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Despite receiving rituximab‐combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA‐1‐60‐expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1‐positive population, and resist current B‐lymphoma agents. TRA‐1‐60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B‐lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA‐1‐60‐positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R‐CHOP)‐treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab‐treated FL cell lines, FL‐18 and DOHH2, wherein TRA‐positive cell numbers increased over 10‐fold compared to the untreated sample. Concordantly, scanty TRA‐1‐60‐positive FL‐18 cells implanted s.c. into mice evinced potent tumor‐initiating capacity in vivo, where tumors were 12‐fold larger in volume (P = 0.0021 < 0.005) and 13‐fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA‐negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA‐1‐60‐positive cells defined a distinct population from that of TRA‐negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA‐1‐60‐expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence. TRA‐1‐60 should be a prominent focus among cellular markers in follicular lymphoma research, by which we ultimately hope to explain clinical intractability against current rituximab‐combination and other therapies, and to better understand the unique population among a range of lymphoma cell types. [ABSTRACT FROM AUTHOR]

Pancreatic cancer has a poor prognosis; hence, novel prognostic markers and effective therapeutic targets should be identified. We aimed to evaluate folate receptor alpha (FR-α) expression in pancreatic cancer and examine its association with clinicopathological features. We utilized tissue samples from 100 primary pancreatic cancer patients who underwent surgery. FR-α was expressed in 37 of 100 cases (37%). The FR-α-positive group (median, 18.8 months) had a significantly poorer prognosis than the FR-α-negative group [median 21.3 months; HR 1.89 (1.12-3.12); P = 0.017]. These groups were not significantly different regarding progression-free survival (P = 0.196). Furthermore, other serum tumor markers including CA19-9 (mean, 186 vs. 822 U/ml; P = 0.001), Dupan-2 (286 vs. 1133 U/ml; P = 0.000), and Span-1 (69.7 vs. 171.9 U/ml; P = 0.006) were significantly downregulated in the FR-α-positive group. CA19-9 was another prognostic factor, in addition to FR-α, and patient prognosis showed clear stratification curves with the expression of these two molecules. Along with CA19-9, FR-α expression was an independent prognostic factor for the overall survival. FR-α and CA19-9 helped predict patient prognosis based on stratification curves. [ABSTRACT FROM AUTHOR]

Aims: Although the neoplastic cells of extranodal natural killer (NK)/T‐cell lymphoma (ENKTL) usually do not express T‐cell antigens, the T‐cell receptor (TCR) gene might be rearranged and TCR protein expressed. The aim is to elucidate the expression of the downstream TCR pathway components and their importance in ENKTL. Methods and results: We used formalin‐fixed paraffin‐embedded tissues from 91 ENKTL samples to immunohistochemically characterise the expression of TCR pathway components. The following proteins were variably expressed: ZAP70 (94%; 83/88), GRAP2/GADS (68%; 60/88), DOK2 (42%; 38/90), LCK (35%; 31/88), and ITK (10%; 9/90). When these tumours were classified as being of T lineage (16%), NK lineage (45%), or indeterminate lineage (38%), the GRAP2/GADS expression rate was higher in T lineage tumours (versus NK, P = 0.0073; versus indeterminate, P = 0.00082). GRAP2/GADS‐positive NK lineage tumours more frequently expressed DOK2 (P = 0.0073), and were more often confined to the nasal areas (P = 0.014). Furthermore, when these tumours were immunophenotypically classified into a T signature (42%) or NK signature (58%), the expression rates of GRAP2/GADS and ITK were higher in T signature tumours (P = 0.00074 and P = 0.067, respectively), whereas that of LCK was higher in NK‐signature tumours (P = 0.10). Conclusions: Although some ENTKL cases were polyclonal for TCR rearrangement and others lacked TCR expression, we speculate that the TCR pathway might be functioning in ENKTLs. A T signature versus a NK signature might be better for delineating the physiology of ENKTL than cellular lineage. Furthermore, ITK may represent a potential therapeutic target for patients with ITK‐expressing tumours. [ABSTRACT FROM AUTHOR]

