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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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved.)

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.

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.

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 20 th 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.

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.

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.

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.

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.

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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (© 2018 by The American Society of Hematology.)

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., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: We have read and understood the BMJ Group policy on declaration of interests and declare the following: DJH has received funding from Gilead Sciences for research on tumour biology and preclinical models of non-Hodgkin lymphoma.

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.

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 1 st , to December 31 st , 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., Competing Interests: There are no conflicts of interest

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Primary cutaneous lymphoma (PCL) is the second most common type of extranodal non-Hodgkin lymphoma, including both cutaneous T-cell and B-cell lymphomas. PCL comprises numerous subtypes and thus has myriad clinical presentations in the skin and subcutaneous tissues. Accurate classification and staging are important for making treatment recommendations for PCL and will further impact patient prognosis significantly. We review the role of fluorine-18-fluorodeoxyglucose (F-FDG) PET (F-FDG PET) and F-FDG PET with computed tomography (CT) in the diagnosis, staging, tumor biological evaluation, treatment response assessment, and early recurrence surveillance of PCL. Although F-FDG PET and PET/CT do not seem to adequately distinguish the plaque, patch, or erythroderma cutaneous lesions of PCL, the imaging modalities are superior to CT, MRI, and other nuclear medicine methods in detecting both the cutaneous and the extracutaneous lesions of PCL. The available literature addressing the clinical role of F-FDG PET and PET/CT in patients with PCL is promising for the use of the modalities in staging, tumor biological evaluation, biopsy guidance, early treatment response assessment, and recurrence surveillance. However, more data are needed to better specify the role of F-FDG PET and PET/CT in the management of PCL.

The distribution of non-Hodgkin lymphoma subtypes varies around the world, but a large systematic comparative study has never been done. In this study, we evaluated the clinical features and relative frequencies of non-Hodgkin lymphoma subtypes in five developing regions of the world and compared the findings to the developed world. Five expert hematopathologists classified 4848 consecutive cases of lymphoma from 26 centers in 24 countries using the World Health Organization classification, and 4539 (93.6%) were confirmed to be non-Hodgkin lymphoma, with a significantly greater number of males than females in the developing regions compared to the developed world (P<0.05). The median age at diagnosis was significantly lower for both low- and high-grade B-cell lymphoma in the developing regions. The developing regions had a significantly lower frequency of B-cell lymphoma (86.6%) and a higher frequency of T- and natural killer-cell lymphoma (13.4%) compared to the developed world (90.7% and 9.3%, respectively). Also, the developing regions had significantly more cases of high-grade B-cell lymphoma (59.6%) and fewer cases of low-grade B-cell lymphoma (22.7%) compared to the developed world (39.2% and 32.7%, respectively). Among the B-cell lymphomas, diffuse large B-cell lymphoma was the most common subtype (42.5%) in the developing regions. Burkitt lymphoma (2.2%), precursor B- and T-lymphoblastic leukemia/lymphoma (1.1% and 2.9%, respectively) and extranodal natural killer/T-cell lymphoma (2.2%) were also significantly increased in the developing regions. These findings suggest that differences in etiologic and host risk factors are likely responsible, and more detailed epidemiological studies are needed to better understand these differences., (Copyright© Ferrata Storti Foundation.)

Background: Histologically, follicular lymphoma (FL) grades 1, 2 and 3A are composed of two distinct cell types, centroblasts and centrocytes. FL grade 3B is composed only of centroblasts and has been shown to differ in immunophenotype and genetics from FL that contain centrocytes. We aimed to understand the pathogenetic and clinical relation between FL grade 3A to FL grade 1/2 on the one hand and FL grade 3B on the other hand., Patients and Methods: Trial patients with long-term follow-up and diagnosis of FL grade 3 were selected and samples underwent a second central pathological review using a multiple-observer approach to assess grading., Results: Interobserver variability for diagnosing FL grade 3 was high. FL grade 3A frequently harbored areas of FL grade 1/2 within the same tissue specimen. FL grade 3B rarely coexisted with grade 1/2 or 3A, suggesting divergent pathogenesis. There was no statistically significant difference in outcome between 47 cases of FL grade 3A and 14 cases of grade 3B. Compared with grade 1/2 FL, both groups showed longer progression-free survival without late events, especially after immunochemotherapy; this outcome difference was retained after adjustment for clinical prognostic factors. The subgroup of FL grade 3A with an additional FL grade 1/2 component or a translocation t(14;18) showed a poorer outcome. In contrast, the FL grade 3A lacking t(14;18) and of localized stage resembled the pediatric type of FL and showed a very good outcome. FL3 with MYC breaks showed a poor outcome., Conclusions: The results suggest that first-line immunochemotherapy might allow long-lasting remissions in a subgroup of FL grade 3A similar to diffuse large B-cell lymphoma. Within FL3A, prognostic subgroups can be identified by analyzing for coexisting FL1/2 and MYC breaks., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Non-Hodgkin lymphoma (NHL) is the third most common malignancy in children, adolescents and young adults (CAYA). NHL is a diverse set of diseases that arise at key regulatory checkpoints during B or T cell development in the bone marrow, germinal centre or thymus. While advances in the use of conventional cytotoxic agents have led to dramatic improvements in survival, these cures are associated with significant acute and long-term toxicities. Moreover, the prognosis for CAYA patients with relapsed or refractory NHL remains dismal, with the vast majority dying of their disease. Thanks to a large number of candidate-based biological studies, together with large-scale sequencing efforts, there has been an explosion of knowledge regarding the molecular pathophysiology of B- and T-NHL. This has ushered development of a flurry of novel therapeutic approaches that may simultaneously provide new hope for relapsed patients and an opportunity to reduce the therapeutic burden in newly diagnosed CAYA. Here we review a selection of the most promising new therapeutic approaches to these diseases. While the vast majority of these agents are untested in children, on-going work from many cooperative groups will soon explore their use in paediatric disease, in hope of further improving outcomes while maximizing quality of life., (© 2016 John Wiley & Sons Ltd.)

