A systematic review of primary gastric diffuse large B-cell lymphoma: Clinical diagnosis, staging, treatment and prognostic factors.

Primary gastric lymphoma (PGL) is a rare clinical entity accounting for the majority of extra-nodal non-Hodgkin lymphoma (EN-NHL). The most common histological subtype is the primary gastric diffuse large B-cell lymphoma (PG-DLBCL) with a media age of 50-60 years old, mostly in male. Pathogenesis is often related to some bacterial infection such as Helicobacter pylori (H. pylori) infection. However, due to various available staging system, there is still no consensus on the staging of PG-DLBCL. The international prognostic index (IPI) is the most valuable used for the stratification of almost all subtype of NHL and as well as for PG-DLBCL. As for treatment strategies, surgery, chemotherapy, radiation therapy and antibiotic therapy in various combinations have been applied in clinical treatment. There are a few well-known prognostic factors and some of them may constitute prognostic models. Due to the increasing incidence of this neoplasm, it is necessary for clinicians to make deep insight of the diagnosis, staging, treatment and prognostic factors of PG-DLBCL.

New developments in non-Hodgkin lymphoid malignancies.

The revised fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (2017) reflects significant advances in understanding the biology, genetic basis and behaviour of haematopoietic neoplasms. This review focuses on some of the major changes in B-cell and T-cell non-Hodgkin lymphomas in the 2017 WHO and includes more recent updates. The 2017 WHO saw a shift towards conservatism in the classification of precursor lesions of small B-cell lymphomas such as monoclonal B-cell lymphocytosis, in situ follicular and in situ mantle cell neoplasms. With more widespread use of next generation sequencing (NGS), special entities within follicular lymphoma and mantle cell lymphoma were recognised with recurrent genetic aberrations and unique clinicopathological features. The diagnostic workup of lymphoplasmacytic lymphoma and hairy cell leukaemia has been refined with the discovery of MYD88 L265P and BRAF V600E mutations, respectively, in these entities. Recommendations in the immunohistochemical evaluation of diffuse large B-cell lymphoma include determining cell of origin and expression of MYC and BCL2, so called 'double-expressor' phenotype. EBV-positive large B-cell lymphoma of the elderly has been renamed to recognise its occurrence amongst a wider age group. EBV-positive mucocutaneous ulcer is a newly recognised entity with indolent clinical behaviour that occurs in the setting of immunosuppression. Two lymphomas with recurrent genetic aberrations are newly included provisional entities: Burkitt-like lymphoma with 11q aberration and large B-cell lymphoma with IRF4 rearrangement. Aggressive B-cell lymphomas with MYC, BCL2 and/or BCL6 rearrangements, so called 'double-hit/triple-hit' lymphomas are now a distinct entity. Much progress has been made in understanding intestinal T-cell lymphomas. Enteropathy-associated T-cell lymphoma, type II, is now known to not be associated with coeliac disease and is hence renamed monomorphic epitheliotropic T-cell lymphoma. An indolent clonal T-cell lymphoproliferative disorder of the GI tract is a newly included provisional entity. Angioimmunoblastic T-cell lymphoma and nodal T-cell lymphomas with T-follicular helper phenotype are included in a single broad category, emphasising their shared genetic and phenotypic features. Anaplastic large cell lymphoma, ALK- is upgraded to a definitive entity with subsets carrying recurrent rearrangements in DUSP22 or TP63. Breast implant-associated anaplastic large cell lymphoma is a new provisional entity with indolent behaviour. Finally, cutaneous T-cell proliferations include a new provisional entity, primary cutaneous acral CD8-positive T-cell lymphoma, and reclassification of primary small/medium CD4-positive T-cell lymphoma as lymphoproliferative disorder.

Non-Hodgkin Lymphomas: Malignancies Arising from Mature B Cells.