Nodal cytotoxic molecule (CM)‐positive peripheral T‐cell lymphoma (CTL) has recently been recognized as a clinicopathologically distinct disease. To further characterize this disease, here we compared 58 patients with Epstein‐Barr virus (EBV)‐negative CTL to 48 patients with EBV‐positive CTL. The two groups did not differ in histopathology, T‐cell receptor (TCR) expression or rearrangement incidences, or survival curves. However, patients with EBV‐negative CTL less frequently showed hepatic involvement (P = .007), B symptoms (P = .020), hemophagocytosis (P = .024), and detectable CD4 (P = .002) and CD5 (P = .009). Univariate and multivariate analyses identified three factors that independently predicted favorable survival, onset age <60 years (P = .002), CD5 expression (P = .002), and mixed morphology (P = .013), TCRαβ was not an independent predictor (P = .30), but was strongly linked with long survivorship among patients younger than 60 years old. A prognostic model incorporating these factors worked well for prognostic delineation, independently of the International Prognostic Index (P = .007 vs P = .082) and Prognostic Index for PTCL (P = .020 vs P = .15). Moreover, this constellation of findings indicated two nodal indolent diseases: CD5+TCRαβ (n = 13), and CD5+ NK‐cell type lacking TCR expression or clonal TCRγ rearrangement (n = 4). The survival curves for these two groups were significantly superior to others (n = 29, P < .001). These diseases appear to be unique in their indolent clinical behavior, and should be managed differently from other diseases. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is the most commonly involved site of extranodal follicular lymphoma (FL). GI-FL shows very indolent clinical behavior and localized at GI tract without any progression or transformation compared to nodal FL. The most frequently involved site of the GI tract was the duodenum followed by the jejunum and ileum, and only 15% of FL arising in the second part of the duodenum were localized there without scattered very small daughter lesions in other GI tract examined by double-balloon endoscopy. The typical macroscopic appearance of GI-FL was multiple white nodules. Microscopically, neoplastic cells were small- to medium-sized lymphoid cells and formed neoplastic follicles. Most of the cases (>95%) were histologically Grade 1 to 2 (low grade). Several pathological and molecular characteristics were seen in GI-FL (especially duodenal FL) compared with nodal FL: immunoglobulin heavy chain deviation to VH4 and VH5; memory B-cell immunophenotype; and molecular features shared by mucosa-associated lymphoid tissue lymphoma. Considering the pathological and molecular uniqueness of this disease, GI-FL should be separately managed from nodal FL. [ABSTRACT FROM AUTHOR]

Aims The central nervous system ( CNS) is a rare primary site of non-Hodgkin lymphoma. Although direct invasion of nasal natural killer ( NK)/T cell tumours into CNS is reported occasionally, primary CNS NK/T cell lymphoma is extremely rare, and the clinicopathological features of primary CNS NK/T cell lymphoma remain largely unknown. Methods and results We identified four cases from our consultation files and analysed the clinicopathological features. Three were immunocompetent and one was immunosuppressed. There were three males and one female and their ages ranged from 21 to 77 years (median: 46 years). Radiotherapy was rendered for all patients, and methotrexate was administered to two patients. The overall survival was 4-29 months (median, 19 months) for the three immunocompetent patients. Neoplastic cells exhibited medium to large atypical nuclei. Angiocentric growth and necrosis were observed. The immunophenotype was typical of NK cell tumours: CD3ε, 100%; CD56, 67%; CD5, 50%; cytotoxic molecules, 100%; Epstein-Barr virus encoded small RNA ( EBER), 100% and T cell receptor ( TCR)-β or γ, 0%. No TCR-gene rearrangements were detected. Reviewing 10 additional cases from the literature and comparing with extranasal NK/T cell lymphoma of the more frequent origins (skin or gastrointestinal tract), primary CNS NK/T cell lymphoma was diagnosed at an earlier stage without B symptoms but exhibited aggressive clinical behaviours. Conclusions Although extremely rare, primary CNS NK/T cell lymphoma does occur and should always be included in the differential diagnosis and we should apply relevant markers routinely in conjunction with exploring the patient background. The accumulation of cases is indispensable to establish an effective treatment strategy for this rare and aggressive malignancy. [ABSTRACT FROM AUTHOR]

