Testicular Diffuse Large B-cell Lymphoma Research Articles

A case of testicular diffuse large B-cell lymphoma with late relapse in the skin: the critical role of comparative phenotypic, clonality, and cytogenetic testing

A case of testicular diffuse large B-cell lymphoma with late relapse in the skin: the critical role of comparative phenotypic, clonality, and cytogenetic testing

IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma

AbstractPrimary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

Testicular diffuse large B-cell lymphoma. Clinical lecture and case report

Testicular diffuse large B-cell lymphoma. Clinical lecture and case report

The Outcome of Diffuse Large B-Cell Lymphoma Patients with Testicular Involvement - Real World Data

Introduction: Patients (pts) with testicular lymphoma (TL) have an increased risk of central nervous system (CNS) relapse. In rituximab era, the reported incidence vary from 10% (in limited disease) to 25% (advanced disease). More data is needed to guide the managment of TL pts in current era. Optimal strategy for CNS relapse prevention is uncertain. Methods: We studied consecutive pts diagnosed between 2000 and 2022 with testicular diffuse large B-cell lymphoma (DLBCL) prospectively observed in the Czech Lymphoma Study Group Project NiHiL (Clinical Trial gov. NCT03199066). Objectives were to analyze the cumulative incidence of CNS relapse, time to CNS relapse, PFS and OS. The impact of various treatment strategies on CNS relapse was analyzed. Results: We identified 229 pts with testicular involvement: 157 pts with primary testicular lymphoma (PTL) in clinical stage I or II and 72 pts in advanced stage (AD) III or IV. Median age was 70 years (range 33 - 87). Rituximab-based chemotherapy received 192 (83.8%) pts including 127 (81%) cases with PTL. Following localized treatments were used more often in PTL compared to AD: unilateral orchiectomy [148 (94.3%) vs. 47 (65.3%); p < 0.0001], testicular irradiation (RT) [116 (61.7%) vs. 40 (38.7%); p = 0.005]. Most patients (85%) received some form of CNS prophylaxis. There were similar rates in use of prophylactic methotrexate (MTX) between PTL and AD (p = 0.88): intrathecal (i.t.) MTX 64 (40.8%) vs. 29 (40.3%), intravenous (i.v.) MTX with or without cytarabine 20 (12.8%) vs. 7 (9.7%); combined i.t. and i.v. MTX 38 (24.2%) vs. 20 (27.8%). Out of 229 cases 25 (15.9%) PTL and 11 (15.3%) AD pts did not receive any CNS prophylaxis. Median follow-up was 51.8 months.Overall 63 (27.5%) pts relapsed including 14 (6.1%) relapses in CNS. Median time to CNS relapse was 21.9 months and to other systemic relapse was 14.7 months (p = 0.63). The 5-year cumulative incidence of CNS relapse in PTL was 4.55% (95% confidence interval [CI], 0.1 - 28.6) and in AD 12.07% (95% CI 0.8 - 39.6), respectively. In univariate analyses, MTX prophylaxis (i.v. and/or i.t.) and testicular RT had no impact on CNS relapse (p = 0.49 and p = 0.60, respectively). Orchiectomy was the single significant factor associated with lower risk of CNS relapse in PTL (hazard ratio [HR] = 0.11[95% CI 0 - 0.124]; p = 0.001). Rituximab significantly reduced CNS relapse in AD with testicular involvement (HR = 0.1002 [95% CI 0.0 - 0.45]; p = 0.0005). Out of 14 pts with CNS relapse 8 died due to lymphoma progression. Median progression-free survival (PFS) and overall survival (OS) in PTL was significantly better when compared to AD (PFS 92.9 vs. 28.1 months, p < 0.0006; OS 108.7 vs. 56.7 months, p = 0.0002). Median PFS2 and OS2 since CNS relapse was dismal in AD compared to PTL (PFS2 1.6 vs. 37.8 months, p = 0.04 and OS2 2.3 vs. 37.8 months, p = 0.05). Conclusions: The rate of CNS relapses in PTL and advanced disease with testicular involvement is lower than previously reported. This study confirmed a significant favorable impact of rituximab in prevention of CNS relapse. Notably, methotrexate prophylaxis i.v. or i.t. did not alter the CNS relapse risk. Prognosis of CNS relapse is particularly poor in advanced disease. This work was supported by grant AZV NU21-03-00411 from the Ministry of Health of the Czech Republic and by the Cooperatio Program, research area “Oncology and Haematology”

