High-grade Gastric Mucosa-associated Lymphoid Tissue Lymphoma Research Articles

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.

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.

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.

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.

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.

Detection of aberrant isotype switch recombination in low-grade and high-grade gastric MALT lymphomas

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma originates from reactive lymphocytic infiltrates during chronic gastritis, closely associated with Helicobacter pylori infection. MALT lymphomas may be either "low grade" or "high grade," and transformation from low grade to high grade can occur. To obtain information on the maturational state of MALT lymphoma cells, we investigated their ability to undergo isotype switch recombination, which together with immunoglobulin variable gene somatic mutation, contributes to normal B-cell maturation. Using specific probes for the immunoglobulin heavy-chain (IgH) switch regions, we found by Southern blot that 3 out of 5 low-grade cases and 2 out of 2 high-grade cases showed rearrangements within IgH switch regions, which appeared aberrant in 4 of the 5 cases. The cloning of two rearranged fragments from one low-grade and one high-grade case confirmed the aberrant nature of the rearranged fragments. A deletion from the switch mu region (S mu) to the first constant mu exon (C mu 1) and a second deletion from the second constant mu exon (C mu 2) to the gamma 3 region (gamma 3) was detected in the low-grade case. In the high-grade case, there was a deletion of the IgH intronic enhancer (E mu) and a 336-base pair (bp) insertion into the S mu region of a gene (KIAA0307) normally located at 15q24. These data demonstrate for the first time the ability of MALT lymphoma cells to undergo aberrant isotype switch recombinations, which might be directly involved in the development or progression of malignancy.

High frequency of CagA+ Helicobacter pylori infection in high-grade gastric MALT B-cell lymphomas.

A high incidence of Helicobacter pylori infection has been found in patients with gastric MALT (mucosa-associated lymphoid tissue) B-cell lymphoma. Recent studies have indicated that the aggressive strains of the bacterium containing the CagA gene may have direct effects on tumourigenesis. To investigate the involvement of CagA+ strains in MALT lymphomagenesis, a sensitive polymerase chain reaction (PCR)-based detection assay for the gene was developed. DNA extracts from paraffin sections of 123 H. pylori-related gastric biopsies from Italy were analysed, including 56 cases of chronic gastritis, 37 low-grade, and 30 high-grade MALT lymphomas: 30.3 per cent (17/56) of the gastritis cases, 37.8 per cent (14/37) of the low-grade, and 76.7 per cent (23/30) of the high-grade MALT lymphomas were found to contain the CagA gene. The frequency of CagA+ strain infection was significantly higher (P < 0.05) in high-grade than in low-grade MALT lymphoma or gastritis. These results suggest that high-grade gastric MALT lymphoma transformation may be more likely to occur following infection by CagA+ strains of H. pylori.

Deletion analysis of the p16 tumor suppressor gene in gastrointestinal mucosa-associated lymphoid tissue lymphomas

BACKGROUND & AIMS: The molecular mechanisms responsible for initiation and progression of gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas are largely unknown. The aim of this study was to analyze the p16 tumor suppressor gene in MALT lymphomas of the stomach and colon. METHODS: Tumor samples were obtained from 28 patients with low-grade (n = 12) and high-grade (n = 14) gastric MALT lymphomas and from 2 patients with colonic MALT lymphomas. DNA was extracted from microdissected areas with at least 80% tumor cells. To detect homozygous p16 deletions, a semiquantitative polymerase chain reaction assay was used, whereby either p16 exon 1 or exon 2 was coamplified with an unrelated sequence as internal control. RESULTS: Homozygous p16 deletions were found in 2 of 14 (14%) cases with high-grade gastric MALT lymphomas. Both patients had Helicobacter pylori-associated gastritis; however, DNA extracted from areas of gastritis showed a normal p16 complement. No deletion was found in any of the low-grade gastric or the colonic MALT lymphoma specimens. CONCLUSIONS: In a subset of gastric MALT lymphomas, homozygous p16 deletions are acquired and may contribute to the transformation from a low-grade to a high- grade malignancy. (Gastroenterology 1997 Jun;112(6):1871-5)

Nucleolar Organizer Regions (NORs) Staining and Proliferating Cell Nuclear Antigen (PCNA) Immunostaining in Mucosa-Associated Lymphoid Tissue (MALT) Gastric Lymphomas

Nucleolar organizer region-associated proteins (AgNOR) and proliferating cell nuclear antigen (PCNA) have been studied by means of a silver staining technique and immunohistochemistry, in paraffin-embedded, gastrectomy specimens of 12 low-grade and 13 high-grade gastric MALT lymphomas respectively. A significant difference was found between the AgNOR count and PCNA index of low-grade lymphomas (mean AgNOR count 2.5 and mean PCNA index 8.33%) and high-grade lymphomas (mean AgNOR count 8.67 and mean PCNA index 49.7%). It is suggested that both methods are useful adjuncts to histopathology for the distinction between low and high grade gastric MALT lymphomas. We also found heterogeneity in AgNOR counts and PCNA index among individual cases of either low or high grade MALT gastric lymphomas. This suggests that the AgNOR count and PCNA index is helpful in the individual approach of the proliferation rate of each tumour, a parameter of potential importance for predicting the biological behaviour of the tumour and the prognosis of the disease.

The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori

An association has been shown between colonisation of gastric mucosa by Helicobacter pylori, acquisition of mucosa-associated lymphoid tissue (MALT), and occurrence of primary B-cell gastric MALT lymphoma. We investigated the immunological response of cells from 3 low-grade primary B-cell gastric MALT lymphomas to H pylori type NCTC 11637 and 12 isolates of H pylori from patients without lymphomas. After co-culture of tumour cells with bacteria, cells were examined for phenotypic evidence of activation and proliferation, and supernatant assayed to detect tumour-derived immunoglobulin and interleukin-2 (IL-2). Neoplastic B cells and non-neoplastic T cells proliferated, and IL-2-receptor expression by most cells in the cultures was increased with stimulating strains of H pylori. There were also increases in tumour immunoglobulin and IL-2 release when activation and proliferation were seen in response to stimulating bacteria. Removal of T cells from the tumour cell suspension reduced proliferation and IL-2-receptor expression. In comparison, no responses were seen in cells from high-grade gastric MALT lymphomas or low-grade B-cell MALT lymphomas of other sites. The response of low-grade B-cell gastric MALT lymphomas to stimulating strains of H pylori is dependent on H-pylori-specific T cells and their products, rather than the bacteria themselves.