A retrospective analysis of mature T-and NK-cell lymphomas

Mature T-and natural killer(NK)-cell lymphomas are heterogeneous groups of malignant lymphoid neoplasms arising from T and NK cells. The incidence of mature T-and NK-cell lymphomas is 2.1 per 100,000 people, according to a US report~1.

Nodal peripheral T-cell lymphomas in the new classification systems

Peripheral T-cell lymphomas(PTCLs)encompass a biologically diverse group of non-Hodgkin lymphomas derived from mature T-lymphocytes.Most PTCLs present as nodal diseases and include several subtypes characterized by distinct clinical and pathologic features,and will be the focus of this editorial.The PTCL group presenting as rare distinctive extranodal diseases will not be discussed.While T-cell neoplasms,like B-cell lymphomas,recapitulate stages of normal differentiation,the biology is notably intricate and exhibits remarkable plasticity.

Gene targeted and immune therapies for nodal and gastrointestinal follicular lymphomas

Follicular lymphoma(FL)is the most common indolent B-cell lymphoma(BCL)globally.Recently,its incidence has increased in Europe,the United States,and Asia,with the number of gastrointestinal FL cases expected to increase.Genetic abnormalities related to t(14;18)translocation,BCL2 overexpression,NF-κB pathway-related factors,histone acetylases,and histone methyltransferases cause FL and enhance its proliferation.Meanwhile,microRNAs are commonly used in diagnosing FL and predicting patient prognosis.Many clinical trials on novel therapeutics targeting these genetic abnormalities and immunomodulatory mechanisms have been conducted,resulting in a marked improvement in therapeutic outcomes for FL.Although developing these innovative therapeutic agents targeting specific genetic mutations and immune pathways has provided hope for curative options,FL treatment has become more complex,requiring combinatorial therapeutic regimens.However,optimal treatment combinations have not yet been achieved,highlighting the importance of a complete understanding regarding the pathogenesis of gastrointestinal FL.Accordingly,this article reviews key research on the molecular pathogenesis of nodal FL and novel therapies targeting the causative genetic mutations.Moreover,the results of clinical trials are summarized,with a particular focus on treating nodal and gastrointestinal FLs.

Endoscopic features of gastro-intestinal lymphomas: From diagnosis to follow-up

Many progresses have been done in the management of gastrointestinal(GI) lymphomas during last decades, especially after the discovery of Helicobacter pylori-dependent lymphoma development. The stepwise implementation of new endoscopic techniques, by means of echoendoscopy or double-balloon enteroscopy, enabled us to more precisely describe the endoscopic features of GI lymphomas with substantial contribution in patient management and in tailoring the treatment strategy with organ preserving approaches. In this review, we describe the recent progresses in GI lymphoma management from disease diagnosis to follow-up with a specific focus on the endoscopic presentation according to the involved site and the lymphoma subtype. Additionally, new or emerging endoscopic technologies that have an impact on the management of gastrointestinal lymphomas are reported. We here discuss the two most common subtypes of GI lymphomas: the mucosaassociated lymphoid tissue and the diffuse large B cell lymphoma. A general outline on the state-of-the-art of the disease and on the role of endoscopy in both diagnosis and follow-up will be performed.

Relationships between lymphomas linked to hepatitis C virus infection and their microenvironment

The relationships between lymphomas and their microenvironment appear to follow 3 major patterns:(1)an independent pattern;(2)a dependent pattern on deregulated interactions;and(3)a dependent pattern on regulated coexistence.Typical examples of the third pattern are hepatitis C virus(HCV)-associated marginal zone lymphomas(MZLs)and mucosa-associated lymphoid tissue lymphomas.In these lymphomas,a regulated coexistence of the malignant cells and the microenvironmental factors usually occurs.At least initially,however,tumor development and cell growth largely depend on external signals from the microenvironment,such as viral antigens,cytokines,and cell-cell interactions.The association between HCV infection and B-cell lymphomas is not completely defined,although this association has been demonstrated by epidemiological studies.MZL and diffuse large B-cell lymphoma are the histotypes most frequently associated with HCV infection.Many mechanisms have been proposed for explaining HCV-induced lymphomagenesis;antigenic stimulation by HCV seems to be fundamental in establishing B-cell expansion as observed in mixed cryoglobulinemia and in B-cell lymphomas.Recently,antiviral treatment has been proved to be effective in the treatment of HCV-associated indolent lymphomas.Importantly,clinically responses were linked to the eradication of the HCV-RNA,providing a strong argument in favor of a causative link between HCV and lymphoproliferation.