Improved Survival with Rituximab-Based Chemoimmunotherapy in Patients with Primary Testicular Diffuse Large B-Cell Lymphoma

Background: Primary testicular lymphoma (PTL) accounts for 1% to 2% of non-Hodgkin's lymphomas. Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of PTL, accounting for 80% to 98% of cases. The introduction of rituximab was a breakthrough in DLBCL treatment. However, the impact of rituximab on primary testicular DLBCL (PT-DLCBL) is controversial. A study by Gundrum et al (Gundrum JD, et al. J Clin Oncol 2009) found that PT-DLBCL survival did not improve in the rituximab era (i.e., after 2000). However, that study was based on a Surveillance, Epidemiology, and End Results (SEER) database cut-off of 2005. The follow-up period of PT-DLBCL patients in the rituximab era was relatively short, at only 4 years (from 2001 to 2005). Considering the wide use of rituximab in all kinds of DLCBL, we conducted a study based on the SEER database to evaluate the potential impact of the introduction of rituximab on PT-DLBCL. Methods: Data from the SEER 13 registries were analyzed in this study. Cases with PT-DLBCL diagnosed from 1992 to 2018 were included. Baseline characteristics, including age at diagnosis, laterality (left, right, bilateral), age, race, Ann Arbor stage, SEER cause-specific death classification, survival months, and vital status, were collected. Cancer-specific survival (CSS) was used as the study endpoint and defined as the time from diagnosis to death from DLBCL or last follow-up. The Kaplan-Meier method was used to build survival curves and the log-rank test used to compare groups. All p values were two-sided, and p-values < .05 considered statistically significant. All analyses were conducted using GraphPad PRISM 6. Results: A total of 961 patients were included in this analysis. Among them, 271 were diagnosed from 1992 through 2000 (pre-rituximab era) and 690 from 2001 through 2018 (rituximab era). In all, 435 patients showed unilateral left-side testicular involvement, 455 right-side, 63 bilateral, and 8 unknown. At last follow-up, 489 patients had died of PT-DLBCL. Patients diagnosed in the pre-rituximab era had more stage I disease than their counterparts in the rituximab era. No difference was found in age, race, or laterality across the two eras. For the entire cohort, there was a significant improvement in CSS in the rituximab era compared with the pre-rituximab era. The median CSS in the pre-rituximab era was 98 months compared to not reached in the rituximab era ( p = .001) (Figure 1A). We also compared the CSS of patients in different stages: early stage (I/II) or advanced stage (III/IV) in the pre-rituximab and rituximab eras. We found that CSS improved significantly in either early or advanced stage (early stage, p < .0017; advanced stage, p = .026; Figure 1B and 1C). We also explored the role of laterality in survival of PT-DLBCL. Compared with the pre-rituximab era, CSS of either left-side (Figure 1D) or right-side (Figure 1E) PT-DLBCL improved significantly (left-side, p < .001; right-side, p = .04) in the rituximab era. The introduction of rituximab decreased CSS by about 50% in patients with left-side PT-DLBCL but only about 30% in those with right-side disease, which indicated that patients with left-side (vs right-side) PT-DLBCL derived greater survival benefit from the introduction of rituximab. Conclusions: Survival of PT-DLBCL patients improved significantly in the rituximab era, with the survival curve reaching a plateau from the tenth year after treatment. Patients with left-side (vs right-side) PT-DLBCL derived greater survival benefit from the introduction of rituximab.

Development and validation of a survival nomogram in patients with primary testicular diffuse large B-cell lymphoma.

We developed and validated a nomogram for overall survival (OS) and cancer-specific survival (CSS) prediction in patients with primary testicular diffuse large B-cell lymphoma (PT-DLBCL). Patients diagnosed with PT-DLBCL were selected from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors were analyzed to establish a nomogram of OS and CSS. Patients were reclassified into high- and low-risk groups; survival was compared using Kaplan-Meier curves and log-rank tests. We collected 1099 PT-DLBCL cases (2000-2019) from SEER and randomized into training (n = 771) and validation (n = 328) cohorts. In univariate and multivariate Cox regression analyses, five prognostic indicators (age, treatment modality, diagnosis year, Ann Arbor stage, laterality) were used to establish a nomogram of OS and CSS. The nomogram demonstrated excellent discrimination and calibration, with concordance indices in the training and validation cohorts of 0.702 (95% confidence interval [CI], 0.677-0.727) and 0.705 (95% CI 0.67-0.74) for OS and 0.694 (95% CI 0.663-0.725) and 0.680 (95% CI 0.63-0.72) for CSS. The calibration curve and ROC analysis indicated good predictive capability of the nomogram. The constructed prognostic model showed good predictive value for PT-DLBCL to assist clinicians in developing individualized treatment strategies.

