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Gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arises against a background of chronic inflammation caused by persistent Helicobacter pylori infection. The clinical and histopathologic features of the human tumor can be reproduced by Helicobacter infection of BALB/c mice. In this study, we have analyzed the antibody sequences and antigen specificity of a panel of murine and human MALT lymphoma-derived antibodies. We find that a majority of tumors in patients as well as experimentally infected mice are monoclonal. The tumor immunoglobulin heavy chain genes have undergone somatic hypermutation, and approximately half of all tumors show evidence of intraclonal variation and positive and/or negative selective pressure. Recombinantly expressed MALT lymphoma antibodies bind with intermediate affinity to various unrelated self- and foreign antigens, including Helicobacter sonicate, immunoglobulin G (IgG), DNA, and stomach extract; antigen binding is blocked in a dose-dependent manner in competitive enzyme-linked immunosorbent assays. A strong bias toward the use of V(H) gene segments previously linked to autoantibodies and/or polyreactive antibodies in B-cell malignancies or autoimmune pathologies supports the experimental finding of polyreactivity. Our results suggest that MALT lymphoma development may be facilitated by an array of local self- and foreign antigens, providing direct antigenic stimulation of the tumor cells via their B-cell receptor.

Mucosa-associated lymphoid tissue (MALT) lymphoma arising in the thymus is extremely rare and little is known regarding its clinicopathological features. This study examined the clinicopathological features of nine cases of thymic MALT lymphoma. Most patients had autoimmune disease or hyperglobulinemia, and they also had cysts in the tumors. Both increased serum autoantibody levels and polyclonal serum immunoglobulin levels remained essentially unchanged after total thymectomy in all patients. Thymic MALT lymphoma needs to be included in the differential diagnosis in Asian patients with a cystic thymic mass accompanied by autoimmune disease or hyperglobulinemia.

Background: The pathology and clinical course of patients with CD5+ chronic B-cell lymphoproliferative disorders, excluding those that present with typical chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) or mantle cell lymphoma, (i.e. CD5+B-CLPD) are poorly defined., Methods: We studied patients with CD5+B-CLPD to (1) more completely define the clinical features and pathology of CD5+B-CLPD, (2) compare these features to patients presenting with typical CLL, and (3) test the hypothesis that a subset of patients with CD5+B-CLPD could have a unique B-cell malignancy., Results: We identified 229 patients with CD5+B-CLPD. A definitive pathological diagnosis was made in all 61 (27%) CD5+B-CLPD patients with nonbone marrow (BM) biopsy specimens considered adequate for a comprehensive pathological examination. The most common diagnosis among these 61 patients was CLL (44%) followed by the leukemic phase of marginal zone lymphoma (34%), lymphoplasmacytic lymphoma (11%), diffuse large B cell lymphoma (8%), and high-grade B cell lymphoma not otherwise specified (2%). In contrast, among 168 patients without a non-BM tissue biopsy specimen, a specific diagnosis could be made on review of all available data in only 24 (14%) with 144 (86%) remaining "unclassified.", Conclusions: In patients with CD5+B-CLPD, a definitive diagnosis can be made on an adequate non-BM tissue biopsy suggesting that this entity does not include a novel disease. We recommend that all patients with CD5+B-CLPD should have a non-BM tissue biopsy to make a definitive diagnosis prior to initiation of treatment., (© 2010 International Clinical Cytometry Society.)

Splenic marginal zone lymphoma (SP-MZL) is a rare low-grade B-cell neoplasm that often shows leukemic manifestation. Less than 20% of cases of SP-MZL express CD5. We analyzed 11 cases of CD5-positive SP-MZL with leukemic manifestation. The clinical characteristics of these cases did not differ from those of CD5-negative SP-MZL. Flow cytometry revealed positive results as follows : CD3, 0/9 ; CD5, 11/11 ; CD10, 0/11 ; CD11c, 4/10, CD13, 5/11 ; CD19, 11/11 ; CD20, 10/11 ; CD21, 4/4 ; CD22, 7/7 ; CD23, 5/10 ; CD25, 8/11 ; FMC7, 5/7 ; κ type 6/9, and λ type 2/9. All 3 cases with monoclonal γ-globulinemia expressed CD13. Resected spleen exhibited a proliferation of neoplastic cells in white pulp in all 8 splenectomy patients and a marginal pattern was detected in 5 patients. Only 2 cases showed involvement of red pulp. Immunohistochemistry showed that the lymphoma cells were positive for CD5, CD20, and BCL-2 and negative for CD3, CD10, cyclin D1, BCL-6, and MUM-1 in all 11 cases. These results suggest that CD5-positive SP-MZL differs from B-cell chronic lymphocytic leukemia, that CD13 expression is found in about half of CD5-positive SP-MZL cases, and that CD5-positive SP-MZL may be related to memory B-cell neoplasm or plasma cell differentiation.

Anetoderma is a rare condition, consisting of well-circumscribed areas of slack skin, in which dermal elastic fibres are destroyed or deficient. We present the case of a 45-year-old man with a 25-year history of deep nodules and plaques gradually progressing to areas of anetoderma. Histological examination found an infiltrate composed of neoplastic cells with lymphoplasmocytoid morphology. The cells were positive for CD20, CD38 and CD138, and there was a monoclonal kappa light chain gene rearrangement of plasma cells. A diagnosis of cutaneous marginal-zone B-cell lymphoma was made. The pathogenesis of anetoderma remains unknown, but it is possible that cytokines or other soluble factors produced by the infiltrating lymphocytes have a role in this process.

BCL10, required for nuclear factor kappaB (NF-kappaB) activation during antigen-driven lymphocyte responses, is aberrantly expressed in mucosa-associated lymphoid tissue-type marginal zone (MZ) lymphomas because of chromosomal translocations. Emu-driven human BCL10 transgenic (Tg) mice, which we created and characterize here, had expanded populations of MZ B cells and reduced follicular and B1a cells. Splenic B cells from Tg mice exhibited constitutive activation of both canonical and noncanonical NF-kappaB signaling pathways is associated with increased expression of NF-kappaB target genes. These genes included Tnfsf13b, which encodes the B-cell activating factor (BAFF). In addition, levels of BAFF were significantly increased in sera from Tg mice. MZ B cells of Tg mice exhibited reduced turnover in vivo and enhanced survival in vitro, indicative of lymphoaccumulation rather than lymphoproliferation as the cause of MZ expansion. In vivo antibody responses to both T-independent, and especially T-dependent, antigens were significantly reduced in Tg mice. Mortality was accelerated in Tg animals, and some mice older than 8 months had histologic and molecular findings indicative of clonal splenic MZ lymphoma. These results suggest that, in addition to constitutive activation of BCL10 in MZ B cells, other genetic factors or environmental influences are required for short latency oncogenic transformation.

We report fine-needle aspiration cytology (FNAC) obtained from two cases of mucosa-associated lymphoid tissue (MALT) lymphoma with extreme plasma cell differentiation. The patients were 61-year-old and 69-year-old Japanese women presenting with thyroid swelling. The smears contained numerous plasma cells, lymphocytes with plasma cell differentiation and scattered centrocyte-like (CCL) cells. In addition, one case demonstrated occasional atypical giant plasma cells. Occasional intranuclear inclusions (Dutcher bodies) of the plasma cells were observed in the other case. A few cytologic lymphoepithelial lesions-clusters (originating from lymphoepithelial lesions in histology) were also observed in one case. Plasma cells occupied approximately 10% in all of the lymphoid populations in FNAC specimens of Hashimoto thyroiditis, whereas, both cases demonstrated approximately 45% plasma cells and lymphocytes with plasma cell differentiation of all lymphocytes.The cytomorphologic findings of both cases were similar to those of plasmacytoma of the thyroid. However, immunohistochemical and flow cytometry studies demonstrated that both cases were MALT lymphoma with extreme plasma cell differentiation. From a therapeutic perspective, it is important to discriminate MALT lymphoma from plasmacytoma.

