High-grade Mucosa-associated Lymphoid Tissue Research Articles

Acquisition of MYD88 L265P mutation during treatment of diffuse large B cell lymphoma of the parotid gland

Dear Editor, Although the identification of mutations as an initial event is very difficult, the use of next-generation sequencing and high coverage in sequencing data have made it possible to distinguish early mutations from late events, based on the allelic frequency of the mutations. Since recurrently observed among certain subtypes of B cell malignancies, L256P mutation in MYD88 is regarded as one of the initial molecular events [1]. Ten years before death, the patient, a 68-year-old Japanese man, had a gradually growing mass in the left side of the neck. Pathological analysis of an excisional biopsy of the mass led to the diagnosis of primary malignant lymphoma in the parotid gland (the pathological diagnosis at that time was high-grade mucosa-associated lymphoid tissue (MALT) lymphoma that was retrospectively diagnosed as diffuse large B cell lymphoma (DLBCL) according to the 2011 WHO classification: CD10 negative, Bcl-6 positive, MUM1 negative, and 5 % of Ki67 labeling index; Fig. 1a–d). The patient received three courses of chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)) combined with radiotherapy. Although the combined therapy was effective at first, the patient suffered from exacerbation of preexisting chronic hepatitis B during the last course of chemotherapy. Anti-hepatitis B viral therapy with lamivudine was administered for 6 months. After being clinically recurrence-free of malignant lymphoma for 8 years, the patient again developed a mass in the left side of the neck. Biopsy revealed the presence of the non-germinal center B (GCB) subtype of DLBCL (CD10 (−), Bcl-6 (−), MUM1 (+)). From the clinical record, we confirmed that except for BCL2 amplification at the relapsed phase, neither translocations nor breaks were evident in BCL6, IgH, and MYC genes. Three courses of chemotherapy (rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)) were ineffective, however, and the patient died of multiple organ failure. Autopsy revealed aggressive DLBCL infiltrating virtually all the organs, especially the liver (Fig. 1e–h) and the spleen. B cell monoclonality of DLBCL at the parotid K. Fujiishi :R. Kitazawa :Y. Nagai : T. Watanabe :R. Haraguchi : S. Kitazawa (*) Department of Molecular Pathology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0295, Japan e-mail: kitazawa@m.ehime-u.ac.jp

18F-FDG uptake in primary gastric malignant lymphoma correlates with glucose transporter 1 expression and histologic malignant potential

Positron emission tomography (PET) is used for staging and response evaluation in primary gastric lymphoma (PGL). However, the implications of [(18)F]-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in PGL at first diagnosis have not been reported. The relationship between (18)F-FDG uptake and the expression of facilitative glucose transporters (GLUTs), hexokinase II (HK II), and Ki67, as well as malignant potential in PGL, was assessed in this study. We analyzed 23 patients with PGL [nine with diffuse large B-cell lymphoma (DLBCL); seven with high-grade mucosa-associated lymphoid tissue (MALT) lymphoma; and seven with low-grade MALT lymphoma]. The expression levels of GLUT1, GLUT3, HK II, and Ki67 were evaluated according to the percentage of positive area determined by immunohistochemistry. Standardized uptake values correlated significantly with pathological malignant potentials (low-grade/high-grade MALT lymphoma and DLBCL: p=0.001-0.002), Ki67 (p<0.001), and GLUT1 expression (p=0.02). We determined that (18)F-FDG uptake is related to GLUT1 expression and tumor histological grade as well as Ki67 in PGL.

Inhibition of caspase‐8 activity caused by overexpression of bcl10 contributes to the pathogenesis of high‐grade MALT lymphoma

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. 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. 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. 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.

