Primary Testicular Lymphoma Patients Research Articles

Genomic landscape and distinct molecular subtypes of primary testicular lymphoma.

Primary testicular lymphoma (PTL) is a rare lymphoma predominantly occurring in the elderly male population. It is characterized by a limited response to treatment and a heightened tendency towards relapse. Histologically, approximately 90% of PTL cases are classified as diffuse large B-cell lymphomas (DLBCL). Genetic features of PTL were delineated in a limited scope within several independent studies. Some of the articles which analyzed the genetic characterization of DLBCL have incorporated PTL samples, but these have been constrained by small sample sizes. In addition, there have been an absence of independent molecular typing studies of PTL. This report summarizes the common mutational features, copy number variations (CNVs) and molecular typing of PTL patients, based on whole-exome sequencing (WES) conducted on a cohort of 25 PTL patients. Among them, HLA, CDKN2A and MYD88 had a high mutation frequency. In addition, we found two core mutational characteristics in PTL including mutation in genes linked to genomic instability (TP53 and CDKN2A) and mutation in immune-related genes (HLA, MYD88, CD79B). We performed molecular typing of 25 PTL patients into C1 subtype with predominantly TP53 mutations and C2 subtype with predominantly HLA mutations. Notably, mutations in the TP53 gene predicted a poor outcome in most types of lymphomas. However, the C1 subtype, dominated by TP53 mutations, had a better prognosis compared to the C2 subtype in PTL. C2 subtype exhibited a worse prognosis, aligning with our finding that the mechanism of immune escape in PTL was primarily the deletions of HLA rather than PD-L1/PD-L2 alterations, a contrast to other DLBCLs. Moreover, we calculated the tumor mutation burden (TMB) and identified that TMB can predict prognosis and recurrence rate in PTL. Our study underscores the significance of molecular typing in PTL based on mutational characteristics, which plays a crucial role in prognostication and guiding therapeutic strategies for patients.

RCHOP Plus High-Dose Methotrexate As First-Line Therapy in Large B-Cell Lymphoma with Testis Involvement

Primary testicular lymphoma (PTL) and diffuse large B-cell lymphoma with secondary testicular involvement (DLBCL-T) are rare subtypes of lymphomas associated with poor prognosis and a high risk of central nervous system (CNS) relapse. The optimal CNS prophylaxis strategy for these subtypes remains uncertain. High-dose methotrexate (HD-MTX) is debated for CNS prophylaxis, but its efficacy in this setting is unknown. This study aimed to retrospectively analyze the use of HD-MTX in combination with chemotherapy (R HD-MTX CHOP) as frontline treatment for PTL and DLBCL-T and to compare the biological characteristics of these two forms of testicular involvement. Data from patients who received R HD-MTX CHOP as first-line treatment for DLBCL-T or PTL between 2010 and 2020 were collected retrospectively. The study included 15 patients, 5 with PTL and 10 with DLBCL-T. The overall response rate was 86%, with 73% of patients achieving complete remission. Treatment-related adverse events were generally manageable, with febrile neutropenia being the most common. Two patients experienced CNS relapse, both from the DLBCL-T subgroup, with a median time of 10.7 months from diagnosis to CNS relapse. None of the PTL patients receiving HD-MTX experienced relapse during the median follow-up of 6.08 years (Figure 1A), compared to 8/10 DLBCL-T (p=0.007). All five PTL cases had a non-germinal center phenotype, while 7 out of 10 DLBCL-T cases were non-germinal center. One DLBCL-T case exhibited high-grade lymphoma. Myc expression was positive in 3 out of 10 patients assessed, of whom all were double expressors. Bcl-2 expression was positive in all 13 assessable patients, while Bcl-6 expression was positive in 6 patients. Myc, Bcl-2, and Bcl-6 rearrangements were assessed in 10 patients and were present in 1 patient who was found to have triple-hit lymphoma. No other patient had double-hit lymphoma or any significant rearrangement. Polysomy of Myc, Bcl-2, and/or Bcl-6 was found in 2 patients. PDL1 expression was observed in one out of six patients analyzed, while no PD1 expression was detected. In 8 out of 15 patients with available tissue material, next-generation sequencing using a panel targeting 43 lymphoid genes was performed. Among these 8 patients, 87% exhibited gain-of-function mutations in MYD88 (MYD88 L265P), and 62% had missense mutations in CD79B at position Y196. Multiple mutations in the PIM1 gene, a known target of aberrant somatic hypermutation, were also observed in 7 patients. Non-recurrent mutations were detected in various genes, including PRDM1, CD58, B2M, CREBBP, CIITA, CARD11, CDKN2A, EP300, CCDND3, FOXO1, IRF4, NFKBIE, and TCF3 (Figure 1B). Ig rearrangement was analyzed in 4/9 patients with available DNA. All 4 were clonal, with distinct but mutated VH segments (sequence identity between 81 and 89%). This study suggests that HD-MTX in combination with RCHOP chemotherapy is highly effective in preventing CNS relapse in PTL but less so in DLBCL-T. DLBCL-T had a higher risk of CNS relapse and poorer outcomes compared to PTL. Further studies are needed to determine the optimal timing and sequence of HD-MTX in DLBCL-T, as well as alternative treatment approaches. PTL and DLBCL-T have distinct clinical presentations and responses to frontline chemotherapy with HD-MTX prophylaxis. PTL may benefit from HD-MTX in preventing relapse, while alternative treatments should be explored for DLBCL-T. Future studies should consider PTL and DLBCL-T as separate entities to better understand their characteristics and optimize treatment strategies.