Background & Objectives: The PAX5, a paired box transcription factor and B-cell activator protein (BSAP), activates B-cell commitment genes and represses non-B-cell lineage genes. About 14 transcript variants of PAX5 have been observed in human. Any alteration in its expression pattern leads to lymphogenesis or associated diseases and carcinogenesis in non-lymphoid tissues. Its mechanisms of function in pathophysiology of non-Hodgkin's lymphoma (NHL) are unclear. This study was intended to explore influence of PAX5 in cascade of NHL pathogenesis and diagnosis., Methods: Samples of 65 patients were evaluated by immunohistochemical staining for cellular localization of PAX5, CD19, CD3, cABL, p53, Ras and Raf and by TUNEL assay, RNA-isolation and reverse transcriptase (RT)-PCR, w0 estern blot analysis, and lactate dehydrogenase (LDH) specific staining., Results: B-cell type NHL patients were positive for PAX5, p53, Ras, CD19, Raf and CD3. All of them showed TUNEL-positive cells. The differential expression pattern of PAX5, CD19, p53, CD3, Zap700 , HIF 1α, Ras, Raf and MAPK (mitogen-activated protein kinase) at the levels of transcripts and proteins was observed. The LDH assay showed modulation of LDH4 and LDH5 isoforms in the lymph nodes of NHL patients., Interpretation & Conclusions: The histological observations suggested that the patients represent diverse cases of NHL like mature B-cell type, mature T-cell type and high grade diffuse B-cell type NHL. The findings indicate that patients with NHL may also be analyzed for status of PAX5, CD19 and ZAP70, and their transcriptional and post-translational variants for the differential diagnosis of NHL and therapy., Competing Interests: None.

The recent application of next-generation sequencing technologies lead to significant improvements in our understanding of genetic underpinnings of non-Hodgkin lymphomas with identification of an unexpectedly high number of novel mutation targets across the different B-cell lymphoma entities. These recently discovered molecular lesions are expected to have a major impact on development of novel biomarkers and targeted therapies as well as patient stratification based on the underlying genetic profile. This review will cover the major discoveries in B-cell lymphomas using next-generation sequencing technologies over the last few years, highlighting alterations associated with relapse and progression of these diseases.

Objective: To analyze the frequencies of histological types of lymphoma, diagnosed with complete immunohistochemical profile in younger and older age group., Study Design: Cross-sectional analytical study., Place and Duration of Study: Dow Diagnostic Research and Reference Laboratory, Dow University of Health Sciences, Karachi, from January 2009 to September 2013., Methodology: Consecutive cases of lymphomas, which were diagnosed using immunohistochemistry, were analyzed according to WHO classification. Frequency and percentages for different types of lymphomas were calculated. Hodgkin and non-Hodgkin lymphomas characteristics in two age groups of less than and more than 40 years were compared, applying chi-square test., Results: Out of the 318 cases, 79 (25%) were Hodgkin Lymphomas (HL) and 239 (75%) were Non-Hodgkin Lymphomas (NHL). Mixed Cellularity Hodgkin Lymphoma (MCHL) was the commonest (n=48). Amongst the NHL, 215 (89.95%) were B cell lymphomas and 24 (10.05%) were T-cell lymphomas. Diffuse Large B-Cell Lymphoma (DLBCL) was the commonest lymphoma (n=165, 69.95% of NHL). Anaplastic T-Cell Lymphoma (ALCL, n=10) was the commonest T-cell lymphoma. The frequency of HLwas significantly higher in the younger age group and that of NHLwas higher in the older age group (p < 0.001). Primary lymph node involvement was reported in 175 (55%) and cervical lymph node was the most frequent site. Extra nodal involvement was seen in 93 (29%) of all cases and was reported in 87 (36.4%) of NHLand 6 (7.5%) of HL. The most common extra nodal site was the gastrointestinal tract., Conclusion: Hodgkin lymphoma comprises 25% and non-Hodgkin lymphoma comprises 75% of all lymphomas. Both occur in younger age groups than reported in the West. B-cell NHLis three times more common than T-cell lymphoma. DLBCLis the most frequent lymphoma. ALCLis the most common T-cell, and mixed cellularity is the most common Hodgkin lymphoma.

