Gastric Extranodal Marginal Zone Lymphoma Research Articles

Ultra Low-Dose Radiation for Extranodal Marginal Zone Lymphoma of the Lung

Definitive radiation treatment (RT) for extranodal marginal zone lymphoma (ENMZL) of mucosal associated lymphoid tissue historically involves treatment to 24-30 Gy. There is increasing data supporting the use of ultra-low dose RT as part of a response-adapted approach in the treatment of orbital and gastric ENMZL. With this approach, patients receive initial treatment with 4 Gy, and additional RT is considered for those with persistent or locally progressive disease. However limited data to date assesses the efficacy of 4 Gy in the management of ENMZL of the lung. We performed an IRB-approved retrospective review of 17 patients with ENMZL of the lung treated with 4 Gy between 7/2015 and 12/2022 with response assessed after RT. Clinical/treatment characteristics, response, and toxicity were extracted from medical records. Statistics were performed using Mann-Whitney U and Fisher's Exact Test. Eight patients (47%) were female, 15 (88%) white, and 1 (6%) Hispanic. Median age at RT was 66 (interquartile range (IQR) 59-77). All had disease limited to the lung at diagnosis and 15 had stage IE disease. Four patients (24%) were diagnosed incidentally on screening/surveillance imaging in the absence of symptoms. Sixteen patients received 4 Gy in 2 fractions, while one patient received a single fraction of 4 Gy. Median SUVmax prior to RT was 4.5 (IQR 3.2-7.2). Median planning target volume (PTV) was 74 cc (IQR 47-130cc). Six patients (35%) had respiratory symptoms prior to RT, which improved or resolved in 3 (50%). A larger PTV was associated with improvement in symptoms following RT with a median PTV of 266 cc (IQR 171-402) in those who experienced improvement vs. 64 cc (IQR 42-100) in those who did not (p = 0.032). One patient experienced toxicity following RT with pleuritic chest pain, which resolved with corticosteroids. At a median follow-up of 15 months following RT (IQR 7-43 months), the overall response rate (ORR) was 100% (CR, n = 15; PR, n = 2). Fourteen patients had follow-up PET/CT, of whom 13 had a complete metabolic response (CMR) at a median of 3 months following RT (IQR 3-5 months). Two additional patients had a complete response (CR) on CT while one had a partial response on CT. Achieving a CR was not associated with SUV prior to RT (p = 0.50) or PTV size (p = 0.62). In patients with stage IE disease, the ORR rate was 100% and there have been no distant failures to date. Fifteen of 17 patients were alive at last follow-up; two passed away of unrelated causes (one from Alzheimer's disease and one from recurrent squamous cell carcinoma). Ultra-low dose radiation of 4 Gy is associated with excellent local control in the management of ENMZL of the lung and is very well tolerated. Four Gy was effective for local control and symptom palliation even for larger tumors and is an effective initial therapy as part of a response-adapted approach even in limited stage patients.

Gastrointestinal Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma with Synchronous Precancerous/Malignant Epithelial Mucosal Lesions: A Clinico-Pathologic Review