Gastrointestinal B-cell lymphomas:From understanding B-cell physiology to classification and molecular pathology

The gut is the most common extranodal site where lymphomas arise. Although all histological lymphoma types may develop in the gut, small and large B-cell lymphomas predominate. The sometimes unexpected finding of a lymphoid lesion in an endoscopic biopsy of the gut may challenge both the clinician (who is not always familiar with lymphoma pathogenesis) and the pathologist (who will often be hampered in his/her diagnostic skill by the limited amount of available tissue). Moreover, the past 2 decades have spawned an avalanche of new data that encompasses both the function of the reactive B-cell as well as the pathogenic pathways that lead to its neoplastic counterpart, the B-cell lymphoma. Therefore, this review aims to offer clinicians an overview of B-cell lymphomas in the gut, and their pertinent molecular features that have led to new insights regarding lymphomagenesis. It addresses the question as how to incorporate all presently available information on normal and neoplastic B-cell differentiation, and how this knowledge can be applied in daily clinical practice (e.g., diagnostic tools, prognostic biomarkers or therapeutic targets) to optimalise the managment of this heterogeneous group of neoplasms.

Area under the curve of methotrexate and creatinine clearance are outcome - determining factors in primary CNS lymphomas

Although high-dose methotrexate(HD-MTX)is the most effective drug against primary CNS lymphomas(PCNSL),outcome-de-termining variables related to its administration schedule have not been defined.The impact on toxicity and outcome of the area under thecurve(AUC(MTX)),dose intensity(DI(MTX))and infusion rate(IR(MTX))of MTX and plsamatic creatinine clearance(CL(crea))was investigated in a retrospective series of 45 PCNSL patients treated with three different HD-MTX-basedcombinations.Anticon-vulsants were administered in 31 pts(69%).Age>60 years,anticonvulsant therapy,slow IR(MTX)(

NUCLEOLAR ORGANIZER REGIONS IN CUTANEOUS T CELL LYMPHOMAS

The present work studied the application of AgNOR count to differential diagnosis between cutaneous T cell lymphoma (CTCL) and cutaneous pseudolymphoma (CPL). Paraffin sections from 50 mycosis fungoides (22 MFI-Premycotic stage, 24 MF Ⅰ infiltrative stage and 4 MF Ⅲ - tumor stage), 2 nonepidermotropic cutaneous T cell lymphoma (NECTCL) and 9 CPL were investigated. In each case, 200 cells randomly selected were examined using a × 100 oil immersion lens. The mean number, standard deviation and standard error of the mean of AgNOR counts were as follows: MFⅠ 1.17±0.09, SEM = 0.01; MⅡ 1.17±0.01, SEM = 0.01; MF Ⅲ. 3.55±0.87, SEM = 0.43; NECTCL 4.5±0.28, SEM -0.199; CPL 1.17±0.1, SEM ± 0.03. The results revealed a highly significant difference between CTCL (MFⅢ+NECTCL) and CPL (t = 4.75, P<0.001), tumor stage (MF Ⅲ) and pretumor stage (MFI, MF Ⅱ) of mycosis fungoides (t = 4.75, P<0.001). Thus. AgNOR count is valuable in differential diagnosis.

