Primary gastric mucosa associated lymphoid tissue lymphoma： Clinical data predicted treatment outcome

AIM： To determine clinical characteristics and treatment outcome of gastric lymphoma after chemotherapy and immuno-chemotherapy. METHODS： Thirty four patients with primary gastric mucosa associated lymphoid tissue （MALT） lymphoma （Ann Arbor stages Ⅰ to Ⅳ） were enrolled. All had upper gastric endoscopy, abdominal ultrasonography, CT and H pylori status assessment （histology and serology）. After anti-H pylori treatment and initial chemotherapy, patients were re-examined every 4 mo. RESULTS： Histological regression of the lymphoma was complete in 22/34 （64.7%） and partial in 9 （26.5%） patients. Median follow up time for these 31 responders was 60 mo （range 48-120）. No regression was noted in 3 patients. Among the 25 （73.5%） H pylori positive patients, the eradication rate was 100%.CONCLUSION： Using univariate analysis, predictive factors for overall survival were international prognostic index （IPI） score, hemoglobin level, erythrocyte sedimentation rate （ESR）, and platelet numbers （P 〈 0.005）. In addition to this, Cox proportion hazard model differentiate IPI score, ESR, and platelets as predictors of survival.     

Primary gastric non-Hodgkin's lymphoma: a clinicopathological study of 41 patients

Pathological findings in 41 patients (male/female ratio: 1.3/1) with primary localized gastric non-Hodgkin's lymphoma (NHL) were retrospectively studied and correlated with survival. The median observation period after diagnosis was 32 (0–189) months. Nineteen patients were low-grade NHL, all but one B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) type. Twenty-two patients had primary (n-7) or secondary (n=15) high-grade lymphomas; Musshoff stage IE was found in 29 and II E in 12 cases. The median age at diagnosis was 61 years (range, 26–88 years), and proliferation, measured by the number of mitosis and Ki-67 antigen positivity (MIB-1), was high or moderately high in 24 cases and low in 17 cases. Follicular lymphatic hyperplasia could be found in 25 of 34 evaluable cases, more often in low-grade than in high-grade NHL. Most of the patients were treated by resective surgery and additional ratio- or chemotherapy. Thirteen patients (31%) died (median survival: 10 months), 5 of them within 3 months after surgery owing to postoperative complications. Survival was superior, though not statistically significant, in low-grade lymphomas. Our retrospective anlysis of heterogeneously treated gastric lymphomas reveals that gastric lymphomas, especially of the low-grade MALT type, often remain a localized disease with a good long-term prognosis. Our study confirms previous reports indicating that lymphomas of the MALT type represent a specific clinicopathological entity.     

Prognostic factors of Chinese patients with primary pulmonary non-Hodgkin’s lymphoma: the single-institute experience in Taiwan

Primary pulmonary lymphoma (PPL) accounts for less than 1% of patients with non-Hodgkin’s lymphoma, with no report in Chinese patients. This study aims to analyze the clinical features and prognosis of this population. Patients with biopsy-proven pulmonary lymphoma were reviewed and re-classified by a hema-pathologist. Between 1992 and 2005, a total of 22 patients were identified (16 men and six women), with a mean age of 70 years. The histological subtypes included marginal zone B-cell lymphoma of mucosa-associated lymphoid tissues (MALT) in 12 patients (54%), diffuse large B-cell lymphoma in nine (41%), and one case of lymphomatoid granulomatosis. Diseases mainly manifested as pulmonary nodules or masses in 73% of patients, with a higher rate of hilar/mediastinal lymphadenopathy in non-MALT patients (8% vs. 80%, P = 0.002). In eight patients (36% of 22), diagnoses were only conclusive until the biopsy via thoracotomy. Eighteen patients (82%) received chemotherapy. The 5-year rates of overall survival (OS) were 91% and 21% for MALT and non-MALT types of PPL, respectively. Patients who had received surgical resection tended to have a better 5-year OS rate (P = 0.077). The Cox-regression analysis showed that two factors—elevated serum lactate dehydrogenase level and hilar/mediastinal lymphadenopathy at diagnosis—were independently associated with a poor OS, with a hazard ratio of 10.370 and 5.171 (P = 0.01 and 0.033), respectively. In conclusion, the histological subtypes of Chinese PPL patients were similar to those in previous reports, with no increasing incidence of T-cell immunophenotype. The two prognostic factors provided additional information in managing these patients. YHH and LTH have equal contribution.     

