PCR analysis and specific immunohistochemistry revealing a high prevalence of non-Helicobacter pylori Helicobacters in Helicobacter pylori-negative gastric disease patients in Japan: High susceptibility to an Hp eradication regimen.

BACKGROUND: The clinical significance of non-Helicobacter pylori Helicobacter (NHPH) is still unknown. There are many reports of NHPH-infected patients suffering from gastric diseases. Here, we investigated the polymerase chain reaction (PCR) positivity of NHPH infection in gastric disease patients who were negative for H. pylori (Hp) by the rapid urease test and by pathological observation. MATERIALS AND METHODS: We collected the 296 endoscopically obtained gastric mucosal samples of Hp-negative gastric disease patients diagnosed based on a rapid urease test and pathology from 17 hospitals in Japan from September 2013 to June 2019, and we analyzed the existence of Hp and NHPH by PCR. The samples were also treated by indirect immunohistochemistry using an anti-Helicobacter suis VacA paralog antibody and were observed by confocal laser microscopy. RESULTS: Among the 236 non-Hp-eradicated cases, 49 cases (20.8%) were positive for NHPH. Among them, 20 cases were positive for Helicobacter suis, 7 cases were positive for Helicobacter heilmannii sensu stricto/ Helicobacter ailurogastricus (Hhss/Ha), and the other 22 cases could not be identified. The regional differences in the infection rates were significant. Forty percent of the nodular gastritis cases, 24% of the MALT lymphoma, 17% of the chronic gastritis cases, and 33% of the gastroduodenal ulcer cases were NHPH positive. Forty-five patients had been treated with one of the four types of combinations of a proton pump inhibitor and two antibiotics, and in all of these cases, the NHPH diagnosed by PCR was successfully eradicated. Immunohistochemistry using the Helicobacter suis-specific HsvA antibody coincided well with the PCR results. Among the 29 post-Hp eradication cases, three were NHPH positive, including one Hhss/Ha-positive case. Thus, approx. 20% of the Hp-negative non-Hp-eradicated gastric disease patients treated at 17 hospitals in Japan were infected with NHPH.

Clinicopathologic analysis of gastric mucosa-associated lymphoid tissue lymphoma with or without c-Met expression.

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach is mainly associated with Helicobacter pylori infection, and H. pylori eradication therapy is often effective. However, 20-30% of the cases of MALT lymphoma are resistant to the eradication therapy, and translocation of the API2-MALT1 gene is often found in these cases. Most cases without translocation of API2-MALT1 are localized to the stomach, whereas some cases with this translocation are a more advanced stage of MALT lymphoma that spreads to other organs. The c-Met receptor is a prognostic factor involved in infiltration and metastasis in many malignant tumors, including gastric, pancreatic, lung, and kidney cancer. In the present study, the expression of c-Met in 43 cases of gastric MALT lymphomas was immunohistochemically examined and compared with clinicopathological factors. To elucidate the significance of c-Met in MALT lymphoma, the expression intensity of c-Met in 22 API2-MALT1 translocation-positive and 21 API2-MALT1 translocation-negative cases was scored, compared, and examined. The immunohistochemistry analysis revealed strong staining for c-Met in 21 API2-MALT1 translocation-positive cases and in 1 translocation-negative case (P = 0.00). This result indicates the relationship between strong expression of c-Met and the progression of MALT lymphoma with API2-MALT1 gene translocation.

Anti-Helicobacter pylori therapy in localized gastric mucosa-associated lymphoid tissue lymphoma: A prospective, nationwide, multicenter study in Japan.