Primary testicular lymphoma demonstrates overexpression of the Wilms tumor 1 gene and different mRNA and miRNA expression profiles compared to nodal diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) shows a high degree of clinical and biological heterogeneity. Primary testicular lymphoma (PTL) is an extranodal variant of DLBCL associated with a higher risk of recurrence, including contralateral testicles and central nervous system sanctuary sites. Several molecular aberrations, including somatic mutation of MYD88, CD79B, and upregulation of NF-kB, PDL-1, and PDL-2, are thought to contribute to the pathogenesis and poor prognosis of PTL. However, additional biomarkers are needed that may improve the prognosis and help understand the PTL biology and lead to new therapeutic targets. RNA from diagnostic tissue biopsies of the PTL-ABC subtype and matched nodal DLBCL-ABC subtype patients was evaluated by mRNA and miRNA expression. Screening of 730 essential oncogenic genes was performed, and their epigenetic connections were examined using the nCounter PAN-cancer pathway, and Human miRNA assays with the nCounter System (NanoString Technologies). PTL and nodal DLBCL patients were comparable in age, gender, and putative cell of origin (p>0.05). Wilms tumor 1 (WT1) expression in PTL exceeded that in nodal DLBCL (>6-fold; p=0.01, FDR <0.01) and WT1 associated pathway genes THBS4, PTPN5, PLA2G2A, and IFNA17 were upregulated in PTL (>2.0-fold, p<0.01, FDR <0.01). Additionally, miRNAs targeting WT1 (hsa15a-5p, hsa-miR-16-5p, has-miR-361-5p, has-miR-27b-3p, has-miR-199a-5p, has-miR-199b-5p, has-miR-132-3p, and hsa-miR-128-3p) showed higher expression in PTL compared to nodal DLBCL (≥2.0-fold; FDR 0.01). Lower expression of BMP7, LAMB3, GAS1, MMP7, and LAMC2 (>2.0-fold, p<0.01) was observed in PTL compared to nodal DLBCL. This research revealed higher WT1 expression in PTL relative to nodal DLBCL, suggesting that a specific miRNA subset may target WT1 expression and impact the PI3k/Akt pathway in PTL. Further investigation is needed to explore WT1's biological role in PTL and its potential as a therapeutic target.

Detection of Cell Free Tumor DNA in Plasma of Patients with Large B-Cell Lymphoma of the Sanctuary Sites By Digital Droplet PCR