Transformed mucosa-associated lymphoid tissue lymphomas: A single institution retrospective study including polymerase chain reaction-based clonality analysis

Given the lack of consistent data regarding the clinico-pathological features and clonal lymphomagenesis of patients with mucosa-associated lymphoid tissue (MALT) lymphoma and histological transformation (HT), we have systematically analysed 379 patients (32% gastric, 68% extra-gastric; median follow-up 52 months) diagnosed with HT at the Medical University Vienna 1999–2017, and reassessed tissues of identified patients by polymerase chain reaction (PCR)-based clonality analysis. HT was documented in 12/379 patients (3·2%) and occurred at a median time of 22 months (range; 6–202 months) after diagnosis of MALT lymphoma. By PCR-based clonality analysis, we detected a clear-cut clonal relationship of MALT lymphoma and diffuse large B-cell lymphoma (DLBCL) in 8 of 11 analysed cases proving that the large majority of DLBCL following MALT lymphoma are clonally-related and constitute a real transformation. Interestingly, HT occurred within the first 2·5 years after diagnosis in patients with clonal relationship, whereas time to aggressive lymphoma was longer in patients identified as clonally-unrelated (most likely secondary) lymphoma (82–202 months), suggesting that HT is an early event in this disease. Survival of patients with HT was poor with 6/12 dying at 1·5–33 months after HT, however, patients with localized gastric transformation had a superior outcome with only 1/6 dying due to progression of lymphoma.     

Primary gastric diffuse large B‐cell Lymphoma (DLBCL): analyses of prognostic factors and value of pretreatment FDG‐PET scan

Objectives: We report a single institution experience with gastric diffuse large B‐cell lymphoma (DLBCL) in an attempt to evaluate the roles of different treatment modalities, to assess the value of pretreatment positron emission tomography (PET) scan, and to identify potential prognostic factors. Methods: Among 384 patients diagnosed with DLBCL between 1995 and 2008, 75 patients had primary gastric DLBCL and were reviewed and analyzed. Results: The median age was 66. International prognostic index (IPI) risk was low in 52%, low‐intermediate in 23%, high‐intermediate in 9%, and high in 16%. Pretreatment PET scan was highly sensitive in detecting gastric lesions except stage I gastric DLBCL without detectable mass by CT or gastroscopy. As a general rule, patients with limited‐stage disease were treated with three times of CHOP (with or without rituximab) and radiotherapy, and those with advanced‐stage disease were treated with eight cycles of CHOP (with or without rituximab), and radiotherapy was given to residual diseases after chemotherapy. Three‐year overall survival (OS) rate was 78%. Multivariate analysis revealed that low albumin, hemoglobin <12.0 g/dL, and treatment without rituximab were independently associated with shorter OS. Low albumin, hemoglobin <12.0 g/dL,and advanced stage were independently associated with shorter progression‐free survival. Conclusion: We showed the survival benefit of rituximab and potential prognostic value of pretreatment hemoglobin and serum albumin levels in gastric DLBCL.     

