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Crystal-storing histiocytosis is an uncommon form of nonneoplastic histiocytic proliferation that in most patients complicates an underlying lymphoproliferative or plasma cell disorder. Lung is a common site of involvement in patients with localized disease. We present an illustrative example from a 54-year-old woman with an asymptomatic solitary lung nodule. The tumor was characterized by sheets of histiocytes with abundant cytoplasm expanded by distinctive eosinophilic inclusions. Focal necrosis was present. Aggregates of monocytoid lymphocytes and clusters of peribronchiolar plasma cells were overshadowed by the histiocytic infiltrate. Immunohistochemical stains showed CD68 staining in nonneoplastic histiocytes and CD20 staining in monocytoid lymphocytes. In situ hybridization studies showed κ light-chain restriction in plasma cells. These results, combined with the histologic findings, supported the diagnosis of crystal-storing histiocytosis complicating marginal zone lymphoma of mucosa-associated lymphoid tissue. We review the literature pertaining to pulmonary crystal-storing histiocytosis, highlighting the differential diagnosis for this rare phenomenon.

Objectives: To examine the immunoarchitectural patterns of the germinal center (GC)-associated markers CD10, BCL6, and LMO2 and their utility in the differential diagnosis of marginal zone lymphoma (MZL) vs follicular lymphoma (FL)., Methods: Forty-two cases of MZL involving lymph nodes and 88 cases of FL were examined., Results: Interfollicular staining for GC markers was uncommon in MZL but common in FL, including BCL2-positive and BCL2-negative cases. Two atypical patterns of intrafollicular GC staining were identified that were more common in MZL than in FL., Conclusions: Staining for LMO2 in addition to CD10 and BCL6 facilitates the detection of a GC phenotype in FL. Lymph nodes involved by MZL frequently show characteristic alterations of GC immunoarchitecture. Recognizing these altered patterns assists in the distinction between MZL and FL.

Cutaneous lymphomas can usually be distinguished by architectural features, where most atypical lichenoid infiltrates implicate cutaneous T-cell lymphoma (CTCL). We report a case of an 80-year-old man who presented with asymptomatic golden brown patches and diffuse pink papules on his trunk, buttocks and hips. Biopsies revealed a lichenoid infiltrate and areas of epidermotropism. Although the overall architectural pattern was compatible with mycosis fungoides, the lymphocytes had a more monocytoid and plasmacytoid appearance, and there were interspersed mature plasma cells. Immunohistological studies revealed that the pleomorphic lymphocytes were predominantly B cells (CD20\+ and CD79a\+) with a subpopulation of smaller bland T cells (CD3\+). Moreover, the B-cell immunophenotype was compatible with marginal zone differentiation (bcl-2+, bcl-6-, CD10- and CD5-) and showed a lambda light chain restriction, confirming monoclonality. These findings were diagnostic for cutaneous marginal zone B-cell lymphoma (MZL) with epidermotropism an entity which has only been reported twice in the literature, once in the setting of primary cutaneous disease, and once as cutaneous involvement of systemic disease. This case illustrates a rare pattern of cutaneous MZL, and underscores the importance of immunophenotypic characterization of cutaneous lymphomas in order to prevent the misdiagnosis of a CTCL., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

MALT lymphoma of the ileum is extremely rare: only several cases have been reported. A 34-year-old woman presented abdominal pain and melena. Colorectal and small intestinal endoscopes revealed multiple tumors and ulcers of the entire ileum. Biopsy was taken. Histologically, the biopsy consisted of 6 tissue specimens taken from the various sites of the ileum. All the tissue specimens showed infiltration of small atypical cells resembling centrocyte-like cells (CLC). Immunoblastic cells were scattered, though the number was scant. Monocytoid, plasma cell differentiation, and germinal centers were seen. Lymphoepithelial lesions (LEL) were scattered. Some small atypical lymphocyte were destructive the vessels and stromal tissues. Giemsa and Gram stains demonstrated no Helicobacter pylori and any bacteria. Immunohistochemically, the atypical small lymphocytes were positive for vimentin, but negative for various kinds of cytokeratins (CKs), EMA, CEA and CA19-9. The CK highlighted the LEL. They were positive for CD45, and B-cell markers (CD20, CD79a, CD10, CD23, bcl-2). CD138-positive plasma cells were seen in large number. CD68-positive macrophages were scattered. CD30- and CD15-positive immunoblastic cells were scattered. Most of the lymphoid cells were negative for T-cell markers (CD3, CD4, CD5, CD45RO, and CD43) and negative for NK cell markers (CD56 and CD57). The lymphoid cells were positive for κ-chain but negative for λ-chain; thus the light chain restriction was seen. TdT and cyclin D1 were negative. P53 was positive and Ki-67 labeling index was 67%. The lymphoid cells were negative for neuroendocrine markers (NCAM, NSE, chromogranin, and synaptophysin). The pathological diagnosis was MALT lymphoma of the ileum. Post-biopsy imaging techniques including CT, MRI, PET endoscope and gallium scintigraphy identified no tumors and no lymphadenopathy in the body except the ileum. The stomach was free from MALT lymphoma. She was treated by low dose chemotherapy and strictly followed up.

We investigated the expression of Bcl10 gene mutations in mucosa-associated lymphoid tissue-type ocular adnexal lymphoma (OAL), atypical lymphoid hyperplasia (ALH), and reactive lymphoid hyperplasia (RLH) in the Chinese population and its role in clinical diagnosis and pathogenesis. Forty-three samples were collected during patient surgeries. Pathological diagnosis confirmed OAL in 23 cases, ALH in 10 cases, and RLH in 10 cases. Normal peripheral lymph tissues from 12 cases were used as negative controls. Bcl10 gene expression was examined using molecular biological methods, and DNA sequences and mutations were compared with published data. The protein expression of Bcl10 and nuclear factor kappaB (NF-κB) were detected with immunohistological and immunofluorescence colocalization. Bcl10 gene expression was detected in 15 OAL cases. Novel mutations were found in 11 cases. Notably, 1 mutation, which matched a published mutation, was detected in 1 ALH case; 1 novel mutation was found in 1 RLH case; and no Bcl10 gene mutation was found in controls. Most novel mutations were truncation mutations, resulting in a truncated protein product of 99 amino acids (compared to the full-length 233 amino acids; GenBank accession No. EF189176). Results of tests for abnormal Bcl10 gene expression in nuclei or cytoplasm were consistent with changes in NF-κB translocation. This report is the first of newly discovered mutations in the Bcl10 gene in the Chinese population. The distribution of the mutations is consistent with and more sensitive than that of the pathological diagnosis. These mutations can be used to identify the stage and clinical characteristics even when morphological changes are absent.