Abstract Introduction/Objective Mucosa-associated lymphoid tissue (MALT) lymphoma of the gastrointestinal(GI) tract and synchronous precancerous/malignant epithelial lesions have been sporadically reported in literature. We sought to assess the incidence of GI MALT lymphoma and synchronous epithelial lesions. Methods/Case Report We performed a retrospective study by searching the pathology files at our institution from 1992 to December 2021, for GI lymphomas including extranodal marginal zone lymphoma(E-MZL). Results (if a Case Study enter NA) There were a total of 178 cases of lymphoma involving the GI tract. The basis of this report was formed by the 40/178(22.5%) cases, which were E-MZL. Twenty-four were males and 16 females(age range:37-80 years; mean:62 years). Sites of tumors were stomach(21), colon(6), ileum(4), duodenum(4), rectum(3), and cecum(2). Four cases were multifocal. Lymph nodes were assessed in 8/40, of which 4 were positive. One patient had malignant pleural effusion and another had retroperitoneal soft-tissue involvement. Overall, 11/40(27.5%) cases had a synchronous precancerous/malignant epithelial lesion. Gastric E-MZL were the most common (21), out of which 8(38%) were associated with synchronous epithelial lesion (3 gastric adenocarcinomas and 5 tubular adenomas(TA) at different colorectal locations). Out of 6 colonic E-MZL, 2 were associated with synchronous TAs at different colorectal sites and one rectal E-MZL was associated with cecal TA. Conclusion In our cohort, precancerous/malignant epithelial lesions were seen in 11/40(26.8%) of GI E-MZL cases. Gastric adenocarcinomas comprised 3/8 (37.5%) of gastric synchronous precancerous/malignant epithelial lesions; the association of E-MZL and gastric adenocarcinoma is well-known, arising in the background of chronic atrophic gastritis and intestinal metaplasia secondary to chronic inflammatory disorders. The remaining 8 cases of synchronous mucosal epithelial lesions were TAs at different colorectal sites. Based on our observations, unlike gastric adenocarcinoma, the association of colorectal pre-cancerous lesions with E-MZL is less likely, since, in all cases, the TAs were seen in sites other than E-ZML sites and also, sporadic colorectal TAs are a common pathology. However, possible association between E-MZL and precancerous mucosal epithelial lesions needs more work and further investigation.

Comparable Efficacy of Reduced Dose Radiation Therapy for the Treatment of Early Stage Gastric Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue

PurposeThis study compares reduced (<27 Gy) to standard dose (≥30 Gy) radiation therapy (RT) in the treatment of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (gMALT lymphoma). Methods and MaterialsForty-two patients with stage I or II disease were retrospectively reviewed. Response to RT was assessed with endoscopy after RT. Complete response rate (CR), freedom from treatment failure, and overall survival (OS) were calculated. ResultsAll patients were stage I (n = 40) or II (n = 2). All patients had residual biopsy proven gMALT lymphoma before RT. Twenty-six patients (61.9%) were treated with standard dose RT, 30 to 36 Gy, and 16 (38.1%) with the reduced dose RT, 23.5 to 27 Gy. The median follow-up was 29.5 months (range, 6-85). Thirty-six patients (86%) achieved complete response (CR), and 6 patients (14%) achieved partial response (PR). The complete response rate (CR) at the first endoscopic assessment, median time of 3 months, was 81% (95% confidence interval, 0.61%-0.93%) for standard RT, and 94% (confidence interval, 0.69%-0.99%) for reduced RT. Among CR patients, one patient had locally relapsed disease at 50 months. The 1-year overall survival (OS) was 100% in both groups. The 1-year freedom from treatment failure (FFTF) was 100% in the reduced RT group and 92% in the standard RT group. The 2-year FFTF and OS of the whole cohort were 92% and 96%, respectively. There was no significant difference in the OS, FFTF, and CR between the 2 treatment groups (P = .38, P = .18, and P = .267, respectively). For toxicity, the mean liver dose and the mean V20 heart dose were significantly lower in the reduced RT group (P <.001 and P = .001, respectively). However, incidence and severity of reported toxicities were similar between the 2 groups. ConclusionsReduced dose RT (23.5-27 Gy) achieved excellent complete response rates with minimal toxicity, comparable with standard dose RT (30-36 Gy), for gMALT.

Marginal Zone Lymphoma: State-of-the-Art Treatment.