Importance of maintaining the relative dose intensity of CHOP-like regimens combined with rituximab in patients with diffuse large B-cell lymphoma

CHOP-like regimen combined with rituximab is a standard chemotherapy for diffuse large B-cell lymphoma (DLBCL). The relative dose intensity (RDI) was proposed as an index of the dose and administration interval of agents. Previous studies reported that the maintenance of the RDI during CHOP therapy improved the treatment results. However, few studies regarding RDI have reviewed patients receiving combination therapy with CHOP and rituximab. We investigated the influence of RDI maintenance, involving combination therapy with rituximab, on therapeutic effects in patients with DLBCL. We retrospectively examined 152 DLBCL patients who were treated with CHOP-like regimen combined with rituximab in whom the RDI could be followed up. Multivariate analysis revealed that international prognosis index (IPI) high intermediate-high (HI-H) (p = 0.005) and RDI of less than 70% (p = 0.007) were independent prognostic factors for low progression free survival. Concerning overall survival, IPI HI-H (p = 0.027) and an RDI of less than 70% (p = 0.002) were involved in an unfavorable prognosis. In addition, age over 60 years (p = 0.003), R-THPCOP (p = 0.034), or the presence of febrile neutropenia (p = 0.004) made RDI maintenance difficult, and prophylactic G-CSF therapy (p = 0.026) was useful for maintaining the RDI. Maintaining the RDI is important even in the era of rituximab-combined chemotherapy for DLBCL.     

Risk factors for poor treatment outcome and central nervous system relapse in diffuse large B-cell lymphoma with bone marrow involvement

Although several studies have described the prognostic implication of bone marrow (BM) involvement (BMI) in lymphoma, studies focused on BM-involved diffuse large B-cell lymphoma (DLBCL) are very rare and small-sized. This study was performed to examine the prognostic impact of morphologic findings of BMI by lymphoma and risk factors for central nervous system (CNS) relapse in BM-involved DLBCL. Between 1993 and 2005, 675 patients were diagnosed with DLBCL, and 88 patients who had BMI at initial diagnosis were eligible for this study. The median overall survival (OS) and failure-free survival (FFS) of 88 patients were 36.6 and 20.1 months, respectively. When three variables from BM morphologic findings (the pattern of BM infiltration, extent of BMI by lymphoma, and percentage of large cells in the infiltrate) were simultaneously included into multivariate model, the increased extent of BMI by lymphoma (≥10%) in BM area was the only negative prognostic factor, independent of the International Prognostic Index (IPI). Patients with both lower IPI scores and less extent of BMI showed an excellent prognosis with chemotherapy alone (5-year OS and FFS rates, 80% and 69%). However, morphologic BM features were not independent predictive factors for CNS recurrences. An increased lactate dehydrogenase (LDH) level at initial diagnosis was the only independent predictive factor for CNS relapse. Further efforts should be directed toward finding optimal treatment modalities based on the IPI and the extent of BMI by lymphoma. CNS prophylaxis may be considered only in patients with initial elevated LDH levels. K.-W. Lee and J. Yi equally contributed to this study.     

Helicobacter pylori eradication in gastric diffuse large B cell lymphoma

Diffuse large B cell lymphoma(DLBCL) of the stomach is a heterogenous disease. There are tumors without histological evidence of mucosa-associated lymphoid tissue(MALT) lymphoma, which are classified as pure or de novo DLBCL and those with evidence of MALT, which are classified as DLBCL(MALT). The association between Helicobacter pylori(H. pylori) and gastric MALT lymphoma and remission with H. pylori eradication was shown in the 1990 s. In recent years, scientists from Taiwan and others have shown that high-grade gastric lymphomas may be dependent on H. pylori and eradication of this microorganism is effective in these cases. This entity is biologically distinct from H. pylori(-) cases and has a better clinical outcome. There are sufficient data about the complete remission in some of these cases with brief treatment with antibiotics. With this strategy, it is possible to save some of these cases from the harmful effects of standard chemotherapy. It is time to treat these cases with H. pylori eradication. However, strict histopathological follow-up is crucial and histopathological response must be evaluated according to the scoring system proposed by Groupe d’Etude des Lymphomes de l’Adulte. If there is no sufficient response, chemotherapy must be given immediately. These results suggest that H. pylori dependency and high-grade transformation in gastric MALT lymphomas are distinct events.     