BACKGROUND: Helicobacter pylori eradication therapy was approved in Japan for the first-line, standard treatment of H. pylori-positive gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although several retrospective studies or small-scale single-center studies have been reported, a prospective, large-scale, nationwide, multicenter study has not been reported from Japan. MATERIALS AND METHODS: We conducted a prospective, nationwide, multicenter study to evaluate the clinical efficacy of rabeprazole-based triple H. pylori eradication therapy for patients with localized gastric MALT lymphoma in practice-based clinical trial. A total of 108 H. pylori-positive patients with stage I/II1 gastric MALT lymphoma underwent H. pylori eradication therapy. The primary endpoints were complete remission (CR) rate and the rate of transfer to secondary treatment. The secondary endpoints were CR maintenance duration and overall survival (OS). RESULTS: CR of lymphoma was achieved in 84 of 97 patients (86.6%), during the period 2.0-44.7 months (median, 5.3 months) after starting H. pylori eradication treatment. CR was maintained in 77 of 81 patients (95.1%) for 0.4-53.2 months (median, 33.1 months). Secondary treatments (radiotherapy, rituximab, or gastrectomy) for gastric MALT lymphoma were needed in 10 of the 97 patients (10.31%). During follow-up, OS rate was 96.9% (94/97) and the causes of 3 deaths were not related to lymphoma. CONCLUSIONS: Rabeprazole-based H. pylori eradication therapy demonstrated a high CR rate, long CR maintenance, and a good OS for patients with localized gastric MALT lymphoma in this prospective, practice-based, multicenter study.

Watch-and-wait policy versus rituximab-combined chemotherapy in Japanese patients with intestinal follicular lymphoma.

BACKGROUND AND AIM: Few reports have demonstrated the effectiveness of treatments for intestinal follicular lymphoma (FL) because of the limited number of patients who undergo comprehensive small intestinal examinations. This study compared the efficacy of rituximab-combined chemotherapy in patients with asymptomatic and low tumor burden (LTB) intestinal FL, according to the criteria of the Groupe d'Etude des Lymphomes Folliculaires, with that of a "watch and wait" (W&W) approach. METHODS: The endoscopic examination for entire gastrointestinal tracts was performed in 29 Japanese patients with intestinal FL. These patients had CD21-positive follicular dendritic cells arranged in a duodenal pattern. In a prospective, two-center, open-label trial, this study evaluated the efficacy of rituximab-combined chemotherapy ([cyclophosphamide, doxorubicin, vincristine, and prednisone] or [cyclophosphamide, vincristine, and prednisone]) and prolonged treatment with rituximab (R-Chemo+prolongedR) in 14 patients and compared their outcomes with those of 15 patients managed with a W&W approach. RESULTS: Four patients managed with the W&W plan showed worsening macroscopic findings, lesion area enlargement, or clinical stage progression but stayed on this plan because they had LTB and experienced no changes in bowel function. In the R-Chemo+prolongedR group, all patients achieved complete remission; recurrence occurred in one patient, who was subsequently managed with the W&W plan because of LTB. There were no significant differences in progression-free survival between the two groups (P = 0.1045). Overall survival was 100% in both groups. CONCLUSIONS: The prognoses of patients with asymptomatic intestinal FL and LTB who were managed with a W&W strategy were comparable with those of patients receiving R-Chemo+prolongedR.

Recent progress in follicular lymphoma in Japan and characteristics of the duodenal type.

The incidence of lymphoma has rapidly increased over the last 40 years in Japan, following a trend that is very similar to that of breast cancer. In particular, the relative frequency of follicular lymphoma (FL) has reached that in Western countries. Given its indolence, a "watch-and-wait" approach is often applied to FL patients. We have shown that FL is often detected in the second portion of the duodenum and has a distinct follicular dendritic cell distribution and heavy chain variable usage similar to mucosa-associated lymphoid tissue (MALT) lymphoma. Although the t(14;18)(q32;q21) frequency is the same as in the nodal subtype of FL, there are also ongoing mutations, immunopositivity for cluster of differentiation 10 and B-cell lymphoma (BCL)6, and overexpression of BCL2. Gene expression profiling has shown that it is more similar to gastric MALT lymphoma than to nodal FL. Duodenal-type FL lacks the activation-induced cytidine deaminase (AID) expression observed in nodal ones, although this may be compensated for by BTB domain and CNC homolog 2. Based on these findings, duodenal-type FL has been included in the Revised 4th edition of the World Health Organization classification published in late 2017.