Objective: To study the clinicopathologic features and differential diagnosis of splenic B-cell marginal zone lymphoma (SMZL) involving bone marrow., Methods: The clinical and pathologic features of 22 patients with SMZL were retrospectively studied. Immunophenotypic analysis was carried out by flow cytometry and immunohistochemistry. Immunoglobulin heavy chain rearrangement study was performed using polymerase chain reaction-based method., Results: Villous lymphocytes were found in peripheral blood smears of 11/18 of the patients. In bone marrow aspirates, lymphocytosis (> 20%) was demonstrated in 15 cases (15/18) and villous lymphocytes in 6 cases (6/18). Flow cytometry showed CD19(+) CD20(+) FMC7(+) CD22(+) CD10(-) CD2(-) CD3(-) CD7(-) in 18 cases. Bone marrow biopsies of all the 22 patients revealed various degrees and patterns of neoplastic infiltration, as follows: mild (4 cases, 18.2%), moderate (11 cases, 50.0%) or severe (7 cases, 31.8%); intrasinusoidal (16 cases, 72.7%), interstitial (14 cases, 63.6%), nodular (11 cases, 50.0%) or diffuse (1 case, 4.5%). Reactive germinal center formation (CD23(+) bcl-2(-)) was found in 2 cases (91.0%). Immunohistochemical study showed the following results: CD20(+) PAX5(+) CD3(-) CD5(-) CD10(-) cyclin D1(-) CD23(-) CD43(-) Annexin A1(-) CD11C(-) CD25(-) in all the 22 cases, CD38(+) in 2 cases (9.1%) and CD138(+) in 2 cases (9.1%)., Conclusions: Different and overlapping patterns of bone marrow involvement are observed in SMZL. As the histologic and immunophenotypic features are not specific to SMZL, distinction from other types of mature B-cell lymphomas is necessary.

Objective: To identify the immunohistochemical patterns of follicular dendritic cell (FDC) meshwork and Ki-67 labeling index in small B-cell lymphomas (SBLs) and their significance in differential diagnosis., Methods: Sixty-eight cases of SBLs were included collected from November 2008 to June 2012. The patterns of FDCs and Ki-67 expression were studied on paraffin sections by CD21, CD23 and Ki-67 immunohistochemistry. The characteristic staining patterns of FDCs and Ki-67 expression among different SBLs were analyzed statistically., Results: The age of SBL patients ranged from 28 to 85 years with a mean of 55.2 years. The male to female ratio was 1.2:1. Fifty-five cases involved only lymph nodes (80.9%), and the remaining cases involved multiple extra-nodal sites. Histological classification of the cases was made according to the 2008 WHO lymphoma classification criteria: 22 were low-grade follicular lymphomas (FLs, including grade 1 and grade 2), 19 marginal zone lymphomas (MZLs), 17 mantle cell lymphomas (MCLs), and 10 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLLs). FDC meshwork limited to the central part of neoplastic follicles was characteristic for FL (90.9%, 20/22). The germinal center FDC meshwork was destroyed primarily at periphery in MZL (14/19). The absence or scattered FDC clusters were typical of SLL/ CLL. Irregular FDC was seen in 7/17 of MCL, while 7/17 MCL displayed FDC pattern similar to that of CLL/SLLs. The pattern of FDCs was a significantly diagnostic feature in distinguishing the four types of SBLs (P < 0.01). Ki-67 was also a statistically significant parameter (P < 0.05) with decreasing labeling index as the following: MCL, FL, SLL and MZL. Ki-67 showed scattered pattern in germinal centers with loss of polarity in FLs. MZL presented uniformly scattered positive pattern in interfollicullar areas. Ki-67 staining was uniform in MCL, but its labeling index varied from 5% to 90%. The Ki-67 index was higher in the morphological "proliferation centers" of all CLL/SLLs., Conclusion: Immunohistochemical staining patterns of FDC meshworks and Ki-67 labeling index offer a significant discriminatory power in the differential diagnoses among SBLs.

In Helicobacter pylori gastritis, constant antigenic stimulation triggers a sustained B-cell proliferation. Errors made during this continuous DNA replication are supposed to be corrected by the DNA mismatch repair mechanism. Failure of this mismatch repair mechanism has been described in hereditary non-polyposis colorectal cancer (HNPCC) and results in a replication error phenotype. Inherent to their instability during replication, microsatellites are the best markers of this replication error phenotype. We aimed to evaluate the role of defects in the DNA mismatch repair (MMR) mechanism and microsatellite instability (MSI) in relation to the most frequent genetic anomaly, translocation t(11;18)(q21;q21), in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Therefore, we examined 10 microsatellite loci (BAT25, BAT26, D5S346, D17S250, D2S123, TGFB, BAT40, D18S58, D17S787 and D18S69) for instability in 28 patients with MALT lymphomas. In addition, these tumors were also immunostained for MLH1, MSH2, MSH6 and PMS2, as well as screened for the presence of t(11;18)(q21;q21) by real-time polymerase chain reaction (RT-PCR). We found MSI in 5/28 (18%) lymphomas, with MSI occurring in both t(11;18)(q21;q21)-positive and -negative tumors. One tumor displayed high levels of instability, and, remarkably, this was the only case displaying features of a diffuse large B-cell lymphoma. All microsatellite unstable lymphomas showed a loss of MSH6 expression. In conclusion, our data suggest that a MMR-defect may be involved in the development of gastric MALT lymphomas, and that a defect of MSH6 might be associated with those MSI-driven gastric lymphomas.

Platelet satellitism is believed to be an in vitro phenomenon induced at room temperature in ethylenediamine tetraacetic acid-anticoagulated blood. Most reports involve neutrophils; involvement with circulating lymphoma cells are exceedingly rare. Normally, mature B cells exhibit allelic exclusion in which a single class of surface immunoglobulin light chains (either κ or λ) is expressed. The simultaneous expression of both κ and λ immunoglobulin light chains is rare. Herein, we report the unusual case of a patient with splenic marginal zone lymphoma in which circulating lymphoma cells express dual surface immunoglobulin light chains and exhibit platelet satellitism. In addition to clinical findings, a comprehensive analysis of the peripheral blood including correlated light and electron microscopy as well as flow cytometry are described., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Chemokine receptors have a crucial role in the development and progression of lymphoid neoplasms. To determine the chemokine receptor expression profile in gastric mucosa-associated lymphoid tissue (MALT) lymphoma, we performed an expression analysis of 19 chemokine receptors at mRNA levels by using real-time RT-PCR, as well as of five chemokine receptors--CCR8, CCR9, CXCR4, CXCR6 and CXCR7--by immunohistochemistry on human tissue samples of Helicobacter pylori-associated gastritis, gastric MALT lymphoma and gastric extranodal diffuse large B-cell lymphoma originating from MALT lymphoma (transformed MALT lymphoma). Following malignant transformation from H. pylori-associated gastritis to MALT lymphoma, an upregulation of CCR7, CXCR3 and CXCR7, and a loss of CXCR4 were detected. The transformation of gastric MALT lymphomas to gastric extranodal diffuse large B-cell lymphoma was accompanied by upregulation of CCR1, CCR5, CCR7, CCR8, CCR9, CXCR3, CXCR6, CXCR7 and XCR1. Remarkably, CXCR4 expression was exclusively found in nodal marginal B-cell lymphomas and nodal diffuse large B-cell lymphomas but not at extranodal manifestation sites, ie, in gastric MALT lymphomas or gastric extranodal diffuse large B-cell lymphomas. Furthermore, the incidence of bone marrow infiltration (16/51 with bone marrow involvement vs 35/51 with bone marrow involvement; Spearman ρ=0467 P<0.001) positively correlated with CXCR4 expression. CXCL12, the ligand of CXCR4 and CXCR7, was expressed by epithelial, endothelial and inflammatory cells, MALT lymphoma cells and was most strongly expressed by extranodal diffuse large B-cell lymphoma cells, suggesting at least in part an autocrine signaling pathway. Our data indicate that CXCR4 expression is associated with nodal manifestation and a more advanced stage of lymphomas and hence, might serve as useful clinical prognostic marker.