A multicentre study of primary breast diffuse large B‐cell lymphoma in the rituximab era

Primary breast diffuse large B‐cell lymphoma (DLBCL) is a rare subtype of non‐Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow‐up of 4·5 years (range 0·6–20·6 years), the Kaplan–Meier estimated median progression‐free survival was 10·4 years (95% confidence interval [CI] 5·8–14·9 years), and the median overall survival was 14·6 years (95% CI 10·2–19 years). Twelve patients (16%) had CNS relapse. A low stage‐modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage‐modified IPI score is associated with survival.     

Rituximab in combination with CHOP chemotherapy for the treatment of diffuse large B cell lymphoma in Chinese patients

The objective of this study is to evaluate the long-term efficacy and safety of rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in Chinese patients with newly diagnosed diffuse large B cell lymphoma (DLBCL). The study comprised a retrospective analysis of patients treated at a single center. Patients received four to six infusions of rituximab (375 mg/m² per dose) on day 1 of each cycle of CHOP chemotherapy. CHOP was initiated on day 3 of each cycle; cycles were repeated at 21-day intervals. A total of 82 patients with a median age of 45 years (range 18–76 years) was included. The overall response (OR) and complete response (CR) rates were 90.2 and 70.7%, respectively. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 56.4 ± 8.3% and 74.1 ± 7.4%, respectively. Patients with International Prognostic Index (IPI) scores ≤2 had significantly higher OR, CR, PFS, and OS rates (p = 0.01, p = 0.02, p = 0.01, p < 0.001, respectively) compared with patients with IPI scores >2. The hematologic toxicity was mild. Five patients with a history of chronic hepatitis B experienced a reactivation of viral hepatitis. The rituximab–CHOP combination was effective and well tolerated in Chinese patients with newly diagnosed DLBCL. This study was conducted in accordance with the Chinese Good Clinical Practice (GCP), including ethical approval.     

Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori: Scratch and win

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is generally associated with Helicobacter pylori infection and, in the great majority of patients, regresses after eradication. H. pylori-negative MALT lymphoma occurs in a small minority of cases in which treatment is based on surgery or chemoradiotherapy. In the search for H. pylori based on histology and the C¹³ urea breath test, this report describes a case with a series of false-negative results, thus confirming the possibility of a lower detectability of H. pylori in patients with MALT gastric lymphoma and supporting the use of additional tests in evaluating such pathology, including polymerase chain reaction. Additionally, treatment with CD20 monoclonal antibody (rituximab) is suggested as an alternative to surgery or treatment with chemotherapy or radiotherapy in patients with truly H. pylori-negative gastric MALT lymphoma.     

Primary non-Hodgkin’s lymphoma of the breast: eight-year follow-up experience

The objective of this study is to analyze the clinical characteristics and treatment of patients with primary non-Hodgkin's lymphoma of the breast (PNHLB). Forty-five patients with PNHLB treated in our hospital during a 15-year period were retrospectively analyzed. Forty-four were females and one male, with a median age of 47 years. Forty-two patients were at stage I or II and 82.2% had diffuse large B cell lymphoma (DLBCL). Local control rate was 95.2 and 66.7% for patients with and without radiotherapy, respectively (P = 0.020). Median overall survival and progression-free survival (PFS) of all patients was 6.8 and 4.3 years, respectively. For patients with DLBCL or T cell lymphoma, median PFS was 6.5 years with chemoradiation and 3.9 years with chemotherapy or radiation only (P = 0.029). Patients who used rituximab had not reached median PFS, while those treated without rituximab had a median PFS of 5.1 years (P = 0.301). International prognostic index (IPI) score and bilateral breast involvement were two independent prognostic factors for survival. Chinese patients with PNHLB have early occurrence in lifespan. Radiation confers a better local control. Patients with intermediate or high-grade PNHLB might be treated with chemotherapy, radiotherapy, and for CD-20 positive disease, rituximab. Bilateral disease and IPI are two prognostic factors.     