Objective: To explore the clinical values of detecting immunophenotype and analyzing DNA ploid by flow cytometry for patients with non-Hogkin's lymphoma (NHL)., Methods: Eighty NHL patients admitted in our hospital from August 2007 years to March 2015 Years were included in the observation group, 20 patients with reactive lymphoid hyperplasias were selectod as control group. The immunophenotypes were detected and the DNA ploid was analyzed by flow cytometry., Results: The detected rate of DNA aneuploidy, DAN index (DI) and SPF in observation group were higher than those in control group, there was signifificant difference (P < 0.05). The SPF and DI in patients with NHL-I, NHL-II had no statistical difference as compared with that in control group (P > 0.05); but the SPF and DI in pateints with NHL-III and patients with NHL-IV showed statistical significance as compared with that in control group (P < 0.05). The SPF and DI in patients with low malignancy group and middle malignancy group showed statistical significance as compared with control group (P < 0.05). The SPF and DI in middle malignancy group had statistical significance as compared with that in low malignancy group (P < 0.05)., Conclusion: the immunophenotype detection and DNA ploid analysis by flow cytometry can reflect the tumor proliferation and deterioration of patients with Non-Hogkin's lymphoma, predicting the prognosis.

Background: In 2008, non-Hodgkin lymphoma ranked tenth among other malignancies worldwide with an incidence of around 5 cases per 100,000 in both genders. The latest available rates in Tunisia are from 2006., Materials and Methods: This study aimed to provide an update about NHL incidence for 2009 and its trend between 1998 and 2009 as well as a projection until 2024, using data from the Salah Azaiz Institute hospital registry and the Noth Tunisia cancer registry., Results: In 2009, the NHL incidence in the north of Tunisia was 4.03 cases per 100,000, 4.97 for men and 3.10 for women. Diffuse large B-cell lymphoma (DLBCL) accounted for 63.2% of all NHL subtypes. Between 1998 and 2009, the overall trend showed no significant change. When we compared the trend between two periods (1998-2005 and 2005-2009), joinpoint regression showed a significant decrease of NHL incidence in the first period with an annual percentage change (APC) of -6.7% (95% CI:[-11.2%;-2%]), then the incidence significantly increased from 2005 to 2009 with an APC of 30.5% (95% CI: [16.1%; 46.6%]. The analyses of the different subtype trends showed a significant decrease in DLBCL incidence between 1998 and 2000 (APC:-21.5; 95% CI: [-31.4%;-10.2%]) then the incidence significantly increased between 2004 and 2007 (APC: 18.5; 95% CI: [3,6%;35.5%]). Joint point analysis of the age-period-cohort model projection showed a significant increase between 2002 and 2024 with an APC of 4.5% (%95 CI: [1.5%; 7.5%]). The estimated ASR for 2024 was 4.55/100 000 (95% CI: [3.37; 6.15])., Conclusions: This study revealed an overall steady trend in the incidence of NHL in northern Tunisia between 1998 and 2009. Projection showed an increase in the incidence in NHL in both genders which draw the attention to the national and worldwide burden of this malignancy.

Large and systematic studies of non-Hodgkin lymphoma (NHL) in the Far East (FE) with good comparative data are scarce in the literature. In this study, five expert hematopathologists classified 730 consecutive cases of newly-diagnosed NHL from four sites in the FE (excluding Japan) using the World Health Organization classification. The results were compared to 399 cases from North America (NA). We found a significantly higher male to female ratio in the FE compared to NA (1.7 versus 1.1; p < 0.05). The median ages of patients with low-grade (LG) and high-grade (HG) B-NHL in the FE (58 and 51 years, respectively) were significantly lower than in NA (64 and 68 years, respectively). The FE had a significantly lower relative frequency of B-NHL and a higher frequency of T-NHL (82 vs. 18 %) compared to NA (90.5 vs. 9.5 %). Among mature B cell lymphomas, the FE had a significantly higher relative frequency of HG B-NHL (54.8 %) and a lower frequency of LG B-NHL (27.2 %) than NA (34.3 and 56.1 %, respectively). Diffuse large B cell lymphoma was more common in the FE (49.4 %) compared to NA (29.3 %), whereas the relative frequency of follicular lymphoma was lower in the FE (9.4 %) compared to NA (33.6 %). Among T-NHL, nasal NK/T cell NHL was more frequent in the FE (5.2 %) compared to NA (0 %). Peripheral T cell lymphoma was also more common in the FE (9.1 %) than in NA (5.3 %). Further epidemiologic studies are needed to better understand the pathobiology of these differences.