Background: Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare mature B-cell lymphoproliferative diseases that arise at immunological sanctuary sites. Cytomorphology (CM) and flow cytometry (FCM) analysis of spinal fluid is diagnostic in about 15% of PCNSL. In the remaining patients, a tumor biopsy is necessary, which carries the risk of complications. Response assessment in PCNSL and PTL relies on imaging studies. However, MRI scans and 18F-FDG PET-scans often cannot differentiate between active tumor and scar tissue. Hence, there is a need for non-invasive tools to aid in diagnosis and help in response assessment. PCNSL and PTL are characterized by a high incidence of hotspot mutations in MYD88 and CD79B. Detection of these mutations in cell free DNA (cfDNA) might aid in diagnosis and follow-up of disease activity in patients with PCNSL and PTL. Digital droplet PCR (ddPCR) offers a robust inexpensive tool with a fast turnaround time allowing sensitive detection of such hotspot mutations. Methods: Plasma was available for a total of 26 patients (20 PCNSL and 6 PTL) in the OncoLifes biobank of the University Medical Center Groningen. All patients gave informed consent. Corresponding tumor samples were available for 17 cases (14 PCNSL and 3 PTL). A ddPCR was performed for MYD88 L265P and in case of sufficient cfDNA also for CD79B Y196X (Bio-Rad Laboratories, Hercules, USA). The ddPCR Assay for CD79B Y196X targets the mutation Y196H c.586T>C, Y196D c.586T>G, Y196S c.587A>C, Y196C c.587A>G, and Y196F c.587A>T. The cut off value for the allele frequency (AF) used was ≥0.5%. Results: The MYD88 L265P and CD79B Y196X mutations were detected in 9/14 (64.2%) and 2/13 (15.4%) of the PCNSL tissue samples. The two CD79B Y196X positive tissue cases had a concomitant MYD88 L256P. The MYD88 L265P mutation was detected in 2/20 (10%) cfDNA samples. The CD79B Y196X mutation was detected in 1/19 (5.2%) cfDNA samples; remarkably, this mutation was not detected in the corresponding tissue sample. In PTL, MYD88 L265P mutations were detected in 3/3 of tumor tissues and a CD79B Y196X mutation was detected in 1/2 of tumor tissues, which co-occurred with the MYD88 L265P. In PTL, 2/6 (33.3%) and 1/6 (16.6%) cfDNA samples were positive for MYD88 L265P and CD79B Y196X. Overall, hotspot MYD88 and/or CD79B mutations were detected in cfDNA in 5 /26 cases (18.4%) (Figure 1). Figure 1. ddPCR results of MYD88 and CD79BConclusion: We explored the feasibility of using a combination of two common hotspot mutations in MYD88 and CD79B in PCNSL and PTL plasma samples to aid in diagnosis and disease monitoring. The data presented show that the value of ddPCR for hotspot mutations in plasma of PCNSL and PTL patients is limited. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genomic Landscape and Distinct Molecular Subsets of Primary Testicular Lymphoma

Primary testicular lymphoma (PTL) is a malignant aggressive tumor that occurs in older men, and which is 90% histologically diffuse large B-cell lymphoma (PT-DLBCL). However, as a malignant tumor occurring in an immune privileged site, it is not very effective against a wide range of treatments and its prognosis is not satisfactory. To gain insight into the pathogenesis of PTL and the factors associated with its poor prognosis, the whole-exome sequencing analysis of 25 PTL patients were performed. Single-nucleotide variation (SNV) were analyzed through GATK and ANNOVAR workflows. In summary, we identified a number of high-frequency mutant genes, such as MYD88, HLA-A, PIM1 and so on. These high-frequency mutated genes are compatible with the high-frequency mutated genes that have appeared in previous studies on the genetic characteristics. However, we also identified some high-frequency mutated genes that have been rarely mentioned in previous articles. In addition, we calculated the TMB in order to see if the mutation had any impact on the prognosis and recurrence rate of the patients, and the results showed that a high TMB predicted a low progression-free survival (PFS). Notably, we will further analyze TMB and CNV to differentiate molecular subsets groups of PTL patients, which will have a basis for future immunotherapy in PTL.

Characteristic features of primary testicular lymphoma and survival trends: a multicenter clinical study

ABSTRACT Objectives To retrospectively investigate the clinical characteristics, prognosis, treatment, and therapy outcome of Chinese patients with primary testicular lymphoma (PTL). Methods we collected data of 49 PTL patients from four hospitals over 13 years. The median age was 63 years old. We described the clinical characteristics of the patients including the laterality, serum lactate dehydrogenase (LDH), pathology classification, stage, International prognostic index (IPI) scores and more. Results Complete remission (CR) was achieved in 34 patients and partial remission (PR) in 3 patients; Progressive disease (PD) was detected in 11 patients, and 10 patients died. The average progression-free survival (PFS) of all patients was 43.92 months, and the average overall survival (OS) was 47.55 months. The Ann Arbor stage, IPI score, and LDH were associated with OS, while Ann Arbor stage, IPI score, LDH, and histotype were significantly associated with PFS. Chemotherapy and radiotherapy following orchiectomy was associated with a significantly longer PFS. Conclusion Most patients can achieve CR after induced therapy or orchiectomy. However, there are many associated prognostic factors.