Aims Epstein-Barr virus-positive (EBV+) intestinal T/natural killer ( NK) cell lymphoma ( ITNKL) is an uncommon tumour with an extremely aggressive clinical behaviour. However, the clinicopathological characteristics of this tumour, including T cell receptor ( TCR) phenotype and the patient's background, remain unknown. The aim of this study was to elucidate the detailed clinicopathological profile of EBV+ ITNKL. Methods and results We enrolled 12 patients with EBV+ ITNKL without nasal involvement into the study. All patients were characterized by involvement of the small intestine with concurrent lesions of the large intestine in two patients. Seven patients (58%) had Lugano stages IIE/IV disease and eight (67%) were categorized as high-intermediate/high-risk according to the Prognostic Index for PTCL ( PIT). Three patients (25%) with an age of onset of less than 50 years had chronic active EBV infection ( CAEBV). Five CD56-positive patients (42%) had a poorer prognosis than those without CD56 expression ( P = 0.008). NK cell-type lymphoma defined by the absence of any TCR expression or clonal TCR-γ rearrangement was found in six patients (50%). Interestingly, EBV+ intra-epithelial lymphocytosis was observed in one case with a background of CAEBV. Conclusions This study is the first to shed light on the significant heterogeneity of EBV+ ITNKL and its relationship with CAEBV, especially in patients younger than 50 years of age. These observations will provide a guide for diagnostic and therapeutic approaches in routine practice. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma ( DLBCL) is the most common B-cell lymphoma subtype, and the Epstein-Barr virus ( EBV)-positive subtype of DLBCL is known to show a more aggressive clinical behavior than the EBV-negative one. BTB and CNC homology 2 ( BACH2) has been highlighted as a tumor suppressor in hematopoietic malignancies; however, the role of BACH2 in EBV-positive DLBCL is unclear. In the present study, BACH2 expression and its significance were studied in 23 EBV-positive and 43 EBV-negative patient samples. Immunohistochemistry revealed BACH2 downregulation in EBV-positive cases ( P < 0.0001), although biallelic deletion of BACH2 was not detected by FISH. Next, we analyzed the contribution of BACH2 negativity to aggressiveness in EBV-positive B-cell lymphomas using FL-18 ( EBV-negative) and FL-18- EB cells ( FL-18 sister cell line, EBV-positive). In BACH2-transfected FL-18- EB cells, downregulation of phosphorylated transforming growth factor-β-activated kinase 1 ( pTAK1) and suppression in p65 nuclear fractions were observed by Western blot analysis contrary to non-transfected FL-18- EB cells. In patient samples, pTAK1 expression and significant nuclear p65, p50, and p52 localization were detected immunohistochemically in BACH2-negative DLBCL ( P < 0.0001, P = 0.006, and P = 0.001, respectively), suggesting that BACH2 downregulation contributes to constitutive activation of the nuclear factor-κB pathway through TAK1 phosphorylation in BACH2-negative DLBCL (most EBV-positive cases). Although further molecular and pathological studies are warranted to clarify the detailed mechanisms, downregulation of BACH2 may contribute to constitutive activation of the nuclear factor-κB pathway through TAK1 activation. [ABSTRACT FROM AUTHOR]

Follicular lymphoma ( FL) shows co-expression of B-cell lymphoma 2 ( BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal ( GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed ( CD10down) GI- FL. The diagnosis of CD10down FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10down GI- FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI- FL and nodal FL when the analysis was confined to primary GI- FL (55.2% vs 3.5%, P < 0.001). Compared to CD10+ GI- FL, CD10down GI- FL significantly involved the stomach or large intestine ( P = 0.015), and additionally showed the downexpression of BCL6 ( P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10down group ( P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10down GI- FL, and an identical clone was found between CD10down follicles and CD10+ BCL2+ neoplastic follicles. In the diagnosis of cases with CD10down BCL2+ follicles, careful examination with molecular studies should be carried out. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women ( P = 0.041) and elevated LDH ( P = 0.002) and soluble interleukin-2 receptor ( P = 0.033). Small intestinal DLBCL more frequently showed anemia ( P = 0.031) and elevated CRP ( P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P. [ABSTRACT FROM AUTHOR]