Objective: To investigate the clinicopathologic features of lymphoplasmacytic lymphoma (LPL) with Waldenström's macroglobulinemia (WM) and to evaluate the usefulness of immunophenotype analysis in diagnosis and differential diagnosis of the tumor., Methods: A total of 40 cases of LPL with WM diagnosed according to the 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues were analyzed using immunophenotype and follow-up information., Results: The mostly common initial clinical presentations were non-specific symptoms, such as fatigue, anemia and hemorrhage. Lymphadenopathy, splenomegaly and hepatomegaly were found in 42.5%, 20.0% and 12.5% of the patients respectively. The pattern of bone marrow involvement included mixed type (47.2%), diffuse type (41.7%) and interstitial type (11.1%). The nodal architecture was completely destroyed in one case and partially effaced with residual germinal centers and dilated sinuses in 8 cases. All of the neoplastic cells expressed CD20 and CD79a. Neoplastic plasma cells were positive for CD138 and CD79a. No cases expressed CD5. Four cases weakly expressed CD23. No significant prognosis related factors were identified in the survival analysis., Conclusions: LPL with WM is a rare indolent small B-cell lymphoma, which is commonly seen, in older male patients. The tumor frequently involves bone marrow and shows various clinical manifestations. Combination analyses of the bone marrow biopsy histology, immunophenotypic study and clinical data, especially the serum examination are important for the diagnosis of LPL with WM.

Splenic marginal zone lymphoma (SMZL) is a well-recognized entity in which chromosomal aberrations seem to be potential markers in diagnosis, prognosis and disease monitoring. FOXP1 is a transcriptional regulator of B lymphopoiesis that is deregulated in some types of NHL. Translocation t(3;14)(p14;q32) has been described in marginal zone lymphomas but few series have studied FOXP1 involvement in SMZL. We performed cytogenetic, fluorescence in situ hybridization (FISH) and immunohistochemical (IHC) studies in a series of 36 patients in order to study the status of FOXP1 in this entity. According to our results, FOXP1 is not rearranged in SMZL, although we were able to demonstrate gains of FOXP1 gene due to trisomy 3/3p by FISH. FOXP1 protein expression seemed to be not related to any aberration and IHC studies are not conclusive.

Objective: To investigate the clinicopathologic features, diagnosis, differential diagnosis and the prognosis of hairy cell leukemia (HCL)., Methods: Fifteen splenectomy specimens of HCL patients were investigated retrospectively using HE and immunohistochemistry in correlation with the follow-up information., Results: (1) The male to female ratio was 2.75:1, age ranged from 36 to 68 years with a median of 47 years. The most consistent clinical feature at presentation was marked splenomegaly (100%). Other symptoms included anemia (80.0%), thrombocytopenia (60.0%), leucocytosis (53.3%), pancytopenia (20.0%) and the absence of B-symptom. (2) The proportion of hairy cells was (14.6 +/- 7.2)% in periphery blood and (47.3 +/- 23.8)% in bone marrow. The positive rate of TRAP assay was 62.5% in bone marrow; 85.7% for TPA test and the detection rate for RLC was 25% by transmission electric microscopy. The frequency of bone marrow involvement was 100%. (3) The average weight of 15 spleens was (3012 +/- 1974) g. The size of 6 spleens ranged from 16 cm x 10 cm x 5 cm to 32 cm x 20 cm x 14 cm. The white pulp of spleen showed a characteristic atrophy feature or even absent due to leukemic infiltration, predominantly involving the red pulp with some sinusoidal pattern. "Blood pool" change was an infrequent feature (3/15 cases). The nuclei of leukemic cells were round (13 cases) or bean-shaped (2 cases), nucleoli inconspicuous or disappeared. The abundant cytoplasm and prominent cell border resulted in a "fried egg" appearance. By immunohistochemistry, leukemic cells were positive for CD45RA, CD20, PAX-5, CD25, CD11c, Annexin A1 and cyclinD1, but negative for CD3 and CD43. (4) 13 cases (86.7%) have been followed-up and all are alive. Among them, 9 cases are living well more than 5 years and 7 more than 10 years., Conclusions: Splenomegaly is frequently the first manifestation of patients with HCL and occurred predominantly in the middle to elderly adults. Definite diagnosis of HCL requires a combined histological and immunohistochemical assessment of the splenectomy specimen, bone marrow biopsy and aspirate.

Objective: To investigate the difference of the prevalence of t(11;18)(q21;q21)/API2-MALT1 fusion gene between gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL)., Methods: A total of 57 cases gastrointestinal MALT lymphomas (38 gastric and 19 intestinal lymphomas), 32 DLBCL (28 gastric and 4 intestinal lymphomas) and 7 cases gastric DLBCL accompanied MALT lymphoma were collected from the Cancer Hospital of Fudan University. API2-MALT1 fusion gene was detected by fluorescent in situ hybridization (FISH) using both dual fusion translocation and break apart probes., Results: Among gastrointestinal MALT lymphomas, API2-MALT1 fusion gene was found in 12 of 57 cases (21.1%, 10 gastric and 2 intestinal lymphomas). In contrast, the fusion gene was not found in all 32 DLBCL and 7 gastric DLBCL with MALT lymphoma component. There was statistical significant difference between two groups (chi(2) = 9.383, P = 0.001)., Conclusions: API2-MALT1 fusion gene is a distinctive genetic aberration in MALT lymphomas, and is not present in DLBCL. The findings suggest that gastrointestinal tract MALT lymphomas with API2-MALT1 fusion gene may not transform into DLBCL, which may represent primary lymphoma or transformed API2-MALT1 negative MALT lymphomas.

Clinical and biological studies on nodal marginal zone lymphoma (NMZL) are hampered by the lack of specific diagnostic markers and the low reproducibility of this diagnosis. A comparative expression-profiling study has shown a set of markers to be differentially expressed in NMZL compared with follicular lymphoma (FL), including myeloid cell nuclear differentiation antigen (MNDA), a nuclear protein expressed by myeloid cells and a subset of B-cells. The aim of this study was to characterize the expression of MNDA in normal and reactive human tissue, and in a large series of non-Hodgkin's B-cell lymphomas, with particular emphasis on NMZL and FL. Our results showed that MNDA is expressed in normal tissue by a subset of the marginal zone B cells. They also showed MNDA expression in subgroups of chronic lymphocytic leukemia, mantle-cell lymphoma, and diffuse large B-cell lymphoma, but MNDA was especially expressed by lymphomas derived from the marginal zone, such as mucosa-associated lymphoid-tissue lymphoma, splenic marginal-zone lymphoma and NMZL. MNDA expression was rarely observed in FL, a characteristic that is of potential value in distinguishing between NMZL and FL. MNDA expression is thus a useful tool for the recognition of NMZL.

