moderate Mild Mild Mild Mild Eosinophils Mild None Minimal None Mild None Mild Plasma cells Interfollicular Moderate Mild Moderate Moderate Moderate Moderate Moderate Intragerminal center Moderate Moderate Moderate Moderate Moderate Moderate Moderate PTGC Focal Focal Focal None Focal Focal Focal Perifollicular granuloma Concentric Concentric Concentric Crescent-like Crescent-like Crescent-like Concentric and crescent-like Distribution pattern of IgG4-positive plasma cells Intra-germinal center and interfollicular Intra-germinal center Intra-germinal center and interfollicular Intra-germinal center Intra-germinal center Intra-germinal center and interfollicular IgG4/IgG ratio 70% 70% 50% 60% 70% 70% 70% Intra-germinal center and interfollicular DM diabetes mellitus, CAD coronary artery disease, PTGC progressive transformation of germinal centers

4 210 J Hematopathol (2011) 4: (case 5) was identified following a retrospective search for lymph nodes with unspecified types of granulomatous inflammation, representing one of 15 cases. The remaining 14 cases in the latter group (control group) displayed varying patterns of histiocytic infiltrates and/or granulomas but without the characteristic perifollicular granulomatous inflammation or an increase in IgG4-positive plasma cells. Clinical features Limited clinical information was available (Table 1). Among the IgG4-positive cases, patient ages ranged from 12 to 83 years of age with median of 50 years (mean age of adults, 56 years); there were six males and one female. Sites of involvement included cervical and axillary lymph nodes (four and two patients, respectively). None of the patients had constitutional symptoms. Cases 2 and 3 had PET scan results available, and both showed low uptake in the involved sites. The patient in case 3 had a positive antinuclear antigen (1:1,280), and lactate dehydrogenase levels were normal in case 2. One of these patients (case 3) had serum IgG subclass data available, which demonstrated an increased serum IgG4 level of mg/dl (reference range 4 to 86), while total IgG, IgG1, IgG2, and IgG3 levels were in the normal range. Due to the referral and/or retrospective nature of the remaining cases, serum IgG4 levels were not available on the other patients. Case 5 represents an unusual pediatric patient with IgG4 plasmacytosis. This patient was a 12-year-old African American boy with a history of poorly controlled asthma and chronic cervical lymphadenopathy, which was first noted at the age of 6. He had no evidence of immunodeficiency. He received inhaled steroids for his asthma, but it was unclear if he received high dose oral steroids. The lymph node enlarged intermittently and persisted in spite of antibiotics. He had no systemic symptoms, fever, or weight loss. Laboratory workup revealed normal angiotensin converting enzyme, C3, C4, erythrocyte sedimentation rate, and C-reactive protein levels; antinuclear antigen titer was not increased. An extensive infectious disease workup was negative, including serologic testing for cat scratch disease, Lyme disease, HIV, and cytomegalovirus. Immunoglobulin levels (IgG, IgA, IgM, IgE) were normal, except for an elevated IgE at 896 IU/ml. IgG subclass values were not determined. Of 14 control cases, seven were male and seven female. Ages ranged from 2 to 71 with median of 49 years. Eight cases had a single site of lymphadenopathy, while the remaining six had more than one enlarged lymph node. Lymph nodes included five cervical, two post-auricular, and seven other lymph node sites. Four patients had a past history of malignancy, one had allogeneic bone marrow transplant for sickle cell disease, one had clinical history of asthma/ulcerative colitis, and the remaining eight had no known prior history. All except one case did not manifest systemic symptoms. The duration of lymphadenopathy prior to nodal excision ranged from 1 to 12 months with median of 2 months. Pathologic findings IgG4-positive cases The index case (case 1) demonstrated a constellation of histologic findings, which were nonspecific but raised suspicion for IgG4-associated lymphadenopathy, including follicular hyperplasia, focal PTGC, interfollicular immunoblasts and scattered eosinophils, obliterative phlebitis, dense capsular fibrosis, and sclerotic bands containing a lymphoplasmacytic infiltrate (Fig. 1a c). Plasma cells were increased both within germinal centers as well as moderately in the interfollicular areas. The possibility of syphilis (luetic lymphadenitis) was considered in this case but was considered clinically unlikely and was not supported by additional workup (see Immunohistochemical and special stains). The remaining six cases also demonstrated marked follicular hyperplasia (6/6) and most also showed focal PTGC (5/6). Plasma cells were mildly to moderately increased in the interfollicular areas, without