Unusually aggressive primary testicular diffuse large B-cell lymphoma initially presenting as systemic disseminating metastases in older adult men: a case report.

Herein, the authors describe the case of a 64-year-old man with the chief complaint of a painless unilateral scrotal mass. Computed tomography scans of the abdomen and a pelvic examination demonstrated a left testicular tumor with multiple lymphadenopathies partially aggregated in the para-aortic area and disseminated to multiple soft tissues and organs. Subsequently, the patient underwent a left radical orchiectomy. Pathological and immunohistochemical examinations confirmed the diagnosis of left PT-DLBCL with systemic disseminating metastases. PTL often aggressively spreads to other extranodal organs, such as the contralateral testis, central nervous system, lung, pleura, Waldeyer's ring, and soft tissues. In men over 60 years of age, PT-DLBCL is the most common testicular malignancy. However, extensive systemic metastasis as the initial presentation is extremely rare. PT-DLBCL has a dismal prognosis and requires radical orchiectomy followed by multimodal therapy and central nervous system prophylaxis or systemic intervention to improve survival. The diagnosis of PT-DLBCL through preoperative and imaging examinations is often challenging. Thus, histopathology and immunohistochemical markers play a crucial and valuable role in the definite diagnosis and differential diagnosis of PTLs.

A rare testicular diffuse large B-cell lymphoma case with neurological initial presentation.

A rare testicular diffuse large B-cell lymphoma case with neurological initial presentation.

Comparison of International Prognostic Indices and Validation Study for Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

ABSTRACT In diffuse large B-cell lymphoma (DLBCL), patients needing new alternative regimens in first-line treatment should be selected with better risk classification. After International Prognostic Index (IPI), Revised-IPI (R-IPI), National Comprehensive Cancer Network (NCCN)-IPI, and Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO)-IPI, have been developed to improve risk predictions. This study compared performances of four prognostic indices concerning differentiation of overall survival (OS), the most critical endpoint. The study was conducted on 116 patients diagnosed with DLBCL. Patients with primary nervous system and testicular DLBCL, and post-transplant lymphoproliferative disorders, were excluded. The fitting of prognostic indices for database and the prediction of patient discrimination were compared using Akaike’s information criterion and concordance index. Of the study cohort, 63.8% were male, the median age was 56 (18-88), and median follow-up term was 45.6 (0.3-75.2) months. All factors, constituting IPI and R-IPI scores, demonstrated a significant difference in OS. Involvements of the extranodal regions specified in NCCN-IPI and elevated serum beta-2 microglobulin levels in GELTAMO-IPI had prognostic significance (p= 0.005 and p= 0.040, respectively). Each of the four prognostic indices, resulted in risk groups with significantly different OS. R-IPI provided the best fit for database, while NCCN-IPI provided the best discrimination between patients with high and low OS. Although NCCN-IPI provides the best discrimination between patients with short and long OS, using original IPI still seems acceptable in the rituximab era. Integration of tumor molecular characteristics into NCCN-IPI may better characterize high-risk group in new treatment approaches. Keywords: International Prognostic Index, National Comprehensive Cancer Network, Validation, Diffuse Large B-Cell Lymphoma, Rituximab

What factors are associated with the prognosis of primary testicular diffuse large B-cell lymphoma? A study based on the SEER database.

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL) is a relatively rare urological tumor with a high degree of malignancy and a poor prognosis. This study aimed to investigate the prognostic risk factors for survival of patients with PT-DLBCL, and then to construct a predictive model and verify its reliability. First, we selected subjects from the SEER database (2000-2018) and analyzed the survival of PT-DLBCL patients by Kaplan-Meier test. Then, we analyzed prognostic factors by Cox regression. Finally, the data from the training cohort were used to construct a prediction model and represented with a nomogram. We evaluated the nomogram using the consistency index (C-index), decision curve analysis (DCA), and the area under the subject operating characteristic curve (ROC). In addition, calibration curves were plotted to assess the agreement between the column plot model and the actual model. We identified five independent risk factors for patient prognosis affecting OS and CSS in patients with PT-DLBCL by univariate and multivariate analysis, including age, transversality, Ann Arbor staging, chemotherapy, and radiotherapy. According to the above factors, we constructed prognostic nomograms, and found that age contributed the most to the survival of patients with PT-DLBCL. The C-indexes for the nomogram of OS and CSS in the training cohort were 0.758 (0.716-0.799) and 0.763 (0.714-0.812), and in the validation cohort were OS and CSS 0.756 (0.697-0.815) and 0.748 (0.679-0.817). We produced the first nomogram of PT-DLBCL, and it can be used to evaluate the CSS and OS of patients to determine the prognosis of patients.

