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Malignant lymphoma of the stomach is a relatively rare neoplasm of the stomach. While the majority are derived from mucosa associated lymphoid tissue (MALToma), others may be derived from follicular center cells, similar to the majority of non-Hodgkin's nodal based lymphomas. Finally, there are rare subsets which may not be easily classified into the previous categories.


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Instability of clonality in gastric lymphoid infiltrates: a study with emphasis on serial biopsies.

Lo WY, Li JY, Chan YK, Lai LS, Yeung YW, Lo ST, Tsui WM, Ng CS.

From the Pathology Service, Caritas Medical Centre, Kowloon, Hong Kong, China.

Am J Surg Pathol. 2005 Dec;29(12):1582-92. Abstract quote  

The evolution of low-grade B-cell mucosa-associated lymphoid-tissue (MALT) lymphoma of the stomach is a multistage process, reflected in the histologic continuum from Helicobacter pylori-chronic gastritis, to low-grade and high-grade lymphoma. Interestingly, in daily gastric biopsy sign-out, the authors observed that some biopsies showed monoclonality on polymerase chain reaction (PCR) even though there were no definite histologic features of malignancy and vice versa.

To address the question, the authors studied the endoscopic gastric biopsies at first presentation of 46 patients to examine any clonality differences among various histologic patterns within the spectrum of MALT lymphoma evolution. The gastric biopsies were reviewed histologically and graded according to the Wotherspoon-Isaacson histologic scoring system from grade 0 (normal) to grade 5 (MALT lymphoma). The clonality of cases in each grade was determined by performing nested PCR for immunoglobulin heavy chain (IgH) gene rearrangement using FR2/JH and FR3/JH primer sets. The monoclonality rates among different grades were as follows: grade 2, 6.3% (1 of 16); grade 3, 27.3% (3 of 11); grade 4, 83.3% (5 of 6); grade 5, 69.2% (9 of 13). Statistically significant difference of monoclonality rate is demonstrated in histologic grade 4 versus grades 2 and 3, and grade 5 versus grade 2 (P < 0.05, Fisher exact test). The authors went on to examine the progress of disease by following up the clinical status, histologic changes, and clonality fluctuation of these cases. Four of the 8 patients with monoclonality on PCR, but no definite lymphoma at first presentation later progressed to frank MALT lymphoma.

Our study shows that, during the progression to MALT lymphoma, there is an instability of clonality. Clonality can fluctuate between polyclonality, oligoclonality, and monoclonality, none of which defines an irreversible stage for progression to MALT lymphoma. Monoclonality is a risk factor for development of MALT lymphoma. Those cases with dense gastric mucosal lymphoid infiltrate (without definite MALT lymphoma) and monoclonality on PCR need to be closely monitored and Helicobacter infection promptly treated if present. In combination with clinicohistologic examination, PCR can serve as a complementary tool in arriving at a definite diagnosis of MALT lymphoma in cases with borderline histologic features.

Clonal Evolution of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue Type

Amane Yamauchi, M.D., Yasuhiko Tomita, M.D., Hideaki Miwa, M.D., Haruhiko Sakamoto, M.D., Haruo Sugiyama, M.D. and Katsuyuki Aozasa, M.D.

Second Department of Pathology (AYHS), Kagawa Medical University, Kagawa, Japan; and Departments of Pathology (YT, HM, KA) and Clinical Laboratory Science (HS), Osaka University Medical School, Suita, Japan

Mod Pathol 2001;14:957-962 Abstract quote

Development of multiple lesions is frequent in gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type.

Presence of clonal components in multiple lesions was examined on the resected samples from 18 cases by using PCR-based method for immunoglobulin heavy-chain gene rearrangement.

There were two or more lesions in 10 cases, and 2 to 12 samples were obtained from each lesion. The remaining eight cases had a single large lesion, from which two to six samples were collected from separate areas from each other. A total of 86 samples were analyzed. Histologic findings in each sample were categorized as follows: proliferation of exclusively centrocyte-like cells (CCL), large cells, and combined CCL and large cells. Monoclonal or biclonal pattern (single or two bands) was observed in 42 samples, oligoclonal pattern (three or more bands) in 30, polyclonal (smear) in 11, and no products in 3. Large-cell–type lesions showed fewer bands than those with other histologic types, and 75% of cases with large-cell type had mono- or biclonal proliferation. Common clones were found among lesions in about 60% of cases. Especially in 4 cases including 2 cases with large-cell type, every lesion in the same case contained the common clones.

These findings suggested that gastric MALT lymphoma started as multi- or oligoclonal proliferation of cells, in which separate lesions composed of different clones from each other. As disease advances, dominant clones appear in some lesion and disseminate to other lesions via homing properties of the proliferating B lymphocytes.