The histogenesis of primary cutaneous marginal zone B-cell lymphoma (PCMZL) has not yet been clarified. Plasma-cytoid dendritic cells (PDC) play a crucial role in the initiation of immune responses and activation of T-cells and B-cells. We analyzed the presence of PDC by immunohistochemistry in various forms of primary cutaneous B-cell lymphomas and in B-cell pseudolymphomas. Clusters of CD123+PDC were observed in all PCMZL (23 of 23 cases; 100%) and in two-thirds of cutaneous B-cell pseudolymphomas (14 of 22; 64%), but only in a minority of primary cutaneous follicle center lymphoma (4 of 31; 13%) and not in primary cutaneous diffuse large B-cell lymphoma, leg type. CD123+ PDC clusters were found in close proximity to monoclonal plasma cells and T-cells and were already present at high numbers in early lesions and initial recurrences of PCMZL. In conclusion, the detection of larger clusters of PDC in PCMZL provides a useful adjunctive diagnostic marker and suggests a pathogenetically relevant role of these cells in PCMZL. Furthermore, the occurrence of PDC could explain the high number of T-cells typically found in PCMZL. We propose considering PCMZL as a unique and potentially antigen-driven neoplasm with PDC, T-cells, and B-cells as the constitutive tumor components.

MALT (mucosa-associated lymphoid tissue) lymphomas are low-grade extranodal B-cell lymphomas that may involve various sites in the head and neck including the thyroid, salivary, and lacrimal glands. Development of MALT lymphoma in the head and neck is often associated with autoimmune diseases such as Sjögren syndrome or Hashimoto thyroiditis. Here we report a case of a MALT lymphoma of the floor of the mouth that likely arose in the sublingual gland. The patient was successfully treated with external-beam radiation therapy and remained disease-free at the 4-year follow-up.

Nodal marginal zone lymphoma (NMZL) represents a rare and heterogeneous group that lacks markers specific for the diagnosis. We evaluated morphologic and immunoarchitectural features of 51 NMZLs, and the following immunostains were performed: CD20, CD21, CD23, CD5, CD3, CD43, CD10, Ki-67, BCL1, BCL2, BCL6, HGAL, and LMO2. Four immunoarchitectural patterns were evident: diffuse (38 [75%]), well-formed nodular/follicular (5 [10%]), interfollicular (7 [14%]), and perifollicular (1 [2%]). Additional features included a monocytoid component (36 [71%]), admixed large cells (20 [39%]), plasma cells (24 [47%]), compartmentalizing stromal sclerosis (13 [25%]), and prominent blood vessel sclerosis (10 [20%]). CD21 highlighted disrupted follicular dendritic cell meshwork in 35 (71%) of 49 cases, and CD43 coexpression was present in 10 (24%) of 42 cases. A panel of germinal center-associated markers was helpful in eliminating cases of diffuse follicle center lymphoma. Our results highlight the histologic and immunoarchitectural spectrum of NMZL and the usefulness of immunohistochemical analysis for CD43, CD23, CD21, BCL6, HGAL, and LMO2 in the diagnosis of NMZL.

Objective: To study the clinicopathologic features, diagnosis and differential diagnosis of splenic marginal zone B-cell lymphoma (SMZL)., Methods: The clinical data, histologic findings and immunophenotype of 8 SMZL cases were studied. IgH gene rearrangement was performed in 1 case. Follow-up information was available in 4 patients., Results: The median age of the patients was 61.5 years (range: 36 to 75 years). The male-to-female ratio was 1.7:1. All cases presented with massive splenomegaly. Five of six cases had abnormal blood counts: neutropenia and thrombocytopenia with two of them showing anemia. After splenectomy, the blood counts in 3/3 cases returned to normal levels. Post-operative fludarabine-based chemotherapy was given to 3 patients, two of them achieved complete remission and 1 case died during the course of chemotherapy. The average survival time was 21.5 months (range: 6 to 60 months). Histologically, all of the 8 cases showed micronodular white pulp lesions. Six of them exhibited the classic biphasic appearance with central aggregates of small B cells rimmed by a peripheral zone of atypical monocytoid B cells. The remaining 2 cases had a monomorphous appearance, consisting mainly of atypical monocytoid B cells. There was infiltration of tumor cells in the red pulp, sheets in appearance in all 8 cases. Immuno-histochemical staining showed CD20-positive (8/8), IgD-positive in 2 of the 4 cases (2/4), CD5-positive in 1 of the 4 cases (1/4), 6 of the 6 cases were bcl-2-positive, cyclin D1-negative and bcl-6/CD10-negative, CD43-negative in 5 of the 6 cases (5/6). The proliferation index, as highlighted by Ki-67 immunostaining, was low (< 15%)., Conclusions: SMZL is an indolent B-cell non-Hodgkin lymphoma. The main clinical manifestations are splenomegaly and abnormalities in blood counts. The main modality of treatment is splenectomy. Adjuvant fludarabine-based chemotherapy helps to achieve complete remission. In general, the prognosis of this lymphoma type is good. The lymphoma cells predominantly grow in micronodular pattern, with atypical monocytoid B cells rimming around the small B cells, which aggregates in the center. The differential diagnosis includes other small B-cell lymphomas and lymphoid hyperplasia of spleen.

Unlabelled: RATIONALE/HYPOTHESIS: Forkhead box protein P1 (FOXP1) is one member of the forkhead box protein P (FOXP) subfamily, which are transcription factors that mediate signaling and affect gene regulation, and elevated expression of FOXP1 has been reported to correlate with poor prognosis of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 expression occurs in mucosa-associated lymphoid tissue (MALT) lymphomas., Objective: FOXP1 expression and its relationship to morphology and prognosis in a series of 43 gastric MALT lymphomas were investigated retrospectively., Findings: The FOXP1 nuclear expression (44.2%, 19/43) of tumors between mono- and polymorphic histology (4 of 26 [15.4%] vs. 15 of 17 [88.2%]) was significantly different (p < 0.001). All 14 relapsed tumors after operation featured strong nuclear FOXP1 positivity. A significantly shorter cumulative 10-year survival (52.6%,10/19) was found in high FOXP1 expression patients, compared with patients with negative expression (83.3%, 20/24) (p < 0.01). Also, the cumulative 10-year survival rate (30.8%, 4/13) for stage IIE+IV was significantly shorter than that (83.3%, 25/30) in stage I+II (p < 0.01). Moreover, high FOXP1 expression and advanced stage IIE+IV were independent prognostic factors in multivariate Cox regression analysis., Conclusions: Our results show that FOXP1 expression is correlated with morphic histology, and FOXP1 and clinical staging appear to be independent prognostic factors in gastric MALT lymphomas., (Copyright 2009 S. Karger AG, Basel.)