Real-World Data Analysis of Survival Outcomes and Central Nervous System Relapses in Testicular Diffuse Large B Cell Lymphoma.

Primary testicular lymphoma is a rare type of non-Hodgkin lymphoma, mostly of the diffuse large B cell lymphoma (DLBCL). Although a consensus on standard treatment has been established, unresolved issues remain, such as recurrence in the central nervous system (CNS). We retrospectively analyzed the clinical characteristics and survival outcomes of 65 testicular DLBCL patients according to clinical settings and treatment modalities. The median age of the patients in our study was 65 years, and two-thirds of them had disease limited to one testis. There was no right or left lateralization of testicular involvement. Over a median follow-up of 53.9 months (95% confidence interval 34.0-73.7 months), patients with stage I disease and a low international prognostic index score showed better survival outcomes than those in other categories. Orchiectomy, six cycles of chemotherapy, and radiation therapy (RT) to the contralateral testis demonstrated survival benefits, whereas CNS prophylaxis therapy did not reduce CNS recurrence. During the follow-up period, the survival curves showed continuous decline, mostly due to disease progression. CNS recurrence was observed in 15% of patients, and parenchymal involvement was dominant. However, no factors were associated with CNS recurrence in our analyses. Although our molecular analyses were performed in a small number of patients, MYD88, CD79B, and PIM1 mutations were frequent. In our study, treatment with orchiectomy, six cycles of immunochemotherapy, and contralateral RT was effective. However, because CNS prophylaxis is an essential part of testicular DLBCL management, better treatment strategies than intrathecal therapy are required.

Relapse of Ocular Lymphoma following Primary Testicular Diffuse Large B-cell Lymphoma

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The single-cell landscape reveals unique tumor subsets and microenvironments associated with poor clinical outcomes in primary testicular diffuse large B-cell lymphoma

The single-cell landscape reveals unique tumor subsets and microenvironments associated with poor clinical outcomes in primary testicular diffuse large B-cell lymphoma

Clinicopathologic characteristics and prognostic analysis of testicular diffuse large B-cell lymphoma

Objective: To analyze the clinicopathologic characteristics and prognosis of testicular diffuse large B-cell lymphoma (DLBCL) . Methods: A retrospective analysis was performed on 68 patients with testicular DLBCL admitted to Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine from October 2001 to April 2020. The gene mutation profile was evaluated by targeted sequencing (55 lymphoma-related genes) , and prognostic factors were analyzed. Results: A total of 68 patients were included, of whom 45 (66.2% ) had primary testicular DLBCL and 23 (33.8% ) had secondary testicular DLBCL. The proportion of secondary testicular DLBCL patients with Ann Arbor stage Ⅲ-Ⅳ (P<0.001) , elevated LDH (P<0.001) , ECOG score ≥ 2 points (P=0.005) , and IPI score 3-5 points (P<0.001) is higher than that of primary testicular DLBCL patients. Sixty-two (91% ) patients received rituximab in combination with cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP) -based first-line regimen, whereas 54 cases (79% ) underwent orchiectomy prior to chemotherapy. Patients with secondary testicular DLBCL had a lower estimated 5-year progression-free survival (PFS) rate (16.5% vs 68.1% , P<0.001) and 5-year overall survival (OS) rate (63.4% vs 74.9% , P=0.008) than those with primary testicular DLBCL, and their complete remission rate (57% vs 91% , P=0.003) was also lower than that of primary testicular DLBCL. The ECOG scores of ≥2 (PFS: P=0.018; OS: P<0.001) , Ann Arbor stages Ⅲ-Ⅳ (PFS: P<0.001; OS: P=0.018) , increased LDH levels (PFS: P=0.015; OS: P=0.006) , and multiple extra-nodal involvements (PFS: P<0.001; OS: P=0.013) were poor prognostic factors in testicular DLBCL. Targeted sequencing data in 20 patients with testicular DLBCL showed that the mutation frequencies of ≥20% were PIM1 (12 cases, 60% ) , MYD88 (11 cases, 55% ) , CD79B (9 cases, 45% ) , CREBBP (5 cases, 25% ) , KMT2D (5 cases, 25% ) , ATM (4 cases, 20% ) , and BTG2 (4 cases, 20% ) . The frequency of mutations in KMT2D in patients with secondary testicular DLBCL was higher than that in patients with primary testicular DLBCL (66.7% vs 7.1% , P=0.014) and was associated with a lower 5-year PFS rate in patients with testicular DLBCL (P=0.019) . Conclusion: Patients with secondary testicular DLBCL had worse PFS and OS than those with primary testicular DLBCL. The ECOG scores of ≥2, Ann Arbor stages Ⅲ-Ⅳ, increased LDH levels, and multiple extra-nodal involvements were poor prognostic factors in testicular DLBCL. PIM1, MYD88, CD79B, CREBBP, KMT2D, ATM, and BTG2 were commonly mutated genes in testicular DLBCL, and the prognosis of patients with KMT2D mutations was poor.