Microsatellite instability in gastric MALT lymphoma.

Niv E, Bomstein Y, Bernheim J, Lishner M.

[1] 1Department of Medicine, Meir Hospital, Kfar-Saba, Israel [2] 2Oncogenetic Laboratory, Meir Hospital, Kfar-Saba, Israel.
Mod Pathol. 2004 Nov;17(11):1407-13. Abstract quote  

The role of microsatellite instability and defects in DNA mismatch repair mechanism in the pathogenesis of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type is still controversial, as both negative and positive findings have been reported. This may be explained mainly by arbitrary selection of the tested loci, the use of various techniques of microsatellite instability analysis and by different definitions of replication error positive phenotype.

The aim of our study was to evaluate the instability at selected microsatellite markers using the GeneScan Analysis Software. DNA from paraffin-embedded tissue blocks of 13 previously untreated patients with localized gastric MALT lymphoma was extracted. Five microsatellite markers, which are located in hMSH2, hMLH1, P16, APC and MLL loci, were selected from the genetic database. We found genetic instability in tumors of 9/13 patients with gastric MALT lymphoma (69%). Seven of them had replication-error-positive phenotype (54%). Microsatellite instability was found in 39% of the samples in the MLL locus, 39% in the APC, 46% in the P16, 23% in the hMLH1 and none in the hMSH2. This study demonstrates that microsatellite instability has more prominent role in pathogenesis of gastric MALT lymphoma than reported to date.

We suggest that microsatellite instability should be analyzed with markers adjacent to chromosomal loci that are involved in lymphomas. Our findings support the 'Real Common Target genes' theory of high rate of microsatellite instability in specific genes, which are associated with related tumors.

Promoter hypermethylation and protein expression of the p16 gene: analysis of 43 cases of B-cell primary gastric lymphomas from China.

Huang Q, Ai L, Zhang ZY, Fan CY, Weiss LM.

Division of Pathology, City of Hope National Medical Center, Duarte, CA 91010, USA.
Mod Pathol. 2004 Apr;17(4):416-22. Abstract quote

The p16 (CDKN2a/INK4a) gene is an important tumor-suppressor gene, involved in the p16/cyclin-dependent kinase/retinoblastoma gene pathway of cell cycle control. The p16 protein is considered to be a negative regulator of the pathway. Promoter hypermethylation resulting in inactivation of the p16 gene has been found in various hematopoietic malignancies, including non-Hodgkin's lymphoma, and may play a role in transformation/clinical aggressiveness of those tumors. However, the p16 protein expression in primary gastric lymphoma has not been studied.

In this study, we characterize protein expression and promoter hypermethylation of the p16 gene in B-cell primary gastric lymphomas from China. In all, 43 cases of B-cell primary gastric lymphoma were investigated. They consisted of 24 (56%) cases of diffuse large-cell lymphoma, 12 (28%) cases of extranodal marginal zone lymphoma, six (14%) cases of extranodal marginal zone lymphoma with large-cell transformation and one (2%) case of follicular lymphoma. Loss of p16 protein expression was found in 34 (79%) out of 43 cases, while the remaining nine (21%) cases showed positivities for the p16 protein. All 43 cases were further characterized by methylation-specific polymerase chain reaction (PCR) to analyze p16 promoter hypermethylation status. In total, 11 (26%) of 43 cases were positive for p16 promoter hypermethylation. Among those, 10 (30%) out of the 33 cases negative for the p16 immunostaining showed promoter hypermethylation, whereas only one (10%) out of the 10 cases that were positive for the p16 immunostaining displayed promoter hypermethylation. Of the 43 cases, 30 had limited pathologic data at the time of resection. Primary gastric lymphoma involved extragastric sites (lymph node or liver) in 17 (57%) of 30 cases, while the remaining 13 (43%) cases were only limited to the stomach. Loss of p16 protein expression was found in 14 (82%) of 17 cases with extragastric involvement and in 11 (85%) of 13 cases without such involvement.

In conclusion, loss of p16 protein expression is frequent in those B-cell primary gastric lymphomas and approximately one-third of such loss correlated with promoter hypermethylation. Despite limited pathologic data, loss of p16 protein expression appears not to be correlated with extragastric involvements.




Differentiation of low-grade gastric MALT lymphoma and high-grade gastric MALT lymphoma: the clinical value of Ga-67 citrate scintigraphy--a pilot study.

Hsu CH, Sun SS, Kao CH, Lin CC, Lee CC.

Division of Gastroenterology, China Medical College Hospital, Taichung, Taiwan.

Cancer Invest 2002;20(7-8):939-43 Abstract quote

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.