Diagnosis and Treatment of Gastric MALT Lymphoma

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma represents approximately 40% of gastric lymphomas, and its incidence is increasing. An early diagnosis for gastric MALT lymphoma is important, but not easy due to non-specific symptoms and endoscopic findings. Diagnosis is based on the histopathologic evaluation of multiple, deep and repeated biopsies taken from normal and any abnormal appearing sites of the stomach. In addition, the presence of Helicobacter pylori (H. pylori) infection must be determined to determine therapeutic approach. Endoscopic ultrasonography (EUS) is essential for the evaluation of regional lymph nodes and the depth of tumor invasion in the gastric wall, for predicting response to H. pylori eradication, and for monitoring tumor regression or recurrence. The eradication of H. pylori is recommended as an initial treatment for low-grade gastric MALT lymphoma with H. pylori infection. Both radiation therapy and chemotherapy are suitable alternative options for H. pylori-negative, refractory, or high-grade gastric MALT lymphoma. But, the role of surgery is diminishing. After treatment, strict endoscopic regular follow-up including EUS is recommended with multiple biopsies. However, controversy remains regarding the best diagnosis, treatment and follow-up strategy for this disease.

Accumulation of aberrant CpG hypermethylation by Helicobacter pylori infection promotes development and progression of gastric MALT lymphoma

Aberrant DNA hypermethylation is an important mechanism for the inactivation of tumor-related genes in human tumors. Gastric mucosa-associated lymphoid tissue (MALT) lymphomas arise from Helicobacter pylori-associated chronic gastritis; most patients are H. pylori-positive and eradication therapy is highly effective. In the present study, we used methylation-specific PCR to analyze the DNA methylation status of 11 tumor-related genes (Kip2, p16, hMLH-1, p15, p73, MGMT, DAPK, MINT1, MINT2, MINT31 and HCAD) in 21 specimens of MALT lymphoma, 5 specimens of MALT lymphoma with large cell component (high-grade MALT lymphoma), 15 specimens of diffuse large B-cell lymphoma (DLBCL), 8 specimens of complete remission of MALT lymphoma after eradication therapy, 5 specimens with no evidence of malignancy and PBMCs from 10 healthy donors. The average number of methylated genes was significantly greater in gastric lymphomas as compared to normal controls (P<0.001). The CpG island methylator phenotype (CIMP) was observed in 93.3% (14/15) of DLBCLs, 100% (5/5) of high-grade MALT lymphomas and 61.9% (13/21) of MALT lymphomas; in contrast, CIMP was not found in the control group (0%). The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as p16, MGMT and MINT31, was consistently associated with H. pylori infection. These findings strongly suggest that H. pylori infection causes the aberrant DNA hypermethylation of specific genes and induces CIMP, which is an important epigenetic mechanism for the development and progression of gastric MALT lymphoma; additionally, our findings provide new epigenetic markers.

Mucosa-associated lymphoid tissue lymphoma of the ileum as the cause of an intestinal invagination

We herein report a case of a 14-year-old male with mucosa-associated lymphoid tissue (MALT) lymphoma of the ileum as the cause of an intestinal intussusception. The patient was referred to the hospital with abdominal pain and dyspeptic complaints and was operated on with a prediagnosis of acute abdomen. Abdominal exploration revealed an ileoileal intussusception induced by a 2-cm tumor. A segmental ileal resection was done at the operation. The histopathologic examination of the specimen revealed atypical lymphocytes starting from the mucosae infiltrating the muscular layer and the serosae. Based on these findings, the tumor was diagnosed as a high-grade MALT lymphoma. The patient recovered uneventfully after the surgery, and chemotherapy was started.

Treatment of gastric mucosa-associated lymphoid tissue lymphoma: Helicobacter pylori eradication and beyond

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the paradigm of lymphomas developing in extranodal areas after antigen stimulation. In the stomach, Helicobacter pylori colonization induces the appearance of MALT and, eventually, MALT-derived lymphoma. This type of lymphoma is initially a localized form of disease, but may disseminate and transform into high-grade lymphoma, making full staging (as for nodal lymphomas) and endoscopic ultrasonography to evaluate the penetration of the lymphoma through the gastric wall mandatory. In localized gastric MALT lymphoma, the first step in treatment is eradication of H. pylori, which results in 60–90% regression. This response is maintained for years in most patients, with only 10–15% relapse, frequently precipitated by H. pylori reinfection. A component of high-grade lymphoma, penetration to gastric serosa or beyond and translocation t(11;18) are the main factors that make lymphoma resistant to eradication. Surgery or radiotherapy can cure localized lymphomas in 75–90% of patients. Chemotherapy with alkylating agents, combination chemotherapy and purine analogs, and anti-CD20 antibodies can also induce remission of localized lymphomas refractory to eradication, as well as locally advanced and disseminated lymphomas. The optimum chemotherapy treatment for advanced disease has not yet been established; however, combination therapy, including purine analogs with or without anti-CD20, may be a promising option. Despite histological responses and prolonged remissions, residual molecular disease can be demonstrated in most cases treated with H. pylori eradication, radiotherapy or alkylating agents, and even after more intense chemotherapy, although this does not seem to lead to late relapses. High-grade gastric MALT lymphoma should be treated with chemotherapy, with cyclophosphamide, doxorubicin, oncovin and prednisone being the best first-line option. All gastric MALT lymphomas associated with H. pylori should receive eradication treatment in addition to other required treatment.