MP01-17 THALLIUM EXPOSURE TO 3D HUMAN TESTICULAR ORGANOIDS TO STUDY miRNA BIOMARKER EXPRESSION AND DOWNSTREAM mRNA REGULATION

You have accessJournal of UrologyCME1 Apr 2023MP01-17 THALLIUM EXPOSURE TO 3D HUMAN TESTICULAR ORGANOIDS TO STUDY miRNA BIOMARKER EXPRESSION AND DOWNSTREAM mRNA REGULATION Janmejay Hingu, Adam Cohen, Nima Pourhabibi Zarandi, Anthony Atala, and Hooman Sadri-Ardekani Janmejay HinguJanmejay Hingu More articles by this author , Adam CohenAdam Cohen More articles by this author , Nima Pourhabibi ZarandiNima Pourhabibi Zarandi More articles by this author , Anthony AtalaAnthony Atala More articles by this author , and Hooman Sadri-ArdekaniHooman Sadri-Ardekani More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003212.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Previous studies have demonstrated that heavy metal exposure can negatively impact male infertility and testicular carcinogenesis due to increased oxidative stress. This can lead to molecular dysfunction, part of which is mediated by small non-coding RNA known as miRNA, which may serve as potential biomarkers of disease. We present a miRNA analysis following thallium exposure to three-dimensional human testicular organoids (HTOs). METHODS: 3D HTOs were created from 2D testicular cell cultures derived from three brain-dead adult patients. HTOs were exposed to either thallium or ultrapure water. The miRNA analysis was performed using the Nanostring nCounter Human v3b miRNA panel, representing 827 unique miRNA probes. Nanostring nSolver 4.0 was used to execute target normalization with the geometric mean of the top 100 miRNAs detected, followed by background subtraction of 57 counts, which was the average of exogenous negative controls in the panel plus two standard deviations. All miRNAs with average counts <5 within a sample group were excluded to ensure robust expression. Qiagen Ingenuity Pathway Analysis (IPA) miRNA target filter was used to select for experimentally observed mRNAs associated with reproductive pathology and testis cells. RESULTS: 9 miRNAs were uniquely expressed within the thallium HTOs compared to 3 in the control. Seven of the 107 miRNAs expressed in both were significantly differentially expressed (miR-574-3p, miR-374a-5p, miR-423-5p, miR-106a-5p+miR-17-5p, miR-29b-3p, and miR-26b-5p were upregulated; miR-145-5p was downregulated). However, none survived the application of the false discovery rate. IPA miRNA target filter showed that these miRNAs regulated 161 mRNAs, including BCL2, MYC, CDKN1A, CCNA2, CCND1, and E2F1. CONCLUSIONS: Certain miRNAs have previously been linked to male infertility (miR-145-5p, miR-574-3p, miR-26b-5p), asthenozoospermia (miR-423-5p), and testicular diffuse large B-cell lymphoma (miR-17-5p). Previous studies have also demonstrated that oxidative stress from thallium-containing compounds can induce apoptosis by affecting Bcl-2 (BCL2) expression and activate nucleolar stress by altering c-Myc (MYC) and p21 (CDKN1A) expression. Thallium has also been shown to modify cell cycle progression through cyclin A (CCNA2), cyclin D1 (CCND1), and E2F-1 (E2F1). Although only 4 of these miRNAs have been implicated in male infertility and testicular cancer, further studies may elucidate other miRNAs and their downstream regulation of mRNA. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e9 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Janmejay Hingu More articles by this author Adam Cohen More articles by this author Nima Pourhabibi Zarandi More articles by this author Anthony Atala More articles by this author Hooman Sadri-Ardekani More articles by this author Expand All Advertisement PDF downloadLoading ...