Detection of the integrin subunit CD103 is a useful diagnostic tool in the diagnosis of hairy cell leukemia (HCL). Currently, flow cytometric analysis (FC) and frozen section immunohistochemistry (IHC) represent the only available methods of detection. This study is the first to describe the successful use of a CD103 antibody to identify HCL and HCL-variant in paraffin sections of formalin- or Bouin solution- fixed specimens (n = 68) using an immunoperoxidase technique. In other B-cell lymphoproliferative disorders that morphologically may resemble HCL, including chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 32), mantle cell lymphoma (n = 23), lymphoplasmacytic lymphoma (n = 27), follicular lymphoma (n = 7), and marginal zone lymphoma (n = 13), lymphoid cells are nonreactive for CD103. In HCL, the CD103 staining pattern is predominantly membranous with delineation of delicate cytoplasmic projections. This CD103 antibody is an extremely valuable addition to the IHC panel for the diagnosis of HCL, especially in cases lacking FC analysis.

Aims:   Bone marrow (BM) biopsies of some mucosa-associated lymphoid tissue (MALT) lymphoma patients show scattered or small clusters of CD20+ cells without definite lesions (subtle CD20 positivity). The aim of this study was to evaluate the clinical significance of BM involvement and subtle CD20 positivity in 122 patients diagnosed with MALT lymphoma., Methods and Results:   Patients were divided into three categories: BM involvement [BM(+)], subtle CD20 positivity, and no BM involvement [BM(-)]. Eleven (9%) showed BM involvement, and 17 (14%) showed subtle CD20 positivity. BM(+) patients had significantly worse progression-free survival (PFS) than BM(-) patients [hazard ratio (HR) 6.25, P = 0.01], but there was no significant difference between subtle CD20 positivity and BM(-) patients. Patients with >30 CD3+ cells among 100 nucleated cells in the areas with increased numbers of CD3+ cells had significantly worse PFS than those with <15 CD3+ cells (HR 5.49, P = 0.02). BM(+) patients with >30 CD3+ cells had worse PFS than those with ≤30 CD3+ cells (P = 0.029), with an extent of BM(+) involvement of >10% positively correlating with >30 CD3+ cells (P = 0.015)., Conclusions:   Patients with BM(+) MALT lymphoma showed significantly worse PFS than those with subtle CD20 positivity and BM(-) MALT lymphoma, but the PFS of patients with subtle CD20 positivity MALT lymphoma was not significantly different from that of those with BM(-) MALT lymphoma. Increased numbers of BM T cells in MALT lymphoma patients might be suggestive of a worse prognosis., (© 2012 Blackwell Publishing Ltd.)

Ocular lymphomas can be divided into intraocular lymphomas and ocular adnexal lymphomas. The vitreoretinal lymphoma-usually a diffuse large B-cell lymphoma (DLBCL) of high-grade malignancy-is the most common lymphoid malignancy arising in the eye, while the extranodal marginal zone B-cell lymphoma (EMZL), an indolent often recurrent tumour, occurs most frequently in the ocular adnexal tissue. The two lymphoma subtypes differ significantly in their clinical presentation, subsequent course and outcome as well as in their underlying morphological, immunophenotypical and genetic features. The molecular processes involved in DLBCL and EMZL development are complex, and include chromosomal translocations, mutations caused by aberrant somatic hypermutation, sporadic somatic mutations, and copy number alterations, characterized by deletions and amplifications. These lead to alterations in particular signalling pathways, which in turn activate transcription factors, such as nuclear factor NF-κB. This review provides an overview of the histological features of DLBCL and EMZL, and discusses the current insights into the molecular mechanisms underlying the development of these tumours, when they occur systemically and particularly when they arise in ocular tissues.

Low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach, gastric MALT lymphoma, is associated with Helicobacter pylori infection. The eradication of H pylori using antibiotics is successful in 60% to 80% of affected patients. In contrast to the previous paradigm, we and other investigators have shown that a certain proportion of patients with H pylori-positive early-stage diffuse large B-cell lymphoma (DLBCL) of the stomach with histological evidence of MALT lymphoma, including high-grade transformed gastric MALT lymphoma and gastric DLBCL(MALT), achieved long-term complete pathological remission (pCR) after first-line H pylori eradication therapy, indicating that the loss of H pylori dependence and high-grade transformation are separate events in the progression of gastric lymphoma. In addition, patients with H pylori-positive gastric DLBCL without histological evidence of MALT (gastric pure DLBCL) may also respond to H pylori eradication therapy. A long-term follow-up study showed that patients who achieved pCR remained lymphoma free. Gastric MALT lymphoma is indirectly influenced by H pylori infection through T-cell stimulation, and recent studies have shown that H pylori-triggering chemokines and their receptors, H pylori-associated epigenetic changes, H pylori-regulated miRNA expression, and tumor infiltration by CD4+CD25+ regulatory T cells contribute to lymphomagenesis of gastric MALT lymphoma. Recent studies have also demonstrated that the translocation of CagA into B lymphocytes inhibits apoptosis through p53 accumulation, BAD phosphorylation, and the up-regulation of Bcl-2 and Bcl-XL expression. In gastric MALT lymphoma, CagA may stimulate lymphomagenesis directly, through the regulation of signal transduction, and intracellular CagA is associated with H pylori dependence. These findings represent a substantial paradigm shift compared with the classical theory of H pylori-reactive T cells contributing indirectly to the development of MALT lymphoma. In conclusion, a wide range of H pylori-related gastric lymphomas have been identified. The use of antibiotics as the sole first-line therapy for early-stage gastric pure DLBCL requires validation in a prospective study. The clinical and biological significance of the CagA oncoprotein in the lymphomagenesis of gastric MALT lymphoma warrants further study.

Nowadays, it is believed that the main role in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma plays Helicobacter pylori infection. This world-wide distributed bacteria is in charge of most cases of not only upper gastrointestinal tract disorders but also some of extragastric problems. Constant stimulation of the immune system causes a B-lymphocytes proliferation, which is considered to be responsible for the neoplastic transformation. On the other hand, there are 10%-20% of patients who do not respond to Helicobacter pylori eradication treatment. This group has often a chromosome translocation, which suggests that there is another unknown, so far, pathogenetic mechanism of MALT lymphoma. Majority of genetic abnormalities are connected with nuclear factor-κB (NF-κB) pathway, which activates the uncontrolled proliferation of neoplastic cells. Translocations already described in studies are t(11;18)(q21;q21), which is the most common, t(14;18)(q32;q21), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). This non-Hodgkin's lymphoma is an indolent type originated outside lymph nodes. In more than 50% of cases, it occurs in the stomach. Occasionally, it can be found in salivary and thyroid gland, lung, breast, bladder, skin, or any other place in the human body. This paper is a review of the current knowledge on etiology, pathogenesis, treatment, and follow-up of gastric MALT lymphoma.