Despite being the second most common indolent non-Hodgkin's lymphoma (iNHL), marginal zone lymphoma (MZL) remains largely understudied, and given its underlying disease heterogeneity, it is challenging to define a single treatment approach for these patients. For localized disease, local therapy is recommended such as triple therapy for H. pylori in gastric extranodal MZL, splenectomy for splenic MZL, and radiotherapy for nodal MZL. For disseminated disease with low tumor burden, a watch and wait or single-agent rituximab can be used. However, for symptomatic disease, a similar approach to follicular lymphoma (FL) can be used with chemoimmunotherapy approaches such as bendamustine and rituximab. High FDG uptake is not common in MZL and is not diagnostic by itself of transformation to high-grade lymphoma but informs the choice of the site to be biopsied. Transformation into a large B cell lymphoma is treated with R-CHOP-like regimens. Patients with relapsing disease after at least one CD20-based therapy have several recently approved chemotherapy-free options including B cell receptor inhibitors such ibrutinib (approved specifically in MZL) and immunomodulatory agents such as lenalidomide and rituximab (FDA approved in MZL and FL). Phosphoinositide 3-kinase (PI3K) inhibitors have shown excellent activity in iNHL, specifically in MZL, with breakthrough designation status for copanlisib and umbralisib, allowing off label use of this class of agents in clinical practice. With the availability of prospective clinical trials using chemo-free approaches, specifically those targeting abnormal signaling pathways activated in MZL tumors and its microenvironment, treating physicians are encouraged to enroll patients on these clinical trials in order to better understand the underlying biology, mechanisms of response, and resistance to current therapies and help design future rationale combination strategies.

Outcomes After Reduced-Dose Intensity Modulated Radiation Therapy for Gastric Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma

In patients with gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, the standard radiation therapy (RT) dose is ≥30Gy. We report the outcome of patients treated with reduced dose 24Gy compared with those treated with ≥30Gy. We reviewed results from 32 patients who received a diagnosis of gastric MALT lymphoma between 2007 and 2017 who were treated with involved site RT using intensity modulated radiation therapy (IMRT). Response to therapy was based on post-RT endoscopic biopsy. Freedom from local treatment failure (FFLTF), freedom from treatment failure (FFTF), and overall survival (OS) outcomes were determined. The median age of patients at diagnosis was 58years. Therapy for MALT was given prior to RT in 14 patients with residual biopsy proven disease documented in all cases (anti-microbial, n=11; rituximab, n=2; rituximab, cyclophosphamide, doxorubicin, vincristine, n=1). One patient received RT (36Gy) and concurrent rituximab. The median RT dose was 30Gy; it was 30 to 36Gy in 66% of patients (n=21) and 24Gy in 34% of patients (n=11). Post-RT biopsy documented a complete response in all patients. Failures occurred in the stomach and duodenum, respectively, at 3.6 and 4.5years, after 30Gy. At a median follow-up of 55.2months (73.8 for ≥30Gy compared with 28.7 for 24Gy; P<.001), the 2-year FFLTF, FFTF, and OS were 100%, 100%, and 97%, respectively. No association was found between the lower (24-Gy) dose and FFLTF (P=.819), FFTF (P=.819), or OS (P=.469). Contemporary RT with involved site targeting using IMRT is associated with high complete response rates for patients with gastric MALT lymphoma, even using reduced doses of 24Gy. Additional follow-up and increased patient numbers are required to confirm equivalent disease control.

Targeted deep sequencing of gastric marginal zone lymphoma identified alterations of TRAF3 and TNFAIP3 that were mutually exclusive for MALT1 rearrangement

Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.

Antisecretory medication is associated with decreased Helicobacter pylori detection in gastric marginal zone lymphoma.

Helicobacter pylori status influences the prognosis and management of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), so accurate determination of H pylori status is of clinical importance. The low rate of histologic H pylori positivity among gastric MALT lymphoma cases at our institution prompted investigation for possible causes. A case series of 24 patients as having gastric MALT lymphoma (with no diffuse large B-cell component) in a tertiary care setting between 1997 and 2010 was identified, and clinical records were reviewed. Immunohistochemical staining for H pylori and BCL10 was performed. This study received institutional review board approval (protocol number M13-033). Thirty-nine percent of cases (9/23) were H pylori positive by histology, and 4 additional patients had positive serologic results; overall, 57% of cases (13/23) were positive for H pylori. Treatment with antisecretory medications was associated with a lower likelihood of histologic positivity (13% among treated patients vs 75% among untreated; P = .04). Nuclear localization of BCL10 was seen in 2 cases and was not associated with H pylori status. Antisecretory medications decrease the likelihood of histologic detection of H pylori in gastric MALT lymphoma cases. Incorporation of results of serologic or other testing is needed to ensure correct classification with respect to H pylori status.