Clinical Characteristics and Prognosis of Patients with Primary Testicular Diffuse Large B-Cell Lymphoma

To analyze the clinical manifestations, therapeutic response and prognosis of patients with primary testicular diffuse large B-cell lymphoma (PT-DLBCL). Thirty-eight patients with PT-DLBCL were enrolled, who hospitalized from January 2010 to April 2021, and their clinical characteristics, treatment regimen and efficacy were collected and analyzed retrospectively. The median age of the patients was 56 years old (ranged from 38 to 79 years). There were 4 cases (10.5%) with bilateral lesions, 13 cases (34.2%) with left lesions, and 21 cases (55.3%) right lesions. There were 2 cases(5.3%) with B symptoms, 6 cases (15.8%) of germinal center B-cell-like(GCB) subtype and 32 cases(84.2%) of non-GCB subtype. Efficacy was evaluated in 36 cases, including 10 cases with CHOP regimen, 21 cases with R-CHOP regimen (7 cases were treated with rituximab combined with high-dose methotrexate injection chemotherapy at intervals of R-CHOP regimen), and 5 cases with other regimens. In 36 patients, the efficacy evaluation of initial chemotherapy showed that the overall response rate (ORR) was 86.1%, 29 cases (80.6%) reached complete response (CR), and 2 cases (5.5%) reached partial response (PR). The R-CHOP group was superior to CHOP group in ORR (95.2% vs 60.0%, P=0.027) and CR (90.4% vs 50.0%, P=0.022). Of the 36 patients, 7 cases had central nervous system(CNS) recurrence and 4 cases had contralateral testicular recurrence. Compared with the CHOP group, the CNS recurrence rate in the R-CHOP group was significantly lower (4.8% vs 50.0%, P=0.007), and the testicular recurrence rate in the R-CHOP group was also lower than the CHOP group, but the difference was not statistically significant (4.8% vs 30.0%, P=0.087). The median follow-up time was 27(3-135) months, and the 5-year PFS and OS were 71% and 74%, respectively. Kaplan-Meier univariate analysis showed that the R-CHOP regimen significantly improved the patients' PFS (P=0.024) and OS (P=0.025) compared with the CHOP regimen. PT-DLBCL is mainly treated with comprehensive treatment. Compared with CHOP regimen, R-CHOP regimen can improve the CR rate and ORR, reduce CNS recurrence and contralateral testicular recurrence, and improve the patients' survival. Patients may benefit from high-dose methotrexate combined with rituximab interlaced with R-CHOP regimen.

Primary testicular diffuse large B-cell lymphoma in young patient: an uncommon presentation

Primary testicular lymphoma (PTL) is a rare form of extranodal lymphoma, this neoplasm is the most common malignant tumor of the testis in the elderly age, and the majority of cases are histologically diffuse large B-cell lymphoma (DLBCL), accounting for 80% to 98% of non-hodgkin lymphoma. Patients with primary testicular DLBCL show a continuously high risk of recurrence with no plateau in the survival curves and a tendency to involve other extranodal sites, especially the central nervous system and the contralateral testis. We report a rare and uncommon presentation of a primary testicular diffuse B cell lymphoma in young patient.

Tumor Microenvironment and It's Prognostic Value Is Different in Testicular and Systemic Diffuse Large B-Cell Lymphoma