Non-Hodgkin lymphomas (NHLs) are a diverse group of entities, both clinically and molecularly. Here, we review the evolution of classification schemes in B-cell lymphoma, noting the now standard WHO classification system that is based on immune cell-of-origin and molecular phenotypes. We review how lymphomas arise throughout the B-cell development process as well as the molecular and clinical features of prominent B-cell lymphomas. We provide an overview of the major progress that has occurred over the past decade in terms of our molecular understanding of these diseases. We discuss treatment options available and focus on a number of the diverse research tools that have been employed to improve our understanding of these diseases. We discuss the problem of heterogeneity in lymphomas and anticipate that the near future will bring significant advances that provide a measurable impact on NHL outcomes.

Advances in Classification and Treatment of Non-Hodgkin Lymphoma: Mantle Cell.

Mantle cell lymphoma is a rare, aggressive, and largely incurable form of non-Hodgkin lymphoma. There are a number of well-characterized prognostic features but nothing that can help guide therapy. Treatment with chemotherapy is generally effective in the short term, but relapse is inevitable and subsequent treatment is challenging. The use of Bruton tyrosine kinase inhibitors, however, has transformed practice. These agents are highly active in relapsed disease and are very well-tolerated drugs. Chemotherapy-free combinations using Bruton tyrosine kinase inhibitors look very exciting and will likely evolve to be part of frontline care in the future.

Molecular Classification of Large B-Cell Non-Hodgkin Lymphoma.

Large B-cell lymphomas (LBCLs) represent a frequent but clinically and morphologically heterogeneous group of tumors. Technological advances over the last 2 decades prompted the development of new classification schemas to sharpen diagnoses, dissect molecular heterogeneity, and identify rational treatment targets. Despite increased molecular understanding of these lymphomas, the clinical perspectives of patients largely remain unchanged. Recently finished comprehensive genomic studies discovered genetically defined LBCL subtypes that predict outcome, provide insight into lymphomagenesis, and suggest rational therapies with the hope of generating patient-tailored treatments with increased perspective for patients in greatest need. Here, we summarize notable examples of how high-throughput technologies aided in better molecular understanding of LBCLs and provided examples of rationally designed targeted treatments.

Drug Resistance in Non-Hodgkin Lymphomas.

Non-Hodgkin lymphomas (NHL) are lymphoid tumors that arise by a complex process of malignant transformation of mature lymphocytes during various stages of differentiation. The WHO classification of NHL recognizes more than 90 nosological units with peculiar pathophysiology and prognosis. Since the end of the 20th century, our increasing knowledge of the molecular biology of lymphoma subtypes led to the identification of novel druggable targets and subsequent testing and clinical approval of novel anti-lymphoma agents, which translated into significant improvement of patients' outcome. Despite immense progress, our effort to control or even eradicate malignant lymphoma clones has been frequently hampered by the development of drug resistance with ensuing unmet medical need to cope with relapsed or treatment-refractory disease. A better understanding of the molecular mechanisms that underlie inherent or acquired drug resistance might lead to the design of more effective front-line treatment algorithms based on reliable predictive markers or personalized salvage therapy, tailored to overcome resistant clones, by targeting weak spots of lymphoma cells resistant to previous line(s) of therapy. This review focuses on the history and recent advances in our understanding of molecular mechanisms of resistance to genotoxic and targeted agents used in clinical practice for the therapy of NHL.

Clinical analysis of 20 patients with non-Hodgkin lymphoma and autoimmune hemolytic anemia: A retrospective study.