CT scan and MRI  

Low grade gastric MALT Lymphoma: radiographic findings.

Brown JA, Carson BW, Gascoyne RD, Cooperberg PL, Connors JM, Mason AC.

Department of Radiology, St. Paul's Hospital, Vancouver, B.C.

Clin Radiol 2000 May;55(5):384-9 Abstract quote

AIMS: Gastric MALT (mucosa-associated lymphoid tissue) lymphoma is now recognized as a distinct entity within extranodal non-Hodgkin's lymphoma. The purpose of this study was to describe the radiographic findings in low grade gastric MALT lymphoma.

MATERIALS AND METHODS: We retrospectively reviewed the radiographic findings in 22 cases of low-grade gastric MALT lymphoma. The study group consisted of 15 men and seven women (median age 68 years, range 41-91 years). Lesions were designated as infiltrative or polypoid by consensus of two radiologists. Polypoid lesions were categorized by number and size. Anatomical site within the stomach and presence of transpyloric or oesophagogastric extension was determined for each case. The presence of abdominal lymphadenopathy was categorized as regional or distant. The presence of Helicobacter pylori was determined from endoscopic and surgical biopsies.

RESULTS: Computed tomography (CT) revealed abnormalities of the stomach in 19 cases of the 21 in which it was performed. There were 14 infiltrative lesions and five polypoid lesions. Of the 14 infiltrative lesions, the mean gastric wall thickness was 2.2 cm (range 0.8-6.0 cm). There were three single and two multiple polypoid lesions (mean size 2.2 cm, range 1. 5-2.7 cm). Transpyloric extension was observed in two cases and oesophagogastric extension in one. Abdominal lymphadenopathy was observed in 10 of 21 patients. Helicobacter pylori was found in 19 of 22 cases (86%).

CONCLUSION: Low grade B cell gastric MALT lymphomas present with an infiltrative form on CT in about three-quarters of cases and a polypoid pattern in the remainder. Abdominal lymphadenopathy is seen in approximately one-half of cases. There is a high association with Helicobacter pylori.


Gastric MALT Lymphomas Are Divided Into Three Groups Based on Responsiveness to Helicobacter Pylori Eradication and Detection of API2-MALT1 Fusion.

Inagaki H, Nakamura T, Li C, Sugiyama T, Asaka M, Kodaira J, Iwano M, Chiba T, Okazaki K, Kato A, Ueda R, Eimoto T, Okamoto S, Sasaki N, Uemura N, Akamatsu T, Miyabayashi H, Kawamura Y, Goto H, Niwa Y, Yokoi T, Seto M, Nakamura S.

From the Departments of *Pathology and daggerInternal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya; double daggerDepartment of Gastroenterology, section signPathology and Molecular Diagnosis, Aichi Cancer Center Hospital; Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya; paragraph signDepartment of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo; #Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto; **Third Department of Internal Medicine, Kansai Medical University, Moriguchi; Departments of daggerdaggerGastroenterology and double daggerdouble daggerClinical Pathology, Kure Kyosai Hospital, Kure; section sign section signDepartment of Gastroenterology, International Medical Center of Japan, Tokyo; Departments of Endoscopy and paragraph sign paragraph signInternal Medicine and Gastroenterology, Shinshu University Medical School, Matsumoto; and ##Department of Therapeutic Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Am J Surg Pathol. 2004 Dec;28(12):1560-1567. Abstract quote  

Gastric MALT lymphoma shows unique features including regression by Helicobacter pylori eradication and API2-MALT1 fusion. We performed a molecular and clinicopathologic study for 115 cases. All eradication-responsive cases were devoid of API2-MALT1 fusion. All tumors positive for the fusion and all negative for H. pylori infection were nonresponsive to the eradication.

Consequently, gastric MALT lymphomas were divided into three groups: Eradication-responsive and fusion-negative (group A, n = 72), eradication-nonresponsive and fusion-negative (group B, n = 22), and eradication-nonresponsive and fusion-positive (group C, n = 21). Group A tumors were characterized by low clinical stage and superficial gastric wall involvement, and group C tumors by low H. pylori infection rate, advanced clinical stage, and nuclear BCL10 expression. All group C tumors showed exclusively low-grade histology. Group B tumors, which have not been well recognized, frequently showed nodal involvement, deep gastric wall involvement, and advanced clinical stage, and sometimes an increased large cell component.