Objective: To investigate whether the expression level of valosin-containing protein (VCP) is correlated with the prognosis of primary orbital mucosa-associated lymphoid tissue (MALT) lymphoma., Methods: VCP expression in 58 samples from primary orbital MALT lymphoma patients was determined by immunohistochemisty using monoclonal antibodies. Correlations between VCP expression level and prognosis were clarified by statistical analysis., Results: It was found that the percentage of VCP positive cells in samples of primary orbital MALT lymphoma ranged from 32% to 95%. The samples were divided into two groups (level 1 and level 2) according to the median value (45%) of the percentage of VCP positive cells. It was found that the expression level of VCP was significantly correlated with recurrence (P=0.003) and tumor size (P=0.008). At the same time, the 5-year disease-free and overall survival rate of patients of level 1 was significantly better than that of level 2 (P=0.001; P=0.032). There was no observed correlation between the expression level of VCP and other clinical features., Conclusion: VCP could be a useful marker for predicting the prognosis of primary orbital MALT lymphoma.

Objective: To study the clinicopathologic features, immunohistochemical findings, differential diagnosis and prognosis of type II enteropathy-associated T-cell lymphoma (EATL)., Methods: Fourteen cases of type II EATL encountered in Department of Pathology, Nanjing General Hospital were retrospectively reviewed. The clinical data, histologic features, immunohistochemical findings and follow-up information were analyzed, with literature review., Results: There were altogether 12 males and 2 females. The median age of patient was 49 years. The sites of involvement included jejunum (10 cases) and ileum/colon (4 cases). The patients often presented with an abdominal mass, abdominal pain, diarrhea and constitutional symptoms such as fever, night sweating and cachexia. There was no clinical evidence of gluten-sensitive enteropathy. Histologically, the lymphoma cells showed full-thickness infiltration of the intestinal wall. They contained round hyperchromatic nuclei and pale cytoplasm. The stroma was minimally inflamed, with or without associated coagulative necrosis. A remarkable finding was the presence of villous atrophy, cryptal hyperplasia and intraepithelial lymphocytosis. Immunohistochemical study showed that the tumor cells expressed CD3, CD43 and CD8 (14/14). Some of them were also positive for CD56 (11/14) and CD30 (2/14). The staining for CD4, CD20, CD79a and myeloperoxidase was negative. A high proliferation index was demonstrated by Ki-67 immunostain. In-situ hybridization for EBER was negative. Follow-up data were available in 9 cases. The duration of follow-up ranged from 6 months to 36 months. Seven patients died within 14 months., Conclusions: EATL is a rare type of lymphoma with intestinal involvement. Associated enteropathy is not demonstrated, in contrast to cases encountered in Nordic countries. A correct diagnosis requires evaluation of clinical manifestations, pathologic features and ancillary study results.

The forkhead box protein P1 (FOXP1) expression resulted from chromosome translocation was found in MALT lymphoma, and its nuclear expression in diffuse large B cell lymphoma has been believed to be a poor prognostic factor. In our study, FOXP1 expression was investigated in its relationship to the occurrence of large tumor cells, clinical features, and prognosis in a series of 115 MALT lymphomas divided into two groups with or without the large tumor cells. All cases were morphologically reviewed, and FOXP1 expression was detected both in mRNA and protein levels by real-time PCR, immunochemical staining, and Western blot hybridization. All available clinical data were collected. In the MALT lymphoma with large cells, FOXP1 expression was higher at both mRNA (P = 0.008) and protein (P = 0.000) levels than that in group without large cells, and most large tumor cells showed FOXP1 positivity. It was also found that cases beyond Ann Arbor stage I have a higher FOXP1 expression rate than cases in stage I (P = 0.01), moreover, FOXP1-positive group has more plasmacytic differentiation (P = 0.025), deeper filtrating depth in digestive tract (P = 0.039), and a higher Ki67 proliferation index (P = 0.022). However, no statistical significance was identified in the involved anatomic sites and prognosis. Our data demonstrated the close relationship between FOXP1 nuclear expression and the occurrence of large tumor cells in MALT lymphoma, which suggested the possibility of large cell transformation of FOXP1-positive cases. And FOXP1 positivity was associated with enhanced invasion and proliferation ability of tumor cells. In the thyroid cases, the FOXP1 positivity showed a poorer prognosis (P = 0.043), but the significance was not found in the overall survival analysis (P = 0.1123).

Nodal marginal zone B cell lymphoma is a rare type of malignant lymphoma and appears to be heterogeneous. Here we report a 60-year-old woman with stage I splenic type of nodal marginal zone B cell lymphoma with prominent follicular colonization. She was treated only by radiation therapy, and remained free of disease on examination for 4 years. The lymph node cells showed an abnormal chromosome of deletion 13, although neither bone marrow cells nor peripheral blood cells demonstrated the same abnormal chromosome. This type of chromosomal abnormality has not been previously reported and may be related to good prognosis in the present case., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Genetic aberrations, including trisomies 3 and 18, and well-defined IGH translocations, have been described in marginal zone lymphomas (MZLs); however, these known genetic events are present in only a subset of cases. Here, we report the cloning of an IGH translocation partner on chromosome X, t(X;14)(p11.4;q32) that deregulates expression of an poorly characterized orphan G-protein-coupled receptor, GPR34. Elevated GPR34 gene expression was detected independent of the translocation in multiple subtypes of non-Hodgkin lymphoma and distinguished a unique molecular subtype of MZL. Increased expression of GPR34 was also detected in tissue from brain tumors and surface expression of GPR34 was detected on human MZL tumor cells and normal immune cells. Overexpression of GPR34 in lymphoma and HeLa cells resulted in phosphorylation of ERK, PKC, and CREB; induced CRE, AP1, and NF-κB-mediated gene transcription; and increased cell proliferation. In summary, these results are the first to identify a role for a GPR34 in lymphoma cell growth, provide insight into GPR34-mediated signaling, identify a genetically unique subset of MZLs that express high levels of GPR34, and suggest that MEK inhibitors may be useful for treatment of GPR34-expressing tumors.