Anticancer drug sensitivity affects prognosis in ovarian carcinoma. Previously, we purified spectrin αII and βII tetramers from cisplatin-resistant ovarian serous adenocarcinoma cells and demonstrated that they contribute to platinum anticancer drug resistance. In this clinical study, we focused on the role of spectrin αII expression. It is our objective to demonstrate the potential of spectrin αII expression as a useful predictor of anticancer drug resistance and postoperative prognosis in epithelial ovarian carcinoma. Spectrin αII expression in the ovarian adenocarcinoma surgical specimens of 193 patients was examined by immunohistochemical staining. Staining strength was scored 3+, regarded as positive expression, and 2+, 1+, and 0, regarded as non-positive expression. Prognoses obtained from clinical records were evaluated by statistical analysis. In the 193 cases studied, positive spectrin αII expression was associated with worse overall survival when compared with non-positive expression ( P < 0.001 by log-rank test), and spectrin αII expression was identified as an independent predictive factor of overall survival (hazard ratio[HR]: 3.77, 95% confidence interval[CI]: 1.77-8.00; P < 0.001 by multivariate Cox's proportional hazards model). In the study about progression-free survival, spectrin αII expression was not associated with prognoses. However, similar results as overall survival were obtained for survival after recurrence of the 92 recurrent cases ( P = 0.0051 by log-rank test, HR: 4.49, 95% CI: 2.06-9.79; P < 0.001 by multivariate Cox's proportional hazards model). In a detailed overall survival study of 66 serous adenocarcinoma patients and 127 nonserous adenocarcinoma patients, similar results were also obtained. Spectrin αII expression is a useful predictor of anticancer drug resistance and postoperative prognosis in epithelial ovarian carcinoma.. [ABSTRACT FROM AUTHOR]

Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with human immunodeficiency virus (HIV) infection. Herein we describe a rare case of PBL that spontaneously regressed. An 80-year-old man was referred to our hospital owing to an exophytic gingival tumor in the right maxillary second molar region. He had no significant past medical history, and a screening test for HIV was negative. Imaging showed that the tumor measured 26 × 23 × 16 mm and was confined in the alveolar bone. The tumor was histologically comprised of highly proliferative immunoblastic cells positive for CD138 and Epstein-Barr virus (EBV)-encoded RNA. Monoclonal IgH chain gene rearrangement was detected via polymerase chain reaction. After biopsy and diagnosis of PBL, the tumor began to decrease in size and had apparently disappeared at the time of surgery. There was no histological evidence of a residual lesion in the surgical specimen. In conclusion, a minority of immunosenescence-associated PBLs in the elderly should be recognized as a unique clinicopathological entity distinct from common aggressive PBL. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukaemia/lymphoma (ALL/LBL) is an aggressive form of non-Hodgkin's lymphoma (NHL) affecting B-cells or T-cells, respectively. The serum level of soluble interleukin-2 receptor (sIL-2R) is known to reflect the immune activity and tumour volume in aggressive NHL; however, the release of sIL-2R in LBL has not been extensively studied. Further, the relationship between sIL-2R release and the expression level of IL-2R α subunit (CD25) remains unknown. In the present study, we examined the serum level of sIL-2R in 23 patients with T lymphoblactic lymphoma (T-LBL) and compared these with the levels in 20 patient with T acute lymphoblastic leukaemia (T-ALL), 40 patients with diffuse large B-cell lymphoma (DLBCL) and 40 patients with peripheral T-cell lymphoma (PTCL), not otherwise specified. The release of sIL-2R into the serum in patients with T-LBL was significantly lower than that for T-ALL, DLBCL and PTCL (p<0.001). Immunohistochemistry revealed that CD25 expression was correlated with the serum level of sIL-2R in T-LBL (p=0.0069), whereas no correlation was found to exist between serum sIL-2R levels and CD25 expression in patients with DLBCL (p=0.348) and PTCL (p=0.266). Furthermore, double immunohistochemical analysis revealed that CD25-positive cells were also found to be Foxp3-positive non-neoplastic T-cells. In conclusion, CD25-positive non-neoplastic T-cells in T-LBL are presumed to be the primary source of sIL-2R, and the low number of cells present results in a lower level of sIL-2R released into the serum compared with the other aggressive and highly aggressive lymphomas. [ABSTRACT FROM AUTHOR]