胃肠道淋巴瘤放疗进展

原发胃肠道淋巴瘤是最常见的结外非霍奇金淋巴瘤。胃肠道淋巴瘤为异质性的肿瘤,弥漫大B细胞淋巴瘤和粘膜相关淋巴瘤是最常见的病理类型,放疗在不同部位和病理类型的淋巴瘤治疗中地位不同。原发胃淋巴瘤接受保留胃功能的治疗可取得良好预后,弥漫大B细胞淋巴瘤化疗后（包括完全缓解）接受放疗可提高局控率和生存率,美罗华时代大肿块患者仍需要接受放疗以提高局部控制率。早期胃MALT淋巴瘤抗HP失败后,接受单纯放疗即可取得良好的预后。原发肠道侵袭性淋巴瘤的治愈手段仍为外科治疗,惰性淋巴瘤亦可选择放疗。     

Higher fungal infection rate in elderly patients (more than 80 years old) suffering from diffuse large B cell lymphoma and treated with rituximab plus CHOP

Although adding rituximab to standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy is an efficacious and well-tolerated regimen in elderly patients with diffuse large B cell lymphoma (DLBCL), it may increase susceptibility to opportunistic infections, and such cases have been reported. Our study was to identify the risk factors for fungal infection in a retrospective case-control matched study of 34 elderly DLBCL patients treated with rituximab plus CHOP (R-CHOP) and 35 control patients treated with the standard CHOP regimen at the Taipei Veterans General Hospital, Taiwan. The rate of overall infection was similar in both groups. However, subgroup analysis found that the fungal infection rate was significantly different, 41.7 and 17.1%, in the R-CHOP and CHOP groups, respectively, (P = 0.03). Univariate analysis identified the rituximab plus CHOP chemotherapy regimen (P = 0.03), age older than 80 years (P = 0.04), and bone marrow involvement (P = 0.04) as risk factors for development of fungal infection, whereas, multivariate regression analysis identified only rituximab plus CHOP and old age. Adding rituximab to the standard CHOP regimen in elderly DLBCL patients might increase the incidence of fungal infection especially in those older than 80 years old.     

老年弥漫性大B细胞淋巴瘤预后因素及治疗分析

目的探讨老年弥漫性大B细胞淋巴瘤（DLBCL）预后因素,不同治疗方案对其生存的影响。方法回顾性分析72例初发老年DLBCL的性别、年龄、临床分期、B症状、ECOG-PS评分、结外病灶、血清LDH水平、血红蛋白水平、IPI评分与预后的相关性,其中可评价的为64例。比较接受3周CHOP方案34例和接受3周R-CHOP方案30例的生存情况。结果老年DLBCL患者中位生存期40．3个月,2年OS率67．43％,3年OS率49．89％。多因素分析显示年龄、ECOG-PS、临床分期、IPI评分是影响老年DLBCL患者预后的独立危险因素（P〈0．05）。CHOP组和R-CHOP组2年及3年OS率差异均有统计学意义,2年OS率（53．3％VS72．1％,P〈0．05）,3年OS率（39．2％VS60．8％,P〈0．05）。结论年龄、ECOG-PS、临床分期、IPI评分是老年DLBCL患者的预后相关因素,R-CHOP方案疗效优于CHOP方案。     

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

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.     