Objective: To evaluate the feasibility of conducting a collaborative study and efficacy of lymphoblastic non-Hodgkin's lymphoma (LBL) treatment protocols in children with LBL in China retrospectively and to explore the clinical and prognostic features as well as treatment response of LBL, in order to better regulate the treatment for further improving the prognosis., Method: Seven tertiary referral centers for childhood cancer actively participated in this study. Shanghai Children's Medical Center (SCMC) 2007, SCMC-2011 and NHL-2010 protocols of treatment were modified based on BFM-90/95 regimen originated from Germany. SCMC-2007 and SCMC-2011 were used in Shanghai Children's Medical Center and NHL-2010 was used in other centers. Uniform data collection forms were sent out to all the centers and collected back via e-mail. The clinical data were then analyzed with primary focus on clinical presentations, and laboratory findings. Kaplan-Meier method was used to compare the survival rates between groups, while multiple factors logistic regression was used to identify the prognostic/relapse factors., Result: (1) A total of 96 patients were recruited. The median age at diagnosis was 8.6 (1.1-16.2) years. The male-to-female ratio was 3.2:1. (2) The immunophenotype was T-cell LBL in 77 patients (80%) and precursor B-cell LBL in 19 patients (20%), respectively. According to St. Jude staging classification, 6 patients (6%) were divided into stage I, 6 patients (6%) into stage II, 51 patients (53%) into stage III, 32 patients (33%) into stage IV and 1 patient with isolated bone involvement. (3) With a median follow up of 21 months (0.3-60.7 months), the 2-year overall survival (OS) rates and event-free survival (EFS) rates were (89±3)% and (68±5)%, respectively, and the 5-year probability of OS and EFS were (88±4)% and (64±6)%, respectively in all patients. Out of all, 23 patients received SCMC-2007 protocol, 15 patients received SCMC-2011 protocol and 58 patients received NHL-2010 protocol. The 2-year OS and EFS were (91±6)% and (70±10)% in SCMC-2007 study, 100% and (92±8)% in SCMC-2011 study, (83±6)% and (72±6)% in NHL-2010 study, respectively. For patients with complete response on day 33, the 2-year EFS was (77±6)% compared with (17±10)% for patients with incomplete response (P<0.005). (4) In 13 patients (20%) the disease relapsed. The median relapse time range was 8 months (1-31 months). Six patients suffered from progressive disease. Logistic regression analysis showed that incomplete response on days 33 was an independent unfavorable prognostic factor (OR=4.138, P=0.035)., Conclusion: Despite the apparent existence of gap between China and International states in the diagnostic and treatment approaches towards childhood LBL in China, with implementation of further modification of treatment protocols to strengthen cooperation between domestic tertiary centers, the long-term survival rate and reduction of recurrence of childhood LBL in China can be markedly improved.

The distribution of non-Hodgkin lymphoma (NHL) subtypes varies around the world, but a systematic study of South-eastern Europe (SEEU) has never been done. Therefore, we evaluated the relative frequencies of NHL subtypes in three SEEU countries--Croatia, Romania and Macedonia. Five expert haematopathologists reviewed 632 consecutive cases of newly diagnosed NHL from the three SEEU countries using the World Health Organization classification. The results were compared to 399 cases from North America (NA) and 580 cases from Western Europe (WEU). The proportions of B- and T-cell NHL and the sex distribution in SEEU were similar to WEU and NA. However, the median ages of patients with low- and high-grade B-NHL in SEEU (60 and 59 years, respectively) were significantly lower than in NA (64 and 68 years, respectively; P < 0·05). SEEU had a significantly lower proportion of low-grade B-NHL (46·6%) and higher proportion of high-grade B-NHL (44·5%) compared to both WEU (54·5% and 36·4%, respectively) and NA (56·1% and 34·3%, respectively). There were no significant differences in the relative frequencies of T-NHL subtypes. This study provides new insights into differences in the relative frequencies of NHL subtypes in different geographic regions. Epidemiological studies are needed to better characterize and explain these differences., (© 2015 John Wiley & Sons Ltd.)

Bone marrow infiltration (BMI), categorized as an extra-nodal site, affects stage and is associated with poor prognosis in newly diagnosed lymphoma patients. We have evaluated the accuracy of PET/CT and bone marrow biopsy (BMB) to assess BMI in 372 lymphoma patients [140 Hodgkin Lymphoma (HL) and 232 High Grade B-cell non-Hodgkin Lymphoma (HG B-NHL), among them 155 Diffuse Large B-Cell Lymphoma (DLCL)]. For HL cases, and taking into account PET/CT, sensitivity, negative predictive value (NPV) and accuracy were 96.7, 99.3, and 99.3% while those of BMB were 32.3, 83.8, and 85%, respectively. For HG B-NHL and considering PET/CT, sensitivity, NPV, and accuracy were 52.7, 81.7, and 84.1%, while those of BMB were 77.6, 90.2, and 90.7%, respectively. In the HG B-NHL group, 25 patients would have been under-staged without BMB. These results lead us to recommend PET/CT and the avoidance of BMB to assess BMI in HL. In the case of HG B-NHL, bone marrow status should be assessed firstly by means of PET/CT; only in either focal or diffuse PET/CT with low borderline SUV max values or in negative cases, should BMB be carried out afterwards. In the HG B-NHL setting and at the present moment, both techniques are complementary., (© 2015 Wiley Periodicals, Inc.)