Gastrointestinal follicular lymphoma: Current knowledge and future challenges.

The gastrointestinal (GI) tract is the most commonly involved site of extranodal follicular lymphoma (FL). GI-FL shows very indolent clinical behavior and localized at GI tract without any progression or transformation compared to nodal FL. The most frequently involved site of the GI tract was the duodenum followed by the jejunum and ileum, and only 15% of FL arising in the second part of the duodenum were localized there without scattered very small daughter lesions in other GI tract examined by double-balloon endoscopy. The typical macroscopic appearance of GI-FL was multiple white nodules. Microscopically, neoplastic cells were small- to medium-sized lymphoid cells and formed neoplastic follicles. Most of the cases (>95%) were histologically Grade 1 to 2 (low grade). Several pathological and molecular characteristics were seen in GI-FL (especially duodenal FL) compared with nodal FL: immunoglobulin heavy chain deviation to VH4 and VH5; memory B-cell immunophenotype; and molecular features shared by mucosa-associated lymphoid tissue lymphoma. Considering the pathological and molecular uniqueness of this disease, GI-FL should be separately managed from nodal FL.

CD10 down expression in follicular lymphoma correlates with gastrointestinal lesion involving the stomach and large intestine.

Follicular lymphoma (FL) shows co-expression of B-cell lymphoma 2 (BCL2) and CD10, whereas downexpression of CD10 is occasionally experienced in gastrointestinal (GI) FL with unknown significance. Gastrointestinal FL is a rare variant of FL, and its similarity with mucosa-associated lymphoid tissue lymphoma was reported. We investigated the clinicopathological and genetic features of CD10 downexpressed (CD10down ) GI-FL. The diagnosis of CD10down FL was carried out with a combination of pathological and molecular analyses. The incidence of CD10down GI-FL was shown in 35/172 (20.3%) cases, which was more frequent than nodal FL (3.5%, P < 0.001). The difference was additionally significant between GI-FL and nodal FL when the analysis was confined to primary GI-FL (55.2% vs 3.5%, P < 0.001). Compared to CD10+ GI-FL, CD10down GI-FL significantly involved the stomach or large intestine (P = 0.015), and additionally showed the downexpression of BCL6 (P < 0.001). The follicular dendritic cell meshwork often showed a duodenal pattern in the CD10down group (P = 0.12). Furthermore, a lymphoepithelial lesion was observed in 5/12 (40%) gastric FL cases, which indicated caution in the differentiation of mucosa-associated lymphoid tissue lymphoma. Molecular analyses were undertaken in seven cases of CD10down GI-FL, and an identical clone was found between CD10down follicles and CD10+ BCL2+ neoplastic follicles. In the diagnosis of cases with CD10down BCL2+ follicles, careful examination with molecular studies should be carried out.

The role of "watch and wait" in intestinal follicular lymphoma in rituximab era.

OBJECTIVE: There is no consensus regarding the best treatment for intestinal follicular lymphoma (FL). We used "watch and wait" for patients with intestinal FL with low-tumor-burden (LTB) criteria and without mass formation causing bowel obstruction. We investigated the overall survival (OS) and time to treatment required (TTR). METHODS: Thirty-three intestinal FL patients [clinical stage (CS) I:16, II1:0, II2:7, IV:10; median observation period: 45.5 months, range: 13-110 months] were diagnosed via endoscopy. Detailed clinical and pathological examinations were performed, and neoplastic process behavior was monitored. RESULTS: All of the 33 patients were WHO grade 1. FL lesions in the digestive tract were found frequently in the second-fourth portion of the duodenum in 91% of the patients; 87% of those patients had lesions in a broader area including the small intestine. Two patients had an enlargement of the area of the lesions and a worsening of the macroscopic findings. Three patients had CS progression; however, these remained within the indication for "watch and wait." Two patients with transformation into diffuse large B-cell lymphoma received rituximab and chemotherapy, which led to complete remission. The OS was 100%. The time to treatment required (TTR) was 49 months in one patient and 37 months in one patient. CONCLUSION: Intestinal FL in CS I-IV with broad infiltration of the digestive tract meeting the criteria for LTB had a remarkably slow course. This study suggests that "watch and wait" is appropriate for the treatment of LTB intestinal FL even in the era of rituximab.