Non-Hodgkin lymphoma (NHL) can co-exist with autoimmune hemolytic anemia (AIHA), a phenomenon known as AIHA-associated NHL (AIHA/NHL). However, few studies have reported AIHA/NHL incidence or its clinical characteristics. We conducted a retrospective analysis of 20 AIHA/NHL patients treated at our hospital from 2009 to 2018. AIHA/NHL was presented by only 0.91% of the NHL and 9.8% of the AIHA patients. In addition, AIHA occurred most frequently with angioimmunoblastic T-cell lymphoma (AITL) (7.31%), followed by marginal zone B-cell lymphoma (MZBL) (6.25%), B-cell lymphoma-unclassified (BCL-U) (4.25%), chronic lymphocytic leukemia/small lymphocyte lymphoma (CLL/SLL) (2.50%), and mantle cell lymphoma (MCL) (2.30%). In addition to the CLL/SLL patients with impaired bone marrow, 66.7% of the AIHA/NHL patients had lymphoma bone marrow infiltration (LBMI), of which 4 patients presented LBMI in bone marrow smears (BMS) but not in bone marrow biopsy (BMB) and 6 were positive for BMB but not BMS. The 1-, 3- and 5-year survival rates of AIHA/NHL patients were 70%, 30% and 20%, respectively, and they responded poorly to chemotherapy. In conclusion, AIHA can co-exist with various NHLs and the defining clinical characteristic of AIHA/NHL is the high incidence of LBMI. However, both BMS and BMB should be performed to avoid missed diagnosis.

Prognostic value and clinicopathological characteristics of PD-L1 overexpression in non-Hodgkin lymphoma: a meta-analysis.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) has already been detected in various carcinomas. In non-Hodgkin lymphoma (NHL), however, the prognostic value of PD-L1 overexpression remains unclear. METHODS: A meta-analysis of 2321 NHL patients from 12 studies was performed. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the correlation between PD-L1 overexpression and prognosis of NHL, and odds ratios (ORs) with 95% CIs were used to assess the association of PD-L1 overexpression with clinicopathological factors. RESULTS: The results showed that no significant difference between PD-L1 positive and negative groups was detected in NHL (HR: 1.40, 95% CI: 0.90-2.19; P = 0.137). Nevertheless, the results indicated that PD-L1 overexpression was associated with poor prognosis in the subtype of diffuse large B cell lymphoma (DLBCL) (HR: 1.70, 95% CI: 1.05-2.74; P = 0.031). We also performed subgroup analyses and meta-regression. The pooled OR showed that PD-L1 overexpression was associated with B symptoms, higher international prognostic index (IPI) score (3, 4, and 5 points) and Ann Arbor Stages III and IV. CONCLUSIONS: The meta-analysis demonstrated that PD-L1 expression was not associated with prognosis of NHL but was associated with prognosis of DLBCL.

Glyphosate use and associations with non-Hodgkin lymphoma major histological sub-types: findings from the North American Pooled Project.

Objectives Some epidemiological studies have suggested positive associations between glyphosate use and non-Hodgkin lymphoma (NHL), but evidence is inconsistent and few studies could evaluate histological sub-types. Here, associations between glyphosate use and NHL incidence overall and by histological sub-type were evaluated in a pooled analysis of case-control studies. Methods The analysis included 1690 NHL cases [647 diffuse large B-cell lymphoma (DLBCL), 468 follicular lymphoma (FL), 171 small lymphocytic lymphoma (SLL), and 404 other sub-types] and 5131 controls. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for NHL overall and sub-types with self-reported ever/never, duration, frequency, and lifetime-days of glyphosate use. Results Subjects who ever used glyphosate had an excess of NHL overall (OR 1.43, 95% CI 1.11-1.83). After adjustment for other pesticides, the OR for NHL overall with "ever use" was 1.13 (95% CI 0.84-1.51), with a statistically significant association for handling glyphosate >2 days/year (OR 1.73, 95% CI 1.02-2.94, P-trend=0.2). In pesticide-adjusted sub-type analyses, the ordinal measure of lifetime-days was statistically significant (P=0.03) for SLL, and associations were elevated, but not statistically significant, for ever years or days/year of use. Handling glyphosate >2 days/year had an excess of DLBCL (OR 2.14, 95% CI 1.07-4.28; P-trend=0.2). However, as with the other sub-types, consistent patterns of association across different metrics were not observed. Conclusions There was some limited evidence of an association between glyphosate use and NHL in this pooled analysis. Suggestive associations, especially for SLL, deserve additional attention.