Background: Non-Hodgkin lymphoma (NHL), the most common cancer of the lymphatic system, is of unknown etiology. The identification of etiologic factors in the onset of NHL is a key event that could facilitate the prevention and cure of this malignancy. Simian virus 40 (SV40) has been considered an oncogenic agent in the onset/progression of NHL., Methods: In this study, an indirect enzyme-linked immunosorbent assay with 2 synthetic peptides that mimic SV40 antigens of viral capsid proteins 1 to 3 was employed to detect specific antibodies against SV40. Serum samples were taken from 2 distinct cohorts of NHL-affected patients (NHL1 [n = 89] and NHL2 [n = 61]) along with controls represented by oncologic patients affected by breast cancer (BC; n = 78) and undifferentiated nasopharyngeal carcinoma (UNPC; n = 64) and 3 different cohorts of healthy subjects (HSs; HS1 [n = 130], HS2 [n = 83], and HS3 [n = 87])., Results: Immunologic data indicated that in serum samples from NHL patients, antibodies against SV40 mimotopes were detectable with a prevalence of 40% in NHL1 patients and with a prevalence of 43% in NHL2 patients. In HSs of the same median age as NHL patients, the prevalence was 16% for the HS1 group (57 years) and 14% for the HS2 group (65 years). The difference was statistically significant (P < .0001 and P < .001). Interestingly, the difference between NHL1/NHL2 patients and BC patients (40%/43% vs 15%, P < .001) and between NHL1/NHL2 patients and UNPC patients (40%/43% vs 25%, P < .05) was significant., Conclusions: Our data indicate a strong association between NHL and SV40 and thus a need for innovative therapeutic approaches for this hematologic malignancy., (© 2015 American Cancer Society.)

The relative distribution of non-Hodgkin lymphoma (NHL) subtypes differs markedly around the world. The aim of this study was to report this distribution in Algeria. A panel of four hematopathologists classified 197 consecutive cases according to the World Health Organization classification, including 87.3% B-cell and 12.7% T- or natural killer (NK)-cell NHLs. This series was compared with similar cohorts from Western Europe (WEU) and North America (NA). Algeria had a significantly higher frequency of diffuse large B-cell lymphoma (DLBCL: 52.8%) and a lower frequency of follicular lymphoma (FL: 13.2%) compared with WEU (DLBCL: 32.2%; FL: 20.0%) and NA (DLBCL: 29.3%; FL: 33.6%). The frequency of mantle cell lymphoma was lower in Algeria (2.5%) compared with WEU (8.3%). Smaller differences were also found among the NK/T-cell lymphomas. In conclusion, we found important differences between Algeria and Western countries, and further epidemiologic studies are needed to explain these differences.

Non Hodgkin's lymphomas (NHL) constitute a heterogeneous group of neoplasm of the lymphoid system. There are many histological subtype of NHL based on WHO classification of hematopoietic and lymphoid neoplasm. This cross-sectional study was carried out in the department of Pathology, Dhaka Medical College, Dhaka from January 2009 to December 2010 to observe the different subtypes of NHL using immunohistochemistry (IHC) with CD3. A total of 50 microscopically diagnosed case of NHL irrespective of age and sex were included in the study. The diagnostic morphologic criteria of each lymphoma subcategory were compiled and diagnosis was made. Mean age of the study subjects were 42.0±19.7 years with range 3-75 years and male female ratio was 1.8:1. Nodal NHL was 66% and extranodal cases were 34%. Maximum number of histolgic subtypes belonged to diffuse large B-cell lymphoma (DLBCL) and male was predominant in all histological subtypes, except peripheral T-cell lymphoma (PTCL). DLBCL was predominant in all B-cell NHL whereas PTCL was predominant in all T-cell NHL. The most childhood patients belonged to lymphoblastic lymphoma. Regarding cell lineage B-cell NHL was more common than T-cell NHL (88% vs. 12%), but high grade pattern was more predominant in T-cell type (83.3% vs. 65.9%). Among 50 study subjects histological (H & E) diagnosis reveals 46 cases as B-cell NHL and 4 as T-cell NHL but IHC confirms 6 cases as T-cell NHL.

While remission and cure rates for Hodgkin and non-Hodgkin lymphoma continue to improve, surveillance approaches remain controversial, especially in light of recent reports suggesting limited benefit for routine radiologic assessment. Routine cross-sectional imaging results in considerable patient expense and anxiety, and this approach does not clearly improve patient outcomes. Next-generation approaches including minimal residual disease detection may provide an opportunity to identify relapse early and intervene prior to progression of clinical disease. This review discusses the role of surveillance imaging in Hodgkin and non-Hodgkin lymphoma and provides an introduction to serologic assessment of minimal residual disease. Future studies will need to focus on the clinical application of minimal residual disease surveillance and its ability to predict relapse, treatment response and survival.