Primary splenic small B-cell lymphomas mostly comprise the distinct entity of splenic marginal-zone lymphoma (SMZL) and the provisional category of splenic lymphoma/leukemia unclassifiable, mainly represented by the hairy cell leukemia variant and splenic diffuse red pulp small B-cell lymphoma (SDRL). Until recently, histopathologic examination of splenectomy specimens was considered mandatory for the diagnosis of SMZL. However, nowadays, mainly because of advances in chemoimmunotherapy, splenectomy is performed much less frequently. We evaluated the diagnostic efficacy of bone marrow biopsy (BMB) histopathology in the diagnostic approach toward SMZL and SDRL and tested whether it may serve as a substitute for spleen histopathology in the differential diagnosis between these 2 entities. To this end, we conducted a paired assessment of BMB and spleen diagnostic samples from 46 cases with a diagnosis of SMZL (n=32) or SDRL (n=14) based on spleen histopathology. We demonstrate that detailed immunohistopathologic BMB evaluation offers adequate evidence for the confirmation of these entities and their differential diagnosis from other small B-cell lymphoma histotypes. Notably, the immunophenotypical profile of SMZL and SDRL was identical in both BMB and spleen specimens for 21 evaluated markers. Paired assessment of BMB and spleen specimens did not identify discriminating patterns of BMB infiltration, cytology, and/or immunohistology between SMZL and SDRL. Accordingly, bone marrow histopathology contributes significantly in confirming the diagnosis of SMZL and SDRL. However, presently it is not possible to distinguish SMZL from SDRL on the basis of BMB evaluation alone; hence, histopathologic examination of the spleen remains the "gold standard" approach.

We describe 4 patients aged 62 to 79 years with splenomegaly and bone marrow involvement by splenic B-cell lymphoma who developed more than 55% prolymphocytes in blood. The diagnosis of B-cell prolymphocytic leukemia was considered clinically based on a markedly elevated leukocyte (up to 131.5×10(9)/L) or prolymphocyte (up to 86%) count. Splenectomy was performed in all patients, and spleen weight ranged from 1500 to 2380 g. In 3 patients, the neoplasms were classified as splenic marginal zone lymphoma, and in 1 patient, the neoplasm was classified as splenic diffuse red pulp small B-cell lymphoma. In 2 patients, splenectomy preceded a B-cell prolymphocytic leukemia-like picture, and the spleen showed splenic marginal zone lymphoma or splenic diffuse red pulp small B-cell lymphoma with increased (10%-20%) nucleolated cells consistent with prolymphocytes. In the other 2 patients, a B-cell prolymphocytic leukemia-like picture prompted splenectomy. Initial examination of bone marrow in these patients suggested splenic marginal zone lymphoma. The spleen specimens showed extensive involvement by splenic marginal zone lymphoma with numerous prolymphocytes. Flow cytometry immunophenotyping in all cases showed lymphocytes positive for monotypic surface immunoglobulin (bright), pan-B-cell antigens, CD11c, CD22, and FMC7. Immunohistochemical analysis in all patients showed moderate to bright p53 expression in the spleen (n=3) or bone marrow (n=2). Annexin A1 and cyclin D1 were negative in all cases. Conventional cytogenetic analysis showed del(7q) in 3 patients. We conclude that splenic B-cell lymphoma of various types can undergo prolymphocytoid transformation with more than 55% prolymphocytes in the blood mimicking B-cell prolymphocytic leukemia., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Knowledge about signaling pathways in malignant cells may provide prognostic and diagnostic information in addition to identify potential molecular targets for therapy. B-cell receptor (BCR) and co-receptor CD40 signaling is essential for normal B cells, and there is increasing evidence that signaling via BCR and CD40 plays an important role in the pathogenesis of B-cell lymphoma. The aim of this study was to investigate basal and induced signaling in lymphoma B cells and infiltrating T cells in single-cell suspensions of biopsies from small cell lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and marginal zone lymphoma (MZL) patients., Methods: Samples from untreated SLL/CLL and MZL patients were examined for basal and activation induced signaling by phospho-specific flow cytometry. A panel of 9 stimulation conditions targeting B and T cells, including crosslinking of the B cell receptor (BCR), CD40 ligand and interleukins in combination with 12 matching phospho-protein readouts was used to study signaling., Results: Malignant B cells from SLL/CLL patients had higher basal levels of phosphorylated (p)-SFKs, p-PLCγ, p-ERK, p-p38, p-p65 (NF-κB), p-STAT5 and p-STAT6, compared to healthy donor B cells. In contrast, anti-BCR induced signaling was highly impaired in SLL/CLL and MZL B cells as determined by low p-SFK, p-SYK and p-PLCγ levels. Impaired anti-BCR-induced p-PLCγ was associated with reduced surface expression of IgM and CD79b. Similarly, CD40L-induced p-ERK and p-p38 were also significantly reduced in lymphoma B cells, whereas p-p65 (NF-κB) was equal to that of normal B cells. In contrast, IL-2, IL-7 and IL-15 induced p-STAT5 in tumor-infiltrating T cells were not different from normal T cells., Conclusions: BCR signaling and CD40L-induced p-p38 was suppressed in malignant B cells from SLL/CLL and MZL patients. Single-cell phospho-specific flow cytometry for detection of basal as well as activation-induced phosphorylation of signaling proteins in distinct cell populations can be used to identify aberrant signaling pathways.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a B-cell neoplasm that is typically CD5 negative. We describe the clinicopathologic, immunophenotypic, and cytogenetic features of 14 cases of CD5+ MALT lymphoma. There were 9 men and 5 women (median age, 68 years; range, 34-87 years). MALT lymphoma was initially diagnosed in salivary glands (n = 4), nasopharynx (n = 2), and 1 case each in conjunctiva, thyroid, stomach, colon, skin, lung, kidney, and retroperitoneum. Two patients had localized disease; 9 had disseminated disease with generalized lymphadenopathy (n = 8), multifocal lymphoma (n = 6), or bone marrow involvement (n = 5). No staging information was available for the remaining patients. None presented with B symptoms, splenomegaly, cytopenias, lymphocytosis, monoclonal gammopathy, or elevated serum lactate dehyrogenase. Serum β2-microglobulin was elevated in 6. Morphologically, the neoplasms had features typical of MALT lymphoma being composed of small- to medium-sized cells with round to slightly irregular nuclear contours and moderate amount of cytoplasm. Lymphoepithelial lesions were noted in 4 cases. CD5 was positive in all cases by immunohistochemistry (n = 12) and/or flow cytometry (n = 11). All cases assessed were negative for cyclin D1 (13/13) and CD10 (11/11). Conventional cytogenetics in 7 cases showed trisomy 3 in 3 and diploid in 4. With a median follow-up of 71 months (range, 2-131 months), overall survival at 5 years was 100%, although 5 patients required chemotherapy. Our results show that CD5 expression is rare in MALT lymphoma, and is often associated with nongastric disease and an increased tendency to present with disseminated disease. Overall survival is excellent with appropriate therapy., (Published by Elsevier Inc.)

Bi-clonality is a rare phenomenon seen in approximately 5% of chronic B-cell lymphoproliferative disorders. Both true bi-clonality and somatic hypermutation resulting in intraclonal evolution have been described. We present the case of a 37-year-old female who developed extranodal marginal zone B-cell lymphoma with immunohistochemical studies showing monotypic immunostaining of plasma cells for immunoglobulin lambda light chain on her right arm in 2008. Three years later, she developed a second focus of extranodal marginal zone B-cell lymphoma on her left arm, but immunohistochemical studies demonstrated monotypic immunostaining of plasma cells for immunoglobulin kappa light chain confirmed after repeat analysis. Evaluation for systemic lymphoma with laboratory and imaging studies was negative. Together, the findings were consistent with bi-clonal, multifocal extranodal primary cutaneous marginal zone B-cell lymphoma. We present this case to highlight a rare phenomenon within primary cutaneous marginal zone lymphomas., (Copyright © 2012 John Wiley & Sons A/S.)