A multivariate discriminant analysis revealed that responsiveness to the eradication could be predicted accurately by negative API2-MALT1 fusion, positive H. pylori infection, low clinical stage, and superficial gastric wall invasion, the former being the most important factor for the prediction. This 3-group categorization may be helpful for a comprehensive understanding of gastric MALT lymphoma.
Large B-cell lymphoma

Am J Surg Pathol 2000;23:1641-1649
Study of 40 cases

Divided into several categories based upon immunohistochemical and morphologic findings:

CD10+, follicular, medium and large cell type
CD10-, diffuse, medium sized cell type (low grade MALToma)
CD10-, diffuse, large cell with low grade MALToma (high grade MALToma)
CD10+, diffuse, large cell type (CD10+, diffuse large cell lymphoma)

Pure cases defined as CD10 -, diffuse,without MALToma had an overall worse survival than high grade MALToma
bcl-6 positive in 10/12 cases

When can complete regression of low-grade gastric lymphoma of mucosa-associated lymphoid tissue be predicted after helicobacter pylori eradication?

Yamashita H, Watanabe H, Ajioka Y, Nishikura K, Maruta K, Fujino MA.

First Department of Pathology, Niigata University School of Medicine, Niigata, Japan.

Histopathology 2000 Aug;37(2):131-40 Abstract quote

AIMS: Recent studies suggest that primary low-grade gastric lymphomas of mucosa-associated lymphoid tissue (MALT) are cured in many cases between 1 and 18 months after H. pylori eradication. The aim of this study is to elucidate when complete regression (CR) of MALT lymphoma can be histologically predicted after H. pylori eradication.

METHODS AND RESULTS: Twenty-one patients with low-grade gastric MALT lymphoma were treated with triple therapy (amoxicillin, clarythromycin and proton pump inhibitor) for 14 days. Subsequently, they were followed up by sequential endoscopy and biopsy (number of biopsy specimens for each endoscopy is 3-8, with an average of 4) from 91 to 657 days (average: 309 +/- 165 days). Eradication of H. pylori infection was achieved in all patients. Nine patients were free of lymphoma at 1 to 2 months after eradication and remained in CR at 163-657 days. Twelve patients showed residual lymphoma at 1 to 2 months after eradication. Five out of 12 patients revealed only one or two small foci of lymphoma-cell aggregation and showed a high incidence (80%) of CR at the latest biopsy (135-434 days, average 276 +/- 115 days after eradication), while seven patients showed diffuse remains of lymphoma cells and indicated CR in only one case (14%) at 362 days, partial regression in five cases at 130-431 days (average 227 +/- 114 days), and no change in one case at 91 days after eradication.

CONCLUSIONS:: These results suggest that CR of low-grade MALT lymphoma can be predicted at 1 to 2 months after eradication therapy by checking histological changes of MALT lymphoma cells.

Clinicopathological features of gastric mucosa-associated lymphoid tissue lymphoma: a comparison with diffuse large B-cell lymphoma without a mucosa-associated lymphoid tissue lymphoma component.

Hiyama T, Haruma K, Kitadai Y, Masuda H, Miyamoto M, Ito M, Kamada T, Tanaka S, Uemura N, Yoshihara M, Sumii K, Shimamoto F, Chayama K.

First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima, Japan

J Gastroenterol Hepatol 2001 Jul;16(7):734-9 Abstract quote

BACKGROUND AND AIMS: The aim of this study was to clinicopathologically distinguish the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B-cell lymphoma without a MALT lymphoma component (DLL).

METHODS: We investigated clinicopathological features of these gastric lymphomas including age, sex ratio, tumor location and depth, macroscopic appearance, and infection with Helicobacter pylori of these gastric lymphomas and hepatitis viruses in 24 patients with gastric low-grade MALT lymphoma, 10 patients with high-grade MALT lymphoma, and 19 patients with DLL. The frequency of H. pylori infection in lymphoma patients was compared with that in age- and sex-matched control subjects.

RESULTS: There was a predominance of females with MALT lymphoma (male to female ratio, 8/16 for low-grade MALT lymphomas and 1/9 for high-grade MALT lymphomas), and there was a predominance of males with DLL (male to female ratio, 13/6); the ratios differed significantly (P < 0.05). Ninety-two percent of low-grade MALT lymphomas and 80% of high-grade MALT lymphomas were confined to the mucosal and submucosal layers, but lymphoma cells invaded the muscular layer or more deeply in 74% of DLL. Helicobacter pylori infection occurred significantly more often in patients with low-grade MALT lymphoma than in age- and sex-matched controls (96 vs 67%, P < 0.01). Conversely, the frequency of H. pylori infection in DLL patients did not differ from that in controls.

CONCLUSIONS: These data suggest that H. pylori infection may be associated with the development of gastric MALT lymphoma, but not DLL, and that MALT lymphoma and DLL may have a different pathogenesis.


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

Kwon MS, Go JH, Choi JS, Lee SS, Ko YH, Rhee JC, Ree HJ.


Am J Surg Pathol. 2003 Jun;27(6):790-8. Abstract quote

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.