Low Expression of T/NK-Cell Signature Predicts Poor Survival in Patients with Primary Testicular and Diffuse Large B-Cell Lymphoma

Primary testicular lymphoma (PTL) is a rare and aggressive disease accounting for 1% of malignant lymphomas. Majority of the PTLs are diffuse large B-cell lymphomas (DLBCL). Recently, the impact of tumor microenvironment (TME) and limited immune surveillance on the lymphoma pathogenesis and survival has been recognized. Here, we aimed to characterize cellular and molecular immunological profiles in PTL, and associate the findings with outcome.We used NanoString digital gene expression profiling with the PanCancer Immune panel to assess the expression of 770 immune response genes in tumor tissue of 60 patients with PTL. RNA-sequencing data from a cohort of 96 patients with primary DLBCL was used to validate the findings.Unsupervised hierarchical clustering revealed clusters of genes with differential expression between the PTL patients. The clusters were enriched for genes related to T-cell and natural killer (NK) cell markers and signaling (e.g. CD3, CD4, CD8, ITGB2, PRF1, GZMA/B/H/M/K), as well as cytokine signaling (e.g. IL4, IL9, IL17A/B, TNFSF11, CXCR1, CCL28). Interestingly, the group of patients with low expression of T/NK-cell signature genes had a significantly worse progression-free survival (5-year PFS 33% vs. 65%, p=0.012) and overall survival (5-year OS 33% vs. 67%, p=0.004), as compared to the other patients. In Cox multivariate analysis with international prognostic index (IPI), T/NK-cell signature retained independence for prediction of better PFS and OS (RR=0.356, p=0.014 and RR=0.306, p=0.006, respectively). The signature was identified also in a cohort of 96 patients with primary DLBCL, but not in Hodgkin lymphoma. Multiplex immunohistochemistry confirmed lower percentage of CD3+, CD3+CD4+, and CD3+CD8+ lymphocytes in the tumor tissue of the group of PTL patients with poor prognosis (11.8% vs. 24.1%, 5.0% vs. 15.6%, and 4.6% vs. 12.3%, respectively), and association of their higher amount with favorable PFS and OS. Moreover, the RNA level expression of MHC class I and II genes was significantly lower in the poor prognosis group.In conclusion, our results demonstrate that loss of T/NK cell signature and MHC class I and II gene expression are associated with high risk of recurrence and death in patients with PTL and DLBCL. They further highlight the importance of the immune escape as a mechanism of treatment resistance. DisclosuresPollari:Takeda: Other: Conference attendance fees and travel expences; BMS: Other: Conference attendance fees and travel expences; Novartis: Other: Conference attendance fees and travel expences; Pierre Fabre: Other: Conference attendance fees and travel expences; Roche: Consultancy. Mannisto:Takeda: Honoraria, Other: Travel expence; Roche: Honoraria, Other: Travel expence; Amgen: Other: Travel expence; Novartis: Other: Travel expence; Celgene: Other: Travel expence; Gilead: Other: Travel expence; Pfizer: Honoraria; SOBI: Honoraria. Mustjoki:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Celgene: Honoraria. Leppa:Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bayer: Research Funding; Merck: Consultancy, Honoraria; Janssen Cilag: Consultancy, Research Funding.

Combined chemotherapy and radiotherapy improves survival in 1897 testicular Lymphoma patients from a contemporary cohort

IntroductionThe standard of care (SOC) for primary testicular lymphoma (PTL) is orchiectomy, chemotherapy (CHT), and radiotherapy (RT). We hypothesized that men may not receive SOC and may have worse outcomes. To assess this, we queried the National Cancer Database (NCDB) to analyze treatment patterns and survival in PTL patients. MethodsThe NCDB was queried (2006–2016) for men diagnosed with extranodal lymphoma with primary site testis. Patients were placed in 2 treatment groups (1) orchiectomy with chemotherapy plus radiotherapy (CHT + RT), named the SOC group; and 2) CHT + orchiectomy, or RT + orchiectomy, or orchiectomy alone, grouped as non-SOC. Propensity score matching and Kaplan-Meier analysis were used to investigate 5-year overall survival (OS). ResultsTwo thousand two hundred thirty-two men with PTL underwent orchiectomy. After exclusions, 891 men were included in the SOC group and 1,006 men were included in the non-SOC group. KM analysis showed 5-year OS was significantly higher in the SOC group vs. non-SOC for all stages (hazard ratio = 0.54, with 95% confidence interval 0.45 to 0.65, P < 0.0001). ConclusionsThis study represents one of the largest PTL cohort reported to date reflecting current treatments and shows men receiving standard of care treatment have significantly improved survival. Additionally, analysis reveals that most men included in the NCDB do not receive the standard of care.