Role of lenalidomide in the treatment of peripheral T-cell non-Hodgkin lymphomas

T-cell lymphomas(TCLs)represent a group of lymphoid neoplasms characterized by an aggressive clinical course,even after an anthracycline-containing regimen.Novel agents for patients with relapsed/refractory TCL are urgently needed.Lenalidomide is an oral drug with immunomodulatory,antiangiogenic and direct antineoplastic effects.These peculiar mechanisms of action make TCL an attractive target for lenalidomide.We have identified five clinical trials in which lenalidomide monotherapy was investigated to treat TCL,including cutaneous TCL(CTCL)and adult T-cell lymphoma/leukemia(ATLL).In the ATLL-002 study,the overall response rate(ORR)was 42%and median progression-free survival(PFS)and overall survival were 3.8 mo and 20.3 mo,respectively.In a phase II trial for CTCL,ORR was 28%and median PFS and overall survival were 8 mo and 43 mo,respectively.For nodal peripheral TCL,ORR was between 10%and 43%in three clinical trials,with a median PFS of about 4 mo,even if some patients had a durable response.Overall toxicity is manageable and grade 3-4 events are mainly hematological and reversible.Combination strategies did not improve PFS.In conclusion,lenalidomide could represent a suitable treatment option for relapsed/refractory TCL,especially for neoplasms with a T-follicular helper origin,such as angioimmunoblastic TCL.

IMMUNOPHENOTYPING OF CUTANEOUS GERMINAL CENTER CELL-DERIVED LYMPHOMAS

Monoclonal antibodies were used to label cutaneous germinal center cell-derived lymphomas <CGCCL) obtained from 10 patients. According to the Kiel classification, they were classified into 2 types. Eight patients had centroblastic/centrocytic <CB/CC) lymphomas while 2 patients and centrocytic (CC) lymphomas. After monoclonal antibody labelling, the results were consistent with those of the clinical and morphologic analyses. Of the 10 cases, 9 were B1 positive, 6 were K positive, and 4 were λ positive. In 8 cases labeled with immunoglobulin, 6 were IgGFab positive, 2 were IgM positive and 8 were IgA negative. Five cases (CB/CC 3, CC 2) were both Bl, K and IgG positive (γ K). Four cases CB/CC were both Bl and A positive. Only one case (CB/CC) was both K and IgM positive (μ K). Two cases (CB CC) were both A and IgG positive (γ λ). The results indicate that Bl, K and A are the most important markers to phenotype cutaneous B-cell lymphomas. Our findings also show a higher percentage of y K types in CGCCL as compared with Western countries.

DETECTION OF BCL-2 GENE MAJOR BREAKPOINT REGION REARRANGEMENT IN HUMAN B-CELL LYMPHOMAS

Objective To investigate the frequency of t(14; 18) in different subtypes of B-cell lymphomas and the ability or the polymerase chain reaction(PCR) to detect this rearrangement in frozen samples. Methods 1o7 cases of B-cell lymphomas were studied uslng DNA extracted from rresh-frozen tissues. The DNA samples were amplified by PCR for bcl-2 MBR/JH. The products of bcl-2/JH rearrangement were hybridized with an internal olignucleotide probe or bcl-2 MBR. Results The rearranged bcl-2MBR/JH gene was detected in 13 of the 25(52. o% ) follicular center lymphomas, according to REAL classification: 8 of 11 (72. 7%) grade 1, 2 of 5(40. 0%) grade I, and 3 of 90 (33. 3%) grade, 17 of 82(2o. 8%) cases or difruse large B-cell lymphomas were found to have detectable bel-2 MBR/J. rearrangement- Conclusion The rrequency or bcl-2 MBR/JH rearrangement in diffuse large B-cell lymphomas is significantly lower than those in follicular center lympkomas(X2= 9. 28, P <o. oo5), suggesting that bcl2/JH rearrangements occur mainly in follicular center lymphomas. in addition, the result of reconstruction experiments suggest that amplification or bcl-2 MBR/JH rearrangements by PCR is both sensitive and specific for detection of t (14; 18 ) translocation.

Contribution of Immunohistochemistry in the Diagnosis of Lymphomas

Objective: Making the interest of using immunohistochemistry clear in addition to histological test in the diagnosis of lymphomas. Methods: This is a retrospective study from January 2011 to June 2013 involving 18 cases of lymphomas collected in the teaching hospitals of Treichville and Yopougon. Results: 1) 38.88% diagnosis of LMNH B large-cell in histology against 38.88% LDGCB with IHC. 2) 11.11% diagnosis of LMNH small cell in histology against 11.11% with IHC. 3) 5.55% diagnosis of T lymphoma in histology against 27.77% diagnosis of T lymphoma with IHC. 4) 5.55% diagnosis of follicular lymphoma in histology against 11.11% diagnosis of LF with IHC. 5) 11.11% diagnosis of Burkitt lymphoma in histology against 5.55% diagnosis of LB with IHC. 6) 5.55% diagnosis of medullary hypoplasia in histology against 5.55% diagnosis of Hodgkin’s disease. Our results confirm the contribution of immunohistochemistry in the diagnosis of lymphomas in addition to histological test. This is striking, especially as there is 27.77% of T lymphoma with immunohistochemistry against only 5.55% with histology.