High-grade Hepatic Mucosa-associated Lymphoid Tissue (MALT) Lymphoma Probably Transformed from the Low-grade Gastric MALT Lymphoma

The Mucosa-associated lymphoid tissue (MALT) lymphoma, which was first described in 1983, is known to be caused by chronic Helicobacter pylori (HP) infection, which triggers lymphoid infiltration and formation of organized lymphoid tissue. In approximately two thirds of cases of MALT, the lymphoma has been observed to regress after treatment of H. pylori infection; this provides strong evidence of a causative role of HP in the etiology of MALT. We report a case of a 67-year-old female patient with a high-grade MALT lymphoma of the liver; this occurred six years after complete remission of a low-grade gastric MALT lymphoma and after complete eradication of H. pylori. there was no recurrence of the previous low-grade gastric MALT lymphoma. Based on radiological and pathologic findings, the high-grade MALT was considered to result from transformation of the low-grade gastric MALT lymphoma.

Surgery and Chemotherapy versus Chemotherapy as Treatment of High-Grade MALT Gastric Lymphoma

Treatment of high-grade MALT (mucosa-associated lymphoid tissue) gastric lymphoma remains uncertain. To assess efficacy and toxicity of the most common therapies--surgery followed by chemotherapy or chemotherapy alone--we began a controlled clinical trial in patients in early stage (I and II 1). One hundred and two patients were randomized to be treated with surgery followed by six cycles of CEOP-Bleo (cyclophosphamide, epirubicin, vincristine, prednisone, and bleomycin at standard doses) (52 cases) or with chemotherapy alone (49 cases). Complete response rates were 94% [95% confidence interval (CI): 88-99%] and 96% (93-100%), respectively. Actuarial curves at 5 yr showed that event-free survival were 70% (95% CI: 59-74%) in patients treated with surgery and chemotherapy, that were not statistically significant to 67% (95% CI: 51-69%) in the patients who received chemotherapy (p = 0.5). Also, overall survival that was not statistically significant: 78% (95% CI: 70-88%) in the combined treatment and 76% (95% CI: 70-87%) in chemotherapy (p = 0.8). Acute and late toxicity were mild and well controlled. No acute leukemia or second neoplasm has been observed. The use of surgery and chemotherapy did not improve outcome in patients with early-stage high-grade gastric MALT lymphoma. It is apparent that chemotherapy alone is sufficient treatment in this select group of patients.

Expression of CD86 and increased infiltration of NK cells are associated withHelicobacter pylori-dependent state of early stage high-grade gastric MALT lymphoma

A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori (H pylori)-dependent. However, unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori-specific intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 (B7.2) and the infiltration of CD56 (+) natural killer (NK) cells can be useful markers to predict H pylori-dependent status of high-grade gastric MALT lymphoma. Lymphoma biopsies from 26 patients who had participated in a prospective study of H pylori-eradication for stage I(E) high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade II or less after H pylori eradication were classified as H pylori-dependent; others were classified as H pylori-independent. The infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry. There were 16 H pylori-dependent and 10 H pylori-independent cases. CD86 expression was detected in 11 (68.8%) of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases (P = 0.001). H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 (+) NK cells than H pylori-independent cases (2.8+/-1.4% vs 1.1+/-0.8%; P = 0.003). CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 (+) NK cells compared to CD86-negative cases (2.9+/-1.1% vs 1.4+/-1.3%; P = 0.005). These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with H pylori-dependent state of early-stage high-grade gastric MALT lymphomas.