Adult primary testicular lymphoma: clinical features and survival in a series of patients treated at a high-volume institution in China

BackgroundTo retrospectively investigate the clinical characteristics, initial treatment, relapse, therapy outcome, and prognosis of Chinese patients with primary testicular lymphoma (PTL) through analysis of the cases of our institute.MethodsFrom December 2008 to July 2018, all patients with PTL were included in this study. Kaplan-Meier method was used to estimate PFS and OS. The Cox proportional hazards model was used to compare the survival times for groups of patients differing in terms of clinical and laboratory parameters.ResultsAll 28 PTL patients (24 DLBCL, three NK/T lymphomas, and one Burkkit’s lymphoma) with a median age of 65.5 years were included in this study. Six patients were observed recurrence among all the 22 individuals evaluated. Following orchiectomy and systemic chemotherapy, with or without intrathecal prophylaxis, complete response was achieved in 15 (68%) patients. For DLBCL patients, the median progression-free survival (PFS) was 44.63 months (95% CI 17.71–71.56 months), and the median overall survival (OS) was 77.02 months (95% CI, 57.35–96.69 months). For all the DLBCL patients, the 5-year PFS and 5-year OS were 35.4% (95%CI, 14.8–56.0%) and 53.4% (95%CI, 30.1–76.7%). Without further chemotherapy following orchiectomy (HR = 3.4, P = 0.03) were associated with inferior PFS of DLBCL patients. Advanced Ann Arbor stage (HR =5.9, P = 0.009) and high (international prognostic index, IPI) score: 3–5 (HR =3.9, P = 0.04) were correlated with shorter OS of DLBCL patients.ConclusionThis study confirms that PTL is an aggressive malignant with a poor prognosis. Limited Ann Arbor stage, further chemotherapy following orchiectomy, and low IPI score (less than 2) are correlated with superior survival for DLBCL patients.

MP86-20 PRIMARY TESTICULAR LYMPHOMA: ONCOLOGIC OUTCOMES AND TREATMENT PATTERNS

You have accessJournal of UrologyGeneral & Epidemiological Trends & Socioeconomics: Value of Care: Cost & Outcomes Measures II1 Apr 2018MP86-20 PRIMARY TESTICULAR LYMPHOMA: ONCOLOGIC OUTCOMES AND TREATMENT PATTERNS Fernando Caumont, John Burns, Mazen Alsinnawi, John Paul Flores, Sydney Akapame, and Christopher Porter Fernando CaumontFernando Caumont More articles by this author , John BurnsJohn Burns More articles by this author , Mazen AlsinnawiMazen Alsinnawi More articles by this author , John Paul FloresJohn Paul Flores More articles by this author , Sydney AkapameSydney Akapame More articles by this author , and Christopher PorterChristopher Porter More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2900AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Primary Testicular Lymphoma (PTL) is the most common testicular cancer in older men. Little documentation of this important disease is available in the urologic literature. Since PTL is not represented in germ cell (GCT) databases, epidemiology can only be ascertained by examination of lymphoma databases. As the US population ages, this disease presents more commonly to urologists. We evaluate the epidemiology of PTL and compare the oncological outcomes and treatment patterns of PTL and GCT. METHODS We examined 2 large databases from the National Cancer Database (NCDB) 2004-13. Using NCDB′s Lymphoma DB diagnosis of extra nodal lymphoma (N=133,172) we compared the frequency of PTL (N=2250) to GCT from the germ cell DB (N=45078). Demographic information (DI), treatment options (TO), and histopathological features were obtained. Kaplan-Meier (KM) survival plots were used to examine OS at 5 & 8 yrs post diagnosis. Classical Cox proportional hazards models assessed the effect of DI and TO on OS in PTL. RESULTS 2,096 PTL patients post orchiectomy were analyzed. PTL represents the most frequent testicular malignancy in men >65 (Fig 1). The Charlson Comorbidity Index (CCI) 0, 1 and 2+ was 79%, 17% and 4% for PTL and 94%, 5% and 1 % for GCT. Analysis of the TO of our PTL cohort showed that 825 (39%) men underwent chemotherapy (ChT); 68 (4%) radiotherapy (RT); 732 (35%) RT + ChT; 471 (22%) no further treatment after orchiectomy. Cox regression showed increased CCI scores were significantly associated with mortality risk in PTL at 5 years (CCI 1 with HR 1.29 [1.04-1.61; p = 0.017], CCI ≥2 with HR 2.17 [1.51-3.11; p = 0.001]) and 8 years (CCI 1 with HR 1.31 [1.07-1.62; p = 0.007], CCI ≥2 with HR 2.08 [1.44-3; p = 0.001]). KM survival analysis showed that 5 & 8 year OS was 65% and 61% respectively for PTL vs. 96% at 5 & 8 years for GCT. CONCLUSIONS NCDB data includes >70% of newly diagnosed US malignancies, allowing us to analyze the largest cohort for PTL to date. PTL becomes more prevalent >65 yrs. Higher CCI adversely impacted OS. Further, we have shown that only 1 in 3 PTL patients received appropriate treatment with ChT+RT following orchiectomy, a significant underutilization of National Comprehensive Cancer Network (NCCN) guidelines (Version 2.2015), underlining the importance of following NCCN guidelines in PTL. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e1186 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Fernando Caumont More articles by this author John Burns More articles by this author Mazen Alsinnawi More articles by this author John Paul Flores More articles by this author Sydney Akapame More articles by this author Christopher Porter More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The survival and prognostic factors of primary testicular lymphoma: two-decade single-center experience.