clustering. Intra-germinal center plasma cells were increased but were not conspicuous on the H&E-stained sections. In contrast to the index case, other features typically associated with IgG4-related lymphadenopathy, including eosinophil infiltration, stromal vascular proliferation, fibrosis, and/or phlebitis were either absent or mild in these cases. Perifollicular granulomatous inflammation was present in all seven cases, seen in approximately two to three follicles per section. Granulomas were closely apposed to follicles, completely or partially surrounding the outer mantle zones. In four cases (cases 1, 2, 3, and 7), the granulomas surrounded the entire follicle, a finding particularly prominent and appreciable at low power in cases 2, 3, and 7 (Fig. 2a, b). Granulomas partially surrounded follicles in the three remaining cases, with an elongated, crescent-like formation, following the contours of the outer mantle zone rim (Fig. 2c). On higher power, the granulomas consisted of epithelioid histiocytes with abundant pink cytoplasm (Fig. 2d). Focal nuclear palisading was noted, and occasional multinucleated giant cells were interspersed (Fig. 2e). None of the perifollicular granulomas penetrated the mantle zones, nor did any encroach on germinal centers, as is typically seen in Toxoplasma lymphadenitis (see below). Immunohistochemical and special stains IgG staining demonstrated both interfollicular plasma cells as well as intra-germinal center plasma cells. The

5 J Hematopathol (2011) 4: Fig. 1 Index case (case 1). The lymph node shows dense capsular fibrosis and sclerotic bands (a, H&E 40). At higher power, the sclerotic areas contain a lymphoplasmacytic infiltrate (b, H&E 400). Interfollicular regions are expanded by a mixed population of immunoblasts, lymphocytes, plasma cells, and eosinophils (c, H&E 400). Obliterative phlebitis is also noted (inset, H&E 400). Some of the follicles are surrounded by a concentric ring of epithelioid histiocytes (d, H&E 100). Immunohistochemical staining demonstrates an increase in interfollicular and intra-germinal center plasma cells, with approximately 70% IgG4/IgG ratio in the follicles (e IgG and f IgG4, respectively, 40) majority of IgG-positive plasma cells were also IgG4- positive (50 70%, Fig. 1e, f). While IgG-positive cells were seen in both interfollicular and intra-germinal center distributions in all cases, IgG4-positive plasma cells were predominantly localized within germinal centers, most often concentrated at the periphery of the germinal centers. In three cases, the pattern was almost exclusively intra-germinal center (Fig. 2e), while four cases had a moderate number of interfollicular IgG4-positive plasma cells as well (Fig. 2f). The numbers of IgG4-positive plasma cells were variable among the follicles, but multiple foci with greater than 50 per high-power field

6 212 J Hematopathol (2011) 4: Fig. 2 Pathologic features of perifollicular granulomas associated with IgG4 plasmacytosis. The granulomas surround follicles without infiltration of the mantle zones. Prominent concentric granulomas surround follicles (a Case 2, H&E, 40; b Case 3, H&E, 40) in a background of follicular hyperplasia. In some cases, crescent-shaped granulomas partially surround follicles, following the contours of the outer mantle zone (c Case 4, H&E 100). On high power, the granulomas consist of epithelioid histiocytes with focal nuclear palisading and occasional multinucleated giant cells (d Case 2, H&E 400). Immunohistochemical staining for IgG4 demonstrates a marked increase in IgG4-positive plasma cells, in an intra-germinal center pattern (e Case 4 100) or a mixed interfollicular and intragerminal center pattern (f Case 7 100) were easily found in all cases. Kappa and lambda stains demonstrated polyclonal plasma cells in all cases. Acidfast and silver stains were performed in each case and were negative for microorganisms. Due to morphologic features suggestive of luetic lymphadenitis in the index case (capsular fibrosis with plasma cells, phlebitis, and interfollicular plasma cells), a Warthin Starry stain and an immunohistochemical stain for spirochetes were performed and were negative for microorganisms. Additional immunohistochemical stains were also performed as appropriate to exclude lymphoma. Control cases The 14 control granulomatous lymphadenitis cases included three cases of Toxoplasma lymphadenitis, two cases of Bartonella henselae infection (cat scratch disease), one Mycobacterium avium intracellulare lymphadenitis, and eight cases with granulomas of unknown cause. While granulomas or histiocytic infiltrates were prominent in all control cases, none demonstrated the distinctive perifollicular pattern seen in the IgG4-positive cases. The granulomas were present in the interfollicular areas, separated from lymphoid follicles, except for the three Toxoplasma cases, in which granulomas were associated with follicles. However, in contrast to the perifollicular granulomas seen in the IgG4-positive cases, which were confined and contoured around the outer mantle zones, Toxoplasma lymphadenitis cases demonstrated granulomas infiltrating the mantle zone, with frequent clusters of epithelioid histiocytes within germinal centers. All three cases of Toxoplasma lymphadenitis in addition showed focal collections of monocytoid lymphocytes in the paracortical areas. While follicular hyperplasia was evident in most of the control cases (12/ 14), only one showed focal PTGC. Interfollicular plas-