In conclusion: 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.

Prognostic Factors  

Histological grading with clinical relevance in gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

de Jong D, Boot H, Taal B.

Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Recent Results Cancer Res 2000;156:27-32 Abstract quote

Treatment choice in gastric mucosa-associated lymphoid tissue (MALT) lymphoma is dependent on the stage and biological rate of progression and transformation as reflected by grade. In pre-treatment, endoscopic biopsy samples, histological and biological criteria to recognize tumor components with a significantly adverse impact on prognosis have to be defined to select patients who may benefit from Helicobacter pylori (H. pylori) eradication as single modality treatment and those who need "classical" anti-cancer therapy.

In a consecutive series of 106 patients with gastric MALT-non-Hodgkin's lymphoma (NHL), it was possible to define criteria to differentiate between low-grade and high-grade (transformed) disease. Moreover, within the low-grade group, a category with a diffuse large cell component of 1-10% with or without non-confluent clusters of blasts could be separated with a significantly worse prognosis (10-year disease-specific survival 90% versus 75%). No clinical parameters of known prognostic significance could account for this difference. In a separate series of 19 patients treated with H. pylori eradication, this morphology was strongly related to the chance of reaching complete remission as an independent risk factor.

This suggests that it is possible to define criteria in endoscopic biopsy samples to recognize clinically relevant tumor-progression and that these criteria may serve as a guideline in the choice of therapy.

Recognition of low and high grade component in
stage I-II B-cell gastric lymphomas

Am J Surg Pathol 2001;25:95-102

Formation of compact clusters of large cells, rather than the amount, is associated with a shorter survival

Presence of scattered large cells ranging from 5-10% were irrelevant in low grade MALTomas

Low grade component and lymphoepithelial lesions were favorable predictors in high grade lymphomas

NOTE: A high grade component was defined as large cell clusters greater than 10% of the neoplastic cell population


Relapse of low-grade gastric MALT lymphoma after Helicobacter pylori eradication: true relapse or persistence? Long-term post-treatment follow-up of a multicenter trial in the north-east of Italy and evaluation of the diagnostic protocol's adequacy.

Savio A, Zamboni G, Capelli P, Negrini R, Santandrea G, Scarpa A, Fuini A, Pasini F, Ambrosetti A, Paterlini A, Buffoli F, Angelini GP, Cesari P, Rolfi F, Graffeo M, Pascarella A, Valli M, Mombello A, Ederle A, Franzin G.

Department of Histopathology, Ospedale S. Orsola FBF, Brescia, Italy.


Recent Results Cancer Res 2000;156:116-24 Abstract quote

The effect of eradication of Helicobacter pylori on early stage gastric low-grade MALT lymphoma in 76 patients with follow-up of at least 1 year (12-63 months, mean 28) is reported. No regression was found in five cases after 12-48 months. In one case surgical resection detected the involvement of perigastric lymph nodes overlooked by endoscopic ultrasonography (EUS). Neither progression of the disease nor a high-grade component was documented by repeated gastric mappings, EUS and complete stagings in the other four cases.

After histological remission five relapses of low-grade and one relapse of high-grade MALT lymphoma were found 12-48 months after eradication. Subsequent histological remission, without any additional therapy, was found in three relapsed cases. A rapid and persistent histological remission was obtained in 56 patients (73%). A late remission was observed in six cases. Monoclonal remission was found in half of the patients and was frequently delayed. Persistent monoclonality was associated with histological remission in the vast majority of patients.

Our data confirm H. pylori eradication as the first choice therapy for early stage gastric low-grade MALT lymphoma and recommend extensive bioptic mapping and endoscopic sonography both in the local staging and in the regression evaluation. The rare cases of late remission encourage us to wait for at least 1 year after eradication of H. pylori.

Longer follow-up studies will clarify the meaning of histological relapse/persistence and late remission. The study of non-responder cases could show us a step in lymphomagenesis.

Microsatellite instability at D18S61 is associated with no regression of gastric mucosa-associated lymphoid tissue lymphoma after Helicobacter pylori eradication.

Hiyama T, Haruma K, Kitadai Y, Ito M, Masuda H, Miyamoto M, Tanaka S, Yoshihara M, Sumii K, Shimamoto F, Chayama K.

First Department of Internal Medicine, Hiroshima University School of Medicine, Minami-ku, Hiroshima 734-8551, Japan.

Oncol Rep 2001 Mar-Apr;8(2):293-7 Abstract quote

Recent studies have shown 70-80% of gastric low-grade mucosa-associated lymphoid tissue (MALT) lymphomas regressing in response to eradication of Helicobacter pylori (H. pylori). Genetic mechanism of regression of gastric MALT lymphoma after H. pylori eradication remains unclear.