Gastric extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MZL-MALT) is speculated to be immune mediated and is notable for responding to treatment by Helicobacter pylori eradication. However, the gastric MZL-MALT with t(11;18)(q21;q21) has been shown to be resistant to treatment by H. pylori eradication. We studied the molecular, immunohistochemical, and histological aspects of 48 cases of gastric MZL-MALT and used a reverse transcription real-time PCR assay to assess the presence of a t(11;18)(q21;q21) in formalin-fixed, paraffin-embedded tissue. Florescence in situ hybridization for t(11:18)(q21;q21) was used to confirm the real-time PCR results. Three distinct morphological subtypes were recognized: monocytoid, small lymphocytic, and plasmacytoid. Morphology, immunophenotype, and immunoglobulin heavy chain (IgH) gene rearrangement were correlated with the results of the t(11:18)(q21;q21) assay. Of the 48 analyzed cases, 15 (31%) were positive for t(11;18)(q21;q21) and 33 (69%) were monoclonal for IgH gene rearrangement. Of the 15, 13 (87%) cases with t(11;18)(q21;q21) translocation showed IgH gene rearrangement by PCR. Of the 33 t(11;18)(q21;q21)-negative cases tested, 20 cases (61%) showed IgH gene rearrangement. The 15 t(11;18)(q21;q21) translocation-positive cases had either monocytoid (12 of 15) or small lymphocytic morphology (3 of 15). Aberrant expression of CD43 was observed in 8 of 15 (53%) t(11;18)(q21;q21)-positive cases and 21 of 31 (68%) t(11;18)(q21;q21)-negative cases. Our data show that t(11;18)(q21;q21)-positive MZL-MALTs frequently show monocytoid morphology, less often small lymphocytic morphology, and not purely plasmacytoid morphology. Identification of a t(11;18)(q21;q21) by reverse transcription real-time PCR is highly specific for MZL-MALT and helps in the diagnosis of MZL-MALT. Studying the correlation between this translocation and morphological features may increase our understanding of the role of this translocation in the pathogenesis and the clinical behavior of gastric MZL-MALT.

The eradication of Helicobacter pylori (H. pylori) with antibiotics induces complete remission in 75% of patients with gastric MALT lymphoma. We investigated the efficacy of H. pylori eradication and assessed the predictive value of BCL10 nuclear expression and t(11;18)(q21;q21) regarding resistance to H. pylori eradication in primary gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients from mainland China. Twenty-two gastric MALT cases (Stage I(E)) underwent H. pylori eradication with antibiotics, and sequential endoscopic-bioptic follow-ups were performed and assessed with regular morphologic and immunohistochemical examinations. BCL10 nuclear expression and interphase fluorescence in situ hybridization (FISH) for MALT1 and API2/MALT1 were tested. Thirteen out of the 22 cases (59.1%) achieved complete regression (CR) after the eradication of H. pylori. The longest follow-up period in the 22 patients was 68 months, with 12 patients longer than 24 months. For the 13 CR patients, the longest follow-up period after H. pylori eradication was 53 months, with 6 patients longer than 24 months. BCL10 nuclear expression was detected by immunohistochemical staining in 9 cases, including 7 (77.8%) of 9 cases who showed no response (NR) and 2 (15.4%) of 13 patients who achieved CR following eradication therapy (P < 0.05). t(11;18)(q21;q21) was evaluated by interphase FISH in 18 cases including 11 CR and 7 NR patients after H. pylori eradication. t(11;18)(q21;q21) was found in 4 (57.1%) of 7 patients who showed NR following H. pylori eradication, but one in 11 CR patients (P < 0.05). A total of 59.1% of patients with early gastric MALT lymphoma recruited in this study achieved CR after H. pylori eradication. BCL10 nuclear expression and t(11;18)(q21;q21)-positive gastric MALT lymphomas are likely to be related to a failure to respond to H. pylori eradication in Chinese patients.

Objective: To detect the BCL10 expression and chromosomal translocations in pulmonary mucosa-associated lymphoid tissue (MALT) lymphomas, including t (11; 18)/API2-MALT1; t (1; 14)/IgH-BCL10 and t (14; 18)/MALT1-IgH, and to determine if aberrant nuclear BCL10 expression is related with chromosomal translocations., Methods: Twenty-three cases of pulmonary MALT lymphomas were collected from Cancer Hospital of Fudan University. BCL10 was detected by immunohistochemistry of EnVision method, and API2-MALT1, BCL10, MALT1, IgH chromosomal abnormalities were detected by fluorescent in situ hybridization (FISH) technique., Results: BCL10 was expressed in 82.6% (19/23) of the pulmonary MALT lymphomas. Among those cases, 9 of 23 (39.1%) were expressed in the cytoplasm, and 10 of 23 (43.5%) were in the nucleus. In the FISH results, 9 cases (39.1%, 9/23) showed API2-MALT1 fusion gene, 1 case with possible BCL10-IgH abnormality, but none showed chromosomal abnormalities related with MALT1 and IgH gene simultaneously. Among 10 BCL10 nuclear expressive cases only 5 harbored genetic abnormalities. There was no correlation between BCL10 aberrant nuclear expression and chromosomal translocations (chi(2) = 0.306, P = 0.685). Follow-up of 10 cases for a period of 7 to 35 months showed that all the patients were alive. Because different treatments applied in different patients (chemotherapy only, surgery with chemotherapy or surgery only), best available treatment could not be confirmed in this study., Conclusions: t (11; 18)/API2-MALT1 was the most common chromosomal abnormality in pulmonary MALT lymphomas, but t (1; 14)/BCL10-IgH and t (14; 18)/MALT1-IgH were rare. Pulmonary MALT lymphomas also had higher nuclear BCL10 expression, which was not correlated with chromosomal abnormalities. As a result, BCL10 nuclear expression and cytogenetic aberration may be helpful in the diagnosis, especially for small biopsy specimens.

A primary hepatic marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) is very rare. We found a solitary mass 27 mm in size in the left lobe of the liver of a 58-year-old Japanese man with a history of hepatitis-C infection. Based on the results of imaging studies, the tumor was diagnosed as a hepatocellular carcinoma (HCC). The left lobe of the liver was lobectomized and microscopic findings showed that the tumor was a hepatic MALT lymphoma, while immunohistochemistry showed it to be positive for CD20 and CD79a. In a fluorodeoxyglucose-positron emission tomography examination integrated with computed tomography scanning (FDG-PET CT) before surgery, the tumor was revealed to have a high standardized uptake value (SUV) for FDG. The patient received chemotherapy after surgery. To the best of our knowledge, 45 cases had been reported with a mean age for all patients of 61.4 years. The pathogenesis remains unclear, although half of the patients had a past history of chronic inflammatory liver disease. Surgical resection was performed in most cases and some patients received postoperative chemotherapy or radiotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed.

IgG4-related disease is a recently proposed clinical entity with several unique clinicopathological features. A chronic inflammatory state with marked fibrosis, which can often be mistaken for malignancy, especially by clinical imaging analyses, unifies these features. Little is known about lymphomagenesis in the context of IgG4-related disease, we recently first reported the ocular adnexal marginal zone B-cell lymphomas arising from IgG4-related disease. To the best of our knowledge, no existing study has ever established the neoplastic potential of IgG4-producing cells. In the present report, we describe the first IgG4-producing lymphoma. The patient was a 72-year-old male who was being followed for an asbestos-related pleural plaque. During follow-up, computed tomography revealed bilateral renal masses and multiple swollen retroperitoneal lymph nodes. A retroperitoneal lymph node biopsy was performed. Histologically, the interfollicular areas were expanded by medium to large plasmacytoid cells. These plasmacytoid cells showed nuclear pleomorphism and had prominent Russell bodies. Immunohistochemistry and double immunofluorescence staining of these cells revealed IgG4 positivity and monotypic lambda-light chain predominance. A portion of these cells were partially positive for CD20, negative for CD3, and somewhat faintly positive for CD138. In addition, serum IgG4 was elevated. Southern blot analysis of the lymph node specimen detected immunoglobulin heavy chain gene rearrangement. The present study indicates that, not only can malignant lymphomas occur in the setting of IgG4-related disease, but IgG4-producing cells can also be neoplastic.