Background: Primary cutaneous B-cell lymphomas (PCBCL) are subdivided into the aggressive form, primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT) and two subtypes of indolent behaviour (primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone B-cell lymphoma). The difference in clinical behaviour can be explained by the tumour cell itself, or the lymphoma microenvironment including the antitumour immune response., Objectives: To investigate the presence of regulatory T cells (Treg), CD4+CD25+FOXP3+, in the microenvironment of PCBCL in correlation with clinical outcome., Methods: Tumour specimens of 55 consecutive cases of PCBCL were blinded and analysed for FOXP3, CD4 and CD25 expression by immunohistochemistry. Confocal images were taken with a Leica SP5. Statistical analyses were performed to determine significance. The test was considered significant when P<0.05., Results: The CD4 and FOXP3 expression as well as the CD4/FOXP3 ratio were significantly increased in PCBCL of indolent behaviour in contrast to PCLBCL, LT (P=0.0002 for CD4, P<0.0001 for FOXP3 and P=0.0345 for FOXP3/CD4 ratio). CD25 expression did not differ in the three groups (P=0.9414). Within the group of patients with PCLBCL, LT we identified a subgroup with FOXP3+ tumour cells as demonstrated by CD20/FOXP3 double stainings. Patients with FOXP3+ PCLBCL, LT tumour cells showed a better prognosis on Kaplan-Meier analysis., Conclusion: High numbers of Treg in the lymphoma microenvironment correlate with a better prognosis in PCBCL. In PCLBCL, LT the presence of FOXP3+ tumour cells is beneficial for prognosis suggesting that FOXP3 expression of PCLBCL, LT tumour cells might serve as a tumour suppressor., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Rituximab (the chimeric anti-CD20 antibody) is widely used in the treatment of CD20 positive non-Hodgkin's lymphoma (NHL). The response rate at relapse after repeated use in prior CD20 positive responders is lower than 50%. Several mechanisms can be responsible for rituximab resistance. CD20 negative relapses which transformed from CD20 positive aggressive and indolent forms of lymphoma can be the one of the reason of secondary resistance to rituximab. The authors report a case with combination of aggressive and indolent form of lymphoma who relapsed after 7 months from the last dose of rituximab therapy. CD20 transformed negative from positive in her relapsed disease. Patients with CD20 positive B cell NHL must rebiopsy after first line rituximab therapy if their disease relapsed or progressed.

Objective: To study clinical and histopathological features, and diagnosis of mediastinal tumours of haematopoietic and lymphoid tissues (MTHL)., Methods: Forty cases of MTHL were analyzed for clinicopathology by microscopy and immunohistochemical staining and in situ hybridization, according to the updated 2008 WHO classification of tumours of haematopoietic and lymphoid tissues., Results: In 40 cases of MTHL, there were 20 males and 20 females. The ratio of male/female was 1:1. The mean age was 31.8 years and median age was 29 years (range, 12 - 70 years).Superior vena cava syndrome was observed in 28 cases. The specimens of 4 cases were obtained by lumpectomy, whereas 36 cases by biopsy (25 cases by thoracoscopy, 1 by core needle aspiration). Twenty cases lay in anterior mediastinum, and 2 in posterior, 1 in superior, 8 in anterior and superior, 2 in posterior and superior, 2 in anterior and middle, 1 in middle and anterior mediastinum.Frozen section were performed in 28 cases, and 17 cases were diagnosed as tumours of haematopoietic and lymphoid tissues (consistency ratio was 60.7%). Twelve cases were classical Hodgkin lymphomas (cHL) (8 were nodular sclerosis subtype, and 3 were mixed cellarity, 1 was lymphocyte-rich subtype), and 10 were primary mediastinal (thymic) large B cell lymphoma (PMBCL), 10 were precursor lymphocyte neoplasm [8 were T lymphoblastic leukemia/lymphomas (T-LBL), 2 were B-LBL], 1 was MALT lymphoma, 1 was composite lymphoma (PMBCL and cHL), 2 were myeloid sarcomas, 4 were gray zone lymphomas (GZL) (3 had morphology reminiscent of cHL, and 1 of DLBCL, all cases were positive for CD20, PAX5, CD30 and CD15).EBER were detected in 11 cases by in situ hybridization, 2 of which were positive (18.2%), and the 2 positive cases were cHL., Conclusions: MTHLs occur predominantly in adolescents and young adults, mainly present as superior vena cava syndrome and anterior mediasinal masses. cHL, PMBCL, T-LBL were the most common MTHLs.GZLs mainly occur in young adults, those whose morphology reminiscent of cHL, immunohistochemistry reminiscent of PMBCL, and vice versa. Thoracoscopy, frozen section and a suitable panel of antibodies were practical approaches to MTHL.

Background: Mucosa-associated lymphoid tissue (MALT) lymphoma comprises approximately 8% of all non-Hodgkin lymphomas and is the most common lymphoma in the gastro-intestinal tract. It is caused by genetic abnormalities or bacterial infections/chronic inflammation. B-cell lymphoma/leukemia 10 (BCL10) overexpression and nuclear expression have been associated with high-grade MALT lymphomas with genetic abnormalities that are unresponsive to Helicobacter pylori eradication treatment. To explore the molecular mechanism of BCL10 overexpression on the pathogenesis and malignant phenotype of MALT lymphoma, we generated EµSR-BCL10 transgenic mice., Procedure: By generation of heterozygous and homozygous EuSR-BCL10 mice and showing BCL10 expression levels in these mice, we quantitatively examined relation of MZ B cell expansion and inhibition of caspase-8 activity with BCL10 protein level. We also investigated API2 and caspase-8 expression by Western blot and their interaction with BCL10 by co-immunoprecipitation., Results: MZ B-cell expansion is directly related to BCL10 protein level in a dose-dependent manner. The activity of caspases-8 and -3, but not caspase-9, was inhibited with increasing of BCL10 protein level. Expanded MZ B cells showed selective survival under stimulation of anti-immunoglobulin M, but not dexamethasone, γ-irradiation, or anti-CD95, implying that overexpressed BCL10 exerts anti-apoptotic effects through B-cell antigen receptor (BCR) pathway. Overexpressed BCL10 protein co-immunoprecipitated with caspase-8 and API2 protein, suggesting an in vivo interaction of them., Conclusion: Our data demonstrate a novel effect of overexpressed BCL10 in the pathogenesis of high-grade MALT lymphoma by increasing expression of API2 and it then forming a protein complex with BCL10/caspase-8 leading to caspase-8 activity suppression., (Copyright © 2011 Wiley Periodicals, Inc.)

Under normal and pathological conditions, lymphocyte migration into the gastrointestinal mucosa to form gut-associated lymphoid tissue is mediated by the L-selectin ligand peripheral lymph node addressin and the integrin α4β7 ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on high endothelial venules (HEVs) and HEV-like vessels. In this review, we discuss these two distinct lymphocyte homing systems involved in the pathogenesis of chronic inflammatory gastrointestinal diseases with reference to our and others' previously published works. We also describe a recently developed recombinant integrin α4β7 heterodimeric IgG chimera that can be used as an immunohistochemical reagent to stain functional MAdCAM-1.