Clinicopathological features of 49 primary gastrointestinal diffuse large B-cell lymphoma cases; comparison with location, cell-of-origin, and frequency of MYD88 L265P.

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4 % cases (stomach, 79 %; small intestine, 70 %; colon, 60 %). MYD88 L265P was detected in 6.1 % cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.

Duodenal follicular lymphoma: comprehensive gene expression analysis with insights into pathogenesis.

Follicular lymphoma (FL) of the gastrointestinal tract, particularly duodenal follicular lymphoma (DFL), is a rare variant of FL with indolent clinical behavior, and this disease is included in the 2008 World Health Organization classification system. In contrast to nodal follicular lymphoma (NFL), DFL occurs most frequently in the second part of the duodenum, lacks follicular dendritic cell meshworks and has memory B-cell characteristics. However, its molecular pathogenesis is still unclear. In the present study, we examined 10 DFL, 18 NFL and 10 gastric MALT lymphoma samples using gene expression analysis. Quantitative RT-PCR experiments and immunohistochemical analysis for 72 formalin-fixed, paraffin-embedded tissues from an independent series, including 32 DFL, 19 gastric MALT lymphoma and 27 NFL samples, were performed for validation of microarray data. Gene expression profiles of the three lymphoma types were compared using 2918 differentially expressed genes (DEG) and results suggested that DFL shares characteristics of MALT lymphoma. Among these DEG, CCL20 and MAdCAM-1 were upregulated in DFL and MALT but downregulated in NFL. In contrast, protocadherin gamma subfamily genes were upregulated in DFL and NFL. Quantitative RT-PCR and immunohistochemical studies demonstrated concordant results. Double immunofluorescence studies revealed that CCL20 and CCR6 were co-expressed in both DFL and MALT. We hypothesize that increased expression of CCL20 and MAdCAM-1 and co-expression of CCL20 and CCR6 may play an important role in tumorigenesis.

Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics.

We have reported previously that duodenal follicular lymphoma (FL) is distinct from nodal FL and showed more resemblance to mucosa-associated lymphoid tissue lymphoma, and that FL frequently involved the duodenal second portion. In the present study, we examined duodenal FLs and gastric/colonic FLs to clarify the clinicopathological and immunological differences between the tumor types. We analyzed 8 samples of gastric FL, 17 of duodenal ones, and 5 of colonic/rectal ones, and characterized them by immunohistochemistry, immunogenotyping, and histology. Gastric and colonic FLs presented in submucosal to subserosal areas, whereas duodenal ones presented in the mucosal to submucosal layers. Immunohistochemical analysis revealed that duodenal FLs exhibited the following phenotypes: CD10 (+), B-cell lymphoma 2 (BCL-2) (+), BCL-6 (+), activation-induced cytidine deaminase (AID) (-), BACH2 (+), CD27 (+), MUM-1 (-), Blimp-1 (-), and loose CD21 network (duodenal pattern). Gastric/colonic FLs exhibited the following phenotypes: CD10 (+), BCL-2 (+), BCL-6 (+), AID (+), BACH2 (+), CD27 (-), MUM-1 (-), Blimp-1 (-), and a dense CD21 network (nodal pattern). Expression of AID and CD27 in lymphoma cells and the CD21 network pattern were considerably different between duodenal FLs and gastric/colonic ones. Moreover, in situ hybridization revealed that, in the duodenal FLs, BACH2 was expressed at the periphery of the tumor follicle and tumor villi. The number of immunoglobulin heavy-chain variable domains VH4 and VH5 were higher in duodenal follicular lymphomoas than in gastric FLs. The lymphoma cells of duodenal FLs are different from those of gastric/colonic FLs, and duodenal FL is distinct even within the gastrointestinal tract. Somatic hypermutation in immunoglobulin genes and CD27 expression are hallmarks of memory B cells. We suggest that duodenal FL cells are in the memory B-cell stage, and require BACH2 instead of AID for ongoing mutation.

Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan.

OBJECTIVE: A multicentre cohort follow-up study of a large number of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma was conducted to elucidate the long-term outcome of the disease after Helicobacter pylori eradication. METHODS: 420 patients with gastric low-grade MALT lymphoma who had undergone successful H pylori eradication and been followed up for at least 3 years were registered from 21 participating institutes. Responders to treatment were defined as patients whose post-treatment biopsies showed complete histological response (ChR) or probable minimal residual disease (pMRD). Treatment failure was defined as the status of progressive disease or lymphoma relapse after ChR/pMRD. RESULTS: 323 patients (77%) responded to H pylori eradication. A logistic regression analysis showed that absence of H pylori, submucosal invasion determined by endoscopic ultrasonography and t(11;18)/API2-MALT1 were independent predictors of resistance to H pylori eradication. During the follow-up periods ranging from 3.0 to 14.6 years (mean 6.5 years, median 6.04 years), the disease relapsed in 10 of 323 responders (3.1%) while progressive disease was found in 27 of 97 non-responders (27%). Thus, 37 of 420 patients (8.8%) were regarded as treatment failures. Of these 37 patients, transformation into diffuse large B cell lymphoma occurred in nine patients. Among the non-responders and relapsed patients, 17 patients were subjected to a 'watch and wait' strategy while 90 patients underwent second-line treatments including radiotherapy (n=49), chemotherapy (n=26), surgical resection (n=6), chemoradiotherapy (n=5), antibiotic treatment (n=2), rituximab monotherapy (n=1) or endoscopic resection (n=1). Probabilities of freedom from treatment failure, overall survival and event-free survival after 10 years were 90%, 95% and 86%, respectively. Cox multivariate analysis revealed endoscopic non-superficial type to be an independent prognostic factor for adverse freedom from treatment failure, overall survival and event-free survival. CONCLUSIONS: The excellent long-term outcome of gastric MALT lymphoma after H pylori eradication was confirmed by this large-scale follow-up study.

Regression of Mucosa-Associated Lymphoid Tissue Lymphoma Arising From the Nonampullary Descending Part of the Duodenum by Treatment With Antibiotics in a Helicobacter pylori-Negative Patient.

We report a 63-year-old male, Helicobacter pylori-negative patient with mucosa-associated lymphoid tissue (MALT) lymphoma of the second part of the duodenum that regressed after antibiotic treatment. Esophagogastroduodenoscopy (EGD) showed flat elevation with shallow depression on the contralateral side of the ampulla of Vater. The lesion was limited to the duodenal second part. The patient had a history of Helicobacter pylori positivity, with successful eradication at 41 years of age. Twelve months after vonoprazan (VPZ)-based antibiotic treatment, the duodenal lesion had obviously regressed, and the pathological diagnosis was complete histological response (ChR). This case suggests that certain bacteria may promote the development of duodenal MALT lymphoma.

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: a multicenter, retrospective analysis in Japan.

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II(1) GI-FL. Of the 125 patients, the small intestine was examined in 70 patients, with double-balloon endoscopy and/or capsule endoscopy. The most frequently involved GI-FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP-positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression-free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI-FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course.

Clinical features of gastrointestinal follicular lymphoma: comparison with nodal follicular lymphoma and gastrointestinal MALT lymphoma.