Extranodal marginal zone B-cell lymphomas (MZBCLs) arise on a background of chronic inflammation resulting from organ-specific autoimmunity, infection, or by unknown causes. Well-known examples are salivary gland MZBCL in Sjögren's sialadenitis and gastric MZBCL in Helicobacter pylori gastritis. MZBCLs express CXCR3, a receptor for interferon-gamma-induced chemokines highly expressed in the chronic inflammatory environment. The immunoglobulin (Ig) variable heavy/light chain (IgV(H)/IgV(L)) gene repertoire of salivary gland and gastric MZBCL appears restricted and frequently encodes B-cell receptors with rheumatoid factor reactivity. Primary cutaneous marginal zone B-cell lymphomas (PCMZLs) are regarded as the skin-involving counterparts of extranodal MZBCLs. Although PCMZLs have been associated with Borrelia burgdorferi dermatitis, PCMZLs generally arise because of unknown causes. We studied an extensive panel of PCMZLs and show that PCMZLs do not conform to the general profile of extranodal MZBCL. Whereas most noncutaneous MZBCLs express IgM, PCMZLs in majority express IgG, IgA, and IgE and do not show an obvious immunoglobulin repertoire bias. Furthermore, the isotype-switched PCMZLs lack CXCR3 and seem to arise in a different inflammatory environment, compared with other extranodal MZBCLs.

Purpose: The well-known translocations identified in MALT lymphomas include t(11;18)/API2-MALT1, t(1;14)/IGH-BCL10, and t(14;18)/IGH-MALT1. Molecular investigations have suggested that these three disparate translocations affect a common pathway, resulting in the constitutive activation of nuclear factor-kappaB. However, the vast majority of MALT lymphomas are negative for any of the above-mentioned translocations and the underlying pathogenesis is unclear., Experimental Design: Fresh tissue of 29 gastric and extragastric MALT lymphomas was studied for genetic aberrations by conventional karyotyping, long-distance inverse PCR (LDI-PCR), fluorescence in situ hybridization (FISH), reverse transcription-PCR (RT-PCR), and real-time quantitative RT-PCR (QRT-PCR)., Results: Conventional cytogenetics, FISH, and RT-PCR identified aberrations in 26 of 29 MALT lymphoma. Balanced translocations were found in 21 cases. IGH was rearranged in the majority of cases with balanced translocations (n = 17/21); 3 cases had t(11;18)/API2-MALT1 and 1 case had novel t(6;7)(q25;q11), respectively. IGH partner genes involved MALT1, FOXP1, BCL6, and four new chromosomal regions on chromosome arms 1p, 1q, 5q, and 9p. LDI-PCR identified three novel partner genes on 1p (CNN3), 5q (ODZ2), and 9p (JMJD2C). FISH assays were established and confirmed LDI-PCR results. QRT-PCR showed deregulation of the novel genes in the translocation-positive cases., Conclusions: Our study expands the knowledge on the genetic heterogeneity of MALT lymphomas.

Objective: To detect the expression of p16 protein and Ki-67 antigen in gastric mucosa-associated lymphoid tissue lymphoma (MALTL) and normal gastric mucosa and to investigate the clinical significance of their expression in the occurrence and development of gastric MALTL., Methods: 47 samples of gastric MALTL diagnosed pathologically in the department of pathology of the PLA General Hospital from March 1993 to June 2005 were collected. By using immunohistochemical methods, the expression of p16 protein and Ki-67 antigen was detected in 20 samples of normal gastric tissue and the 47 samples of gastric MALTL., Results: The positive rate of p16 protein was 21.3% (10/47) and 90.0% in gastric MALTL and normal gastric tissue respectively. The positive rate of p16 protein in gastric MALTL was lower than that in normal gastric tissue (P < 0.05). The expression of p16 was related to the degree of lymph node metastasis. The positive rate of Ki-67 labelling index (LI) in gastric MALTL was higher than that in normal gastric tissue. A negative correlation was found between the expression of p16 protein and Ki-67 LI (P < 0.05)., Conclusions: Detection p16 and Ki-67 may help to predict the possibility of lymph node metastasis and prognosis in gastric MALTL.

We report here a case of marginal zone B-cell lymphoma (MZBL) arising from buccal mucosa resembling inflammatory myofibroblastic tumor (IMT) of the soft tissue. On a low-power field, the lesion is characterized by fibrous granulation tissue and numerous lymphoid follicles with or without atrophic small germinal center. A portion of the lymphoid follicles were surrounded by partial and/or complete thin pale cuff of centrocyte-like (CCL) cells on high power field. The thin rim of the lymphoid follicles contained CCL-cells, plasma cells, cells showing plasma cell differentiation and mature eosinophils. In contrast, the granulomatous areas contained were characterized by haphazardly arranged spindle cells, mature plasma cells, mature eosinophils, small-to-medium lymphocytes and histiocytes. Histologically, IMT was suspected. However, flow cytometry and immunohistochemical study demonstrated a monotypic nature of centrocyte-like cells, plasma cells and their precursor and confirmed the diagnosis of MZBL arising from the buccal mucosa. The differential diagnostic problems between IMT of the soft tissue and classical Hodgkin lymphoma and T-cell lymphoma have been discussed previously. However, the present case indicated that MZBL should be added to the differential diagnosis of IMT of the soft tissue.

To assess the role of interferon regulatory factor (IRF) 8 in B-cell development and lymphomagenesis, we studied its expression in reactive lymphoid tissues, its relationship to other B-cell transcription factors, and its expression in a series of 232 B-cell tumors and 30 cell lines representing a variety of B-cell developmental stages. We found that although IRF8 was detectable in most reactive B-cells, its expression levels differed with developmental stage. Germinal center B cells contained the highest levels of IRF8, with lower levels seen in mantle and marginal zone B cells and none in plasma cells. IRF8 was coexpressed with PAX-5, Pu.1, and B-cell lymphoma (BCL)-6, and similar to BCL-6, was absent from the small population of IRF4-positive germinal center B cells thought to be committed to postgerminal center developmental programs. Similarly, IRF8 was most strongly expressed in lymphomas of germinal center origin with lower levels present in mantle cell lymphomas, chronic lymphocytic leukemia, and marginal zone lymphomas, and no expression observed in plasmacytic/plasmablastic neoplasms. The reciprocal expression pattern with IRF4 in reactive tissues was generally maintained in lymphomas with some exceptions. These results suggest an important role for IRF8 during germinal center B-cell development and in related lymphomas, and provide a new diagnostic marker helpful in distinguishing B-cell non-Hodgkin lymphoma subtypes.