The Wilms tumor 1 (WT1) gene has a complex role as a transcriptional regulator, acting as tumor suppressor or oncogene in different malignancies. The prognostic role of its overexpression has been well-studied in leukemias, especially acute myeloid leukemia (AML), but not in lymphomas. For the first time to our knowledge, we present a study demonstrating the correlation of WT1 expression and survival in various non-Hodgkin lymphomas. We also studied the prognostic implications of WT1 overexpression in adult acute lymphoblastic leukemia (ALL). In our sample of 53 patients--25 with diffuse large B-cell lymphoma (DLBCL), 8 with mantle cell lymphoma (MCL), 9 with peripheral T-cell lymphoma (PTCL), 2 with Burkitt's lymphoma, 2 with mucosa-associated lymphoid tissue (MALT) lymphoma, and 7 with B-cell ALL--, we measured WT1 mRNA from blood samples by quantitative RT-PCR, and divided the patients into subgroups based on the level of expression. Kaplan-Meier survival curves were drawn and compared using the logrank test. In the sample of DLBCL patients, the difference in overall and disease-free survival between WT1-positive and negative subgroups was significant (p = 0.0475 and p = 0.0004, respectively), and in a few observed cases, a sudden increase in WT1 expression signified a relapse soon followed by death. Disease-free survival curves in MCL and ALL were similarly suggestive of a potential role played by WT1. In PTCL, though WT1-positivity was detected in 4 out of 9 cases, it did not seem to affect survival. The few cases of MALT and Burkitt's lymphoma all proved to be WT1-negative.

Non-Hodgkin lymphomas of childhood represent a diverse group of neoplasms with different clinical, pathological, immunophenotypical and genetic features. A vast majority of childhood non-Hodgkin lymphomas could be classified into one of the three major histological subgroups: mature B-cell neoplasms, lymphoblastic lymphomas or anaplastic large cell lymphomas. Modern therapeutic strategies lead to cure in more than 80% of patients. Conversely, refractory diseases, as well as disease relapse convey a dismal prognosis. This fact requires much better stratification based on prognostic markers which would ideally recognize distinct groups of patients requiring different therapeutic regimens. Defining novel diagnostic and prognostic markers should improve diagnosis and prognosis as well as patient follow-up. It should also allow introduction of individually tailored treatment regimens in selected groups of patients with non-Hodgkin lymphomas, with the main goal of improving treatment results and decreasing short- and long-term complications.

Introduction: Non-Hodgkin's lymphomas (NHLs) are heterogeneous group of malignant lymphoproliferative disorders., Study Objectives: This was a retrospective study aimed to classify NHLs into B cell and T cell types; in addition to demonstrate the histological patterns and correlate it with gender, age and site of the biopsy., Methods: The study was conducted in Histopathology Department, National Heath Laboratory, during the period 2007-2010. Formalin fixed paraffin wax embedded tissue blocks which were diagnosed as NHLs by routine Haematoxylin and Eosin (H&E) stain during the period 2000-2008 were used. Haematoxylin and Eosin (H&E) stain were done. Immunohistochemistry stains performed according to Dako cytomation protocol 2007. Lymphoid markers which were used in this study are CD45 (LCA), CD20 (B cell marker), CD3 (T cell marker), CD15 and CD 30. Epithelial marker which was used is CK MNF116. The total number of samples collected was 66; two of them were excluded because of poor processing. Another two specimens were excluded because they are non-reactive with lymphoid markers. The remaining 62 specimens were confirmed to be NHLs and classified into B cell and T cell types., Results: The study showed that B cell NHLs represented 87.1% while T cell NHLs were 12.9%. The Male: Female ratio was 1.6:1. The major affected age group was (47-67) years (38.1% of all specimens). The most frequent histological grade was intermediate grade NHLs (27% of all specimens). The most common site of NHLs in this study is the lymph node (40% of all specimens) followed by stomach (19.4%)., Conclusion: Extranodal locations are the most common sites affected with T cell NHLs. In conclusion; this study confirmed the fundamental role of immunohistochemistry in diagnosis and classification of NHLs.

Background: Malignant lymphoma (ML) is one of the most common cancers and is most prevalent in developed countries. The distribution of different subtypes of ML varies in the different geographical locations according to World Health Organization (WHO) classification., Aims and Objectives: The study was aimed to analyze different patterns of ML in Eastern India and to compare it with other geographical locations., Materials and Methods: Four hundred and fifty five patients of two large hospitals in Eastern India were included over a period of four years and were categorized according to WHO classification, using morphology and immunohistochemistry (IHC)., Results: There were 347 (76.3%) non Hodgkin lymphomas (NHL), and 108 (23.7%) Hodgkin lymphomas (HL). Diffuse large B cell lymphoma (DLBCL) was the most common of the NHL type (35.2%) followed by the follicular lymphoma (19.3%). B cell lymphoblastic lymphoma was the least common type of NHL (1.4%). Mixed cellularity (33.3%) and nodular sclerosis (26.9%) were the two most common type of HL. Childhood lymphoma comprised of 12.5% of all ML. T cell NHL and HL were the common lymphomas in this age group., Conclusion: Incidence of follicular lymphoma is lower compared to western studies and mixed cellularity is most common subtype of HL unlike nodular sclerosis subtype in western world. Burkitt's type NHL though is the most common subtype of childhood ML in many studies but in our study T cell NHL is the most common type of childhood ML.