The role of infectious agents, antibiotics, and antiviral therapy in the treatment of extranodal marginal zone lymphoma and other low-grade lymphomas.

There is strong evidence to corroborate the association with Helicobacter pylori (Hp) to gastric extranodal marginal zone lymphoma (ENMZL) and hepatitis C virus (HCV) to splenic/nodal marginal zone lymphoma. Koch's postulates generally hold for these two associations and eradication of the infectious agent is well supported. Hp eradication (HPE) is recommended as front-line therapy for early stage gastric ENMZL regardless of Hp status. Complete response (CR) rate for Hp-negative patients is not as high as for Hp-positive patients; however, the benign nature of HPE and high rates of salvage allow this strategy to be safe while sparing some Hp-negative patients from systemic therapy or radiation. Similarly for HCV-seropositive patients, treatment with antivirals should be strongly considered as first-line for those who do not require immediate cytoreductive therapy or at some point even after completing chemoimmunotherapy. The controversy regarding the role for antibiotics is greatest for primary ocular adnexal lymphoma (POAL). Considering the low incidence of Chlamydia psittaci (Cp) infection with OAL and the challenges to reliably identifying Cp, we typically do not consider doxycycline in POAL treatment. Involved-field radiotherapy (IFRT) remains the treatment of choice for most with unilateral POAL. However, if reliable detection of Cp is available and Cp is identified, patients with unilateral low tumor stage POAL who do not require immediate radiotherapy could be considered for doxycycline as front-line treatment. Other infectious associations to indolent lymphomas have been made, including Borrelia borgdorferi (Bb) in cutaneous lymphoma and Campylobacter in immunoproliferative small intestinal disease (IPSID), but these associations are not as strong and primary treatment targeting the infectious agents is not recommended.

Synchronous Indolent Primary Gastrointestinal Lymphomas Managed Successfully With Conservative Measures

We report the case of a 65-year-old man who presented with epigastric pain and guaic-positive stool. Upper and lower endoscopy revealed abnormalities in the gastric antrum and terminal ileum. Biopsy of these sites revealed histologically and immunophenotypically distinct lymphomas: gastric extranodal marginal zone lymphoma in the background of Helicobacter pylori infection and follicular lymphoma of the terminal ileum. After treatment with an H. pylori eradication regimen, repeat endoscopy showed resolution of the gastric extranodal marginal zone lymphoma and persistence of the ileal follicular lymphoma. Interestingly, molecular studies performed on the biopsy specimens revealed a common IgH rearrangement, suggesting a common precursor cell responsible for these two malignant processes. We present this unique case with a review of the literature, highlighting treatment principles for these two subtypes of indolent gastrointestinal non-Hodgkin lymphoma.

Gastric MALT Lymphoma Treated With Primary Radiotherapy in the Setting of Autoimmune Disease

Autoimmune and microbial-induced immune reactions are associated with lymphomagenesis, particularly of extranodal marginal zone B-cell lymphomas. This report presents a case of Helicobacter pylori-negative gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) in the setting of Sjögren syndrome and Hashimoto thyroiditis treated with primary involved-field radiotherapy. This report describes etiologic data, diagnostic and treatment considerations, and sophisticated radiation therapy techniques aimed at reducing long-term toxicity in this indolent disease.

Is Elevated Gastric Tissue NOX2 Associated with Lymphoma of Mucosa-Associated Lymphoid Tissue?