Interobserver variation in the histopathological assessment of malt/malt lymphoma: towards a consensus

Background: The classification of mucosa associated lymphoid tissue (MALT) lymphoma is based on characteristic morphologic and immunophenotypic patterns, with distinctive chromosomal aberrations. The critical first step is diagnosis on evaluating H&E-stained sections. We performed an inter-observer study to determine the degree of agreement among pathologists in evaluating gastric lymphocytic infiltrates for MALT lymphoma. Methods: A set of 41 H&E-stained gastric sections (36 endoscopic biopsies and 5 surgically resected sections) that ranged from simple gastritis to primary gastric lymphoma was reviewed separately and independently by 17 participants including hematopathologists, pathologists with a special interest in gastrointestinal pathology, and general pathologists. The participants were from the United States, Europe, and Japan. Results were entered into a standardized data collection form and the results were analyzed using κ statistics. Monte Carlo simulation was used to adjust for multiple biases. Results: Overall, interobserver reproducibility in the morphologic evaluation of gastric MALT was suboptimal. The κappa statistic was 0.3 for simple gastritis, low-grade MALT and for high grade MALT lymphoma. Monte Carlo simulation suggested that the degree of disagreement was directly related to the pathologist's experience in evaluating gastric biopsies for MALT lesions. However, after conjointly reviewing all cases, the Houston workshop agreed on findings that would increase the reproducibility of diagnosis, especially for pathologists with limited experience with this disease. These included the availability of macroscopic data, extensive sampling, the presence of lymphoepithelial lesions, immunophenotyping and particularly abnormal mucosa localization of B-cells, in addition to other molecular finding such as monoclonality and translocationt (11;18). The group also agreed on the need for standardizing the terminology currently used to facilitate future comparison between studies. Conclusions: Though the study shows poor agreement on morphologic MALT lymphoma categorization, the Houston workshop suggested recommendations that should increase the diagnostic accuracy and reproducibility of MALT lymphoma diagnosis. A follow up workshop will be organized to measure the diagnostic reproducibility for MALT lymphoma using the suggested recommendations.

Nuclear expression of BCL10 or nuclear factor kappa B predicts Helicobacter pylori-independent status of early-stage, high-grade gastric mucosa-associated lymphoid tissue lymphomas.

A high percentage of early-stage, high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylori dependent. t(11;18)(q21;q21), a genetic aberration highly predictive of H. pylori-independent status in low-grade gastric MALT lymphoma, is rarely detected in its high-grade counterpart. This study examined whether nuclear expression of BCL10 or nuclear factor kappa B (NF-kappaB) is useful in predicting H. pylori-independent status in patients with stage IE high-grade gastric MALT lymphomas. Twenty-two patients who had participated in a prospective study of H. pylori eradication for stage IE high-grade gastric MALT lymphomas were studied. The expression of BCL10 and NF-kappaB in pretreatment paraffin-embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immunofluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript. Aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H. pylori-independent and in none of 14 H. pylori-dependent high-grade gastric MALT lymphomas (P <.001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-kappaB, compared with only two of 15 patients without nuclear BCL10 expression (P =.002). As a single variable, the frequency of nuclear expression of NF-kappaB was also significantly higher in H. pylori-independent tumors than in H. pylori-dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P =.002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H. pylori-independent lymphomas. Nuclear expression of BCL10 or NF-kappaB is highly predictive of H. pylori-independent status in high-grade gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent.

Critical Evaluation of Bcl-6 Protein Expression in Diffuse Large B-cell Lymphoma of the Stomach and Small Intestine

