Transformation to diffuse large B-cell lymphoma and its impact on survival in patients with marginal zone lymphoma: A population-based study.

Some patients with marginal zone lymphoma (MZL) experience histological transformation to diffuse large B-cell lymphoma (DLBCL). Because of the paucity of long-term data on transformation, we conducted a population-based study to estimate the risk of transformation and its impact on survival in MZL. Using the Surveillance, Epidemiology and End Results database, we identified 23 221 patients with histology-proven MZL between 2000 and 2018. Competing risk method, Kaplan-Meier and Cox proportional hazards regression were performed to analyze time-to-event outcomes. Based on 420 events of transformation, the 10-year cumulative incidence rate of transformation is 2.23% (95% CI: 2.00%-2.46%) in MZL, 1.5% (95% CI: 1.3%-1.8%), 2.7% (95% CI: 2.3%-3.2%) and 5.8% (95% CI: 4.6%-7.1%) in extranodal, nodal and splenic MZL (EMZL, NMZL and SMZL), respectively. Patients with SMZL (subdistribution hazard ratio [SHR], 2.96; 95% CI: 2.21-3.96) or NMZL (SHR, 1.49; 95% CI: 1.17-1.90) have a higher risk of transformation than those with EMZL. For each MZL subtype, patients with transformation had a significantly shorter overall survival. Patients with transformation >18 months since MZL diagnosis had longer OS than those who presented within 18 months (5-year rate, 87.4% [95% CI: 83.7%-91.2%] vs 47.9% [95% CI: 38.8%-59.0%]; P < .001). Compared to patients with matched de novo DLBCL, those whose DLBCL was transformed from MZL had a shorter OS (5-year rate, 56.6% [95% CI: 51.9%-61.8%] vs 46.1% [95% CI: 40.9%-51.9%]; P < .001). We concluded that patients with SMZL had the highest risk of transformation. Regardless of MZL subtype, transformation resulted in significantly increased mortality.

A population-based study of transformed marginal zone lymphoma: identifying outcome-related characteristics.

Histological transformation of marginal zone lymphoma (tMZL) into diffuse large B-cell lymphoma is associated with poor outcomes. Clinical characteristics associated with transformation risk and outcome after transformation are largely unknown due to scarcity of data. In this population-based study, competing risk analyses were performed to elucidate clinical characteristics associated with developing transformation among 1793 MZL patients using the Netherlands Cancer Registry. Cox regression analyses were performed to elucidate clinical characteristics associated with risk of relapse and mortality after transformation. Transformation occurred in 75 (4%) out of 1793 MZL patients. Elevated LDH and nodal MZL subtype at MZL diagnosis were associated with an increased risk, and radiotherapy with a reduced risk of developing tMZL. Most tMZL patients received R-(mini)CHOP (n = 53, 71%). Age >60 years and (immuno)chemotherapy before transformation were associated with an increased risk of relapse and mortality after transformation. Two-year progression-free survival (PFS) and overall survival (OS) were 66% (95% CI 52-77%) and 75% (95% CI 62-85%) for R-(mini)CHOP-treated tMZL patients, as compared to a PFS and OS both of 41% (95% CI 19-63%) for patients treated otherwise. Our study offers comprehensive insights into characteristics associated with transformation and survival after transformation, thereby optimizing guidelines and patient counseling.

Estimating the Burden of Illness of Relapsed Follicular Lymphoma and Marginal Zone Lymphoma in Ontario, Canada.

BACKGROUND: Many patients with advanced follicular lymphoma (FL) and marginal zone lymphoma (MZL) relapse after first-line chemotherapy. OBJECTIVE: To examine healthcare resource utilization (HCRU) and cost, treatment patterns, progression, and survival of patients with FL and MZL who relapse after first-line treatment, in Ontario, Canada. METHODS: A retrospective, administrative data study identified patients with relapsed FL and MZL (1 January 2005-31 December 2018). Patients were followed for up to three years post relapse to assess HCRU, healthcare costs, time to next treatment (TTNT), and overall survival (OS), stratified by first- and second-line treatment. RESULTS: The study identified 285 FL and 68 MZL cases who relapsed after first-line treatment. Average duration of first-line treatment was 12.4 and 13.4 months for FL and MZL patients, respectively. Drug (35.9%) and cancer clinic costs (28.1%) were major contributors to higher costs in year 1. Three-year OS was 83.9% after FL and 74.2% after MZL relapse. No statistically significant differences were observed in TTNT and OS between patients with FL who received R-CHOP/R-CVP/BR in the first line only versus both the first- and second- line. A total of 31% of FL and 34% of MZL patients progressed to third-line treatment within three years of initial relapse. CONCLUSION: Relapsing and remitting nature of FL and MZL in a subset of patients results in substantial burden to patients and the healthcare system.