7 J Hematopathol (2011) 4: macytosis was mild to moderate (12/14 cases), while intra-germinal center plasmacytosis was found in only three cases. Immunohistochemical staining IgG and IgG4 staining was performed in all control cases. No increase in IgG4-positive plasma cells (<5% IgG4/IgG ratio) was seen in any of these cases. Discussion IgG4-related sclerosing disease was originally described in association with autoimmune pancreatitis but subsequently shown to affect a variety of extrapancreatic sites. Indeed, pancreatic disease is no longer considered a criterion for diagnosis, and extrapancreatic manifestations may precede or follow pancreatitis by as much as 15 years [3, 10]. Among extrapancreatic sites of involvement, lymph node involvement is relatively common but can often be overlooked due to the lack of clinical suspicion in isolated cases and absence of well-defined morphologic criteria. Based on a limited number of studies, lymphadenopathy of IgG4-related disease has been divided into a number of heterogeneous patterns, including plasma cell Castleman disease-like, follicular hyperplasia, and interfollicular expansion by plasma cells and immunoblasts [8]. As these features are nonspecific and can be encountered in a variety of reactive lymphadenopathies, more specific criteria would be helpful to develop a systematic approach to these biopsies. In this regard, we have presented findings on seven lymph node cases with a marked increased in IgG4-positive plasma cells, mainly in an intra-germinal center pattern. We confirm that marked follicular hyperplasia and focal PTGC are highly associated with increased IgG4-positive plasma cells, similar to what has been described previously in the follicular hyperplasia subtype. Follicular hyperplasia was observed in all of our cases, and all but one demonstrated PTGC. Other features were less apparent, and while intragerminal center plasmacytosis was present in all cases, this feature was inconspicuous on the H&E-stained sections and often identified only by immunohistochemical stains. Indeed, in three of our cases, plasmacytosis was not recognized, and these cases were originally diagnosed as nonspecific, reactive follicular hyperplasia. In contrast, each of our cases had a distinctive pattern of perifollicular granulomatous inflammation, a finding that we found to be specifically associated with IgG4 plasmacytosis. Granulomatous inflammation is a delayed type hypersensitivity reaction, representing a complex process of macrophage recruitment and organization, controlled by numerous cytokines, T cells, and other mediators [11]. As in other sites, granulomatous inflammation in lymph nodes has a long list of causes, and these can often be distinguished based on the morphologic appearance of the granulomas or pattern of histiocytic infiltrates. Well-known examples include caseating granulomas of tuberculosis or fungal infection, stellate microabscesses of cat-scratch lymphadenitis, sharply demarcated, non-caseating granulomas of sarcoidosis, and epithelioid histiocytes encroaching on or within germinal centers in Toxoplasma lymphadenitis. In contrast to these well-described patterns of nodal granulomas, the perifollicular granulomas seen in association with IgG4 plasmacytosis have a unique morphologic appearance. They consist of epithelioid histiocytes without caseation, arranged in a concentric or crescent-like arrangement at the periphery of follicles. In particular, as opposed to the histiocytic infiltrates of toxoplasmosis, which are also associated with follicles, the perifollicular granulomas of IgG4-related lymphadenopathy are more organized, ringlike, remain confined beyond the mantle zone, and do not show encroachment on germinal centers. Moreover, monocytoid B-cell clusters, which are quite characteristic of Toxoplasma lymphadenitis, are not a feature of IgG4- related lymphadenopathy. Of particular interest is case 5, which occurred in a 12- year-old boy with a 7-year history of lymphadenopathy. To our knowledge, IgG4-related disease has not been reported in the pediatric population. This finding suggests that the clinical spectrum of IgG4-related disease may be more widespread than previously suspected and may