Testicular diffuse large B-cell lymphoma (T-DLBCL) is an aggressive lymphoid cancer with distinct clinical and biological features. Majority of the cases represent non-GCB phenotype, but the genetic landscape with frequent aberrations in MYD88, NFKBIZ, PDCD1LG2, and CD274 differ from systemic non-GCB DLBCL and highlight the significance of immune-escape and tumor microenvironment (TME). We have previously shown that high T-cell gene expression signature and high tumor-infiltrating lymphocyte (TIL) content translate to better survival in testicular but not in systemic DLBCL. We have also described a subpopulation of T-bet+FoxP3+ Tregs that have a significant adverse impact on survival in T-DLBCL but not in in systemic DLBCL. In order to further characterize the differences in the TME between T- and systemic DLBCL, we used NanoString digital gene expression profiling to assess the expression of 770 immune response genes in 60 T-DLBCL and 84 systemic DLBCL samples. In addition, we used multiplex immunohistochemistry (mIHC) to characterize TILs, tumor-associated macrophages (TAMs), NK-cells, checkpoint molecules, cell proportions, and cell interactions in 80 T-DLBCLs and 192 systemic DLBCLs. Unsupervised hierarchical clustering of the gene expression data revealed clusters of genes with differential expression between T- and systemic DLBCLs. In T-DLBCL, 11 HLA genes were downregulated and genes related to B-cell receptor (BCR) signaling upregulated compared to systemic DLBCL. All T-DLBCL patients that clustered among the patients with systemic DLBCL had high T-cell signature expression, and systemic DLBCL patients that clustered among patients with T-DLBCL had significantly higher Ki-67 expression (p=0.00085). Based on the mIHC data, we observed not only a significantly lower proportion of FoxP3+ Tregs altogether but also a higher proportion of T-bet+FoxP3+ double positive Tregs in T-DLBCL compared to systemic DLBCL, confirming our previous findings on the significant role of T-bet+FoxP3+ double positive Tregs in the T-DLBCL TME. We also observed less TAMs in T-DLBCL TME. Unsupervised hierarchical clustering of the cell interaction data verified that distinct interaction clusters are found and separate the patients into different subgroups. Interactions of cytotoxic T-cells were more commonly seen in T-DLBCL whereas interactions of PD-1 expressing cells and interactions between TILs and TAMs were more frequent in systemic DLBCL. Taken together, our results reveal differences in the TME between T- and systemic DLBCL, and further emphasize the impact of immune escape and distinct immune cells in T-DLBCL. Future studies are ongoing in order to further characterize the cell-to-cell interactions, their association with survival, and TME differences between T- and systemic DLBCL, in particular non-GCB DLBCL.

Untargeted Metabolomics of Cerebrospinal Fluid in Patients with Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is characterized by a high degree of malignancy and poor prognosis. The current diagnostic techniques include cerebrospinal fluid (CSF) metabolomics examination, imaging examination, needle biopsy, etc., but each examination has certain limitations, and it is difficult for the early identification and diagnosis of the disease. In terms of treatment, relapse and refractory, neurotoxicity and drug resistance are still the main problems currently faced. Metabolomics can measure the composition of metabolites and the dynamic changes of metabolites in cell models, tissues, organs or the whole organism, and has been widely used in disease diagnosis, efficacy evaluation, nutrition and other fields. Ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS/ technology) has been be used to observe the metabolites changes in CSF. Here, we aimed to explore the application value of metabolomics in the diagnosis and prognosis evaluation of PCNSL. From January 2021 to December 2021, CSF samples from 37 DLBCL patients were collected in Shengli Oilfield Central Hospital and Shandong Cancer Hospital, including 20 male patients and 17 female patients. These patients fall into 4 groups based on clinical presentations: 12 patients in PCNSL group (CNS group), 5 patients in primary testicular diffuse large B-cell lymphoma (DLBCL) group (TE group), 10 patients in Germinal center B (GCB) cell-like DLBCL without central nervous system infiltration (GCB group), and 10 patients in non-GCB DLBCL group without central nervous system infiltration (non-GCB group). The CSF samples were collected before clinical treatment, and the samples were analyzed with UPLC-HRMS/technology. For data analysis, principal component analysis (PCA) was carried out on the obtained components, and the partial least squares discriminant analysis model (PLS-DA) was used for diversification analysis. Analytes with P<0.05 and VIP>1 were considered differential metabolites. The Venn diagram was used to narrow the range of metabolites. By using MetaboAnalyst 5.0 software, pathway enrichment analysis was performed on the identified differential metabolites in CSF, and the corresponding P value was obtained. The metabolic pathways that have a significant effect in CNS group vs TE group, CNS group vs GCB group and GCB group vs non-GCB group were glycerophospholipid metabolism and sphingolipid metabolism. The metabolic pathway that has a significant effect in CNS group vs non-GCB group and TE group vs non-GCB group was glycerophospholipid metabolism. Fatty acid degradation and fatty acid elongation were the significant effects metabolic pathway in TE group vs non-GCB group. We applied Venn diagrams to narrow the range of differential metabolites. There were 47 differential metabolites in the CSF of patients in the PCNSL group vs the non-PCNSL group (Figure 1). Compared with the non-PCNSL group, 33 metabolites such as 3-Hydroxyisovalerylcarnitine, Hesperetin 3'-O-sulfate, and Arteether were up-regulated and 14 metabolites such as Pentaglutamyl folate, Calcipotriol and N-Hexadecanoylpyrrolidine were down-regulated in the CSF of patients in the PCNSL group. In the CNS infiltration high-risk group and the CNS infiltration low-risk group, there were 16 differential metabolites (Figure 2). Compared with the patients in the CNS infiltration low-risk group, 8 metabolites such as 3-Allylphenol sulfate, p-Aminobenzoic acid and 2,3,4-Trichlorophenol were up-regulated and 8 metabolites such as Palmitaldehyde, Carboxamide and Rioprostil were down-regulated in the CNS infiltration high-risk group. In conclusion, glycerophospholipid, sphingolipid, and fatty acid metabolites were the three most important abnormal lipid metabolites existed in PCNSL. This finding may have some value in the development of diagnosis and prognostic tools for evaluating CSF in patients with PCNSL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Genetic Determinants of Isolated and Systemic Testicular Diffuse Large B-Cell Lymphoma Highlight a Disease Spectrum