Non Hodgkin Lymphomas (NHL) in the Pediatric Oncology Unit of the Gabriel TouréTeaching Hospital, Bamako Mali

Background :Non-Hodgkin lymphomas are the first childhood cancer in sub-Saharan Africa. Objective: The purpose of this study was to assess non-Hodgkin lymphomas cases in our setting. Methodology: A retrospective and descriptive study carried out in the pediatric oncology unit of the Gabriel Touré Teaching Hospital Bamako over 10 years from 1st January 2005 to 31th December 2015. Results: We exploited 274 (21.6%) cases of Non-Hodgkin Lymphoma out of 1295 cancer cases registered, the age group 6 - 10 years was the most represented (46.4%);the male sex was predominant with a sex-ratio of 1.8;digestive signs were the most common signs of discovery (44.2%) followed by maxillary swelling (42.7%);the majority of patients (52.9%) consulted between 1 and 3 months after the onset of signs;the malnutrition rate was 39.8%, of which 24.1% were severe cases and 15.7% were moderate rate. Abdominal localization was the most common (43.1%) followed by maxillofacial localization (33.9%). Almost all were Burkitt type cytology (92.7%), the majority (73.4%) were in Murphy stage III. Almost all (96%) had received chemotherapy and the modified LMB 01 protocol was widely used (62.4%). The majority of patients (85%) were chemosensitive at day 7 or after the third cyclophosphamide injection but at the end of induction only 31% were in complete remission. Gastrointestinal toxicity was the most common (37.13%) followed by hematologic toxicity 35.09 %;9.12 % of patients were lost of follow-up and 22.26% died. Tumor progression was the most common cause of death (60.66%) followed by infection (21.31%). Conclusion: In light of these findings, the late diagnosis and the poor management of NHL, as well as the limited ability to primarily treat metabolic complications, explain the high case-fatality rate, hence the important role of early diagnosis and treatment multidisciplinary.

Role of Helicobacter pylori in gastric mucosa-associated lymphoid tissue lymphomas

Mucosa-associated lymphoid tissue(MALT)lymphoma is an indolent extranodal marginal zone B-cell lymphoma,originating in acquired MALT that is induced in mucosal barriers as part of a normal adaptive immune response to a chronic immunoinflammatory stimulus,most notably chronic infection by Helicobacter pylori(H.pylori).This antigenic stimulation initially leads to lymphoid hyperplasia;the acquisition of additional genetic aberrations culminates in the activation of intracellular survival pathways,with disease progression due to proliferation and resistance to apoptosis,and the emergence of a malignant clone.There are descriptions of MALT lymphomas affecting practically every organ and system,with a marked geographic variability partially attributable to the epidemiology of the underlying risk factors;nevertheless,the digestive system(and predominantly the stomach)is the most frequently involved location,reflecting the gastrointestinal tract’s unique characteristics of contact with foreign antigens,high mucosal permeability,large extension and intrinsic lymphoid system.While early-stage gastric MALT lymphoma can frequently regress after the therapeutic reversal of the chronic immune stimulus through antibiotic eradication of H.pylori infection,the presence of immortalizing genetic abnormalities,of advanced disease or of eradication-refractoriness requires a more aggressive approach which is,presently,not consensual.The fact that MALT lymphomas are rare neoplasms,with a worldwide incidence of 1-1.5 cases per105population,per year,limits the ease of accrual of representative series of patients for robust clinical trials that could sustain informed evidence-based therapeutic decisions to optimize the quality of patient care.