Diffuse large B-cell lymphoma (DLBCL) of the gastrointestinal tract is heterogeneous, including mucosa-associated lymphoid tissue (MALT) origin and non-MALT, and they are indistinguishable. MALT lymphoma is a tumor of a post-germinal center (GC) memory B-cell origin, which is negative for Bcl-6 protein expression in low-grade but may become positive in high-grade tumors. Because Bcl-6 expression patterns in lymphoma of GC and non-GC B-cell origins have recently been characterized and CD10 is generally regarded as a specific marker for GC B cells, we critically evaluated gastric and small intestinal DLBCLs to see whether it is possible to identify tumor of GC B-cell origin by immunostaining in archival specimens. High-grade MALT lymphoma (H-ML) of the stomach (n = 20) was defined by the presence of a concomitant lymphoepithelial lesion and/or follicular colonization; and DLBCLs de novo, both gastric (n = 31) and intestinal (n = 21), were defined by the absence of the above features. Immunostaining for Bcl-6 and CD10 was done using formalin-fixed, paraffin-embedded sections and was examined independently by three pathologists. Staining for Bcl-6 was positive (>10% of tumor cells) in 55 of 72 cases. However, two distinct patterns were recognized among those positive: diffusely dense (>75%) and sporadic (<75%). The former was further characterized by a consistency of Bcl-6+ tumor cell density at any given area, resembling the staining pattern of the GC or follicular lymphoma (FL) (GC/FL pattern), whereas the latter was, besides less dense population, by variable density from area to area. The GC/FL pattern was observed in 36% and 38% of gastric and intestinal DLBCLs de novo, respectively, but in none of the gastric H-ML. CD10 was positive in 12 of 71 cases (17%), all coexpressing Bcl-6. CD10+ tumors were more frequent in the intestinal (33%) than in gastric DLBCLs ( approximately 15%). Significantly, CD10 expression was observed in three gastric H-MLs, including one that displayed a distinct lymphoepithelial lesion. 1). tumors showing a diffusely dense pattern of Bcl-6 expression should be distinguished from those showing a sporadic pattern; for the former most likely represents the tumor of GC B-cell derivation, and the latter non-GC, including MALT lymphoma; 2). tumor of GC B-cell origin thus defined accounted for about one third of gastric as well as intestinal DLBCLs de novo but none of the gastric H-ML; and 3). CD10 expression can be seen in MALT lymphomas and should not be used as the marker for GC B cells.

The Relationship Between Primary Gastric B-cell Lymphoma and Immunoglobulin Heavy Chain (IgH) Gene Rearrangement – A Histopathological Study of Primary Gastric Lymphomas

The aim of this study was to review our primary gastric lymphoma cases according to the new WHO classifications and to investigate the histopathological features of B-cell lymphomas. In addition, B-cell monoclonality was analyzed for immunoglobulin heavy chain (IgH) gene rearrangement using the polymerase chain reaction at the site of the lymphoma lesion, transitional lesion, and the non-lymphoma lesion. Specimens resected from 31 primary gastric lymphomas were examined. There were 28 cases (90.3%) of B-cell lymphoma and three cases (9.7%) of T-cell lymphoma. The B-cell lymphomas were classified as low-grade mucosa-associated lymphoid tissue (MALT) lymphoma (LGML) (9%), high-grade MALT lymphoma (HGML) (42%), and diffuse large B-cell lymphoma (DLBCL) (29%). Histopathologically, lymphoepithelial lesions (LEL) were higher in LGML (100%) than in DLBCL (22%), with statistical significance (p < 0.05). A monoclonal pattern of IgH rearrangement was detected in LGML (50.0%), HGML (60.0%), and DLBCL (80.6%), with a statistically significant difference between LGML and DLBCL (p < 0.01). The IgH monoclonal pattern may reflect the gross appearance of lymphoma or the lymphoma infiltration depth. Superficial spreading and shallow growth in LGML may correspond to an oligoclonal pattern, and mass-forming and deep invasive growth in DLBCL may correspond to a more monoclonal pattern.

Radiographic findings of primary B-cell lymphoma of the stomach: low-grade versus high-grade malignancy in relation to the mucosa-associated lymphoid tissue concept.