An 85-year-old Japanese woman was admitted to our hospital because of abdominal fullness. Computed tomography revealed multiple nodules in the liver; the interpretation was metastatic carcinoma. Serum laboratory test revealed extremely elevated α-fetoprotein (AFP) (8820 ng/mL; normal, <10 ng/mL). Upper and lower gastrointestinal endoscopy was performed and identified a large type-2 advanced gastric carcinoma and mucosal irregularity of the antrum. Biopsies were performed. The gastric carcinoma was well-differentiated papillotubular adenocarcinoma. Immunohistochemically, it was positive for pancytokeratins, AFP, hepatocyte paraffin-1 (HepPar1), p53 protein, and Ki-67 antigen (labeling, 70%) but was negative for vimentin, CEA, CA19-9, and lymphoid cell markers. Therefore, the lesion was diagnosed as AFP-producing gastric carcinoma with HepPar1 positivity. The biopsies of the gastric mucosal irregularity revealed severe lymphoid infiltration. The lymphoid cells were centrocyteslike cells with plasma cell differentiation and, immunohistochemically, were composed of CD20-positive B cells. A small number of CD3-positive T cells were also seen. Lymphoepithelial lesions were recognized. Therefore, the lesion was diagnosed as mucosal-associated lymphoid tissue lymphoma. Helicobactor pylori were recognized on Giemsa stain. The present case showed that AFP-producing gastric adenocarcinoma and mucosal-associated lymphoid tissue lymphoma can coexist. They may be associated with H. pylori infection. It was also interesting that the AFP-producing gastric carcinoma expressed HepPar1., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The microtubule associated tumor suppressor gene 1 (MTUS1) is a recently published tumor suppressor gene, which has also been shown to act as an early component in the growth inhibitory signaling cascade of the angiotensin II type 2 receptor (AT2R). In this study we report the generation of MTUS1 knock-out (KO) mice, which develop normally but reveal higher body weights and slightly decreased blood pressure levels. Twenty-eight percent of the studied MTUS1 KO mice also developed heart hypertrophy and 12% developed nephritis, independent of blood pressure levels. Forty-three percent of the MTUS1 KO mice revealed lymphoid hyperplasia affecting spleen (20%), kidney (37%), lung (23%), lymph nodes (17%), and liver (17%) accompanied with leukocytosis, lymphocytosis, and mild anemia. One animal (3%) developed a marginal zone B-cell lymphoma affecting submandibular salivary gland and regional lymph nodes. The symptoms of all mentioned animals are consistent with a B-cell lymphoproliferative disease with features of systemic lupus erythematosus. In addition, body weight of the MTUS1 KO mice was significantly increased and isolated skin fibroblasts showed increased cell proliferation and decreased cell size, compared to wild-type (WT) fibroblasts in response to depleted FCS concentration and lack of growth factors. In conclusion we herein report the first generation of a MTUS1 KO mouse, developing spontaneous heart hypertrophy and increased cell proliferation, confirming once more the anti-proliferative effect of MTUS1, and a SLE-like lymphoproliferative disease suggesting crucial role in regulation of inflammation. These MTUS1 KO mice can therefore serve as a model for further investigations in cardiovascular disease, autoimmune disease and carcinogenesis.

This report describes a 60-year-old man with concurrent gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and classical Hodgkin lymphoma (CHL). Atypical, medium-sized, lymphoid cells proliferated in the mucosa to muscular layer of the stomach showing a lymphoepithelial lesion; admixed with Hodgkin/Reed-Sternberg (HRS) cells and an inflammatory cell background. MALT lymphoma cells expressed CD20, CD79a, PAX5, and BOB.1, and HRS cells expressed CD30, CD15, Epstein-Barr virus-encoded RNA, and EBV-latent membrane protein 1. Only CHL invaded into the regional lymph nodes. Two possibilities of transformation of MALT lymphoma into CHL and de novo CHL within MALT lymphoma are discussed.

Objective: To study the clinicopathologic features of primary thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)., Methods: The clinical and pathologic findings were evaluated in 3 cases of biopsy confirmed thymic MALT lymphoma. The clincopathologic features, treatment and prognosis were discussed and literatures reviewed., Results: One male and two female patients presented with asymptomatic mediastinal masses with a history of Sjögren syndrome. They were aged 36, 35 and 41 years respectively, and only one patient had B symptoms. Grossly, all three tumors were encapsulated and had multiple variable-sized cysts on cut-surface. Histopathologically, the normal thymic lobular architecture was effaced by abnormal dense lymphoid infiltration. Prominent lymphoepithelial lesions were formed by centrocyte-like cells infiltrating and expanding Hassall's corpuscles and epithelial cyst lining. All cases showed apparent plasmacytic differentiation. Immunohistochemically, the tumor cells were positive for CD20, CD79a, bcl-2 and negative for CD3, CD5, cyclin D1, CD43, CD10, bcl-6, and CD23. The plasma cells showed kappa light chain restriction. Immunoglobulin heavy chain rearrangement in three cases was confirmed by PCR. All patients were at early stage and received routine chemotherapy with or without radiotherapy after surgical removal. All patients achieved complete remission with 24, 18 and 3 months follow-up, respectively., Conclusions: Primary thymic MALT lymphoma may be a rare distinctive lymphoma. It can be diagnosed by HE and immunohistochemical study and should be differentiated from reactive lymphoid proliferation, other types of lymphoma and mediastinal thymoma.

The genetics and pathogenesis of splenic marginal zone lymphoma are poorly understood. The lymphoma lacks chromosome translocation, and approximately 30% of cases are featured by 7q deletion, but the gene targeted by the deletion is unknown. A recent study showed inactivation of A20, a "global" NF-κB negative regulator, in 1 of 12 splenic marginal zone lymphomas. To investigate further whether deregulation of the NF-κB pathway plays a role in the pathogenesis of splenic marginal zone lymphoma, we screened several NF-κB regulators for genetic changes by PCR and sequencing. Somatic mutations were found in A20 (6/46=13%), MYD88 (6/46=13%), CARD11 (3/34=8.8%), but not in CD79A, CD79B and ABIN1. Interestingly, these genetic changes are largely mutually exclusive from each other and MYD88 mutation was also mutually exclusive from 7q deletion. These results strongly suggest that deregulation of the TLR (toll like receptor) and BCR (B-cell receptor) signaling pathway may play an important role in the pathogenesis of splenic marginal zone lymphoma.