This study aims to investigate the effect of different local testicular treatments and validate common prognostic factors on primary testicular lymphoma (PTL) patients. We retrospectively reviewed the clinical records of 32 patients from 1993 to 2017 diagnosed with PTL and included 22 patients for analysis. The Kaplan–Meier method, Log-rank test, and multivariate Cox proportional hazard regression analysis were applied to evaluate progression-free survival (PFS), overall survival (OS), and determine prognosis predictors. The median follow-up time was 30 months. Median OS and PFS were 96 months and 49 months, respectively. In univariate analysis, advanced Ann Arbor stage (III/IV) (P < 0.001), B symptoms (P < 0.001), and extranodal involvement other than testis (P = 0.001) were significantly associated with shorter OS and PFS. In multivariate analysis, Ann Arbor stage was significantly associated with OS (OR = 11.58, P = 0.049), whereas B symptom was significantly associated with PFS (OR = 11.79, P = 0.049). In the 10 patients with the systemic usage of rituximab, bilateral intervention could improve median OS from 16 to 96 months (P = 0.032). The study provides preliminary evidence on bilateral intervention in testes in the rituximab era and validates common prognostic factors for Chinese PTL patients.

Nivolumab (Anti-PD1) Therapy for Relapsed/ Refractory Primary Central Nervous System Lymphoma and Primary Testicular Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL) are rare and aggressive extranodal non-Hodgkin lymphomas with shared molecular features and a poor prognosis. PCNSL is currently treated with high-dose methotrexate (HD-MTX) based induction chemotherapy. Younger patients who are healthy and eligible for consolidation treatment are considered for whole brain radiation (WBRT) or high-dose chemotherapy with autologous stem-cell transplant (ASCT). Despite this, nearly 50% of patients with PCNSL relapse within 2 years of diagnosis and one third of patients have primary refractory disease. PTL is treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). However, almost 50% of patients with PTL progress after induction treatment, frequently with CNS or contralateral testicular involvement. Treatment options are limited for patients with recurrent and refractory PCNSL or PTL, and the majority of patients ultimately die of their disease.We recently identified frequent 9p24.1/ PD-L1(CD274)/ PD-L2 (PDCD1LG2) copy number alterations and additional translocations in PCNSL and PTL (Chapuy and Roemer et al Blood 2016; 127:869-81). These genetic alterations are associated with increased expression of the programmed cell death protein 1 (PD-1) ligands, PD-L1 and PD-L2. Activation of PD-1 signaling by PD-L1 or PD-L2 binding leads to a reversible state of T-cell "exhaustion" characterized by decreased T-cell receptor signaling, reduced T-cell proliferation and survival, perturbed metabolism and altered transcription factor expression. The activity of PD-1 blockade in other lymphomas with 9p24.1 alterations such as classical Hodgkin's lymphoma prompted us to test the efficacy of this approach in PCNSL and PTL.Patients and Methods: We treated 5 patients with recurrent/refractory PCNSL and PTL with off-label Nivolumab, a humanized IgG4 monoclonal antibody checkpoint inhibitor that targets PD-1 and blocks binding by PD-L1 or PD-L2. Median age was 64 (range, 54-85) years with a median Karnofsky Performance Score (KPS) of 70 (40-80) %. Four patients had multiply recurrent disease (3 patients with PCNSL and 1 patient with PTL and CNS relapse); 1 patient had primary refractory PCNSL. All patients had been treated with standard of care treatments and had no other available options. Prior therapies included HD-MTX based chemotherapy, pemetrexed, high-dose cytarabine, WBRT and thiotepa-based chemotherapy followed by ASCT. All patients signed informed consent and were treated with nivolumab at 3mg/kg intravenously every 2 weeks. Only 1 patient received corticosteroids (dexamethasone 2mg daily) during initial nivolumab treatment; steroids were rapidly tapered and discontinued in 4 weeks. Additionally, 1 patient received 3 doses of rituximab and 2 others received WBRT.All patients had objective radiographic responses to treatment with nivolumab, including 4 complete responses and 1 partial response. The patient with CNS relapse from PTL had complete radiographic resolution of CNS abnormalities with persistent intraocular disease that required vitrectomy. All responses were confirmed at repeat restaging. The median number of nivolumab treatments to objective radiographic response was 3 (range, 2-4). The 4 patients who were symptomatic at the initiation of nivolumab therapy had complete or near-complete resolution of neurologic signs/symptoms and a marked improvement in KPS. All patients are alive and remain progression-free at this time. Four patients continue to receive treatment. The median progression-free survival is 9 (range, 7-11) months.Conclusion: Our pilot series indicates that nivolumab is active in primary refractory and relapsed/refractory PCNSL and PTL with CNS relapse. Based on our preclinical molecular data and these pilot clinical results, a multi-institutional phase 2 open-label, single-arm trial of nivolumab in recurrent and refractory PCNSL and PTL patients (CA209-647) is scheduled to open shortly. DisclosuresLaCasce:Forty Seven: Consultancy; Seattle Genetics: Consultancy. Armand:Infinity Pharmaceuticals: Consultancy; Merck: Consultancy, Research Funding; Pfizer: Research Funding; Roche: Research Funding; Sequenta Inc: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Shipp:Bayer: Research Funding; Merck, Gilead, Takeda: Other: Scientific Advisory Board; Cell Signaling: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding.