Objective: To compare the TNM and Ann Arbor staging systems in predicting outcome in ocular adnexal lymphoma (OAL)., Methods: Retrospective review of the clinical, imaging and histopathologic records of OALs between 1986 and 2009. Outcome measures included local recurrence and progression., Results: One hundred and sixty patients of OAL were included. Mean age was 65 ± 15 years (range 20-97) and 68 (43%) were male. The median follow-up of all OAL patients was 65 months (range 2.5-238). Histopathology identified low-grade, indolent B-cell lymphomas in 140 patients (87.5%) and rest had aggressive grades. Of 134 indolent OAL patients, those with unilateral disease had a 10-year progression free survival of 72% versus 48% in their bilateral counterparts (p = 0.001). Amongst unilateral OAL patients staged within the T1-2 group, a significantly better outcome was noted for patients without nodal or metastatic involvement compared to those with such involvement (p = 0.0001). The above observations helped to formulate a simple scoring system to prognosticate OALs based on their laterality and node/metastatic status. Amongst the 3 groups identified, group 1 with a score of 0 (unilateral OALs with no nodes or metastasis) had a 10-year progression free survival of 75%; group 2 with score 1 (either bilateral or positive nodes/metastasis) 50% and group 3 with score 2 (both bilateral OAL with positive nodes/metastasis) zero at 10 years (p < 0.00001)., Conclusions: The TNM-based staging system better predicts outcome in OAL than the Ann Arbor system primarily by delineation of bilateral disease and nodal/metastatic involvement at presentation.

Background: Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk., Methods: To refine the genetic association of CLL risk, we conducted Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then conducted fine mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1,521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes., Results: The strongest association with CLL risk was observed with a common single-nucleotide polymorphism (SNP) located within the 3' untranslated region (UTR) of IRF8 (rs1044873, log additive OR = 0.7, P = 1.81 × 10(-6)). This SNP was not associated with the other NHL subtypes (all P > 0.05)., Conclusions: We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology., Impact: These data provide support that a functional variant within the 3'UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.

A retrospective analysis of 1,792 solid tissues suggestive of lymphoma, submitted over a 12-year period, was carried out and flow cytometry (FC) results were compared with histologic findings. The final histologic diagnosis of cases documented in this report is as follows: 1,270 non-Hodgkin's lymphomas (NHL); 17 composite lymphomas; four NHL plus carcinomas; five post-transplant lymphoproliferative disorders; 105 Hodgkin's lymphomas (HL); eight acute leukemias; 42 tissue cancers; and 341 non-neoplastic diseases. A strong correlation between morphology and FC data was observed among hematological malignancies (1,268/1,304, 97.2%) with the exception of HL. Among B-NHL, FC detection of clonally restricted B-cell allowed the identification of lymphomas that were not histologically clear and the differential diagnosis between follicular lymphoma and reactive hyperplasia. A high correlation level (r = 0.83; P < 0.0001) was obtained in comparing proliferation results obtained by FC and immunohistochemistry. Among T-NHL, FC detection of an aberrant phenotype direct histologic diagnosis in cases having less than 20% of neoplastic cells. In nine cases, FC suggested the need to evaluate a neoplastic population, not morphologically evident. Results show that FC routinely performed on tissue samples suspected of lymphomas is a fundamental adjunct to morphology in the diagnosis of NHL and may enhance the performance of the histologic evaluation so as to achieve the final diagnosis. To the best of our knowledge, this is the first report in the literature of a wide series of tissues also studied by FC., (Copyright © 2013 International Clinical Cytometry Society.)

Lymphoma represents the most frequent hematopoietic cancer in dogs, and it shows significant overlap with the human disease. Several environmental factors have been associated with canine lymphoma, suggesting that they may contribute to lymphomagenesis. Canine lymphoma often presents in advanced stage (III-V) at diagnosis and, most commonly, has an aggressive clinical course requiring prompt treatment, which relies on the use of polychemotherapy. In this review, we will summarize the state-of-the-art of canine lymphoma epidemiology, pathobiology, diagnostic work-up and therapy, and will highlight the links to the corresponding human disease, providing evidence for the use of dog as an animal model of spontaneous disease., (Copyright © 2012 John Wiley & Sons, Ltd.)