Chemokine receptors mediate migration and activation of lymphocytes through binding of their ligands. Recent studies have revealed important contributions of chemokine receptors to the development, progression, and dissemination of haematopoietic neoplasms. Because the chemokine receptor expression profile in extragastric MALT lymphoma is unknown, we performed a comprehensive study on tissue samples of parotid glands, parotid glands affected by Sjögren syndrome, extragastric MALT lymphoma, and extranodal diffuse large B-cell lymphoma (eDLBCL) originating from MALT lymphoma (transformed MALT lymphoma). By investigating the expression of 19 chemokine receptors by real-time PCR using a semi-quantitative approach and of four chemokine receptors (CCR1, CCR5, CXCR6, and XCR1) by immunohistochemistry, we show that the chemokine receptor expression profiles of extragastric MALT lymphomas differ substantially from those of extranodal DBLCL, with lower expression of CCR1, CCR8, and CXCR3, and the absence of expression of CX3CR1 and XCR1 in eDLBCL. Expression of CCR6, CCR7, CXCR3, CXCR4, and CXCR5, responsible for B-cell homing to secondary lymphoid tissue, was detected in both B-cell malignancies. Expression of CCR4 was just detected in trisomy 3-positive MALT lymphoma cases. Comparing gastric with extragastric MALT lymphomas, up-regulation of CXCR1 and CXCR2 accompanied by down-regulation of CCR8 and CX3CR1 and loss of XCR1 expression in extragastric MALT lymphomas appear to be key determinants for the site of origin of MALT lymphomagenesis. Our results support a model of stepwise progression of extragastric MALT lymphoma from a non-neoplastic event to Sjögren syndrome, to MALT lymphoma, and finally to overt eDLBCL, guided by differentially expressed B-cell homeostatic and activation-dependent chemokine receptors and their ligands., (Copyright (c) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Heat shock protein B (HspB) is one of the dominant proteins recognized by most Helicobacter pylori-infected persons and is being considered as potential candidates for subunit vaccines. In the present study we describe the generation of an antibody against HspB and its use in immunohistochemical assays on gastric biopsies. We have demonstrated that our rabbit polyclonal antibody against HspB did not recognize any protein in lysates from a lung human epithelial cell (H1299) line and did not cross-react with the other members of human heat shock proteins. Secondly, we have observed that in gastric biopsies, HspB immunostaining was present inside the cytoplasm of human epithelial cells with a particular localization in the apical portion of gastric epithelial cells other than in the extracellular spaces among gastric cells of human stomach. Finally, we have demonstrated a cytoplasmic HspB immunostaining in groups of neoplastic cells of MALT lymphoma. In conclusion, our observations suggest a possible involvement of HspB in the pathogenesis of H. pylori-related pathologies such as gastritis, ulcer and gastric cancer., ((c) 2008 Wiley-Liss, Inc.)

Deregulation of FOXP1 expression plays an important role in lymphoma development although the underlying molecular mechanism is poorly understood. FOXP1 is targeted by chromosome translocations in MALT lymphoma and diffuse large B-cell lymphoma, where high-level protein expression is associated with poor prognosis. Nonetheless, the incidence and nature of FOXP1 abnormalities at both the genetic and protein levels, and their correlation in these lymphomas are not well established. We investigated FOXP1 translocation, copy number change and protein expression in MALT lymphoma (n=321), MALT lymphoma with a diffuse large B-cell lymphoma component (59), nodal diffuse large B-cell lymphoma (64) and extranodal diffuse large B-cell lymphoma (151) by interphase fluorescence in situ hybridization and immunohistochemistry. FOXP1 translocation was found in eight MALT lymphomas and three MALT lymphomas with diffuse large B-cell lymphoma, with all positive cases originating in the stomach. In diffuse large B-cell lymphoma, the translocation was seen in 5 cases originating in the stomach (2), tonsil (1), large intestine (1) and lymph node (1). Immunoglobulin heavy chain gene was the translocation partner in 11 of the 16 positive cases. Fluorescence in situ hybridization mapping revealed FOXP1 breakpoints within the 5' untranslated region of the gene (upstream of exon 6, the first coding exon of full-length FOXP1) in 14 cases, but downstream of exon 6 (most likely upstream of exon 8) in the remaining 2 cases. Three copies of the FOXP1 gene were observed in MALT lymphoma (17%), MALT lymphoma with diffuse large B-cell lymphoma (12%) and diffuse large B-cell lymphoma (32%), including cases with FOXP1 translocation (19%). Immunohistochemistry showed strong/moderate FOXP1 staining in all the cases with FOXP1 translocation. However, FOXP1 expression was independent of FOXP1 translocation or copy number changes. Our findings suggest that (1) FOXP1 translocation may disrupt the full-length FOXP1 transcript and lead to expression of FOXP1 transcript variants with alternate 5' ends and (2) mechanisms other than translocation and copy number changes are also responsible for FOXP1 overexpression in lymphoma.

Described herein is a case of thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Using immunohistochemical double staining it was found that most of the thymic lymphoid follicles in this case possessed cytokeratin-positive and follicular dendritic cell (FDC) marker-positive cells. Moreover, using immunoelectron microscopy it was confirmed that some of the double-positive cells were thymic epithelial cells. The candidate of cytokeratin subtype expressed on the double-positive cells was cytokeratin 1 (CK1), which was expressed only by the epithelium of Hassall's corpuscles in thymuses from age-matched patients with myasthenia gravis. The present case indicates a possibility that some thymic epithelial cells become FDC, although it was uncertain whether they were derived from the epithelia of Hassall's corpuscles or whether they were at the same differentiation stage as Hassall's corpuscles.

Objective: To detect the BCL10 expression and several types of chromosomal translocations [including t (11;18)/API2-MALT1; t (1;14)/IgH- BCL10 and t (14;18)/MALT1-IgH] in ocular adnexal mucosa-associated lymphoid tissue lymphomas (OA-MALT lymphomas)., Methods: Sixty OA-MALT lymphomas were collected from Cancer Hospital of Fudan University. BCL10 was detected by immunohistochemical studies, and API2-MALT1 fusion gene, BCL10, MALT1 and IgH chromosomal abnormalities were detected by fluorescent in situ hybridization (FISH). Fisher's exact test was used to analyze the relation between nuclear BCL10 expression and chromosomal translocation., Results: BCL10 expressed in 85.0% (51/60) OA-MALT lymphomas. Among these positive cases, 25 cases (41.7%) were expressed in the cytoplasm, and 26 cases (43.3%) were expressed in the nucleus. FISH results showed that no chromosomal abnormalities related with BCL10 and IgH genes, except 2 cases with API2-MALT1 fusion gene. Under statistic of Fisher exact test, nuclear BCL10 expression and API2-MALT1 fusion gene were two independent factors (P > 0.05)., Conclusions: BCL10 nuclear expression is common in OA-MALT lymphomas and may be used as a potential marker for the diagnosis of MALT lymphomas arising from ocular adnexa. Aberrant chromosomal translocations reported in the other sites MALT lymphomas are rare in OA-MALT lymphomas.

The chemokines (CKs) CXCL13, CCL21, and CXCL12 are known to play differential roles in the organization of the lymphoid tissues and the development of lymphoid malignancies. We investigated the expression of these CKs and their receptors in the salivary glands of Sjogren's syndrome patients with lymphoepithelial lesions (lymphoepithelial sialadenitis or LESA) and in MALT lymphoma to understand their involvement in salivary gland lymphomagenesis. We demonstrate that within salivary glands with LESA and MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are selectively associated with areas of reactive lymphoid proliferation, whereas no significant expression of these molecules was detected in the malignant lymphoid aggregate. Conversely, CXCL12 was observed predominantly in infiltrated ducts and malignant B cells. Accordingly, CXCL13 and CCL21 transcript levels were significantly increased in LESA samples while CXCL12 levels were increased in MALT lymphoma and isolated tumor cells. Low levels of CK receptors were detected on lymphoma-extracted lymphocytes, suggesting down-regulation in the abundance of ligands. Our findings suggest that in salivary gland MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are directly implicated in the organization of ectopic reactive lymphoid tissue, whereas CXCL12 is associated with the infiltrated epithelium and malignant B cell component and is possibly involved in the regulation of malignant B cell survival.