Primary testicular lymphoma—A single center experience and review of literature

ObjectiveThe purpose of this study is to evaluate the clinical characteristics, pathology, treatment outcomes, and survival of primary testicular lymphoma (PTL) patients treated at our hospital after 1990. Related literature was reviewed. Materials and methodsWe retrospectively enrolled patients diagnosed with PTL between January 1990 and September 2013 in our institute. Clinical features, pathology, and overall survival were analyzed. Results24 patients were enrolled. They had a mean age at diagnosis of 65.0 years (range 10–84 y), mean follow-up duration 57.0 months (range 3–182 mo), and median overall survival of 38 months (range 4.0–184.7 mo). The most common pathology subtype was diffuse large B-cell lymphoma (n = 21, 87.5%). Fourteen patients (58.3%) achieved complete remission of disease and five patients (20.8%) achieved partial remission after treatment. Three patients had a relapse of disease after complete remission: one in the brain parenchyma, one in the pelvis soft tissue and omentum, and one in the left pyriform muscle. Three patients had metastasis after partial remission of disease: two in the brain parenchyma and one in the cauda equina. By univariate analysis, the factors significantly associated with superior overall survival were primary tumor diameter < 7.5 cm, serum lactate dehydrogenase ≤ 250 U/L, Ann-Arbor Stage IE/II, and International Prognostic Index (IPI) ≤ 1 (p < 0.05). Rituximab-containing treatment did not show overall survival benefits in our series. By multivariate analysis, IPI ≤ 1 showed statistical significance (p = 0.019), suggesting a potential prognostic value of IPI in evaluating PTL patients. ConclusionsThe overall survival of PTL patients is poor, especially those with extensive disease (Stage III/IV). The IPI have a prognostic role in PTL. The use of rituximab in the treatment regimen of PTL does not seem to improve survival in our series.

PRIMARY TESTICULAR LYMPHOMA: A SINGLE CENTRE EXPERIENCE

Primary testicular lymphoma (PTL) is an uncommon and aggressive form of extranodal non-Hodgkin's lymphoma (NHL). We aimed to analyse the clinicopathological characteristics and outcomes of our PTL cases. A review was made of the medical records of 339 NHL patients who were treated in the Medical Oncology Department between January 2005 and December 2013. 8 PTL patients were identified from the 339 NHL patients. The average age of the patients was 67.7 ± 7.9 years (range 53-79 years). The mean follow-up time was 24.8 months (range 7-98 months). Inguinal orchiectomy was performed as a diagnostic and initial therapy and all the patients underwent 4-6 cycles of chemoimmunotherapy consisting of cyclophosphamide, doxorubicin, vincristine and prednisone plus rituximab. 4 of 8 patients received intrathecal prophylactic chemotherapy and 6 of 8 patients continued contralateral testis irradiation. Relapse occured in only 1 patient in central nervous system after 6 months who had not received intrathecal prophylaxis. No contralateral testis relapse was observed. Primary testicular NHL is an uncommon entity and we evaluated 8 patients; with one relapse in central nervous system and no relapse in the contralateral testis.