Objective: To investigate the clinical and laboratory characteristics of tumor like Sjögren's syndrome (TLSS) patients and non-tumor like Sjögren's syndrome (NTLSS) and the incidence of lymphoma in patients of Sjögren's syndrome (SS)., Methods: A retrospective analysis was carried out in 199 primary SS (including TLSS) patients who were recruited in Peking University School and Hospital of Stomatology from 1998 to 2010. Clinical and laboratory information were collected. The patients were divided into two groups: TLSS (n = 25) and NTLSS (n = 174). Clinical and laboratory characteristics were compared between these two groups by a statistical analysis., Results: Of the 25 TLSS patients, 23 had enlargements of parotid glands and 2 had enlargements of submandibular glands. There were significant differences of salivary scintigraphy appearance (P = 0.018), hypergammaglobulinemia (P = 0.014), rheumatoid factor positive rate (P = 0.001), formation of the ectopic germinal centers (P = 0.014), double positive rate of anti-SSA antibody and anti-SSB antibody (P < 0.001) between the TLSS and NTLSS patients. Among the 25 TLSS patients, 3 developed lymphomas, accounting for 1.5% (3/199) of the total 199 patients and 12% (3/25) of the TLSS patients. Lymphoma subtypes included one diffused large B-cell lymphoma and two mucosa-associated lymphoid tissue lymphoma. There was no lymphoma detected in NTLSS patients., Conclusions: There are clinical and laboratory differences between TLSS and NTLSS patients, with a more tendency to develop lymphomas in TLSS patients.

The morphologic distinction between cutaneous marginal zone lymphoma (CMZL) and secondary cutaneous involvement by B-cell chronic lymphocytic leukemia (B-CLL) can be difficult. Both entities can show very similar architectural patterns of involvement in the skin and not uncommonly, the skin can be the first site of presentation of B-CLL in the elderly. We reviewed biopsies of 13 patients with cutaneous B-CLL and 14 patients with CMZL to compare their histologic and immunohistochemical features. CMZL and cutaneous B-CLL both predominantly exhibited a nodular pattern of skin involvement (9 of 13 B-CLL, 9 of 14 CMZL) with a minority of cases demonstrating a diffuse pattern (4 of 13 B-CLL, 4 of 14 CMZL). Although reactive germinal centers (12 of 14 cases) and plasma cells (10 of 14 cases) were seen more often in CMZL, plasma cells were also observed in cases of B-CLL (4 of 13). The lesional cells of B-CLL expressed CD79, CD5, CD23, and CD43, although CMZL did not express CD5 or CD43. Although we noted light chain restriction in 13 of 14 cases of CMZL cases, we also observed light chain restriction in 4 of 13 cases of B-CLL. Our results indicate that CMZL and B-CLL can be morphologically similar and both may show light chain restriction. Complete immunophenotyping is necessary to ensure that all cases are correctly classified.

Genetic events underlying pathogenesis of nodal and extranodal marginal zone lymphoma are not completely understood. We report here a novel t(X;14)(p11.4;q32.33) identified in 4 lymphoma cases: 2 with a mucosa-associated lymphoid tissue lymphoma, one with a nodal marginal zone lymphoma and one with gastric diffuse large B-cell lymphoma. In all cases, lymphoma evolved from a previous auto-immune disorder. Fluorescence in situ hybridization and molecular studies showed that t(X;14), which is mediated by immunoglobulin heavy chain locus, targets the GPR34 gene at Xp11.4. Upregulation of GPR34 mRNA and aberrant expression of GPR34 protein has been demonstrated in 3 presented cases by quantitative real-time polymerase chain reaction and immunohistochemistry, respectively. GPR34 belongs to the largest family of cell surface molecules involved in signal transmission that play important roles in many physiological and pathological processes, including tumorigenesis. Although functional consequences of t(X;14) have not been identified, our studies suggest that up-regulated GPR34 activate neither nuclear factor-κB nor ELK-related tyrosine kinase.

Mucosa-associated lymphoid tissue (MALT) lymphoma arising in the thymus is a rare disorder that shows a strong association with autoimmune disease. Several MALT-lymphoma-specific and -associated chromosomal abnormalities, including t(11;18), t(14;18), t(1;14), trisomy 3 and trisomy 18, are known to occur. The former translocation results in apoptosis inhibitor 2 gene (API2)-MALT lymphoma-associated translocation 1 (MALT1) fusion. In this study, we examined 14 cases of thymic MALT lymphomas for API2-MALT1 fusion using multiplex reverse transcription polymerase chain reaction and looked for trisomy 3, trisomy 18 and abnormalities of MALT1 and IGH genes using fluorescence in situ hybridization. Thymic MALT lymphoma cases had a high frequency of trisomy 3 (7/14 cases), a very low incidence of trisomy 18 (1/14) and no detectable MALT1-associated (0/13) or IGH-associated (0/13) gene abnormalities including t(11;18). A review of the literature showed that the pattern of chromosomal aberrations in thymic MALT lymphoma was similar to those of thyroid and salivary gland MALT lymphomas. Although frequently detected, trisomy 3 was not associated with any of the clinicopathological factors analyzed, suggesting that trisomy 3 may play a role in lymphoma development. In conclusion, the present study showed that thymic MALT lymphoma has a characteristic pattern of chromosomal aberrations that may be similar to those of other autoimmune-associated MALT lymphomas., (© 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.)

Aims: Making a differential diagnosis of IgG4-related disease from mucosa-associated lymphoid tissue (MALT) lymphoma or any other chronic inflammation is often challenging. Moreover, the association with secondary lymphoma of ocular adnexal IgG4-related disease needs to be elucidated., Methods and Results: We investigated 14 cases of IgG4-related disease, nine MALT lymphomas and 12 other chronic inflammations involving the lacrimal gland and orbit. Bilateral involvement was frequent in IgG4-related diseases. The number of IgG4-positive cells and the ratio of IgG4/IgG-positive cells were higher in patients with IgG4-related disease than in those with MALT lymphoma (P = 0.016; P < 0.001) and other types of inflammation (P < 0.001; P < 0.001). Monoclonal B cell proliferation was suspected in two cases (14.3%) of IgG4-related disease. One of these patients also displayed monomorphous features suggesting secondary MALT lymphoma. In the other case, κ-chain restriction in IgG4-positive cells was observed, raising the possibility of IgG4-producing MALT lymphoma. Trisomy 3, trisomy 18 or MALT1 translocation was observed in none of the IgG4-related cases. Regulatory T-cell infiltration was higher in cases of IgG4-related disease than in MALT lymphomas (P < 0.001) and other types of inflammation (P = 0.006)., Conclusions: Some genetically and morphologically complicated cases of ocular adnexal IgG4-related disease emphasize the need for in-depth studies to differentiate this disease from MALT lymphoma, and to exclude secondary lymphoma., (© 2011 Blackwell Publishing Limited.)

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is a mature B-cell neoplasm that typically follows an indolent clinical course. Amyloid deposition associated with MALT lymphoma is uncommon. We describe the clinical and pathologic features of 20 cases of MALT lymphoma and associated amyloid deposition across diverse primary sites. Frozen section immunofluorescence performed on 4 cases suggests that these deposits are a localized form of AL amyloid. Clinical follow-up was available for 15 patients. Amyloid deposits distant from the initial site occurred in 5 cases, always at sites also involved by the underlying lymphoma. No definitive evidence of systemic amyloidosis affecting the heart, kidneys, or liver was present in any patient. Given the generally indolent clinical behavior of MALT lymphomas with associated amyloid, we do not recommend extensive follow-up testing for systemic amyloidosis or more aggressive therapy than would be indicated for other MALT lymphomas of similar clinical stage.