The clinicopathological characteristics of gastric cancer and precancerous conditions in gastric DLBCL and MALT lymphoma patients: a multi-center retrospective study.

OBJECTIVE: The objective of this study is to explore the clinicopathological characteristics of gastric cancer and precancerous conditions in patients with primary gastric lymphoma. METHODS: We analyzed 474 cases of primary gastric lymphoma, mainly DLBCL and MALT, from three clinical centres retrospectively, and compared the clinicopathological parameters of primary gastric lymphoma patients complicated with gastric cancer, precancerous conditions, or with no complications. RESULTS: A total of 5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer, including metachronous gastric adenocarcinoma (3.2%) and synchronous gastric adenocarcinoma (1.9%). Of the patients with gastric lymphoma, 14.6% had precancerous conditions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%). Primary gastric lymphoma patients with an ulcerative type (p = 0.009) and Lugano classification stage IIE + IV (p < 0.001) lymphoma had a higher risk of complicating with gastric cancers or precancerous conditions. The rate of infection of Helicobacter pylori (Hp) was 68.4% in patients with primary gastric lymphoma, which was higher in patients with MALT lymphoma (p < 0.001), Lugano classification stage I + II (p < 0.001), and patients complicated with precancerous conditions and gastric cancer (p < 0.001), especially gastric cancer of the intestinal type (p = 0.04). Gastric cancer (95.8%) and precancerous conditions (91.3%) occurred mostly in Hp-infected primary gastric lymphoma patients, with a minor subset of Hp-eradicated patients. Primary gastric lymphoma patients had a higher detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population. CONCLUSIONS: Patients with primary gastric lymphoma have a high risk of developing gastric cancer and precancerous conditions, and this risk may be related to Helicobacter pylori infection. Follow-up of primary gastric lymphoma provides an opportunity for the detection of early gastric cancer.Key messages5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer.14.6% of the patients with gastric lymphoma had premalignant lesions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%).Primary gastric lymphoma patients complicating with gastric cancer had a higher infection rate of Helicobacter pylori (100.0%), a detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population.

Transformation and survival in marginal zone lymphoma: a Finnish nationwide population-based study.

Marginal zone lymphoma (MZL) is an indolent B-cell malignancy with heterogeneous anatomical and clinical presentation. While MZLs are generally associated with long survival, some patients experience histological transformation to aggressive large B-cell lymphoma. Population-based long-term data on the transformation of MZL is limited. We conducted a nationwide population-based study to estimate the risk of transformation and relative survival in patients diagnosed with MZL in Finland from 1995-2018. We identified a total of 1454 patients with MZL from the Finnish Cancer Registry (FCR). The cumulative incidence of transformation was 4.7% (95% CI, 3.6-6.2) at 10 years. The highest incidence of transformation was observed in the patients with splenic MZL (14.0%; 95% CI, 8.6-22.7). The transformation was associated with a substantially increased risk of death (HR, 5.18; 95% CI, 3.58-7.50). Ten-year relative survival was 79% (95% CI, 73‒83%). Transformation, nodal MZL subtype, and older age at diagnosis were associated with increased excess mortality, whereas patients diagnosed at a later calendar period had a lower excess risk of death. We conclude that transformation resulted in a substantially increased mortality irrespective of MZL subtype compared with the patients without transformation. Our results also suggest a reduction in excess mortality in recent years.

Differential survival of systemic B-cell lymphomas initially diagnosed in the skin: a population-based study of 883 patients.