Single-Center Experience in the Treatment of Primary Testicular Lymphoma

Background: Primary testicular lymphoma (PTL) is a rare and highly aggressive extranodal non-Hodgkin's lymphoma. Patients and Methods: We evaluated the clinical and histopathological features and outcomes of 10 PTL patients treated in the period of 2003-2013 with multimodal therapy (rituximab, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), intrathecal prophylaxis, irradiation of the contralateral testis) following orchiectomy. Results: Complete remission was achieved in 8 patients after first-line therapy while 2 patients had disease progression. The median follow-up duration was 30 months (range 6-110 months). Relapse occurred in 3 patients. 1 patient relapsed in the contralateral testis, while the other 2 patients relapsed to the skin and the central nervous system (CNS), respectively. The time to relapse was 2, 8, and 9 months. Patients with disease progression and relapse received ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin) as salvage treatment, except for 1 patient who was treated with palliative radiotherapy. After second-line therapy, only 1 patient had a short partial remission of 2 months. The median overall survival was 48 months, and the mean progression-free survival was 36 months (the median was not reached). Conclusions: We evaluated 10 patients with PTL treated with rituximab plus CHOP, prophylactic intrathecal chemotherapy, and prophylactic irradiation of the contralateral testis, resulting in good outcome and low incidence of relapse in the contralateral testis; however, the benefit of intrathecal chemotherapy is not yet confirmed.

A retrospective study of clinical characteristics and prognostic factors of primary testicular lymphoma

ObjectiveTo assess the clinical characteristics, prognostic factors, and treatment outcomes of primary testicular lymphoma (PTL). Materials and MethodsWe reviewed the medical records of PTL patients diagnosed between January 2000 and May 2012 at four hospitals in Taiwan. The following data were collected and analyzed: patient age at diagnosis, B symptoms (fever, night sweats, and/or weight loss), tumor localization (diffuse or testis alone), tumor site (left, right, or bilateral), stage of disease, histological pattern, International Prognostic Index, treatment method and outcome, relapse, and survival time. Kaplan–Meier curves were constructed to assess the effects of various factors on patient survival. ResultsThirty patients with PTL were included in this study. The median age at diagnosis was 62.5 years (range: 19–89 years) and median overall survival (OS) was 44 months. The majority of the patients had unilateral lymphoma, stage I/II disease, and diffuse large B-cell lymphoma. An absence of B symptoms, limited disease stage, lymphoma localized to testis only, and orchidectomy were considered to be significantly favorable prognostic factors of OS (p < 0.05). The PTL treatment regimen varied among patients and included orchidectomy, chemotherapy, and/or radiotherapy. Interestingly, although 50% patients achieved complete remission (CR) post-treatment, relapse was observed in 42% patients during the follow-up period. Nonetheless, patients who initially underwent orchidectomy appeared to have a significantly better survival rate, whereas chemotherapy proved more advantageous for those with the diffuse-type PTL. ConclusionPTL is characterized by unique clinical features and prognostic factors. Despite differing treatment regimens, 50% of patients achieved CR. Patients with testicular localization who underwent orchidectomy may achieve better outcomes, whereas chemotherapy proved to be beneficial in those with diffuse-type PTL.

Three prognostic factors influence clinical outcomes of primary testicular lymphoma

The standard treatment of primary testicular lymphoma (PTL) has not been well established. Our study aimed to evaluate the relationship between the prognostic factors and clinical outcomes of PTL. We retrospectively reviewed the clinical records of 43 PTL patients and included the 39 patients who were diagnosed with primary testicular diffuse large B cell lymphoma (DLBCL) for analysis of prognostic factors and assessment of treatment modalities. Cox regression analysis showed that poor ECOG performance status (PS, ≥2), infiltration of adjacent tissues (spermatic cord, epididymis, or scrotum), and bulky disease (tumor mass, >9cm) were independent predictors of worse overall survival (OS) for primary testicular DLBCL. According to these three factors, the patients were divided into two groups. Rituximab was found to significantly prolong progression-free survival (PFS) in the low-risk group (P = 0.044) but not in the high-risk group (P = 0.748). And the combination therapy for CNS prophylaxis significantly prolonged the survival in the high-risk group (P = 0.005 for OS; P = 0.004 for PFS), but not in the low-risk group (P = 0.092 for OS; P = 0.191 for PFS). ECOG performance status, infiltration of adjacent tissues, and bulky disease are practical prognostic factors of survival in patients with primary testicular DLBCL. The addition of rituximab is more important for the patients without the prognostics factors, and the combination CNS prophylaxis is more significant for the patients with the prognostics factors.