Primary CNS Lymphoma in India: A 17-Year Experience From the All India Institute of Medical Sciences.

PURPOSE: The information about the outcome of primary CNS lymphoma (PCNSL) in India is scarce, because there is no population-based or large hospital-based data. MATERIALS AND METHODS: This is a retrospective study that spanned 17 years (2001 to 2017) to study the outcome of PCNSL at the All India Institute of Medical Sciences (AIIMS), which is a tertiary care center in Northern India. RESULTS: Only one of 99 patients was positive for HIV serology. Diffuse large B-cell lymphoma was the most common histology (97.7%). The median patient age was 50 years (range, 13 to 70 years), and the ratio of men to women was 1.9. The median duration of symptoms before diagnosis was 3.5 months (range, 0.5 to 48 months), and 58.5% had a performance status (PS) of 3 or more. Multiple intracranial lesions were present in 81.8% of patients. Surgical resection was performed in 45%, and approximately 22% of patients were ineligible for treatment. Most patients (n = 73) were treated with high-dose methotrexate (HDMTX)-based regimens (ie, methotrexate, vincristine, and procarbazine with or without rituximab). Pharmacokinetic monitoring of methotrexate was not available at our center. HDMTX-related mortality was 3.9%. The median follow-up duration, event-free survival (EFS), and overall survival (OS) were 34 months, 20.4 months, and 31.7 months, respectively. Addition of rituximab (n = 27) to MVP resulted in a higher objective response rate (88.9% v 73.9% without rituximab; P = .12), complete remission (81.5% v 56.5%; P = .03), 2-year EFS (57.3% v 40.4%; P = .02), and 2-year OS (61.6% v 53.4%; P = .056). CONCLUSION: This is the largest study of PCNSL from India. The patients were immunocompetent and young but presented with a high-burden disease that precluded treatment in approximately 22%. The treatment with HDMTX appears safe without pharmacokinetic monitoring. The outcome is comparable to those observed in the West, and rituximab use showed additional benefit. There are notable barriers with respect to management of PCNSL in the real world, and efforts are required to improve the outcome more.

Molecular and cellular genetics of non-Hodgkin lymphoma: Diagnostic and prognostic implications.

Non-Hodgkin lymphoma (NHL) is a diverse collection of malignant neoplasms with lymphoid-cell origin which includes all the malignant lymphomas that are not classified as Hodgkin lymphoma. NHL is one of the most common types of cancer diagnosed in men and women in the developed world. In the United States of America, the past few decades have seen a significant rise in the incidence of NHL and it accounts for about 4% of all cancers now. The overall survival of NHL has improved drastically over the past ten years. This can be attributed to better understanding of pathogenesis, refined classification, enhanced supportive care, and data from collaborative clinical trials. The prognosis of a newly diagnosed NHL patient depends, among other factors, on the specific subtype of lymphoma, stage of the disease, and age of the patient. Advances in the fields of molecular biology and innovations in cytogenetic techniques have led to the discovery of several oncogenic pathways involved in lymphomagenesis, which in turn has amplified the diagnostic and therapeutic approaches available for NHL. Our comprehension of the genetic features that determine the character of NHL, and ultimately guide the therapy, has undergone significant shift and it is essential that scientists as well as clinicians stay in tune with this rapidly evolving knowledge. In this review we have summarized the current concepts about cellular and molecular genetics of the common subtypes of NHL and their clinical implications.

Subtype-specific epidemiology of lymphoid malignancies in Taiwan compared to Japan and the United States, 2002-2012.