A retrospective analysis of primary gastric diffuse large B-cell lymphoma with or without concomitant mucosa-associated lymphoid tissue (MALT) lymphoma components

Primary gastric diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease entity that includes patients with (DLBCL/MALT) and without detectable mucosa-associated lymphoid tissue (MALT) lymphoma components (de novo DLBCL). We sought to evaluate the clinical characteristics and outcome of this disease in a large number of cases. Patients with primary gastric DLBCL (n?=?162) seen on 2001–2011 at the Tianjin Medical University Cancer Institute and Hospital and the First affiliated Hospital of Chinese PLA General Hospital were retrospectively reviewed. The distribution of sex, age, Lugano staging, and other main clinical characteristics was similar between the de novo DLBCL and DLBCL/MALT groups (p?>?0.05). However, the proportion of patients with a stage-modified international prognostic index (m-IPI)?≥?2 was higher in the de novo DLBCL (34 %) than the DLBCL/MALT group (17 %) (p?=?0.026). In addition, the Helicobacter pylori infection rates were higher in the DLBCL/MALT (75 %) than the de novo DLBCL group (36 %) (p?<?0.001). Five-year progression-free survival (PFS) and overall survival (OS) estimates were similar for patients in the de novo DLBCL (p?=?0.705) and DLBCL/MALT groups (p?=?0.846). Surgical treatment did not offer survival benefits when compared with chemotherapy for 5-year PFS (p?=?0.607) and OS estimates (p?=?0.554). There were no significant differences in 5-year PFS and OS estimates for patients treated with rituximab–chemotherapy (p?=?0.261) or conventional chemotherapy (p?=?0.227). Non-GCB subtype and m-IPI?≥?2 were independently associated with shorter OS, and advanced stages of lymphoma were independently associated with shorter PFS.     

Membrane PKC-beta 2 protein expression predicts for poor response to chemotherapy and survival in patients with diffuse large B-cell lymphoma

The protein kinase C (PKC) plays an important role in the activation and survival of B cells. The purpose of this study was to analyze the clinical significance of PKC-beta 2 protein expression in patients with diffuse large B-cell lymphoma (DLBCL). Tumors from 76 patients with DLBCL who received anthracycline-containing chemotherapy were examined for PKC-beta 2 protein expression by immunohistochemistry. Twenty-six cases (34%) were positive for PKC-beta 2 protein, and 50 (66%) were negative. Patients with PKC-beta-2-positive tumors showed a lower complete remission rate (31 vs 62%; P=0.015) and a lower 5-year disease-free survival (DFS) (30 vs 60%; P=0.03) than the PKC-beta-2-negative group. Overall survival (OS) was significantly lower in patients with the membranous staining pattern of PKC-beta 2 protein when compared to those with PKC-beta-2-negative tumors (14 vs 64%; P=0.005). In patients with low international prognostic index (IPI), those with tumors showing membrane expression of PKC-beta 2 had a significantly inferior DFS and OS (0 vs 79%, P=0.003; 25 vs 80%; P=0.01) compared to PKC-beta-2-negative tumors. In multivariate analysis for OS, the membrane staining of PKC-beta 2 is the strongest independent adverse prognostic factor (OR=3.4, P=0.011). Our results suggest that membrane expression of PKC-beta 2 protein on DLBCL predicts for poor survival, especially in patients with low IPI.     

p27kip1 expression is inversely related to the grade of gastric MALT lymphoma

Background: Decreased or lost expression of the cyclin-dependent kinase inhibitor p27^kip1 protein has been found to be a poor prognostic factor in many cancers, including gastric cancer. Aim: To evaluate p27^kip1 expression in gastric mucosa-associated lymphoid tissue (MALT) and gastric B-cell lymphoma. Methods: Fifty-two cases of gastric lymphoma, mean age 68.7 yr (range 23–90 yr), 11 of chronic Helicobacter pylori-associated gastritis, and 5 of normal gastric mucosa were studied. Patients were classified into two groups. Stage IE gastric lymphomas were defined as local gastric lymphoma of MALT and more advanced stages as advanced gastric lymphoma. Twenty-three patients diagnosed as stage IE, 13 of these were low-grade and 10 diffuse large B-cell lymphoma (DLBL). Twenty-nine patients were at stage IIE or above, 18 with low-grade and 11 with DLBL. Serial sections were evaluated by immunohistochemistry after staining with antibodies against p27/Kip1 and Ki-67. Results: The proliferative index was higher in gastric DLBL than in low-grade MALT lymphomas, 57.1±31.2 vs 17.3±20.6 (p=0.0001). The mean p27^kip1 expression score for high-grade patients was significantly lower compared with that of low-grade patients, 0.5 ± 0.4 and 1.6±0.8, respectively (p=0.001). Comparative evaluation of p27^kip1 expression in malignant lymphoid cells revealed that B cells of the localized gastric DLBL patients expressed the least p27^kip1, 0.36±0.32. This value was lower than that of malignant lymphoid cells of patients with advanced DLBL, 0.64±0.53, advanced low-grade MALT lymphoma, 1.59±0.79, and localized low-grade MALT lymphoma, 1.59±0.84. In the multivariate model in which all p27^kip1 variables were entered, the expression of p27^kip1 in malignant lymphoid cells was inversely correlated with the grade of the lymphoma irrespective of the stage of the disease (p=0.0001), and significantly predicted grade: OR:0.07, 95% CI 0.07–0.31, p=0.0001. Conclusion: p27^kip1 may be a putative distinct molecular marker to differentiate between low-grade and high-grade gastric lymphoma.     

Early Cancer of the Stomach Arising after Successful Treatment of Gastric MALT Lymphoma in Patients with Autoimmune Disease

Background: Extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma) arises in lymphoid tissue acquired through chronic antigenic stimulation as exemplified by Helicobacter pylori. Secondary development of gastric cancer, however, is thought to be a rare event. The detection of a signet ring cell carcinoma during follow-up endoscopy after successful therapy of MALT lymphoma in a patient with Sjogren's syndrome prompted us to analyse the frequency of subsequent gastric cancer in patients with underlying autoimmune disease (AD). Methods: Patients with early stage MALT lymphoma and an underlying AD were evaluated for the occurrence of a secondary gastric cancer during the course of follow-up. Data analysed included the type of AD, stage of MALT lymphoma, H. pylori status, treatment for MALT lymphoma and response, follow-up, the presence of a secondary cancer, and time to development of cancer. In all patients, histologic samples were reassessed for the extent of gastritis, presence of intestinal metaplasia or focal atrophy at the time of lymphoma diagnosis. Results: A total of eight patients with overt AD at the time of diagnosis of MALT lymphoma were identified. All patients were women aged between 56 and 77 years; 5 had Sjogren's syndrome, 2 had autoimmune thyroiditis (1 along with psoriasis) and 1 suffered from polymyalgia rheumatica. All patients had early stage MALT lymphoma restricted to the mucosa and submucosa at the time of diagnosis, and the presence of H. pylori was found in all cases. Two of these patients achieved complete remission (CR) of the lymphoma following H. pylori eradication, while six were judged unresponsive and underwent chemotherapy, resulting in CR in all cases. One patient died from stroke while being in CR for 2 months following chemotherapy. Two patients (25%) developed early cancer limited to the gastric mucosa while being in CR from lymphoma for 9 and 27 months, respectively, and underwent partial gastrectomy. Final staging of gastric cancer revealed pTlpNOMO in both cases. Of the remaining 5 cases, 1 patient had a local lymphoma relapse 18 months after CR and was salvaged with radiotherapy. In the remaining 4 patients, no evidence of lymphoma recurrence or a second malignancy has been found so far by regular follow-up every 3 months for a time-span between 52 and 63 months after initial diagnosis. Conclusion: Patients with concurrent MALT lymphoma and an underlying autoimmune condition show not only an impaired response to H. pylori eradication but might also be at increased risk for the development of gastric cancer. In view of this, such patients should be followed closely by regular endoscopies after remission of MALT lymphoma.