Background: Development and growth of extranodal marginal zone B-cell lymphomas (eMZBCLs) of mucosa-associated lymphoid tissue (MALT) type are thought to be highly dependent on Helicobacter pylori and autoantigens. Receptors mediating these effects are not characterised so far. Toll-like receptors (TLRs) recognise bacterial proteins and autoantigens, which results in inflammatory reactions and influences tumour development and growth., Materials and Methods: TLR4, 5 and 9 expressions were evaluated by immunohistology and confocal microscopy in gastric eMZBCL in comparison to other lymphomas infiltrating the stomach., Results: TLR4 was exclusively expressed on the cell surface in all eMZBCL (n = 19) and not in chronic lymphocytic leukaemia (CLL, n = 12) or mantle cell lymphoma (MCL, n = 10). TLR5 was strongly expressed in CLL and weak in some eMZBCL (15 of 19), but not in MCL. TLR4, 5 and 9 were negative in all the three lymphoma entities., Conclusions: Exclusive TLR4 expression may enable eMZBCL to interact with H. pylori and autoantigens. Blockade of TLR4 might be a new approach for therapy of eMZBCL of MALT type.

Objective: To investigate the protein expression of cyclooxygenase 2 (COX-2) and nuclear factor kappa B (NF-kappaB) in gastric mucosa-associated lymphoid tissue (MALT) lymphoma and its clinical significance., Methods: Protein expression of COX-2 and NF-kappaB in gastric MALT lymphoma were examined by immunohistochemistry of Envision two-step method. The correlations of COX-2 and NF-kappaB expression with Helicobacter pylori (Hp) infection, clinical stage, depth of tumor invasion, tumor size, recurrent rate and treatment were analyzed by univariate, multivariate and Pearson analysis., Results: The positive expression of COX-2 and NF-kappaB in gastric MALT lymphoma were 48.9%(23/47) and 36.2% (17/47) respectively, and a positive correlation was found between these two factors(r=0.326,P<0.05). Moreover, COX-2 expression was positively correlated with Hp infection,clinical stage, depth of invasion and tumor size (P<0.05). Univariate analysis showed that the overall survival of gastric MALT lymphoma patients with positive COX-2 protein (59.9 months) was shorter than that of patients with negative COX-2 protein (77.8 months), but the difference was not significant (P>0.05). The survival was significantly shorter in gastric MALT lymphoma patients with positive NF-kappaB protein (26 months) than that of patients with negative NF-kappaB protein (123.2 months)(P<0.05). Multivariate Cox regression analysis revealed that clinicopathological stage was independent prognostic factor, and associated with short survival., Conclusion: Up-regulated expression of COX-2 and activation of NF-kappaB are associated with Hp infection in gastric MALT lymphoma, and their protein expression is correlated with the development of tumor and prognosis.

Cyclin D1 overexpression as a result of t(11;14) is a specific marker for diagnosis of mantle cell lymphoma (MCL) and plays an important role in MCL pathogenesis. To set a highly reliable cutoff value that discriminates MCL from other B-cell lymphoproliferative disorders, we performed a retrospective study of cyclin D1 expression. We established cyclin D1 expression level in 116 frozen and formalin-fixed, paraffin-embedded primary tumors from patients diagnosed with a variety of B-cell lymphoproliferative disorders. We used real time quantitative reverse-transcription polymerase chain reaction to quantify levels of cyclin D1 mRNA. The range of cyclin D1 expression in MCLs exceeded the range found in other lymphomas and reactive lymph nodes by a considerable margin. Cyclin D1 overexpression was found in 60/61 MCLs and in none of the other lymphomas, except for 12/19 mucosa-associated lymphoid tissue lymphomas from the lungs and stomach, which also revealed cyclin D1 overexpression. As epithelial tissues are known to express cyclin D1, an admixture of non-neoplastic epithelial cells present in the extranodal specimens probably influenced the quantitative reverse-transcription polymerase chain reaction result. Quantitative cyclin D1 monitoring provides a diagnostic test and an approach for studying MCL pathogenesis and may be of clinical importance.

Background and Aim: Clinicopathologic characteristics and prognosis of Helicobacter pylori eradication-resistant gastric MALT lymphoma have not been well clarified. We analyzed a consecutive series of gastric MALT lymphomas at our institution regarding treatment, clinical course, and prognosis, with special reference to responsiveness to H. pylori eradication and presence of API2-MALT1., Methods: Subjects were 92 consecutive patients with gastric MALT lymphoma. Seventy were H. pylori positive, and 87 received H. pylori eradication therapy. The remaining five cases were API2-MALT1 positive and did not receive eradication treatment. Second-line treatments were radiation therapy, total gastrectomy, and chemotherapy (rituximab, rituximab plus CHOP, or rituximab plus 2-chlorodeoxyadenosine)., Results: Gastric MALT lymphoma was classified into three groups, except one case with API2-MALT1 who responded to H. pylori eradication therapy: responders without API2-MALT1 (group A, N = 56, 65%), nonresponders without API2-MALT1 (group B, N = 16, 19%), and nonresponders with API2-MALT1 (group C, N = 14, 16%). Most cases in group A attained complete remission (CR) in 2 or 3 months and CR persisted for an average of 51.1 months (3-134 months). Recurrence was only seen in one case. In groups B and C, radiation therapy, chemotherapy, and total gastrectomy resulted in CR in 13, 5, and 2 cases, respectively. In 5 group B patients and 6 group C patients who did not undergo second-line therapy, disease did not progress for an average of 10.4 and 40.1 months, respectively. In 1 group C case who did not receive second-line treatment, lymphoma metastasized to the lung 12 yr after eradication. All group B patients and all but 2 group C patients remain alive; one of these deaths was from gastric carcinoma developing 7 yr after eradication., Conclusion: Gastric MALT lymphoma responding to H. pylori eradication demonstrated good prognosis, and for nonresponsive cases, second-line treatments resulted in CR. However, careful observation for development of gastric carcinoma and disease progression is essential during follow-up of API2-MALT1-positive MALT lymphoma when patients decline second-line treatment.

A case of primary conjunctival mucosa-associated lymphoid tissue lymphoma studied by in vivo corneal confocal microscopy (IVCM) is described for the first time. Examination of the lower mediobulbar and forniceal conjunctiva of the left eye of a 37-year-old female patient showed a typical salmon-pink patch. IVCM examination of the conjunctival lesion showed irregular, polygonal, conjunctival bulbar epithelial cells with blurred edges and without visible nucleus. Many small, roundish, hyper-reflective cells were also seen. These cells were arranged diffusely or in nests in cyst-like hypo-reflective spaces. A few highly reflective cells were also visible among deep stromal collagen fibres. The IVCM picture recalled the histological profile of low-grade mucosa-associated lymphoid tissue lymphoma, characterized by sheets of neoplastic cells around reactive follicles. IVCM enabled non-invasive evaluation of the eye surface at high magnification and with good contrast, and could be useful for early differential diagnosis of conjunctival lesions.