Abstract Helicobacter pylori infection plays a crucial role in the pathogenesis of gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). However, the host response to this infection is also important in the development of the disease. In particular, NADPH oxidases (NOXs) which generate reactive oxygen species are known to induce cell damage possibly leading to carcinogenesis. We analyze for the first time NOX expression in a series of well characterized gastric MALT lymphoma (GML) patients in comparison with controls. Our observation leads to the hypothesis that NOX2 expression is significantly associated with GML.

Deregulation of a distinct set of microRNAs is associated with transformation of gastritis into MALT lymphoma

The mechanisms underlying the transformation from chronic Helicobacter pylori gastritis to gastric extranodal marginal zone lymphoma (MALT lymphoma) are poorly understood. This study aims to identify microRNAs that might be involved in the process of neoplastic transformation. We generated microRNA signatures by RT-PCR in 68 gastric biopsy samples representing normal mucosa, gastritis, suspicious lymphoid infiltrates, and overt MALT lymphoma according to Wotherspoon criteria. Analyses revealed a total of 41 microRNAs that were significantly upregulated (n = 33) or downregulated (n = 8) in succession from normal mucosa to gastritis and to MALT lymphoma. While some of these merely reflect the presence of lymphocytes (e.g. miR-566 and miR-212) or H. pylori infection (e.g. miR-155 and let7f), a distinct set of five microRNAs (miR-150, miR-550, miR-124a, miR-518b and miR-539) was shown to be differentially expressed in gastritis as opposed to MALT lymphoma. This differential expression might therefore indicate a central role of these microRNAs in the process of malignant transformation.

Concurrent Gastric MALT and Hodgkin Lymphoma

This report describes a 60-year-old man with concurrent gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and classical Hodgkin lymphoma (CHL). Atypical, medium-sized, lymphoid cells proliferated in the mucosa to muscular layer of the stomach showing a lymphoepithelial lesion; admixed with Hodgkin/Reed-Sternberg (HRS) cells and an inflammatory cell background. MALT lymphoma cells expressed CD20, CD79a, PAX5, and BOB.1, and HRS cells expressed CD30, CD15, Epstein-Barr virus-encoded RNA, and EBV-latent membrane protein 1. Only CHL invaded into the regional lymph nodes. Two possibilities of transformation of MALT lymphoma into CHL and de novo CHL within MALT lymphoma are discussed.

Collision of EBV‐associated gastric carcinoma and primary gastric extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue in the remnant stomach

Reported herein is a case of EBV-associated gastric carcinoma with primary gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). A 69-year-old Japanese man was found to have an ulcer lesion in his stomach on endoscopy, and a biopsy indicated malignancy. He underwent gastrectomy. Microscopically the tumor had features typical of lymphoepithelioma-like carcinoma. The neoplastic epithelial cells proliferated in a trabecular fashion. On in situ hybridization for EBV-encoded RNA, positive signals were observed in most neoplastic epithelial cells. Numerous lymphocytes surrounded the neoplastic epithelial cells. In the stroma, numerous lymphocytes with mild atypia were positive for CD20 and CD79a. In addition, monoclonal proliferation of B cells was confirmed on polymerase chain reaction for IgH. These findings supported MALT lymphoma. The coexistence of EBV-associated gastric carcinoma and MALT lymphoma is extremely rare.

Monitoring gastric lymphoma in peripheral blood by quantitative IgH allele‐specific oligonucleotide real‐time PCR and API2‐MALT1 PCR

Gastric extranodal marginal zone lymphoma (EMZL) often shows prolonged localised disease, but the present study demonstrated the presence of tumour cells in peripheral blood (PB) of low stage patients. We studied the presence of tumour cells in PB in gastric lymphoma patients harbouring or lacking t(11;18)(q21;q21), by real-time immunoglobulin (Ig)H allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) and API2-MALT1 PCR. Tumour cells were exclusively detected in PB of t(11;18)(q21;q21)+-EMZL patients. The presence of tumour cells in PB and gastric biopsy follow-up samples showed a good correlation in these patients, suggesting clinical relevance for monitoring of tumour cells in PB of gastric t(11;18)(q21;q21)+-EMZL patients.