Primary gastric non-Hodgkin lymphomas:Recent advances regarding disease pathogenesis and treatment

Primary gastric lymphomas(PGLs)are distinct lymphoproliferative neoplasms described as heterogeneous entities clinically and molecularly.Their main histological types are diffuse large B-cell lymphoma(DLBCL)or mucosaassociated lymphoma tissue.PGL has been one of the main fields of clinical research of our group in recent years.Although gastric DLBCLs are frequent,sufficient data to guide optimal care are scarce.Until today,a multidisciplinary approach has been applied,including chemotherapy,surgery,radiotherapy or a combination of these treatments.In this minireview article,we provide an overview of the clinical manifestations,diagnosis and staging of these diseases,along with their molecular pathogenesis and the most important related clinical published series.We then discuss the scientific gaps,perils and pitfalls that exist regarding the aforementioned studies,in parallel with the unmet need for future research and comment on the proper methodology for such retrospective studies.Aiming to fill this gap,we retrospectively evaluated the trends in clinical presentation,management and outcome among 165 patients with DLBCL PGL who were seen in our institutions in 1980-2014.The study cohort was divided into two subgroups,comparing the main 2 therapeutic options[cyclophosphamide doxorubicin vincristine prednisone(CHOP)vs rituximab-CHOP(R-CHOP)].A better outcome with immunochemotherapy(R-CHOP)was observed.In the next 2 mo,we will present the update of our study with the same basic conclusion.

Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphomas: A review

Since Isaacson and Wright first reported on the extranodal marginal zone B-cell lymphoma of the stomach in 1983,following studies have clarified many aspects of this disease.We now know that the stomach is the most affected organ by this disease,and approximately90% of gastric mucosa-associated lymphoid tissue(MALT) lymphomas are related to Helicobacter pylori(H.pylori) infection.This implies that approximately 10% of gastric MALT lymphomas occur independent of H.pylori infection.The pathogenesis of these H.pylori-negative gastric MALT lymphomas remains unclear.To date,there have been several speculations.One possibility is that genetic alterations result in nuclear factor-kappa B(NF-κB) activation.Among these alterations,t(11;18)(q21;q21) is more frequently observed in H.pylori-negative gastric MALT lymphomas,and such translocation results in the synthesis of fusion protein API2-MALT1,which causes canonical and noncanonical NF-κB activation.Another possibility is infection with bacteria other than H.pylori.This could explain why H.pylori eradication therapy can cure some proportions of H.pylori-negative gastric MALT lymphoma patients,although the bacteria responsible for MALT lymphomagenesis are yet to be defined.Recent advances in endoscopy suggest magnifying endoscopy with narrow band imaging as a useful tool for both detecting gastric MALT lymphoma lesions and judging the response to treatment.A certain proportion of H.pylori-negative gastric MALT lymphoma patients respond to eradication therapy; hence,H.pylori eradication therapy could be considered as a first-line treatment for gastric MALT lymphomas regardless of their H.pylori infection status.

Intestinal T-cell lymphomas:A retrospective analysis of 68 cases in China

AIM:To investigate the clinical features,diagnosis,treatment and prognosis of intestinal T-cell lymphomas(ITCL)by retrospective analysis.METHODS:Sixty-eight patients who were diagnosed with ITCL in case reports in the Chinese literature were compiled and reviewed.Age,gender,CD56 expression,surgical management,multifocal nature,perforation and cyclophosphamide chemotherapy were analyzed as the prognostic factors.The Kaplan-Meier method was adopted for the univariate analysis and the cumulative survival curve analysis.RESULTS:The male-to-female ratio was 1.52 to 1.The median age was 41.7 years.Twenty-seven patients had symptoms of abdominal pain or diarrhea.Thirty-six of60 patients with temperature records had high fevers at the onset of the illness.Twenty-six of 34 patients who underwent fiberoptic colonoscopy were misdiagnosed with Crohn’s disease,intestinal tuberculosis or cancer.Sixty-one patients underwent surgery.Twelve of 61 surgical patients required a second operation for anastomotic leakage or secondary perforation.The sites of lesion involvement were the jejunum(8.82%),ileum(29.41%),ileum and colon(4.41%),colon(55.88%)and appendix(1.47%).The median cumulative survival rate was 3 mo(3.00±0.48).CONCLUSION:Efforts should be made to correctly diagnose ITCL and select the proper operative approach that may reduce serious complications and create opportunities for further treatment.

Rare gastrointestinal lymphomas: the endoscopic investigation

Gastrointestinal lymphomas represent up to 10%of gastrointestinal malignancies and about one third of nonHodgkin lymphomas.The most prominent histologies are mucosa-associated lymphoid tissue lymphoma and diffuse large B-cell lymphoma.However,the gastrointestinal tract can be the site of rarer lymphoma subtypes as a primary or secondary localization.Due to their rarity and the multifaceted histology,an endoscopic classification has not been validated yet.This review aims to analyze the endoscopic presentation of rare gastrointestinal lymphomas from disease diagnosis to follow-up,according to the involved site and lymphoma subtype.Existing,new and emerging endoscopic technologies have been examined.In particular,we investigated the diagnostic,prognostic and follow-up endoscopic features of T-cell and natural killer lymphomas,lymphomatous polyposis and mantle cell lymphoma,follicular lymphoma,plasma cell related disease,gastrointestinal lymphomas in immunodeficiency and Hodgkin’s lymphoma of the gastrointestinal tract.Contrarily to more frequent gastrointestinal lymphomas,data about rare lymphomas are mostly extracted from case series and case reports.Due to the data paucity,a synergism between gastroenterologists and hematologists is required inorder to better manage the disease.Indeed,clinical and prognostic features are different from nodal and extranodal or the bone marrow(in case of plasma cell disease)counterpart.Therefore,the approach should be based on the knowledge of the peculiar behavior and natural history of disease.

Hepatitis C virus and non-Hodgkin's lymphomas:Metaanalysisof epidemiology data and therapy options

Hepatitis C virus(HCV) is a global health problem affecting a large fraction of the world's population: This virus is able to determine both hepatic and extrahepatic diseases. Mixed cryoglobulinemia, a B-cell "benign" lymphoproliferative disorders, represents the most closely related as well as the most investigated HCVrelated extrahepatic disorder. Since this virus is able to determine extrahepatic [non-Hodgkin's lymphoma(NHL)] as well as hepatic malignancies(hepatocellular carcinoma), HCV has been included among human cancer viruses. The most common histological types of HCV-associated NHL are the marginal zone, the lymphoplasmacytic and diffuse large cell lymphomas. The role of the HCV in the pathogenesis of the B-cell lymphoproliferative disorders is confirmed also by the responsiveness of the NHL to antiviral therapy. The purpose of this review is to provide an overview of the recent literature and a meta analysis of the epidemiology data, to explain the role of HCV in the development of NHL's lymphoma. Furthermore, the possibility to treat these HCV-related NHL with the antiviral therapy or with other therapeutic options, like chemotherapy, is also discussed.

Value of metabolic parameters in distinguishing primary mediastinal lymphomas from thymic epithelial tumors

Objective:A high rate of unnecessary thymectomies has been reported.This study aimed to distinguish primary mediastinal lymphomas(PMLs)from thymic epithelial tumors(TETs)by evaluating volumetric and metabolic parameters with l8F-FDG PET/CT.Methods:A total of 136 patients who were pathologically diagnosed with TETs or PMLs were enrolled,and 18F-FDG PET/CT was performed before therapy.Volumetric parameters,including the mean SUV(SUVmean),metabolic tumor volume(MTV),total lesion glycolysis(TLG),and SUVmax,were determined and compared between the 2 subtypes.The diagnostic performance of these parameters was evaluated with receiver operating characteristic(ROC)curve analysis.Results:All parameters significantly differed between patients with PMLs and TETs.Patients with lymphomas were younger and had higher SUVmean,SUVmax,TLG,and MTV values than patients with TETs.The MTV and TLG values had similar diagnostic performance.ROC analysis indicated that the areas under the curves of the SUVmean and SUVmax values performed similarly(approximately 0.76)in differentiating patients with PMLs from TETs,and both values were better than the MTV and TLG values.When age was included with the SUVmax in differentiating TETs from PMLs,the AUC was 0.91,and the sensitivity and specificity increased to 80%and 93%,respectively.Conclusions:The SUVmax and volumetric parameters of 18F-FDG PET/CT can be used to distinguish patients with PMLs versus TETs,and thus may aid in preventing unnecessary thymectomies or other invasive operations.