Although the majority of lymphomas are diagnosed in lymph nodes, bone marrow, or other viscera, initial diagnosis of systemic lymphomas in the skin is a rare but important occurrence in dermatology. This study seeks to quantify the incidence of initial skin presentation in patients with systemic B-cell lymphomas (BCL) via examination of data in the Surveillance, Epidemiology, and End Results (SEER)-18 database; cases of primary cutaneous B-cell lymphoma were excluded. We found that an initial diagnosis of lymphoma in the skin is a very rare occurrence for systemic B-cell lymphomas, comprising < 0.3% of cases overall. Follicular lymphoma was the most likely to be diagnosed in the skin (1.47%), followed by marginal zone lymphoma (MZL, 0.5%), mantle cell lymphoma (0.4%), diffuse large B-cell lymphoma (DLBCL, 0.23%), Burkitt lymphoma (0.23%), Hodgkin lymphoma (0.04%), and chronic lymphocytic leukemia (0.006%). While indolent systemic lymphomas (MZL and FL) presenting initially in the skin have a better prognosis than those presenting at other sites, the more aggressive systemic DLBCL presenting in the skin does not demonstrate improved prognosis.

Epidemiology and survival outcomes of patients with primary intraocular lymphoma: a population-based analysis.

BACKGROUND: Primary intraocular lymphoma (PIOL) is a rare malignancy with a poor prognosis, but its optimal therapy remains unclear. Herein, we aimed to analyze the epidemiology and survival outcomes of PIOL patients based on a population-based cancer registry in the United States. METHODS: Patients diagnosed with PIOL between 1992 and 2018 were identified from the Surveillance Epidemiology and End Results program. The patients were divided into two groups: those aged < 60 years and ≥ 60 years. We used the chi-squared test to analyze the differences between the two groups. Descriptive analyses were performed to analyze epidemiological characteristics and treatment. The likely prognostic factors were analyzed by Kaplan-Meier curves and Cox proportional hazards models. RESULTS: The overall incidence of PIOL was 0.23/1,000,000, which was steadily increasing from 1992 to 2018, with an annual percentage change of 2.35. In total, 326 patients (mean age, 66.1 years) with PIOL were included in this study, 72.1% were aged ≥ 60 years, 84.4% were White, and 60.4% were female. The most common pathological type was diffuse large B-cell lymphoma (DLBCL), but in patients aged < 60 years, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue was the most common. The disease-specific survival rates were 74.2% and 61.5% 5 and 10 years after diagnosis, respectively. Survival analysis found that surgery, radiation, and chemotherapy did not lead to better prognosis. CONCLUSIONS: PIOL is a rare disease with poor prognosis, and its incidence has been increasing for nearly 30 years. It usually affects people aged ≥ 60 years, and DLBCL is the most common pathological type of PIOL. Patients aged < 60 years and with non-DLBCL type have improved survival. Survival of PIOL has improved in recent years.

Genetic polymorphisms and risk of MALT lymphoma in Greek population.

PURPOSE: MALT lymphoma is thought to have a genetic component. Genetic studies in the greek population are rare and genetic determinants remain to be established. The current study aimed to seek correlations between genetic polymorphisms and risk of MALT lymphoma in the Greek population. PATIENTS AND METHODS: 83 MALT lymphoma patients and 60 age-matched healthy outpatients were recruited. SNPs in TNFa, LTA and CTLA-4 genes and IL1RN-VNTR and GSTT1 and GSTTM1 null polymorphisms were genotyped using published PCR/PCR-RFLP methods, while two novel PCR-RFLP methods were developed for IL-22 rs7314777 and TCF19 rs7750641 SNPs. Part of the results was validated by DNA-sequencing. Statistical analysis was performed using SPSS and the SNPstats bioinformatic tool. RESULTS: The mean age of the patients and controls were 55.9 and 56.2 years respectively. The majority of patients (63) suffered gastric marzinal zone lymphoma (GMZL) and 71.1% were stage I at diagnosis. A statistically significant association was noted for the CTLA-4 49A/ G G variant (OR:2.56,p: 0.006) and the TCF19 rs7750641 SNP T variant (OR: 3.86, p:0.023). CONCLUSIONS: Our study confirmed a role for CTLA-4 49A/G and TCF19 rs7750641 SNPs in the Greek population. Additional studies could help confirm these associations and possibly link them to prognosis or response to treatment parameters.

Risk-tailored treatment of splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a rare lymphoproliferative disease involving B-cells and affecting elderly patients. SMZL plague peripheral blood and bone marrow, spleen. Lymph nodes are generally spared. SMZL is due to a protracted antigen stimulation of B lymphocytes and of microenvironment leading B-cell to polyclonal and then oligoclonal/monoclonal growth, promoting lymphoproliferation. Integration of the NOTCH2 and NFk-B signaling has been recently identified as the primary mechanism of neoplastic proliferation in SMZL. In total 20% of cases carry mutations in NOTCH2. Although SMZL has an indolent course, progression to diffuse large B-cell lymphoma occurs in about 10-15% of patients. Establishing the prognosis is a key step in disease management, depending on both individual risk and patients' health status. This review discusses tailored treatment of SMZL patients. Progression risk factors include nodal and extra-nodal involvement, peripheral lymphocytosis, anemia and thrombocytopenia. Patients with two or more score points have a median survival of <5 years. Watch and wait strategy is appropriate in low-risk and asymptomatic patients, whereas treatment of symptomatic patients ranges from splenectomy to rituximab monotherapy or associated with chemotherapy.

Clinico-biological features and outcome of patients with splenic marginal zone lymphoma with histological transformation.

We describe 36 patients with splenic marginal zone lymphoma (SMZL) with transformation (SMZL-T), including 15 from a series of 84 patients with SMZL diagnosed at the Hospital Clinic of Barcelona (HCB) and 21 diagnosed with SMZL-T in other centres. In the HCB cohort, the cumulative incidence of transformation at 5 years was 15%. Predictors for transformation were cytopenias, hypoalbuminaemia, complex karyotype (CK) and both the Intergruppo Italiano Linfomi (ILL) and simplified Haemoglobin, Platelet count, lactate dehydrogenase (LDH) and extrahilar Lymphadenopathy (HPLL)/ABC scores (P < 0·05). The only independent predictor for transformation in multivariate analysis was CK [hazard ratio (HR) 4·025, P = 0·05]. Patients with SMZL-T had a significantly higher risk of death than the remainder (HR 3·89, P < 0·001). Of the 36 patients with SMZL-T, one developed Hodgkin lymphoma and 35 a diffuse large B-cell lymphoma, 71% with a non-germinal centre phenotype. The main features were B symptoms, lymphadenopathy, and high serum LDH. CK was observed in 12/22 (55%) SMZL-T and fluorescence in situ hybridisation detected abnormalities of MYC proto-oncogene, basic helix-loop-helix transcription factor (MYC), B-cell leukaemia/lymphoma 2 (BCL2) and/or BCL6 in six of 14 (43%). In all, 21 patients received immunochemotherapy, six chemotherapy, one radiotherapy and three splenectomy. The complete response (CR) rate was 61% and the median survival from transformation was 4·92 years. Predictors for a worse survival in multivariate analysis were high-risk International Prognostic Index (HR 5·294, P = 0·016) and lack of CR (HR 2·67, P < 0·001).

A single-center analysis of patients with extranodal marginal zone lymphoma of the breast.

Breast extranodal marginal zone lymphoma (EMZL) is a rare malignancy. We performed the largest published to date single-center retrospective analysis of 13 patients with breast EMZL focusing on clinical characteristics and treatment-related outcomes. The rarity of this disease at our center was concordant with the prevalence reported in the literature, with breast EMZL comprising 2% of 654 MZL cases. Most patients presented with stage I-II disease however four (30.8%) patients had stage IV disease mostly due to occult bone marrow (BM) involvement. Interestingly, EMZL was frequently non-FDG avid (66.7%) on staging PET/CT. With a median follow-up of 3.1 years (range 5 months to 10.2 years), the 3-year progression free survival was 68.7% (95%CI 30.2%-88.9%) and overall survival 80.2% (95%CI 40.3%-94.8%). No patient experienced higher-grade transformation. Herein we show that localized breast EMZL can be effectively treated with radiation therapy providing long term disease control.

Characterization of Second Primary Malignancies in Mucosa-Associated Lymphoid Tissue Lymphomas: A SEER Database Interrogation.