We retrospectively compared the clinicopathological features of primary intestinal follicular lymphomas (FL-GIs), nodal follicular lymphomas (FL-LNs) and gastrointestinal MALT lymphomas (MALT-GIs), and investigated the distribution and the endoscopic appearances of FL-GI to evaluate the effectiveness of treatment modality. The subjects were 28 FL-GI patients, 135 FL-LN patients and 70 MALT-GI patients. In FL-LNs the clinical stage III-IV was 83%, while in FL-GIs clinical stage I-II was 68%. In MALT-GIs clinical stage I-II was 87%. The overall survival was significantly better in MALT-GI patients than in FL-LN patients. All FL-GI patients were alive at the time of evaluation. Regarding the histological grade (WHO), grade 1 was 81% in FL-GI, whereas in FL-LN grade 2 was 28% and grade 3 was 11%. The Follicular Lymphoma International Prognostic Index was low in 61% of FL-GIs, while in FL-LNs it was equally distributed to low, intermediate and high, suggesting that the prognosis is better in FL-GIs than in FL-LNs. The clinicopathological studies revealed the FL-GI has intermediate characteristics between FL-LN and MALT-GI. We recommend a 'watch-and-wait' policy or chemotherapy with rituximab for the therapy of FL-GIs because the lesions are often located in broader areas from the lower duodenum to the small intestine.

Germinal center B-cell-like diffuse large B-cell lymphoma of the duodenum is associated with t(14;18) translocation.

Diffuse large B-cell lymphoma (DLBCL) rarely involves the duodenum, and its clinicopathological characteristics have not been well elucidated. We performed clinicopathological examinations and identified 15 patients with duodenal DLBCL using 18 gastric or colonic DLBCL as a control. Eleven of the 15 patients (73%) were subclassified by immunohistochemical analysis according to the Choi algorithm as germinal center B-cell-like (GCB) type, whereas the 18 control gastric and colonic DLBCL were predominantly subclassified as activated B-cell-like (ABC) type. The classifications according to organ involvement were statistically significant (P= 0.011 and P= 0.035). Macroscopically, the GCB lesions were varied, while all ABC lesions were ulcerative. Fluorescence in situ hybridization analysis revealed a higher frequency of t(14;18) translocation in patients with duodenal DLBCL (3 of 13) as compared with non-duodenal gastrointestinal tract DLBCL (0 of 18), however, the difference was not significant (P = 0.064). Furthermore, the three patients with t(14;18) translocations were classified as GCB. In addition, overall survival of patients was statistically different between those with and without t(14;18) translocation (P= 0.040). In conclusion, duodenal DLBCL predominantly exhibits GCB-type tumors and the frequency of t(14;18) translocation appears to be higher in duodenal GCB-type DLBCL compared to non-duodenal tumors.

A duodenal follicular lymphoma associated with the lesion mimicking MALT lymphoma in terminal ileum and Bauhin valve.

This is a case report of a 66-year-old woman who consulted us with a 1-week history of postprandial epigastric discomfort and dyspepsia. Upper and lower gastrointestinal endoscopy and double-balloon enteroscopy revealed lesions in three parts: a swelling with a shallow depression in the ampulla of Vater, flat and rough nodules in the jejunum, and a mixture of lymphoid polyposis and rough surface of follicular lymphoma of the terminal ileum and Bauhin valve. The histological, immunophenotypic, and molecular findings of the duodenal lesion confirmed the diagnosis of follicular lymphoma. We initially diagnosed the ileal lesion as MALT lymphoma immunohistochemically. However, Southern blot hybridization analysis for immunoglobulin heavy chain gene rearrangement showed identical monoclonal bands in both the duodenal and ileal lesions. The molecular cytogenetic studies were also positive for the 14;18 translocation in both lesions. Therefore, the true diagnosis of this ileal lesion should be a follicular lymphoma with marginal zone differentiation. Primary follicular lymphomas of gastrointestinal tract were suggested to have intermediate features between nodal follicular lymphoma and MALT lymphoma. This case is an important clue to prove the similarity of follicular lymphoma of gastrointestinal tract to MALT lymphoma and will be crucial in considering the therapeutic strategy.