Primary intestinal follicular lymphoma ( FL) is a variant of FL characterized by frequent duodenal involvement and a very indolent clinical behavior without therapy. Unlike nodal FL, there have been no reports of histologic transformation ( HT) or death attributable to primary intestinal FL. Here, we report the first case of primary duodenal FL showing HT. A Grade 1 FL in the duodenum was incidentally detected in a 73-year-old man. A watch-and-wait strategy was adopted because the disease was stage IE. Six months later, bone marrow involvement was suspected. The intestinal lesions had not changed during the first year since the initial diagnosis. Sixty-two months after the initial diagnosis, a biopsy specimen showed diffuse large B-cell lymphoma ( DLBCL). A perforation of the intestine occurred before chemotherapy was started. Partial resection was performed and subsequent chemotherapy was administered. The clone of the initial FL and DLBCL were identical according to PCR analysis, indicating that the primary intestinal FL had transformed into DLBCL. Although HT is rare, it could occur in some patients with primary intestinal FL. Based on this case, it may be necessary to re-evaluate the clinical watch-and-wait strategy for primary intestinal FL in some patients. [ABSTRACT FROM AUTHOR]

While the use of polymerase chain reaction (PCR)-based clonality analysis of formalin-fixed paraffin-embedded (FFPE) tissue has recently become widespread, the detection sensitivity for lymphoma subtypes using FFPE samples is not well known. Here, we analyzed T-cell receptor γ chain (TCRG) gene rearrangement clonality in 100 cases of T- or natural killer (NK)/T-cell lymphoma and examined detection sensitivity according to lymphoma subtype. Clonality was detected in approximately 80% of the major T-cell lymphoma subtypes: peripheral T-cell lymphoma, not otherwise specified, 84% (21/25 cases); angioimmunoblastic T-cell lymphoma, 71% (15/21 cases); and adult T-cell leukemia/lymphoma, 80% (8/10 cases). The number of clonal peaks differed according to subtype. TCRG gene rearrangement was not detected in 63 cases of B-cell lymphoma or reactive lesions. Thus, clonality analysis can effectively and reliably detect TCRG gene rearrangement in T-cell lymphoma cases and could, therefore, be a useful diagnostic tool in routine practice. [ABSTRACT FROM AUTHOR]

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is overexpressed in various cancers and may be important in chronic inflammation-associated oncogenesis. We examined AID expression in IgG4-related sialadenitis (n = 14), sialolithiasis (non-specific inflammation, n = 13), and normal submandibular glands (n = 13) using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Immunohistochemistry revealed significantly more AID-expressing cells in IgG4-related sialadenitis than in sialolithiasis or normal submandibular gland samples (P = 0.02 and P < 0.01, respectively); qPCR yielded similar results. Thus, AID was significantly more up-regulated and had higher expression in extra-germinal centres in IgG4-RD than in non-specific inflammation or normal conditions. This report suggests that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation. Furthermore, chronic inflammation-associated AID-mediated oncogenesis is possible in IgG4-RD. [ABSTRACT FROM AUTHOR]

HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation. [ABSTRACT FROM AUTHOR]

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4+ plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (IL)-4/β-actin, IL-10/β-actin, IL-13/β-actin, transforming growth factor (TGF) β1/β-actin, and FOXP3/β-actin than did IgG4-negative MZL (p < 0.05). This finding further supports our prior observations that a significant subset of ocular MZLs arises in the setting of IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis. [ABSTRACT FROM AUTHOR]