Marginal zone B-cell lymphoma (MZBL) is occasionally associated with prominent plasma cell differentiation. However, MZBL rarely exhibits histological features that resemble plasmacytoma arising from a localized plasma cell variant of Castleman's disease (PCCD). We here report a histologically similar case that was associated with primary cutaneous tumor. The patient was a 57-year-old woman with a 5-year history of cutaneous nodules. Histologically, a prominent proliferation of plasma cells occupied the interfollicular area of the central portion of the cutaneous tumor, whereas various numbers of CD5+ centrocyte-like (CCL) cells, which were arranged in a marginal zone distribution pattern, occupied the peripheral region of the tumor. The majority of the lymphoid follicles had atrophic or regressive germinal centers resembling hyaline-vascular Castleman's disease. CCL cells were observed to have colonized a few of the lymphoid follicles. Immunohistochemistry revealed that these cells had a monotypic intracytoplasmic kappa chain. Without treatment, the patient was quiescent, but 2 years later, there was a transformation to the large cell type. These observations suggest that MZBL needs to be distinguished from PCCD, and that untreated cutaneous MZBL may undergo a high-grade blastic transformation similar to other indolent lymphoproliferative disorders.

Objective: To analyze the clonal relationship between transformed and non-transformed components in mucosa-associated lymphoid tissue (MALT) lymphoma., Methods: Six cases of MALT lymphoma with high-grade transformation were studied. Immunohistochemical study was carried out by EliVision using bcl-10 antibody. Reverse transcription-polymerase chain reaction was used to detect the presence of API2-MALT1 fusion gene transcripts. The target cells were selected by laser microdissection and studied by polymerase chain reaction and sequence analysis for rearrangement of immunoglobulin heavy chain gene., Results: In the 6 cases of MALT lymphoma with high-grade transformation, nuclear and cytoplasmic expression of bcl-10 was demonstrated in 1 case, while API2-MALT1 fusion gene was present in 2 cases. Identical fragments of rearranged immunoglobulin heavy chain gene were detected in both transformed and non-transformed components in each of the 6 cases, except for the differences at 2 nucleotide positions in N or D regions in 2 cases., Conclusion: The tumor cells from both transformed and non-transformed components in MALT lymphoma derive from the same clone.

A rare association between primary pulmonary marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), and pulmonary immunoglobulin light chain (AL) amyloidosis is described in a 65-year-old woman suffering from rheumatoid arthritis (RA). All four nodules in the resected upper lobe of the lung had a similar histological appearance. They were composed of small-medium-sized atypical lymphocytes. Centrocyte-like cells had lymphoepithelial lesions. Immunohistochemically, the tumor cells clonally expressed B-cell markers, and demonstrated clonal rearrangement of the immunoglobulin heavy chain gene on polymerase chain reaction. Based on these findings the diagnosis of primary pulmonary MALT lymphoma was made. In addition, uniform eosinophilic material deposition was identified randomly within the tumor. It was Congophilic and exhibited apple-green birefringence on polarizing microscopy, and remained unaffected by potassium permanganate digestion. Deposited material was immunoreactive to lambda light chain. It was concluded that this material was AL amyloid in primary pulmonary MALT lymphoma. Plasma cells with mRNA of lambda chain was found infiltrated along the border of amyloid deposition. Finally, it is speculated that primary pulmonary MALT lymphoma developing in an autoimmune setting, RA in the present case, is associated with overproduction and abnormal clearance of immunoglobulin by the tumor cells, resulting in AL amyloidosis within the tumor.

We report the case of a patient who showed spontaneous regression of bilateral conjunctival extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). A 72-year-old man underwent excisional biopsy for salmon-pink lesions involving the whole circumference of the conjunctiva in the right eye and the lower fornix in the left eye. Histopathology and immunohistochemistry showed MALT lymphoma with immunoglobulin kappa monotype shared by the lesions in both eyes. Because the patient had recurrent pulmonary tuberculosis, radiation initially planned for the large residual lesion in the right eye was postponed. Over two years, including 6 mon with anti-tuberculous treatment, the large lesion in the right eye showed spontaneous regression. The spontaneous regression of conjunctival MALT lymphoma observed in this patient suggests that following excisional biopsy for histopathological diagnosis, observation is a treatment option.

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) can arise at any anatomic site, but involvement of the kidney is rare. We describe 10 cases of kidney MALT lymphoma, including 6 localized cases. No predisposing inflammatory conditions were identified, with the possible exception of coexistent renal Actinomyces infection in 1 case. We performed fluorescence in situ hybridization (FISH) using a malt1 break-apart probe in 7 cases. A malt1 gene rearrangement was identified in 1 case (14%). This case was further assessed by FISH using an IgH breakapart probe that showed IgH gene rearrangement. These results are suggestive of the t(14;18) involving malt1 and IgH. Immunostaining for NF-kappaB p65 showed nuclear positivity, consistent with NF-kappaB activation, in 3 of 5 cases assessed. Our results indicate that kidney MALT lymphomas share similarities with MALT lymphomas arising at other sites in that MALT lymphoma-associated translocations and NF-kappaB activation occur in a subset of cases.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a low-grade tumor closely associated with chronic inflammation such as that of Helicobacter pylori gastritis, Sjogren's syndrome, and Hashimoto's thyroiditis. Tumor regression by H. pylori eradication alone is well known in gastric MALT lymphoma, but some tumors occur in the absence of pre-existing chronic inflammation. The understanding of MALT lymphoma biology has significantly improved, and recurrent cytogenetic alterations have been detected. These include the trisomies 3 and 18, and the translocations t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). At least some of these alterations result in the constitutive activation of the nuclear factor (NF)-kappaB pathway, and may exert anti-apoptotic action. Apoptosis inhibitor 2-MALT lymphoma-associated translocation 1 (API12-MALT1) fusion, resulting from t(11;18)(q21;q21), is specific to, and is the most common in, MALT lymphomas, and its clinicopathological significance has been studied extensively. The focus of the present review is on the recent progress made in elucidating MALT lymphomagenesis and its clinicopathological impact, especially in terms of the effect of API2-MALT1 fusion on this unique tumor.

Objective: To study the morphologic features, immunophenotype, differential diagnosis and prognosis of nodal marginal zone B-cell lymphoma (NMZL)., Methods: Light microscopic examination and immunohistochemical study were carried out in 10 cases of NMZL. Seven of which had follow-up information available., Results: All cases presented with good performance status at the time of diagnosis. Amongst the 7 cases with follow-up information available, most (6/7) were in advanced clinical stage (stage II to III). The one-year survival rate was 67%. A vaguely nodular growth pattern was observed in most cases of NMZL (5/10). The lymphoma was composed predominantly of atypical lymphoid cells resembling centrocytes (7/10). A predominance of monocytoid B-cell (2/10) or small lymphocytic (1/10) morphology was rare. Instead, the presence of a minor component of monocytoid B cells was not uncommon (5/10). Plasmacytoid or plasmacytic cells were also frequently found (8/10). The proliferation index ranged from 5% to 50%. Follicular dendritic cells appeared atrophic in 7 cases and variably hyperplasic in 3 cases., Conclusions: Primary NMZL is rare. It has a unique growth pattern and most cases are composed predominantly of cells resembling centrocytes. Differential diagnosis includes lymphoplasmacytic lymphoma, lymph node involvement by extranodal marginal zone B-cell lymphoma and T-zone hyperplasia. The clinical stage is often high at presentation, with systemic dissemination. The prognosis of NMZL is thus relatively poor.