We undertook this study to assess how well double-contrast radiography and CT allow radiologists to differentiate low-grade from high-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach. We retrospectively reviewed the upper gastrointestinal radiographs and contrast-enhanced CT scans of 57 patients with pathologically proven primary gastric lymphoma (low-grade [n = 29] and high-grade [n = 28] MALT lymphoma). On upper gastrointestinal radiography, ulceration (39%) was the most common finding in low-grade lymphoma, whereas polypoid appearance (38%) was the most common in high-grade lymphoma. In the 29 patients (33 lesions) with low-grade MALT lymphoma, upper gastrointestinal radiography revealed 13 ulcerative lesions (39%), 10 nodular lesions (30%), four infiltrative lesions (12%), two polypoid lesions (6%), and four combined lesions (12%). In the 28 patients (29 lesions) with high-grade lymphoma, upper gastrointestinal radiography revealed 11 polypoid lesions (38%), nine infiltrative lesions (31%), six ulcerative lesions (20%), one nodular lesion (3%), and two combined lesions (7%). On CT, thickening of the gastric wall in low-grade lymphoma (range, 0.3-2.5 cm; mean, 0.8 cm) was much less than that in high-grade lymphoma (range, 0.7-8.0 cm; mean, 2.5 cm). Abdominal lymphadenopathy was less frequent in low-grade lymphoma (14%) than in high-grade lymphoma (75%). Most low-grade lymphomas show superficial spreading lesions, such as mucosal nodularity, shallow ulcer, and minimal fold thickening, on upper gastrointestinal radiography, whereas most high-grade lymphomas show mass-forming lesions or severe fold thickening.

MUC1 mucin expression in follicular dendritic cells and lymphoepithelial lesions of gastric mucosa-associated lymphoid tissue lymphoma.

Membrane-associated mucin MUC1 is expressed in various adenocarcinoma cells and active T lymphocytes. We tried to find out whether MUC1 is expressed in gastric mucosa-associated lymphoid tissue (MALT) lymphoma lesion. MUC1 was not expressed in infiltrating T lymphocytes; however, MUC1 was found on the cell surface of follicular dendritic cells (FDC) of germinal centers and in the epithelial cytoplasm of lymphoepithelial lesion (LEL) of the lymphoma, which were immunohistochemically detected by monoclonal antibodies DF3 and MY.1E12. MUC1 was also expressed in the FDC of control cases (gastrectomy specimen containing reactive lymphoid follicles, n = 10, MUC1/ DF3, 100%; MUC1/MY.1E12, 40%), and FDC in MALT lymphomas (n = 59) showed lower MUC1 expression rates (MUC1/ DF3, 32%; MUC1/MY.1E12, 0%) than the control (P < 0.001). Lymphoepithelial lesion in the low-grade MALT lymphomas (n = 23) showed a higher MUC1/DF3 expression rate (30%) than those in the high-grade MALT lymphomas (n = 36; 6%; P < 0.05). T lymphocytes in the surface mucosa were more frequent in MALT lymphoma (91.4 +/- 80.6/unit area) than those in the control (20.0 +/- 23.6) (P < 0.001). S100-positive dendritic cells around LEL were more frequent in the low-grade (19.0 +/- 9.4/unit area) than in the high-grade (11.7 +/- 9.7) (P < 0.005). This study demonstrated MUC1 mucin expression on FDC for the first time. Mucosa-associated lymphoid tissue lymphoma, especially low-grade, shows immunologically active state, where FDC MUC1 expression may be suppressed by some factors released from lymphoma cells. Further study to elucidate the pathogenetic role of MUC1 in MALT lymphoma is necessary.

Clinicopathological features of gastric B-cell lymphoma: a series of 317 cases.

The stomach is a common site of extranodal malignant lymphoma. Here we examined the clinicopathological features of 317 gastric B-cell lymphomas and characterized the differences among low-grade mucosa-associated lymphoid tissue (MALT) lymphomas (LG), high-grade MALT lymphomas (HG), follicular lymphomas (FL) and diffuse large B-cell lymphomas (DL). Cases included 126 DL, 71 HG, 98 LG, 10 FL, three Burkitt's lymphoma and nine of undefined type. The age range of patients was as follows: LG, 14-96 years (mean, 61.1); HG, 20-87 years (mean, 63.9); DL, 16-88 years (mean, 62.8); and FL, 54-76 years (mean, 65.5). There were no differences in age with respect to tumor type. There were more women patients with LG (female:male, 55:43), while males predominated among DL patients (54:72). The sexes were represented almost equally in HG cases (34:37). Histological findings, especially in DL tumors, correlated significantly to the gross appearance of mass formation. Dutcher bodies were encountered mainly in HG or LG cases. Our results showed no differences in age, sex or site of disease between LG, HG and DL tumors. However, the grade of malignancy correlated strongly to gross appearance. Dutcher bodies were important for the diagnosis of gastric MALT lymphoma.