BACKGROUND: There are many unrevealed parts regarding lymphoma etiology. Previous studies suggested differences in lymphoma epidemiology among countries existed; however, some were one-center studies that were not enough to represent the whole population. OBJECTIVE: To provide epidemiological information on lymphoma within Taiwanese and to compare the data with that in Japan and the United States. METHODS: We used Taiwan Cancer Registry Database as our data source. Patients with lymphoma were identified through the ICD-O-3 codes and those with non-Hodgkin lymphoma (NHL) were categorized into three major types and 13 subtypes according to 2008 WHO classification. Incidence of lymphoma was adjusted according to the 2000 world standard population. RESULTS: During 2002-2012, 21 929 cases were diagnosed with four major types of lymphoma in Taiwan. Aggressive B-cell lymphoma (52.21%, N = 11 450) was the most common type of NHL. Median age at diagnosis of aggressive B-cell lymphoma was the eldest (63.0-65.0 years). Male excess in T/NK-cell lymphoma was the most obvious (sex ratio: 1.39-2.07). The incidence of NK/T-cell lymphoma, nasal type, was higher (male: 0.16-0.34 per 100 000, female: 0.06-0.16 per 100 000) in Taiwan than that in the United States and Japan. CONCLUSION: This is the first population-based study in Taiwan to investigate subtype-specific epidemiology of lymphoma. The incidence rates of lymphoma in Taiwan are mostly lower than those in the United States and higher or comparable to those in Japan except for NK/T-cell lymphoma, nasal type, whose age-adjusted incidence in Taiwan is the highest.

Molecular classification of primary mediastinal large B-cell lymphoma using routinely available tissue specimens.

Primary mediastinal large B-cell lymphoma (PMBCL) is recognized as a distinct entity in the World Health Organization classification. Currently, the diagnosis relies on consensus of histopathology, clinical variables, and presentation, giving rise to diagnostic inaccuracy in routine practice. Previous studies have demonstrated that PMBCL can be distinguished from subtypes of diffuse large B-cell lymphoma (DLBCL) based on gene expression signatures. However, requirement of fresh-frozen biopsy material has precluded the transfer of gene expression-based assays to the clinic. Here, we developed a robust and accurate molecular classification assay (Lymph3Cx) for the distinction of PMBCL from DLBCL subtypes based on gene expression measurements in formalin-fixed, paraffin-embedded tissue. A probabilistic model accounting for classification error, comprising 58 gene features, was trained on 68 cases of PMBCL and DLBCL. Performance of the model was subsequently evaluated in an independent validation cohort of 158 cases and showed high agreement of the Lymph3Cx molecular classification with the clinicopathological diagnosis of an expert panel (frank misclassification rate, 3.8%). Furthermore, we demonstrate reproducibility of the assay with 100% concordance of subtype assignments at 2 independent laboratories. Future studies will determine Lymph3Cx's utility for routine diagnostic purposes and therapeutic decision making.

Spectrum of lymphoma in Bahrain. A retrospective analysis according to the World Health Organization classification.

OBJECTIVES: To determine the spectrum of various types of lymphoma in Bahrain according to the latest World Health Organization classification criteria.  Methods: A retrospective review was conducted for all new lymphoma cases diagnosed at Salmaniya Medical Complex, Manama, Bahrain during the period from January 2010 to December 2015.  Results: Two hundred and twenty-one new cases of lymphoma in Bahraini patients were diagnosed in the study period. Eighty patients had Hodgkin lymphoma, 140 had non-Hodgkin lymphoma, and one patient had composite lymphoma. In the Hodgkin lymphoma group, nodular sclerosis type was the most frequent type (48.75%), followed by mixed-cellularity type (27.5%), and nodular-lymphocyte predominant type (16.25%). In the non-Hodgkin lymphoma group, 124 (88.6%) cases were B-cell lymphomas, while the remaining were T-cell lymphomas. Diffuse large B-cell lymphoma was the most frequent type of non-Hodgkin B-cell type lymphoma (55.7%), followed by follicular lymphoma (10%).  Conclusion: The distribution of lymphoma in Bahrain is similar to neighboring Middle East countries with a predominance of Hodgkin lymphoma and diffuse large B-cell lymphoma.