INTRODUCTION: Second primary malignancies (SPMs) are long-term complications in cancer survivors. Mucosa-associated lymphoid tissue (MALT) lymphomas are indolent extra-nodal marginal zone lymphomas, the majority of which typically have long-term survival. In this study, we investigated the incidence and pattern of SPMs in adult patients diagnosed with MALT lymphomas between January 2000 and December 2016. METHODS: Using the SEER-18 database and multiple primary standardized incidence ratio (MP-SIR) session of SEER stat software for statistical analysis, we assessed SPMs in MALT lymphomas. RESULTS: During this time, a total of 12,500 cases of MALT lymphomas were diagnosed, of which 1466 patients developed 1626 SPMs (O/E ratio: 1.48, 95% CI:1.41-1.55, P<.001). The median latency period for development of SPMs was 54 months (range 6-201 months). Secondary non-Hodgkin lymphomas, as defined by SEER as distinct from the primary lymphoma, was the most common SPM with 299 cases, followed by lung cancer (O/E ratio: 6.15, 95% CI:5.47-6.89, P<.0001). There were 898 SPMs that developed between 6- 59 months (O/E ratio: 1.47, 95% CI:1.37-1.57, P<.0001) and 728 after 60 months latency (O/E ratio: 1.5, 95% CI:1.39-1.61, P<.0001) after diagnosis of the primary MALT lymphomas. An increased incidence of both solid and hematologic cancers occurred in patients as early as 6 months after diagnosis of MALT lymphoma. CONCLUSION: These findings indicate that despite the indolent nature of most MALT lymphomas, there is an increased risk for SPMs warranting long-term follow up.

Clinical Characteristics, Treatment and Evolution of Splenic and Nodal Marginal Zone Lymphomas-Retrospective and Multicentric Analysis of Portuguese Centers.

INTRODUCTION: Treatment of Splenic (SMZL) and Nodal (NMZL) Marginal Zone Lymphoma is not consensual. Histologic transformation (HT) to aggressive lymphoma is a poorly understood event, with an unfavorable outcome. OBJECTIVES: Describe the clinical characteristics, treatment, outcomes and incidence of HT. METHODS: Characteristics of patients with SMZL and NMZL consecutively diagnosed in 8 Portuguese centers were retrospectively reviewed. Endpoints were overall survival (OS), time to first systemic treatment (TTFST), frequency of HT and time to transformation (TTT). RESULTS: This study included 122 SMZL and 68 NMZL, most of them received systemic treatment: 55.4% and 76.5%, respectively. Splenectomy was performed in 58.7% of patients with SMZL. Different treatment protocols were used. OS or TTFST did not differ significantly according to treatments. Given the small sample size, no conclusion can be made concerning the role of Rituximab in the treatment of NMZL and SMZL based in these results. HT was documented in 18 patients, mainly in SMZL, with a cumulative incidence at 5 years of 4.2%. We confirmed that age is a prognostic factor. CONCLUSION: Randomized prospective trials are needed to standardize treatment in MZL. Patients with HT did appear to have shorter OS in comparison with those who did not experience HT (OS 5 years of 68.4% vs. 80.4%), but the number of HT was too small to reach statistical significance.

Superior outcome for splenectomised patients in a population-based study of splenic marginal zone lymphoma in Sweden.

Splenic marginal zone lymphoma (SMZL) is a rare low-grade B-cell lymphoma where associations with viral hepatitis and autoimmune and inflammatory diseases (AID) have been indicated. We aimed at assessing the prevalence of viral hepatitis and AID at SMZL diagnosis and outcome by treatment in a Swedish population-based study. A total of 277 SMZL patients registered in the Swedish Lymphoma Register in 2007-2017 were included. A history of viral hepatitis was reported in five (2%) patients and AID prior to SMZL in 72/240 (30%) patients. Treatment was given up front for 207 (75%) patients. Splenectomy with or without systemic treatment was performed in 119 (57%) and was associated with statistically significantly better overall survival [hazard ratio, HR = 0·47 (95% confidence interval, CI: 0·23-0·93), P = 0·03] and progression-free survival (HR = 0·55, 95% CI: 0·35-0·86, P = 0·008) compared to non-splenectomised patients in multivariable analyses. The up-front splenectomised group was younger and generally had a lower Ann Arbor stage, but also more frequently B symptoms and high lactate dehydrogenase than the non-splenectomised group. Viral hepatitis and AID history did not affect SMZL outcome. We report high incidence of AIDs and low incidence of viral hepatitis in this population-based study of SMZL. Splenectomy up front was associated with a favourable outcome.

Helicobacter pylori and Gastric Cancer.

Helicobacter pylori is present in approximately one-half of the world's population. There are significant differences in prevalence based on region, age, race/ethnicity, and socioeconomic status. H pylori is the most common cause of infection-related cancers. Studies have demonstrated the relationship between H pylori infection and gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. H pylori has features and enzymatic properties allowing it to survive in the acidic stomach environment, and has specific virulence factors that promote an increased risk of gastric pathology. Eradication of H pylori is first-line therapy for mucosa-associated lymphoid tissue lymphoma and decreases the risk of gastric adenocarcinoma.