rarely occur in childhood. Increased histologic recognition is important for further identification of such patients and future clinicopathologic studies. The mechanism underlying perifollicular granulomas in IgG4-related disease remains to be elucidated and likely represents a complex response to an underlying immune dysregulation. Interestingly, clusters of epithelioid histiocytes are not uncommonly seen surrounding the neoplastic nodules of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL, formerly called Hodgkin paragranuloma). While cases of NLPHL with paragranulomas should not cause diagnostic confusion with IgG4-related disease, it is interesting to speculate on an etiologic association between these processes, since progressive transformation of germinal centers has been associated with both NLPHL and IgG4 lymphadenopathy. While the distinctive pattern of perifollicular granulomatous inflammation appears to be associated with increased IgG4-positive plasma cells, most patients with IgG4-related lymphadenopathy do not demonstrate this finding, and this feature has not been reported in most of the prior studies on IgG4-related lymphadenopathy. Of note, however, in a recent paper on the histopathologic

8 214 J Hematopathol (2011) 4: features of lymph nodes with increased IgG4-positive plasma cells, granulomas were noted in 3/29 cases (~10%) [12]. It may be of interest to compare the clinical features of IgG4-related disease patients with and without perifollicular granulomas. In summary, lymph nodes with marked follicular hyperplasia and the presence of perifollicular granulomas with concentric or crescent-like arrangement around follicles have a strong association with IgG4 plasmacytosis. In at least one patient where serologic information was available, perifollicular granulomas also correlated with markedly elevated serum IgG4 levels. Due to the retrospective nature of this study and the absence of follow-up information, the progression of disease and steroid responsiveness could not be determined in this cohort of patients, which is a limitation of this study. Thus, it remains to be established how specifically this finding is associated with clinically defined, systemic IgG4-related disease. One could argue that the perifollicular granulomas in these cases might be unrelated to the increase in IgG4-positive plasma cells or to the potential presence of IgG4-related disease. While this possibility cannot be entirely excluded, the striking specificity of this finding in relation to increased IgG4-positive plasma cells, our ability to prospectively identify cases with increased IgG4-positive plasma cells based on the presence of this feature, and the absence of any other identifiable cause of granuloma formation in these cases strongly suggest an etiologic association. At minimum, recognition of this morphologic feature should prompt further workup for IgG4-related disease, particularly given the potential steroid responsiveness of this condition. Conflict of Interest of interest. The authors declare that they have no conflict References 1. Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T (2010) IgG4-related disease: historical overview and pathology of hematological disorders. Pathol Int 60(4): Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa K (2001) High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344(10): Cheuk W, Chan JK (2010) IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol 17(5): Zen Y, Nakanuma Y (2010) IgG4-related disease: a crosssectional study of 114 cases. Am J Surg Pathol 34(12): Sah RP, Chari ST (2011) Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol 23(1): Shimizu I, Nasu K, Sato K, Ueki H, Akahane D, Sumi M, Ueno M, Ichikawa N, Asano N, Kojima M, Kobayashi H (2010) Lymphadenopathy of IgG4-related sclerosing disease: three case reports and review of literature. Int J Hematol 92(5): Sato Y, Kojima M, Takata K, Morito T, Asaoku H, Takeuchi T, Mizobuchi K, Fujihara M, Kuraoka K, Nakai T, Ichimura K, Tanaka T, Tamura M, Nishikawa Y, Yoshino T (2009) Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman s disease. Mod Pathol 22(4): Cheuk W, Yuen HK, Chu SY, Chiu EK, Lam LK, Chan JK (2008) Lymphadenopathy of IgG4-related sclerosing disease. Am J Surg Pathol 32(5): Smyrk TC (2011) Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol 23(1): Hamano H, Arakura N, Muraki T, Ozaki Y, Kiyosawa K, Kawa S (2006) Prevalence and distribution of extrapancreatic lesions complicating autoimmune pancreatitis. J Gastroenterol 41 (12): Co DO, Hogan LH, Il-Kim S, Sandor M (2004) T cell contributions to the different phases of granuloma formation. Immunol Lett 92(1 2): Grimm K, Barry TS, Chizhevsky V, Hii A, Weiss LM, Siddiqi I, Brynes RK, O Malley DP (2011) Histopathologic findings in 29 lymph node biopsies with increased IgG4 plasma cells. Mod Pathol (in press)