Purpose: Non-epithelial breast neoplasms cover a large spectrum of histopathological entities. The demographics and clinical features are similar to epithelial breast lesions but the diagnosis, prognosis and management options are often very different., Methods: During 2001-2010, 1362 patients were examined at the Pathology Department of the Aretaieion General Hospital for various breast lesions. All specimens were processed routinely and slides stained with hematoxylin-eosin were re-examined. The patient clinical records were examined for demographics, clinical presentation and therapeutic approach., Results: In 23/1362 cases (1.68%) pathological examination showed non-epithelial lesions: in 12/1362 cases (0.8%) haemangiomas (11 women, one man), in 4 /1362 cases (0.3%) myofibroblastomas (MFB), in 2/1362 cases (0.1%) primary breast non-Hodgkin's lymphoma (NHL), in 3 /1362 cases (0.2%) granular cell tumor (GCT), and in 2/1362 cases (0.1%) angiosarcomas (one developed after radiotherapy for breast cancer)., Conclusions: Non-epithelial primary breast tumors are rare (1.68%) and present significant difficulty in accurate preoperative diagnosis and in certain cases in pathological diagnosis as well, which is necessary for the selection of the appropriate treatment. Avoidance of inappropriate therapies requires a multidisciplinary management approach.

Treatment of gastric marginal zone B cell lymphoma of MALT (mucosa-associated lymphoid tissue) is nowadays standardized as outlined in the German S3 guideline of 2009 and the European (EGILS) consensus report of 2011. The first choice of treatment is Helicobacter pylori eradication in any case irrespective of H. pylori status and lymphoma stage. Some 70-80% of patients reveal complete remission of MALT lymphoma following successful eradication of the bacterium. Those patients with histologically persisting lymphoma residuals are managed by a watch-and-wait strategy. Nonresponders to H. pylori eradication are referred to radiation with a curative intention in stages I and II. The rare cases of MALT lymphoma of stage III and IV should be treated by chemotherapy. Surgery no longer plays a role in the therapy of gastric MALT lymphoma except for very rare complications such as perforation or bleeding that cannot be controlled endoscopically. Diffuse large B cell lymphoma (DLBCL) is the second most common gastric lymphoma. H. pylori eradication may lead to regression of DLBCL in the individual case. However, immunochemotherapy by a combination of rituximab and the CHOP protocol represents the standard treatment approach in patients with DLBCL and offers a good curative chance., (Copyright © 2013 S. Karger AG, Basel.)

Natural killer (NK) cell neoplasms are unusual disorders. In this study we compared results of flow cytometric immunophenotype (FCI) with cytomorphology, histopathology and clinical findings in a series of patients with NK cell neoplasms with peripheral blood and/or bone marrow involvement, and the FCI of neoplastic and normal NK cells were compared. Retrospective data and specimens (bone marrow aspiration or peripheral blood) from 71 cases of NK cell neoplasms were obtained. All patients have been demonstrated laboratory and clinical features consistent with NK cell neoplasms, and the subtypes were determined by integrated clinical estimation. Routine 4-color flow cytometry (FCM) using a NK/T cell related antibody panels was performed. NK cell neoplasms were divided into two major subtypes by FCI, namely malignant NK cell lymphoma, including extranodal nasal type NK cell lymphoma (ENKL, 11 cases) and aggressive NK cell lymphoma/leukemia (ANKL, 43 cases), and relative indolent chronic lymphoproliferative disorder of NK cell (CLPD-NK, 17 cases). The former exhibited stronger CD56-expressing, larger forward scatter (FSC) and more usually CD7- and CD16-missing. FCI of CLPD-NK was similar to normal NK cells, but CD56-expressing was abnormal, which was negative in five cases and partially or dimly expressed in eight cases. Cytomorphologic abnormal cells were found on bone marrow slides of 4 cases of ENKL and 30 cases of ANKL. Eight cases of ENKL were positive in bone marrow biopsies, and other three cases were negative. In 32 cases of ANKL which bone marrow biopsies were applied, 21 cases were positive in the first biopsies. Lymphocytosis was found only in six cases of CLPD-NK by cytomorphology, and biopsy pathology was not much useful for diagnosing CLPD-NK. These results suggest that FCM analysis of bone marrow and peripheral blood was superior to cytomorphology, bone marrow biopsy, and immunohistochemistry in sensitivity and early diagnosis for ANKL, stage III/IV ENKL and CLPD-NK. FCI could not only define abnormal NK cells but also determine the malignant classification. It is beneficial for clinical management and further study of NK cell neoplasms.

The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B-cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P < .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B-cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P < .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P < .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P < .001). Extranodal NK/T-cell NHL was also more common in CSA (P < .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences.

NK/T cell lymphoma, a rare type of non-Hodgkin's lymphoma, is a highly aggressive disease with poor prognosis. Clinically, it is classified into nasal, non-nasal, and aggressive lymphoma/leukemia subtypes. They are characterized by geographic distribution and are universally associated with Epstein-Barr virus (EBV) infection. Due to its low occurrence and dismal clinical outcome, no therapeutic strategy is currently identified in this disease. Combined chemotherapy and radiotherapy have better effects for stage I/II nasal NK cell lymphoma. As for stage III/IV nasal NK cell lymphoma and non-nasal, and aggressive subtypes, chemotherapy is the main treatment method. Recently, some studies have demonstrated promising outcomes in the selected cases by high-dose chemotherapy supplemented with auto- or allo-HSCT.