To clarify the issue, we evaluated microsatellite instability (MSI) at 12 microsatellite loci in 15 patients with gastric low-grade MALT lymphoma, who received eradication therapy of H. pylori. H. pylori infection was observed in all the patients.

After eradication therapy of H. pylori, patients were observed for a median of 21 months (range, 6-49 months). Eradication was achieved in all the patients. Nine of the 15 (60%) patients showed complete regression (CR), 3 (20%) partial regression (PR), and 3 (20%) no change (NC). MSI was detected in 3 of the 15 (20%) patients with low-grade MALT lymphoma. Compared with response to eradication therapy of H. pylori, MSI was detected in 1 of the 12 (8%) CR and PR patients, and in 2 of the 3 (67%) NC patients. Especially, MSI at D18S61 was detected in 2 of the 3 (67%) NC patients but in none of the 12 CR and PR patients. There was a significant difference between frequency of MSI at D18S61 in NC patients and that in CR and PR patients (p<0.05).

These data suggest that MSI at D18S61 may be associated with lack of regression of gastric MALT lymphoma after H. pylori eradication.


Lymph node involvement rate in low-grade gastric mucosa-associated lymphoid tissue lymphoma--too high to be neglected.

Chang DK, Chin YJ, Kim JS, Jung HC, Kim CW, Song IS, Kim CY.

Department of Internal Medicine, Seoul National University College of Medicine, Korea.

Hepatogastroenterology 1999 Jul-Aug;46(28):2694-700 Abstract quote

BACKGROUND/AIMS: Anti-Helicobacter pylori (H. pylori) treatment for low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma has been the subject of attention. The aim of this study was to determine the proportion of such cases which could be suitable candidates for H. pylori eradication for the purpose of cure; we focused on gross morphology and lymph node metastasis.

METHODOLOGY: We retrospectively reviewed the medical records of 53 patients diagnosed and treated for gastric MALT lymphoma at Seoul National University Hospital between 1992 and 1996.

RESULTS: According to Isaacson's classification, 60% of cases were low-grade, and H. pylori was detected in 88% of them. In low-grade disease, gastroscopy revealed superficial lesions in 56% of cases, ulcerofungating lesions were found in as much as 19%, and ulceroinfiltrating in 25%. Even in low-grade disease, invasion of proper muscle, or deeper, was seen in 28% of patients, and lymph node involvement in 36%; even in low-grade disease confined to mucosa and submucosa, the rate of lymph node involvement was 40%. All cases which, on gastroscopy, appeared to be gastritis or benign ulcer-like lesions were free of lymph node metastasis, but in low-grade disease, this proportion was only 16%. In 33% of cases, pre-operative clinical stage I--as shown by abdominal CT--was found post-operatively to be stage II. The negative predictive value of lymph node detection by CT was 68%.

CONCLUSIONS: In low-grade gastric MALT lymphoma, the lymph node involvement rate was too high to be neglected. In detecting lymph node metastasis, the diagnostic accuracy of CT was too low. The proportion of suitable candidates for anti-H. pylori treatment for low-grade gastric MALT lymphoma was not high, and in clinical practice, anti-H. pylori treatment in such cases should at present be very carefully applied.


Treatment of gastric MALT lymphoma by Helicobacter pylori eradication: a study controlled by endoscopic ultrasonography.

Nobre-Leitao C, Lage P, Cravo M, Cabecadas J, Chaves P, Alberto-Santos A, Correia J, Soares J, Costa-Mira F.

Servico de Gastrenterologia, Centro de Investigacao em Patobiologia Molecular, Departamento de Patologia Morfologica, Instituto Portugues de Oncologia Francisco Gentil, Lisboa.


Am J Gastroenterol 1998 May;93(5):732-6 Abstract quote

OBJECTIVE: Previous studies have demonstrated a link between Helicobacter pylori infection and low grade B-cell gastric MALT lymphoma. The aim of this study was to evaluate the effect of Helicobacter pylori eradication in 17 patients with low grade B-cell gastric MALT lymphoma stage EI.

METHODS: For disease staging EUS and CT scan were systematically performed. Eight patients were excluded from the present series because stage EII disease was diagnosed. To demonstrate B-cell monoclonality, immunohistochemistry and polymerase chain reaction were used. H. pylori eradication was performed with triple therapy.

RESULTS: H. pylori was eradicated in all patients after first (n = 15) or second line (n = 2) treatment. Histologic regression of lymphoma was observed in all patients after a median period of 2 mo. Disappearance of monoclonality according to polymerase chain reaction took significantly longer (7 mo). At the end of the study, four of 16 patients still exhibited persistent monoclonal bands. Relapse of lymphoma occurred in two patients associated with H. pylori reinfection/recrudescence.

CONCLUSION: Eradication of H. pylori seems to be an effective therapy in patients with stage EI gastric MALT lymphoma, although long-term results are still uncertain. Endoscopic ultrasonography is useful for a more accurate staging of the disease. The clinical significance of detecting monoclonality by polymerase chain reaction remains to be determined.

Eradication of Helicobacter pylori and stability of remissions in low-grade gastric B-cell lymphomas of the mucosa-associated lymphoid tissue: results of an ongoing multicenter trial.

Thiede C, Wundisch T, Neubauer B, Alpen B, Morgner A, Ritter M, Ehninger G, Stolte M, Bayerdorffer E, Neubauer A.

Medizinische Klinik I, Technische Universitat, Dresden, Germany.

Recent Results Cancer Res 2000;156:125-33 Abstract quote

The normal human stomach is devoid of any organized lymphatic tissue. Acquisition of mucosa-associated lymphatoid tissue (MALT) in the stomach is considered to be a direct consequence of chronic infection with Helicobacter pylori. Thus, MALT appears to be part of the host defense against the pathogen H. pylori. Consequently, lymphomas arising from gastric MALT may be seen as an end point of a clonal evolution starting from the infection.

Cumulative data from several studies show that eradication of H. pylori induces complete histologic remissions in about 70%-80% of the patients.

Here we present data of an extended analysis of an ongoing multicenter trial. Eighty-four patients with low-grade gastric MALT lymphoma in stage EI were treated using a dual regimen to eradicate H. pylori. Complete remission was observed in 68 (81%) patients; a partial remission was found in seven (8%) patients. In contrast, nine (11%) patients revealed "no change" and were referred for alternative treatment strategies. The majority of these cases were found to harbor high-grade lymphomas in deeper mucosal areas.

Polymerase chain reaction (PCR) performed on the VDJ rearrangements of the immunoglobulin heavy chain yielded monoclonal bands in 50 of 65 analyzed patients (77%) at diagnosis. Interestingly, in patients analyzed during follow up after achieving complete histologic remission, ongoing PCR monoclonality was found in 19 of 39 eligible patients (49%). Several patients who developed local relapse of the lymphoma were found in the group with ongoing PCR monoclonality.

Together with data from the literature, these results suggest that the majority of low-grade gastric MALT lymphomas in stage EI respond to eradication of H. pylori. Longer follow-up investigations are necessary to determine whether remissions really indicate a cure from the disease and to elucidate whether PCR monoclonality after complete histological remission is predictive of increased relapse rate.

Helicobacter pylori eradication and remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma: a long-term follow-up study.

Papa A, Cammarota G, Tursi A, Gasbarrini A, Gasbarrini G.

Department of Internal Medicine, Catholic University of Roma, Italy.


J Clin Gastroenterol 2000 Sep;31(2):169-71 Abstract quote

Helicobacter pylori infection plays a crucial role not only in the pathogenesis but also in the treatment of low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma.

The aim of the present study was to evaluate whether H. pylori eradication provides a definite cure in the early stage of this neoplasia by means of a prolonged follow-up. All patients affected by low-grade gastric MALT lymphoma in stage IE that were referred to our department from January 1995 to June 1999 were enrolled in a prospective study. Diagnosis was histologically proved and H. pylori status was evaluated. Staging was performed according to a modified Ann Arbor classification.

All patients who proved positive for H. pylori infection were treated with eradicating therapy, and a prolonged clinical and histologic follow-up was carried out. Until June 1999, seven low-grade gastric MALT lymphomas in stage IE were diagnosed (four men and three women; mean age, 56 years). All patients were H. pylori-positive and eradication was obtained in all of them after the first cycle of antibiotic therapy. Complete histologic regression of lymphoma was observed in all cases in a period variable between 3 and 6 months. The mean follow-up period was 42 months (range, 20-54). Only one patient showed a recurrence of lymphoma 22 months after treatment associated with H. pylori reinfection.

Our results show the high efficacy of H. pylori eradication in determining a prolonged remission of low-grade gastric MALT lymphomas in stage IE. Thus, this therapeutic approach may avoid or delay the indication for more aggressive therapies, such as surgical resection.

A Critical Review of the Effect of Helicobacter pylori Eradication on Gastric MALT Lymphoma.

Wotherspoon AC. Department of Histopathology, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.

Curr Gastroenterol Rep 2000 Dec;2(6):494-8 Abstract quote

Low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are thought to arise within organized lymphoid tissue in the gastric mucosa that is most frequently acquired in response to Helicobacter pylori infection.