Serum soluble interleukin-2 receptor level and immunophenotype are prognostic factors for patients with diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma is the most common form of non-Hodgkin lymphoma. Although many studies have attempted to identify prognostic factors, most have focused on conventionally treated patients. The influence of anti-CD20 antibody (rituximab) should be considered now. We evaluated the prognostic significance of serum soluble interleukin-2 receptor levels and germinal center B-cell-like or non-germinal center B-cell like subgroups in 80 patients with diffuse large B-cell lymphoma, who had been treated with rituximab. Serum soluble interleukin-2 receptor levels ranged from 322 to 39900 U/mL (median 1365 U/mL). Sixteen (20%) were germinal center B-cell-like subgroups, and the remainder (80%) non-germinal center B-cell-like. Survival analysis associated lower serum soluble interleukin-2 receptor level and germinal center B-cell-like phenotype with better overall survival (P = 0.015), whereas multivariate analysis, including International Prognostic Index factors, revealed that only higher performance status score and higher serum lactate dehydrogenase levels significantly affected survival. However, serum soluble interleukin-2 receptor levels were elevated in patients with higher International Prognostic Index scores as well as in the non-germinal center B-cell-like subgroup. Serum soluble interleukin-2 receptor levels, International Prognostic Index, and subphenotypes were strongly correlated with each other. Our study showed that soluble interleukin-2 receptor is quite useful and may serve as a substitute for the International Prognostic Index, especially for patients undergoing treatment. Moreover, the differentiation between the germinal center B-cell-like and non-germinal center B-cell-like phenotypes is also useful for predicting patients with diffuse large B-cell lymphoma, even among those treated with rituximab.

Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations.

Although most follicular lymphomas are believed to be of nodal origin, they sometimes originate from the duodenum. We have reported that the latter differ from nodal follicular lymphomas in having lower clinical stages and uniformly low histological grades, along with variable region of immunoglobulin heavy chain gene (VH) usage that is more similar to mucosa-associated lymphoid tissue (MALT) lymphomas. Little is known, however, about whether they possess other characteristics of nodal follicular lymphomas, particularly ongoing mutations with follicular dendritic cells. We examined 17 cases for which PCR identified the monoclonal bands of the immunoglobulin gene. The duodenal cases showed ongoing mutations, but they lacked activation-induced cytidine deaminase (AID) expression, a statistically significant difference from the nodal cases (P<0.001), and their follicular dendritic cell networks were disrupted. Moreover, not only were VH deviations observed but also they used very restricted VH genes. Although the mechanisms of ongoing mutation without AID and follicular dendritic cell were not clarified, restricted VH usage strongly suggested that antigen stimulation was involved, and that was similar to MALT lymphomas. In conclusion, duodenal follicular lymphomas were shown to be unique, in that they had ongoing hypermutations such as nodal cases, but the mechanisms involved in the hypermutation were quite different; furthermore, restricted VH usage suggested a strong similarity to the antigen-dependent origin of MALT lymphomas.

Predictive value of endoscopy and endoscopic ultrasonography for regression of gastric diffuse large B-cell lymphomas after Helicobacter pylori eradication.

BACKGROUND: Some gastric diffuse large B-cell lymphomas have been reported to regress completely after the successful eradication of Helicobacter pylori. The aim of this study was to investigate the clinical characteristics of gastric diffuse large B-cell lymphomas without any detectable mucosa-associated lymphoid tissue (MALT) lymphoma that went into complete remission after successful H. pylori eradication. PATIENTS AND METHODS: We examined the effect of H. pylori eradication in 15 H. pylori-positive gastric diffuse large B-cell lymphoma patients without any evidence of an associated MALT lymphoma (clinical stage I by the Lugano classification) by endoscopic examination including biopsies, endoscopic ultrasonography, computed tomography, and bone marrow aspiration. RESULTS: H. pylori eradication was successful in all the patients and complete remission was achieved in four patients whose clinical stage was I. By endoscopic examination, these gastric lesions appeared to be superficial. The depth by endoscopic ultrasonography was restricted to the mucosa in two patients and to the shallow portion of the submucosa in the other two patients. All four patients remained in complete remission for 7-100 months. CONCLUSION: In gastric diffuse large B-cell lymphomas without a concomitant MALT lymphoma but associated with H. pylori infection, only superficial cases and lesions limited to the shallow portion of the submucosa regressed completely after successful H. pylori eradication. The endoscopic appearance and the rating of the depth of invasion by endosonography are both valuable for predicting the efficacy of H. pylori eradication in treating gastric diffuse large B-cell lymphomas.