Differentiation of Low-Grade Gastric MALT Lymphoma and High-Grade Gastric MALT Lymphoma: The Clinical Value of Ga-67 Citrate Scintigraphy—A Pilot Study

Ga-67 citrate scintigraphy has been routinely and extensively used to evaluate non-Hodgkin's lymphoma (NHL) for more than 20 years. Gastric lymphoma of mucosa-associated lymphoid tissue (MALT) is by far the most common extranodal primary NHL. Gastric MALT lymphoma can be classified as low-grade (LG) or high-grade (HG). Low-grade gastric MALT lymphoma can be cured by eradication of Helicobacter pylori; but radiotherapy and/or chemotherapy and/or surgery are the major methods of treatment for the HG gastric MALT lymphoma. However, it is difficult to differentiate these two groups by clinical parameters and endoscopic findings. The purpose of this study was to determine whether Ga-67 citrate scintigraphy can distinguish the LG gastric MALT lymphoma from the HG gastric MALT lymphoma. Twenty-one patients (11 men and 10 women ranging in age from 38 to 83 years) with histologically confirmed gastric MALT lymphoma were enrolled. Twelve patients had LG and nine patients had HG. All 21 patients underwent Ga-67 citrate scintigraphy before treatment. The results of Ga-67 citrate scintigraphy were classified as positive or negative. In the LG group, nine patients had negative results and three patients had positive results. In the HG group of nine patients, all patients had positive results. Among the three patients who had positive results in the LG group, the uptake of gastric MALT lymphoma was lower than that of the liver. The Ga-67 citrate scintigraphy is of good clinical value for the differentiation of the LG gastric MALT lymphoma and the HG gastric MALT lymphoma. We think that the major value of Ga-67 citrate scintigraphy will be in following the patients with HG gastric MALT lymphoma after treatment to assess response of therapy and to detect possible recurrence and perhaps in determining transformation from the LG to HG gastric MALT lymphoma. However, further investigation is needed to understand the relationship between the uptake of Ga-67 citrate in gastric MALT lymphoma and transformation.

Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach.

High-grade mucosa-associated lymphoid tissue (MALT) lymphomas of the stomach are generally believed to be Helicobacter pylori-independent, autonomously growing tumors. However, anecdotal cases of regression of high-grade lymphomas after the cure of H pylori infection had been described. The present prospective study was conducted to evaluate the effect of anti-H pylori therapy in stage I(E) high-grade gastric MALT lymphomas. Sixteen patients with H pylori infection and stage I(E) gastric high-grade MALT lymphoma consented to a brief antibiotic therapy as first-line treatment from June 1995 through April 2000. Then, patients underwent intensive endoscopic follow-up examinations (+/- endoscopic ultrasonography) with biopsy to evaluate tumor response. Patients with significant improvement of gross lesions that accompanied regression of large cells were followed up without additional treatment. Patients without significant improvement were immediately referred to systemic chemotherapy. Eradication of H pylori was achieved in 15 patients and was accompanied by rapid gross tumor regression and disappearance of large cells in 10. All 10 of these patients with early response had subsequent complete histologic remission of lymphoma. The complete remission rate was 62.5% (95% confidence interval, 35.8% to 89.1%). The response rate was not affected by the tumor grading (proportion of large blast cells within the tumor) but was adversely affected by the depth of tumor invasion. At a median follow-up of 43.5 months (range, 21.1 to 67.4 months), all 10 of these patients remained lymphoma-free. The median duration of complete response was 31.2 months (range, 14.4 to 49.1 months). These results suggest that high-grade transformation is not necessarily associated with the loss of H pylori dependence in early-stage MALT lymphomas of the stomach.

Regression of primary gastric diffuse large B-cell lymphoma after eradication of Helicobacter pylori

Primary gastric high-grade mucosa-associated lymphoid tissue (MALT) lymphoma is generally considered refractory to eradication therapy for Helicobacter pylori and therefore is usually treated by surgical resection or by chemotherapy with or without irradiation as for malignant lymphoma.1,2 There are several reports of regression of primary gastric high-grade MALT lymphoma after eradication therapy of H pylori alone.3-5 This is a description of a case of gastric diffuse large B-cell lymphoma that regressed after eradication therapy for H pylori, and a discussion of the potential use of this form of treatment.