Applicability of 2008 World Health Organization classification system of hematolymphoid neoplasms: Learning experiences.

BACKGROUND: 2008 World Health Organization (WHO) classification of hematolymphoid neoplasms (HLN) has classified them based on morphology, results of various ancillary techniques, and clinical features.[1] There are no studies looking at the applicability of WHO classification. AIMS: The aim of the study was to calculate proportions of all HLN subtypes seen during 1-year period based on 2008 WHO classification of HLN and study applicability and also shortcomings of practices in a tertiary care center in India. MATERIALS AND METHODS: This was a 1-year retrospective study (January 1st, to December 31st, 2010) where cases were identified using hospital/laboratory electronic records. Old follow-up and referral cases were excluded from the study. Only newly diagnosed cases classified into categories laid down by 2008 WHO classification of HLN included. RESULTS: Out of 2118 newly diagnosed classifiable cases, 1602 (75.6%) cases were of lymphoid neoplasms, 489 (23.1%) cases of myeloid neoplasms, 16 (0.8%) cases of histiocytic and dendritic cell neoplasms, and 11 (0.5%) cases of acute leukemias of ambiguous lineage. Overall, most common HLN subtype was diffuse large B-cell lymphoma (n = 361, 17.0%). Precursor B-lymphoblastic leukaemia/lymphoma (n = 177, 48.2%) was the most common subtype within pediatric age group. CONCLUSIONS: All major subtypes of HLN were seen at our center and showed trends almost similar to those seen in other Indian studies. Molecular/cytogenetic studies could not be performed on a significant number of cases owing to logistic reasons (unavailability of complete panels and also cost-related issues) and such cases could not be classified as per the WHO classification system.

Linfoma primario difuso de células B grandes de mucosa gingival, en paciente VIH y EBV negativos / Primary gingival diffuse large b-cell lymphoma in HIV/EBR negative patient abstract

El linfoma difuso de células B grandes (LDCBG) es el linfoma más frecuente. La presentación clínica puede ser nodal o extranodal y sus síntomas dependen de la localización tumoral; en la mayoría de los casos están asociados a algún tipo de inmunodeficiencia. Referiremos un caso de LDCBG de presentación atípica en una localización muy infrecuente. Es importante tener en cuenta estas situaciones, ya que pueden simular otros procesos patológicos, retrasando así su correcto diagnóstico y por lo tanto un adecuado tratamiento. (AU)

Diffuse large cell lymphoma B (LDCBG) is the most common type of lymphoma. It´s clinical presentation can be nodal or extranodal and it's symptoms depend where the tumor is located and whether is associated or not with an immunodeficiency disease. We present an atypical presentation of a LDCBG in a very unusual location. It´s important to consider these kind of appearance, as they can mimic other oral pathological processes, delaying their correct diagnosis and therefore an appropriate treatment. (AU)

Features based on the percolation theory for quantification of non-Hodgkin lymphomas.

Non-Hodgkin lymphomas are a health problem that affects over 70,000 people per year in the United States alone. The early diagnosis and the identification of this lymphoma are essential for an effective treatment. The classification of non-Hodgkin lymphomas is a task that continues to rank as one of the main challenges faced by hematologists, pathologists, as well as in the producing of computer vision methods due to its inherent complexity. In this paper, we present a new method to quantify and classify tissue samples of non-Hodgkin lymphomas based on the percolation theory. The method consists of associating multiscale and multidimensional approaches in order to divide the image into smaller regions and then verifying color similarity between pixels. A cluster labeling algorithm was applied to each region of interest to obtain the values for the number of clusters, occurrence of percolation and coverage ratio of the largest cluster. The method was tested on different classifiers aiming to differentiate three different groups of non-Hodgkin lymphomas. The obtained results (AUC rates between 0.940 and 0.993) were compared to those provided by methods consolidated in the Literature, which indicates that the percolation theory is a suitable approach for identifying these three classes of non-Hodgkin lymphomas, those being: mantle cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia.