Testicular Diffuse Large B-cell Lymphoma Research Articles

5-Hydroxymethylation alterations in cell-free DNA reflect molecular distinctions of diffuse large B cell lymphoma at different primary sites

Background5-Hydroxymethylcytosine (5hmC), an important DNA epigenetic modification, plays a vital role in tumorigenesis, progression and prognosis in many cancers. Diffuse large B cell lymphoma (DLBCL) can involve almost any organ, but the prognosis of patients with DLBCL at different primary sites varies greatly. Previous studies have shown that 5hmC displays a tissue-specific atlas, but its role in DLBCLs at different primary sites remains unknown.ResultsWe found that primary gastric DLBCL (PG-DLBCL) and lymph node-involved DLBCL (LN-DLBCL) patients had a favorable prognosis, while primary central nervous system DLBCL (PCNS-DLBCL) patients faced the worst prognosis, followed by primary testicular DLBCL (PT-DLBCL) and primary intestinal DLBCL (PI-DLBCL) patients. Thus, we used hmC-CATCH, a bisulfite-free and cost-effective 5hmC detection technology, to first generate the 5hmC profiles from plasma cell-free DNA (cfDNA) of DLBCL patients at these five different primary sites. Specifically, we found robust cancer-associated features that could be used to distinguish healthy individuals from DLBCL patients and distinguish among different primary sites. Through functional enrichment analysis of the differentially 5hmC-enriched genes, almost all DLBCL patients were enriched in tumor-related pathways, and DLBCL patients at different primary sites had unique characteristics. Moreover, 5hmC-based biomarkers can also highly reflect clinical features.ConclusionsCollectively, we revealed the primary site differential 5hmC regions of DLBCL at different primary sites. This new strategy may help develop minimally invasive and effective methods to diagnose and determine the primary sites of DLBCL.

Primary Testicular Diffuse Large B-cell Lymphoma Presenting in a Young Adult

Primary testicular lymphoma is a rare type of extranodal non-Hodgkin lymphoma (NHL), its positive diagnosis is based on histopathological findings. Treatment modalities consist of surgical excision, chemotherapy, and radiation therapy but the accurate procedures are not standardized. The authors report a new case of primary testicular lymphoma, and we discuss its diagnostic and therapeutic aspects. Sperm cryopreservation was carried out. The patient was started on chemotherapy with cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) regime.

The Mutation of BTG2 Gene Predicts a Poor Outcome in Primary Testicular Diffuse Large B-Cell Lymphoma.

IntroductionPrimary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a rare and aggressive form of mature B-cell lymphoma commonly found in elder males, but its genetic features are poorly understood. In this study, we had performed target-sequencing of 360 lymphoma-related genes on 76 PT-DLBCL patients with a median age of 65 (33–89). Our data provide a comprehensive understanding of the landscape of mutations in a small subset of PT-DLBCL.MethodsA total of 76 PT-DLBCL patients were sequenced, and their clinical data and follow-up data were collected. The relationship between mutated genes, clinical data and prognosis and survival of PT-DLBCL patients was retrospectively analyzed by statistical software.ResultsWe observed a median of 15 protein-altering variants per patient in our data and was identified recurrent oncogenic mutations of 360 lymphoma-related genes involved in PT-DLBCL, including PIM1 (74%), MYD88 (50%), KMT2D (38%), KMT2C (34%), BTG2 (34%), TBL1XR1 (34%) and ETV6 (24%). Compared with classic DLBCL, PT-DLBCL showed an increased mutation frequency of PIM1, MYD88, BTG2, while NOTCH1 appeared exclusive mutated with PIM1, MSH3 and ETV6. Cox risk model regression analysis showed that age ≥60 years, IPI 3–5 points, BTG2 gene mutation and extranodal organ invasion suggested poor prognosis. Finally, we constructed an OS predict model of PT-DLBCL patients using above factors with a high accuracy.ConclusionIn conclusion, our results revealed genomic characterization of PT-DLBCL, and the mutation of BTG2 was an independent factor predicting a poor prognosis.

Loss of 5-hydroxymethylcytosine as a Poor Prognostic Factor for Primary Testicular Diffuse Large B-cell Lymphoma.

Background: 5-Hydroxymethylcytosine (5-hmC), a stable epigenetic marker, is closely related to tumor staging, recurrence and survival, but the prognostic value of 5-hmC in primary testicular diffuse large B-cell lymphoma (PT-DLBCL) remains unclear. This study aimed to investigate the 5-hmC expression in PT-DLBCL and evaluate its prognostic value.Methods: A total of 34 patients with PT-DLBCL treated in the Department of Hematology from August 2000 to August 2020 were included in this study. The expression of 5-hmC in PT-DLBCL tissues and normal testicular tissues were assessed by immunohistochemistry. 5-hmC staining is estimated as a percentage under every nuclear staining intensity score (0-3), 0 or 1 of which were regarded as 5-hmC reduction. The quantification of 5-hmC reduction is defined as the percentage of cells with 5-hmC staining scores of 0 and 1. According 5-hmC reduction of 80%, a 5-hmC reduction of <80% is regarded as "5-hmC high-level group", and a 5-hmC reduction of ≥80% is regarded as "5-hmC low-level group". Furthermore, Cox regression model was used to evaluate the prognostic value of all covariates.Results: The median percentage of 5-hmC reduction in the PT-DLBCL group was 77.50% (60%-90%), the median 5-hmC reduction in the normal testicular tissues was 30% (20%-50%). Compared with normal testicular tissue, 5-hmC levels in PT-DLBCL tissue were significantly decreased (p<0.05). Of the 34 PT-DLBCL patients, 17 had tumors with relatively low 5-hmC expression (5-hmC reduction of ≥80%) and 17 had tumors with relatively high 5-hmC expression (5-hmC reduction of < 80%). 5-hmC expression was negatively correlated with international prognostic index (p = 0.037), while there was no significant difference in 5-hmC decrease among different groups of age at diagnosis, lactate dehydrogenase, testicular lymphoma involvement (unilateral or bilateral), Ki-67 and tumor diameter. Relatively low 5-hmC expression indicated shorter overall survival (OS) (5-year OS 50.2% vs 81.3%, p=0.022) and progression-free survival (PFS) (5-year PFS 38.5% vs 70.7%, p=0.001). Cox multivariate analysis of IPI (2-3 vs. 0-1), intrathecal prophylaxis (No vs. Yes), and 5-hmC reduction (≥80% vs. <80%) showed that 5-hmC reduction ≥80% (hazard ratio: 7.252, p = 0.005) and not receiving intrathecal prophylaxis (hazard ratio: 7.207, p =0.001) are independent risk factors for poor prognosis of PT-DLBCL.Conclusion: Our results suggested that 5-hmC decline can be identified as a poor prognostic predictor for PT-DLBCL. It is necessary to further explore the underlying mechanism of this epigenetic marker to identify methods to re-establish 5-hmC levels and provide new targets for cancer therapy.

Primary Testicular Lymphoma a Rare Extra Nodal Involvement of NHL

Primary testicular lymphoma is a collection of neoplasms that constitutes only 1–9% of testicular tumors. Although uncommon in the general population, it is the most common type of malignant testicular tumor in men ≥50 years of age. There are various subtypes, including diffuse large B-cell lymphoma (DLBCL), Burkitt’s lymphoma and follicular lymphoma. In the adult testis, primary DLBCL represents the most frequent subtype of lymphoma (80–90%), whereas the majority of testicular lymphomas in children consist of secondary involvement by Burkitt’s lymphoma, DLBCL or lymphoblastic lymphoma. The typical clinical sign is a painless testicular mass of variable size that is usually unilateral. Primary testicular lymphoma may be identified during the initial presentation of primary or systemic malignant lymphomas, or during a clinical follow-up of patients with lymphoma. Historically, primary testicular lymphoma has been reported to exhibit a poor prognosis with an overall 5-year survival rate of 17–48%, particularly primary testicular DLBCL, whose clinical behavior has been reported to be aggressive and to demonstrate a high propensity to disseminate to the central nervous system (CNS) and skin at presentation and relapse. The underlying mechanisms responsible for this aggressive behaviour have yet to be elucidated. In the present study, a patient with primary testicular DLBCL was examined from histological examination and immunohistochemical staining in the diagnosis of testicular DLBCL.

Next-Generation Sequencing Reveals Molecular Heterogeneity in Primary Testicular DLBCL

Background:Primary testicular lymphomas (PTLs) are extra-nodal large B-cell lymphomas (LBCLs) that respond poorly to current empirical treatment options. To date, no PTL whole-exome sequencing analysis based on the Chinese population has been reported. The main objective of this study was to explore the genomic landscape of PTDLBCL, correlating the results with clinical, histological, and immunogenetic features.Methods:We retrospectively analyzed the disease characteristics in a series of 20 patients (13 paired data and 7 unpaired data). In all cases, the diagnosis of PTL was made using appropriate diagnostic criteria for the 2008 WHO classification of lymphoid tumors with combinations of histologic, immunohistochemical, flow cytometric, and genetic evaluation. Medical records were reviewed for demographic and clinical data. We performed whole-exome next-generation sequencing (NGS) and mapped the mutational landscape. Based on the differential gene results, we performed KEGG and GO enrichment analysis, and five potential new pathogenic genes for DLBCL were obtained based on the Polyphen score.Results:A total of 20 DLBCL samples were collected. All samples were subjected to whole-exome sequencing (WES). A standard bioinformatics analysis process was used to identify somatic mutations in each sample, and an average of 1200 somatic mutations was identified, involving an average of 420 mutated genes. (Figure 1.) More than 85% of the somatic mutations were found in only 1 sample, indicating that somatic mutations are highly heterogeneous. In the matched 13 cases, we validated common gene mutations that have been reported, including PIM1 53.84% (7/13), CD79B 38.46% (5/13), CDKN2A 15.38% (2/13), and MYD88 15.38% (2/13). Venn diagram shows that 25% of the mutated genes were specific to the relapsed sample. GO analysis (Figure 2) shows the functional enrichment and differences between relapsed and non-relapsed samples. Non-relapsed samples are enriched in the herpes simplex virus 1 infection pathway. (Figure 3). Focusing on relapsed/non-relapsed samples, we identified 12 mutated genes specific to relapsed samples. Mutation Polyphen scores were calculated to assess mutation deleteriousness. Five potential new pathogenic genes for DLBCL were obtained.Conclusions:Based on whole-sequencing data, we validated the previously reported common genes for PTDLBCL. In addition, we performed GO and KEGG analysis according to the relapsed and non-relapsed groups. In addition, based on the difference in enrichment results, 12 significantly enriched mutated genes in relapsed DLBCL samples are obtained, and mutation Polyphen scores are calculated to assess mutation deleteriousness. And 5 potential new pathogenic genes of DLBCL are identified. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Testicular Diffuse Large B-Cell Lymphoma-Clinical, Molecular, and Immunological Features.

Simple SummaryTesticular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive lymphoma entity that mainly affects elderly men. It has a high relapse rate with especially the relapses of the central nervous system associating with dismal outcome. T-DLBCL has a unique biology with distinct genetic characteristics and clinical presentation, and the increasing knowledge on the tumor microenvironment of T-DLBCL highlights the significance of the host immunity and immune escape in this rare lymphoma, presenting in an immune-privileged site of the testis. This review provides an update on the latest progress made in T-DLBCL research and summarizes the clinical perspectives in T-DLBCL.Primary testicular lymphoma is a rare lymphoma entity, yet it is the most common testicular malignancy among elderly men. The majority of the cases represent non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) with aggressive clinical behavior and a relatively high relapse rate. Due to the rareness of the disease, no randomized clinical trials have been conducted and the currently recognized standard of care is based on retrospective analyses and few phase II trials. During recent years, the tumor microenvironment (TME) and tumor-related immunity have been the focus of many tumor biology studies, and the emergence of targeted therapies and checkpoint inhibitors has significantly modulated the field of cancer therapies. Testicular DLBCL (T-DLBCL) is presented in an immune-privileged site of the testis, and the roles of NF-κB pathway signaling, 9p24.1 aberrations, and tumor-infiltrating immune cells, especially immune checkpoint expressing lymphocytes and macrophages, seem to be unique compared to other lymphoma entities. Preliminary data on the use of immune checkpoint inhibitors in the treatment of T-DLBCL are promising and more studies are ongoing.

The importance of genomic predictors for clinical outcome of hematological malignancies

The importance of genomic predictors for clinical outcome of hematological malignancies

CNS Prophylaxis in DLBCL: A Ten Year Single-Center Review in the Rituximab Era

Introduction:The role of prophylactic treatment for central nervous system (CNS) relapse in DLBCL is not clearly established. The selection of patients (pts) and the optimal regimens, including choice of agents, timing of administration, dosing, route, etc., remain unclear. In an effort to develop a uniform approach to this strategy, we have reviewed the practice of CNS ppx in DLBCL at Memorial Sloan Kettering during 2004-2014.Methods:We retrospectively reviewed 1) all newly diagnosed pts with DLBCL from 2004-2014 who received CNS ppx, and 2) all pts with DLBCL who developed CNS relapse/progression during the same period. All pts were treated with rituximab-based chemotherapy. Prophylactic agents included methotrexate (MTX) and/or cytarabine (ara-C). Pts with CNS or ocular involvement upon presentation were excluded. All data was compiled and analyzed using SPSS (IBM).Results:Three hundred and three pts received CNS ppx. CNS-IPI (Schmitz et al. J Clin Oncol, 2016) classified pts as low (18.2%), intermediate (43.6%), or high risk (38.2%) for CNS relapse. Seventy-six percent of pts presented with stage IV disease and a mean of 2.1 EN sites, frequently involving bone (53.8%) (vertebrae specifically, 33.7%), lung/pleura (20.1%), GI tract (18.2%), sinuses (17.5%), testes (10.5%) and others.Thirty-five percent of pts had high risk CNS IPI scores and received ppx. Most frequently, pts received ppx due to the presence of EN disease (36.6%), and of these pts 66.4% had multiple EN sites involved. CNS ppx was also administered to pts with primary testicular (24), sinus (30), and breast (8) DLBCL in addition to pts with isolated bone (21) vertebrae (14), and GI tract (5) lesions. The remaining 3.6% of pts received ppx for other reasons including high risk molecular profiles or bulky disease.Intrathecal (IT) MTX alone was administered to 271 of 303 prophylaxed pts, and 17 (5.9%) developed CNS involvement. High dose intravenous (HD) MTX alone was given to 7 pts; 1 developed CNS involvement. IT MTX and IT ara-C were given to 10 pts; 1 developed CNS involvement. IT and HD MTX plus IT ara-C were given to 2 pts; 1 developed CNS involvement. Additional combinations can been reviewed in Table 1.Twenty pts (6.6%) failed CNS ppx, with a median (mdn) time from diagnosis to detection of CNS involvement of 12.7 months. No pts developed CNS disease while on first-line therapy. Of 20 pts, 11 had isolated CNS relapses (mdn= 8.9 months). 7 relapsed systemically with CNS involvement (mdn =26.8 months). Two had primary refractory disease with CNS involvement detected at 10.2 and 12.7 months. The difference in time to CNS relapse based on involvement pattern (leptomeningeal, parenchymal or both) or the context of CNS involvement (isolated CNS relapse vs systemic relapse with CNS involvement) was not statistically significant. The pt treated with HD and IT MTX and IT ara-C relapsed in the CNS at 3.5 months, significantly earlier than pts treated with IT MTX (mdn 12.7 mo, p=0.02), but notably received only 3 cycles of R-CHOP due to wound dehiscence.There were 776 DLBCL pts from the same time period who were not treated with ppx, and 25 (3.2%) developed CNS involvement. One pt relapsed after 48d during R-CHOP. Three additional pts had primary refractory disease with CNS involvement at a median of 5.2 months. Fifteen had isolated CNS relapses (mdn 8.5 months), and 6 had systemic relapses with CNS involvement (mdn 12.0 months). There was no significant difference in the time to CNS relapse comparing pts who received CNS ppx to pts who did not.Conclusions:In our study, pts with DLBCL at high risk for CNS relapse treated with rituximab-based chemotherapy developed CNS involvement after systemic therapy was complete. Administering CNS ppx concurrently with R-CHOP poses many challenges, often resulting in dose adjustments or delays in treatment. Our results suggest that CNS ppx can be delayed until the completion of R-CHOP without compromising the effects of ppx. [Display omitted] DisclosuresMoskowitz:Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Merck: Consultancy, Research Funding.

Different chemokine profile between systemic and testicular diffuse large B-cell lymphoma

Although treatment for diffuse large B-cell lymphoma (DLBCL) has taken some notable steps in the 2000s, there are still subgroups of patients suffering from high mortality and relapse rates. To further improve treatment outcomes, it is essential to discover new mechanisms of chemotherapy resistance and create new treatment approaches to overcome them. In the present study, we analyzed the expression of chemokines and their ligands in systemic and testicular DLBCL. From our biopsy sample set of 21 testicular and 28 systemic lymphomas, we were able to demonstrate chemokine profile differences and identify associations with clinical risk factors. High cytoplasmic CXCL13 expression had correlations with better treatment response, lower disease-related mortality, and limited stage. This study suggests that active CXCR5/CXCL13 signaling could overtake the CXCR4/CXCL12 axis, resulting in a better prognosis.

Testis‐Specific Thioredoxins TXNDC2, TXNDC3, and TXNDC6 Are Expressed in Both Testicular and Systemic DLBCL and Correlate with Clinical Disease Presentation

DLBCL is the most common type of non-Hodgkin lymphoma with a substantial group of patients suffering a poor prognosis. Therefore more specific markers are required for better understanding of disease biology and treatment. This study demonstrates that testis-specific antioxidant enzymes TXNDC2, TXNDC3, and TXNDC6 alongside oxidative stress marker 8-OHdG are expressed in both testicular and systemic DLBCL, and their presence or absence has correlations with clinical risk factors such as the number of extranodal effusion, the appearance of B-symptoms, and treatment response. Biopsy samples were collected from 28 systemic and 21 testicular male DLBCL patients. The samples were histostained with TXNDC2, TXNDC3, TXNDC6, and 8-OHdG, then graded by a hematopathologist blinded to clinical data. Immunoelectron microscopy was used as a second method to confirm the reliability of the acquired immunohistochemistry data. The absence of nuclear TXNDC2 expression in testicular DLBCL cells correlated with worse primary treatment response, cytoplasmic TXNDC3 expression in testicular and systemic DLBCL associated with lower frequency of B-symptoms, and TXNDC6 expression in cytoplasm in systemic DLBCL had a clinical significance with higher LD levels suggesting a role in the biological nature of these lymphomas. Overall, TXNDC3 cytoplasmic expression is correlated with a more positive outcome in both testicular and systemic DLBCL, while TXNDC6 cytoplasmic expression is associated with a negative outcome in systemic DLBCL.

Adverse prognostic impact of regulatory T-cells in testicular diffuse large B-cell lymphoma.

Testicular diffuse large B-cell lymphoma (T-DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor-infiltrating lymphocytes (TILs) and PD-1 expressing TILs associate with better survival in T-DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival. We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T-cells (CTLs; CD8+ , OX40+ , Granzyme B+ , Ki-67+ , LAG-3+ , TIM-3+ , PD-1+ ), CD4+ T-cells (CD3+ , CD4+ , TIM-3+ , LAG-3+ ), regulatory T-cells (Tregs; CD3+ , CD4+ , FoxP3+ ), and T helper 1 cells (Th1; CD3+ , CD4+ , T-bet+ ) in 79 T-DLBCLs, and correlated the findings with patient demographics and outcome. We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8+ TILs were Ki-67+ and TIM-3+ CTLs, whereas the most prominent CD4+ TILs were FoxP3+ Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T-bet+ FoxP3+ Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features. Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T-DLBCL.

Low Absolute Lymphocyte Counts in the Peripheral Blood Predict Inferior Survival and Improve the International Prognostic Index in Testicular Diffuse Large B-Cell Lymphoma.

Low absolute lymphocyte counts (ALC) and high absolute monocyte counts (AMC) are associated with poor survival in patients with diffuse large B-cell lymphoma (DLBCL). We studied the prognostic impact of the ALC and AMC in patients with testicular DLBCL (T-DLBCL). T-DLBCL patients were searched using Southern Finland University Hospital databases and the Danish lymphoma registry. The progression free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox proportional hazards methods. We identified 178 T-DLBCL patients, of whom 78 (44%) had a low ALC at diagnosis. The ALC did not correlate with survival in the whole cohort. However, among the patients treated with rituximab (R) containing regimen, a pre-therapeutic low ALC was associated with an increased risk of progression (HR 1.976, 95% CI 1.267–3.086, p = 0.003). Conversely, intravenous (iv) CNS directed chemotherapy translated to favorable outcome. In multivariate analyses, the advantage of an iv CNS directed chemotherapy was sustained (PFS, HR 0.364, 95% CI 0.175–0.757, p = 0.007). The benefit of R and intravenous CNS directed chemotherapy was observed only in non-lymphopenic patients. The AMC did not correlate with survival. A low ALC is an adverse prognostic factor in patients with T-DLBCL. Alternative treatment options for lymphopenic patients are needed.

Clinical analysis of primary testicular diffuse large B-cell lymphoma

Objective To investigate the clinical features, diagnosis, treatment and prognosis of primary testicular diffuse large B-cell lymphoma (PT-DLBCL). Methods The clinical data of 2 patients with PT-DLBCL in the Second People's Hospital of Lianyungang treated in May 2013 and April 2018 was retrospectively analyzed. The clinical features, diagnosis, treatment and prognosis of PT-DLBCL were summarized with review of these 2 cases combining with other 42 cases reported in domestic literature. Results Case 1, a 71 years old man, complained of bilateral scrotal enlargement with pain and discomfort for 2 months. Case 2, an 85 years old man, presented with left scrotal mass for 3 months. All 2 patients underwent orchiectomy. Both of the 2 patients were diagnosed as PT-DLBCL and non-germinal center B-cell (non-GCB) subtype and had Ann Arbor stage ⅠE after operation. Case 1 received only 2 cycles of CHOP (cyclophosphamide, epirubicin, vincristine, prednisone) due to lack of financial support. Case 2 refused chemotherapy and right testis irradiation because of advanced age. They were followed up for 71 months and 12 months, respectively. They were both alive without recurrence at last time of the follow-up. The median age of 44 patients (2 cases in this study and 42 cases reported in the domestic literature) was 64 years old (range 45-87 years old). The most common symptom was unilateral painless testicular swelling (left testis 17 cases and right testis 24 cases). Twenty-one patients were Ann Arbor stage Ⅰ, 6 patients were stage Ⅱ, 6 patients were stage Ⅲ, and 11 patients were stage Ⅳ. Thirty-one patients were non-GCB subtype. Twelve patients were international prognostic index (IPI) score ≥3. Serum lactate dehydrogenase (LDH) level was elevated in 13 patients. All patients underwent orchiectomy. CHOP/R-CHOP chemotherapy was given to 40 patients and prophylactic radiation to contralateral testis was given to 12 patients. Twenty-two patients received prophylactic intrathecal chemotherapy. After a median follow-up of 17 months (range 3-135 months), 14 patients died and the median overall survival time was 13 months (range 3-96 months). Conclusions PT-DLBCL is rare. Its diagnosis mainly depends on pathology, with the majority of patients diagnosed in early Ann Arbor clinical stage and non-GCB subtype. The radical orchiectomy and R-CHOP chemotherapy is recommended due to local relapse and systemic dissemination. It is curable in the early stage while patients with advanced stage have a very poor prognosis. Prophylactic radiation to contralateral testis and intrathecal chemotherapy can decrease the risk of recurrence. Key words: Testicular neoplasms; Lymphoma, large B-cell, diffuse; Diagnosis; Treatment; Prognosis

CLINICAL CHARACTERISTICS OF PRIMARY EXTRANODAL VERSUS NODAL DIFFUSE LARGE B-CELL LYMPHOMA: A RETROSPECTIVE COHORT STUDY IN A CANCER CENTER.

The outcome of patients with primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) varies according to the primary site involved. Primary gastrointestinal, breast, bone, craniofacial, and testicular DLBCL are rare extranodal manifestations of DLBCL. The objective of the study was to describe the clinical course of patients with PE-DLBCL disease in a referral cancer center. From 637 patients, 51 (8.77%) were considered as having PE-DLBCL (25 gastrointestinal, 12 craniofacial, 6 breast, 5 bone, and 3 with primary testicular DLBCL). Complete remission was higher in all PE-DLBCL sites (100% in testicular, 92.6% craniofacial, 83.3% breast, 80% bone, and 80% gastrointestinal) compared with 73.3% in nodal DLBCL. Although 2 cases with breast PE-DLBC relapsed, they achieved a complete response with chemotherapy. The overall survival at 5 years was 100%, 80%, 78%, 58%, 58%, and 62% for patients with primary breast, primary bone, gastrointestinal, primary craniofacial, primary testicular, and nodal DLBCL, respectively. PE-DLBCLs constitute rare, primary sites of lymphoproliferative disorders in most cases, with localized disease and good prognosis. They require a combined chemoimmunotherapy with radiotherapy in most cases to improve local and systemic disease.

The Prognostic Value of Blood-Based Biomarkers in Patients With Testicular Diffuse Large B-Cell Lymphoma.

Objectives: Previous studies have reported the prognostic value of neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), lymphocyte/monocyte ratio (LMR), and systemic immune-inflammation index (SII). However, the prognostic performance of these indices in patients with testicular lymphoma has not yet been studied. This study was to systematically evaluate the role of NLR, PLR, LMR, and SII in predicting survival for patients with testicular diffuse large B-cell lymphoma.Methods: In this study, 28 patients with testicular diffuse large B-cell lymphoma were enrolled. We performed univariate and multivariate analyses to assess associations of indices incorporating blood cell counts with progression-free survival (PFS) and overall survival (OS).Results: The results of univariate analysis revealed that International Prognostic Index (IPI) score (p = 0.010, p = 0.034, respectively), NLR (p = 0.003, p = 0.025, respectively), and LMR (p = 0.004, p = 0.010, respectively) were significantly associated with PFS and OS. Lactic dehydrogenase (LDH) (p = 0.017), absolute neutrophil counts (p = 0.018), absolute monocyte counts (p = 0.001), and SII (p = 0.005) were significantly associated with the risk of disease progression, while ECOG performance status (p = 0.016) was shown to be related to the risk of death. In the multivariate analysis, NLR (HR 9.069, p = 0.001) and absolute monocyte counts (HR 37.076, p = 0.001) were shown to be independently associated with risk for disease progression, while LMR (HR 0.077, p = 0.028), and ECOG performance status (HR 20.013, p = 0.026) were proved to be independent predictors of OS.Conclusions: In conclusion, high absolute monocyte counts, high NLR and low LMR may indicate unfavorable prognosis in testicular diffuse large B-cell lymphoma patients. Since indices incorporating blood cell counts are low cost parameters, they may provide additional prognostic value beyond standard clinicopathological parameters. However, further studies are needed to confirm our findings.

Prognostic Significance of LDH Ratio in Serum/Cerebral Spinal Fluid of Patients with Primary Testicular Diffuse Large B-Cell Lymphoma.

ObjectivePrimary testicular diffuse large B-cell lymphoma (PT-DLBCL) is relatively rare, and risk factors of this disease are still not well understood. This study aims to identify clinical features and prognostic factors of PT-DLBCL patients.MethodsThirty-two patients were included in this retrospective study who were diagnosed as PT-DLBCL and treated in Fudan University Shanghai Cancer Center between November 2010 and May 2018. The demographic details, clinico-pathological characteristics of the patients were summarized, and the impact on progression-free survival (PFS) and overall survival (OS) was analyzed.ResultsThe median age of the patients was 57 (range 36–76) years old. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 4–6 cycles and central nervous system (CNS) prophylaxis, with a CR rate 87.5% and an ORR 96.9%. Nineteen patients continued prophylactic contralateral testis radiation therapy (PCTRT) in our hospital. The 3-year PFS and OS rates were 79% and 92%, respectively. None of the 19 patients who received PCTRT experienced local recurrence. All three patients who suffered from CNS relapse were germinal center B-cell subtype. Kaplan–Meier analyses showed that PT-DLBCL patients with late-stage (Stage IV) (P =0.022), higher IPI score (IPI≥ 2) (P =0.017), B symptoms (P =0.004), and elevated LDH level (P =0.03) had a shorter PFS. More importantly, we found that patients with the ratio of the LDH level in serum to that in CSF ≥ 6.5 suffered from a worse PFS (P =0.028).ConclusionOur work revealed that staging IV, IPI score ≥2, having B symptoms and elevated LDH level were risk factors for PT-DLBCL patients. Significantly, the PT-DLBCL patients with a high ratio of LDH level in serum to that in CSF were indicated to have a worse PFS.

Central Nervous System Prophylaxis Is Required and Associated with a Prolonged Overall Survival in Both Early and Advanced-Stage Primary Adrenal/Renal Diffuse Large B-Cell Lymphoma

Introduction Primary adrenal lymphoma (PAL) and primary renal lymphoma (PRL) are rare extranodal lymphomas, predominantly of diffuse large B-cell lymphoma (DLBCL) subtype. Adrenal/renal involvement is one of six risk factors that define the Central Nervous System International Prognostic Index (CNS-IPI), the most commonly used tool in determining the risk of CNS relapse in DLBCL. However, guidelines regarding CNS prophylaxis in early stage PAL/PRL (Ann Arbor IE and IIE) and advanced stages without high-risk CNS-IPI, and optimal route of administration have not been clearly elucidated. Here we provide an analysis of over 400 cases of PAL/PRL, the largest collection to date, including data on disease biology, risk of CNS relapse, CNS prophylaxis, and outcomes. Methods We conducted a comprehensive literature review on adult PAL/PRL cases reported from Jan 1st 1998 to July 1st 2019 in PubMed. Additionally, we collected cases available at our institution and through international collaborators. We excluded cases with CNS involvement at onset, unknown staging, and histology other than DLBCL. Data were tabulated regarding the following variables: age, gender, stage, laterality, cell-of-origin (germinal center B-cell-like (GCB) vs. activated B-cell-like (ABC)), chemotherapy, CNS prophylaxis (and type), CNS relapse, and overall survival (OS). OS was calculated using the Kaplan-Meier method, and comparison between OS curves made using the log-rank test, with statistical significance set as p-value &lt; 0.05. Results/ Discussion With over 700 PAL/PRL cases available for review, 405 met inclusion criteria (258 from PubMed, 147 through collaboration). Analyzing the fraction of reported cases, patients were predominantly advanced stage (68%; 274/405), male gender (77%; 167/218), older than 60 years (73%; 157/214), had bilateral involvement (70%; 130/186), and were of ABC cell-of-origin (69%; 101/146) (Fig. 1A). Only 45 patients had available CNS-IPI scores (13 low/intermediate and 32 high), which limits drawing strong conclusions. The low/intermediate-risk group did not have a CNS relapse event, with 46% (6/13) receiving CNS prophylaxis. The high-risk group had 22% (7/32) CNS relapse rate overall, with 21% (3/14) relapse among the CNS prophylaxis subset. For the CNS-IPI group overall, a strong correlation was noted between disease stage and CNS-IPI risk: 85% of the low-risk CNS-IPI group had early-stage disease (stages IE and IIE), and 84% of the high-risk IPI group had advanced stage. Therefore, we sought to examine the rate of CNS relapse and impact of CNS prophylaxis for early vs. advanced-stage PAL/PRL. CNS relapse was documented in 15% of all cases (60/405), but was notably higher in advanced stage (20%; 55/275) vs. early stage (4%; 5/131) disease (Fig. 1A). Intriguingly, CNS prophylaxis did not affect CNS relapse rate in the advanced-stage group (26% vs. 28% with prophylaxis), while in the early-stage group it was beneficial (17% vs. 0% with prophylaxis) (Fig. 1B). Nevertheless, CNS prophylaxis was associated with a prolonged OS regardless of the disease stage (Fig. 1C). We then analyzed whether type of CNS prophylaxis used - intrathecal methotrexate or cytarabine (IT-chemo) vs. high-dose systemic methotrexate (HD-MTX) with or without IT-chemo - affected OS and CNS relapse rate. The OS curve favored HD-MTX in a limited size of 26 cases (Fig. 1D). CNS relapse data was available in 35 cases. CNS relapse was not found with HD-MTX (0/10), while it was observed in 32% (8/25) of the IT-chemo group, all of which were advanced stage (8/20). This can explain, at least in part, the lack of difference in rate of CNS relapse between the prophylaxis and non-prophylaxis groups in the setting of advanced stage. Consequently, a strong trend toward a better OS (p=0.12) was observed when HD-MTX was used in the setting of advanced-stage disease. Conclusion PAL/PRL is a rare presentation of DLBCL, more likely to be associated with high-risk features such as ABC cell-of-origin and advanced-stage disease. CNS prophylaxis should be used regardless of disease stage, preferably with HD-MTX in the setting of advanced-stage disease. Given the close relationship between stage and CNS-IPI, our findings suggest that, akin to primary testicular DLBCL, PAL/PRL could be an independent and significant predictor for CNS relapse regardless of the CNS-IPI, implicating the need for CNS chemo-prophylaxis in all cases. Disclosures Ferreri: Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding. Safah:Amgen: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Jazz: Speakers Bureau; Verastem: Honoraria, Speakers Bureau; Celgene: Speakers Bureau. Saba:Pharmacyclics: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau.

Laterality and Survival Outcomes in Patients with Primary Testicular Diffuse Large B Cell Lymphoma

Introduction: Patients with diffuse large B cell lymphoma (DLBCL) arising from the testis have a relatively poor outcome. Age, stage and use of radiation and surgery are important prognostic factors in patients with primary testicular DLBCL. Additionally, the study by Gundrum et al suggested that laterality was also an important predictor of outcomes in patients with primary testicular DLBCL, with left side involvement being associated poorer prognosis. However, most patients included in the study by Gundrum et al were diagnosed in the pre-rituximab era, therefore, the role of laterality in the prognostification of patients with primary testicular DLBCL remains to be explored. In this study, the Surveillance, Epidemiology, and End Results (SEER) database was used to evaluate the prognostic roles of laterality in patients with primary testicular DLBCL. Methods: Data from the SEER 18 Registries were used to conduct this study. Cases with newly-diagnosed testicular (International Classification of Diseases for Oncology, 3rd Edition [ICDO-3] codes 9823, sites: C62.0-C63.2) in the time period between 1973 and 2015 were included. Exclusion criteria included history of cancer, unknown laterality, unknown survival data and unknown cause of death. For each case we included age at the time of diagnosis, laterality (left, right, bilateral), SEER cause-specific death classification, survival months and vital status. Overall survival (OS) was defined as time from diagnosis to death or last follow-up and cancer-specific survival (CSS) was calculated as time from diagnosis to death from DLBCL or last follow-up. Survival curves were plotted by the Kaplan-Meier method and the log-rank test was used for comparison. P value was 2-sided and P&lt;0.05 was considered to be statistically significant. All analyses were conducted using Graphpad Prism 6. Results: A total of 1213 patients were included in this analysis. The median follow-up was 43 months (interquartile range[IQR]: 13-90 months). Of these patients, 372 patients were diagnosed from 1973-2000 (pre-rituximab era) and 841 patients were diagnosed from 2001-2015 (rituximab era). We found that patients with bilateral testis involvement had a significantly decreased CSS (median CSS: 53 vs. 142 months, P=0.0035) and OS (median OS: 32 vs. 77 months, P=0.0008) compared with those with unilateral involvement. Patients with left-side involvement had a similar CSS (median CSS: 136 vs. 153 months, P=0.2997) and OS (median OS: 76 vs. 80 months, P=0.7360) compared to those with right-side involvement. For patients with left-side involvement, patients diagnosed in the rituximab era had a significantly longer CSS(hazards ratio[HR]: 0.4140, 95% confidence interval[CI]: 0.3065 to 0.5593, P&lt;0.0001) (Figure 1A)and OS (HR: 0.5522, 95% CI: 0.3926 to 0.6340, P&lt;0.0001 ) (Figure 1B) than those diagnosed in the pre-rituximab era. For patients with right-side involvement, patients diagnosed in the rituximab era had a significantly longer CSS (HR: 0.7146, 95% CI: 0.5218 to 0.9029, P=0.0057) (Figure 1A)and OS (HR: 0.7116, 95% CI: 0.5407 to 0.8311, P=0.0011) (Figure 1B)than those diagnosed in the pre-rituximab era. The different HRs suggested patients with left-side primary testicular DLBCL benefited more from the introduction of rituximab. Additionally, the improvement in median OS from the pre-rituximab era to the rituximab era was 68 months for patients with left-side involvement but only 35 months for patients with right-side involvement. Conclusion: our study demonstrated that laterality was not a prognostic factor for patients with primary testicular DLBCL. And the improvement in the prognosis from pre-rituximab era to rituximab era was more remarkable in primary testicular DLBCL patients with left-side involvement than those with right-side involvement. These data suggest primary testicular DLBCL from different sides had different responses to therapy and may have different biological characteristics. Figure 1 Disclosures No relevant conflicts of interest to declare.

First Case Report of Primary Testicular Diffuse Large B-Cell Lymphoma from the Western Region of Saudi Arabia

Primary testicular lymphoma (PTL) represents 1-2% of all types of non-Hodgkin lymphomas (NHLs) and 1-10% of testicular neoplasms. Up to the best of my knowledge, this is the first case of PTL of the diffuse large B-cell lymphoma (DLBCL) in a 60-year-old man presented with a painless mass in the left testis as revealed by physical examination in a tertiary care hospital in Al-Madinah Al-Munwarah in the western region of the Kingdom of Saudi Arabia (KSA). Radiological examination revealed a large well-defined heterogeneous predominantly hypo-echoic mass with increased vascularity in the upper portion of the testis. On the other hand, histopathological examination revealed a tumor involving the whole left testis, which was large (measuring 6 3.5 3.3 cm), solid and dark red with focal areas of hemorrhage and epididymal infiltration. Immunohistochemistry showed positivity of leucocyte common antigen (LCA), pan B-cell marker (CD20) and negativity of pan T-cell marker (CD3). Other immunohistochemical markers such as CD10, placental alkaline phosphatase (PLAP), cytokeratin, vimentin, desmin and S100 protein were also negative. However, there was a marked expression of Ki67 and Bcl2 markers. Accordingly, the diagnosis of DLBCL was established. The tumor was classified as stage I according to the Ann Arbor system. The case was treated by orchiectomy followed by prophylactic anthracycline-based chemotherapy and irradiation of the contralateral testis and central nervous system.