This close association between the organism and the lymphoma is further reflected by the demonstration that the proliferation of the lymphoma cells can be driven by the presence of H. pylori organisms through a complex path of cellular interactions involving specific T cells. From these observations it was suggested that removal of one of the proliferative drives to the neoplastic cells in the form of eradication of the organism might induce a remission in the tumor.

Several large multicenter studies are now underway to consider this question, and interim reports suggest that long-term remissions can be induced in low-grade MALT lymphomas in 70% to 80% of cases. The lymphomas that are most likely to respond to H. pylori eradication are those that are located superficially within the gastric mucosa. It has been suggested that certain genetic abnormalities, such as t(11;18) and the Bcl-10 mutation, may be associated with lack of response to this therapy.

Recurrences of low-grade lymphoma are encountered in patients treated by H. pylori eradication, but these appear to be infrequent and may be self-limiting and spontaneously regress without further therapy.

Helicobacter pylori eradication therapy for high-grade mucosa-associated lymphoid tissue lymphomas of the stomach with analysis of p53 and K-ras alteration and microsatellite instability.

Hiyama T, Haruma K, Kitadai Y, Ito M, Masuda H, Miyamoto M, Tanaka S, Yoshihara M, Sumii K, Shimamoto F, Chayama K.

First Department of Internal Medicine, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan.


Int J Oncol 2001 Jun;18(6):1207-12 Abstract quote

Recent studies have shown that 70-80% of low-grade mucosa-associated lymphoid tissue (MALT) lymphomas regress in response to eradication of Helicobacter pylori (H. pylori). However, there are no reports on whether gastric high-grade MALT lymphomas regress after H. pylori eradication.

We performed H. pylori eradication therapy in 4 patients with stage I, high-grade MALT lymphoma after obtaining their informed consent. H. pylori infection was observed in all 4 patients. The patients were treated with proton-pump inhibitor-based eradication therapy for 1 or 2 weeks, and then underwent endoscopic examination and biopsy sampling. H. pylori eradication was achieved in all 4 patients. Six months after eradication treatment, 2 patients showed complete regression of the lymphoma and 2 patients showed no change. The 2 patients with non-responding lymphoma were then treated with an additional chemotherapy (CHOP regimen), whereupon the tumors completely regressed. These patients, followed-up at least 18 months after eradication treatment, showed no recurrence.

We also examined genetic alteration of the p53 and K-ras genes and microsatellite instability in these high-grade MALT lymphomas. One patient with a tumor that showed no change after H. pylori eradication, had a loss of heterozygosity of the p53 gene. No other genetic alterations were detected among the patients.

Our results indicate that the eradication of H. pylori may be effective not only for patients with low-grade MALT lymphoma but also for patients with high-grade MALT lymphoma. The treatment may be efficacious as a first-line therapy for patients with high-grade MALT lymphoma. However, our sample size was limited and further studies are needed to clarify the issue.

Regression of gastric high grade mucosa associated lymphoid tissue (MALT) lymphoma after Helicobacter pylori eradication.

Montalban C, Santon A, Boixeda D, Bellas C.

Department of Internal Medicine, Hospital Ramon y Cajal, Madrid, Spain.

Gut 2001 Oct;49(4):584-7 Abstract quote

BACKGROUND: Most low grade gastric lymphomas arising from the mucosa associated lymphoid tissue (MALT) are related to Helicobacter pylori colonisation. Cases with disease limited to the stomach can be cured after H pylori eradication and remain in remission for years. In contrast, high grade lymphomas of the stomach, although also related to H pylori, do not usually respond to eradication treatment.

CASE REPORT: A 36 year old patient was referred from another hospital with a diagnosis of a low grade gastric MALT lymphoma associated with H pylori. The patient was in stage I and while waiting for the biopsies to be reviewed H pylori eradication therapy was given as the first step of treatment. Review of the biopsies showed a high grade immunoblastic lymphoma with areas of low grade gastric MALT lymphoma (high grade gastric MALT lymphoma or diffuse large B cell lymphoma with areas of MALT type lymphoma of the WHO classification). The patient received no further treatment but has been closely followed up for 32 months with sequential endoscopies to obtain biopsies for histological studies, H pylori cultures, and polymerase chain reaction analysis of the IgH gene.

RESULTS: After H pylori eradication the patient had a complete histological response that has been maintained for 32 months. Monoclonal IgH gene rearrangement persisted for 32 months.

CONCLUSION: The response of this patient indicates the possibility that some cases of high grade gastric MALT lymphoma (possibly patients in stage I with a superficial or limited disease) may still be responsive to H pylori antigenic drive and may be cured with eradication therapy. Prospective studies should be performed to identify patients with high grade gastric MALT lymphomas that may respond to eradication therapy and be spared of other more aggressive treatments.

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