Introduction Primary (diffuse) large B-cell lymphoma of the testis (PTL) is an aggressive extranodal B-cell lymphoma characterized by frequent relapses in the central nervous system (CNS) and other extranodal sites. While PTL has now been recognized as a distinct lymphoma in the latest classifications (International Consensus Classification and WHO HAEM5), however, the allowable extent of involvement outside of the testes is unclear from these publications. PTL are largely assigned to the MCD genetic subtype of diffuse large B-cell lymphoma (DLBCL) by LymphGen with frequent MYD88L265P mutations and have 6p loss associated with immune evasion. BCL6 rearrangements (BCL6-R), a feature of BN2, have been associated with an increased risk of CNS relapse (Twa et al., Blood 2021), though the mechanisms enabling tumor establishment in the CNS remain unclear. Here, we provide a characterization of the genomic landscape of DLBCL involving the testes, aiming to understand whether systemic disease is distinct from disease isolated to the testes and whether there are genetic features associated with patient outcomes. Methods Patients with DLBCL involving the testis, treated with R-CHOP immunochemotherapy, were identified in the BC Cancer Lymphoid Cancer database, yielding archival formalin-fixed paraffin-embedded orchidectomy samples from 65 patients. BCL6-R were identified by break-apart fluorescent in situ hybridization (FISH). High confidence simple somatic mutations (SSMs) from whole exome sequencing were selected using a voting approach of four variant callers (Strelka2, Lofreq, Mutect2, SAGE). Candidate copy number alterations (CNAs) were identified using CNVkit and PureCN and high confidence CNAs were determined using GISTIC2.0. LymphGen was run with SSMs to annotate genetic subgroups. Clinical endpoints included time to progression (TTP), disease-specific survival (DSS) and CNS relapse cumulative risk. Results The study cohort had a median age of 72 years (range 26-93) and median follow-up of living patients was 5.5 years. In 30 patients lymphoma was isolated to the testes (Stage IE), 27 had concurrent involvement outside of the testes (Stage II/E-IV), and eight had DLBCL isolated to the testes with low grade lymphoma in the bone marrow (herein labelled "BM" - excluded from isolated vs systemic comparisons). BCL6-R were detected in 29% of the tumors. The majority of the tumors (69%) were assigned to the MCD subgroup by LymphGen with 73% and 66% of tumors harboring MYD88L265P and PIM1 mutations, respectively, though 40% of BCL6-R tumors were assigned to BN2 or Other. To address whether there are biological differences between disease isolated to the testes versus those that also have systemic involvement, we compared tumors from patients with stage I vs II-IV disease. There were no significant differences in the proportions of BCL6-R or LymphGen subgroups. Similarly, there was no difference in CNAs and the mutational landscapes were largely the same, with the exception of two significant differences. There was a significant enrichment for CD58 truncating mutations in stage II-IV (31%; q < 0.1), with a missense mutation observed in one stage IE tumor. Secondly, BTG2 mutations were more frequently observed in stage I disease (37% vs 8%; q < 0.1). We observed significantly superior TTP (Hazard ratio (HR) = 0.46, P < 0.05) and DSS (HR = 0.34, P < 0.01) in patients with stage I vs stage II-IV diseases. In stage II-IV disease, the MCD (n=18) (vs non-MCD (n=9)) subgroup was associated with significantly superior TTP (2-year 72% vs 22% TTP; HR = 0.36, P < 0.05) and DSS (2-year 72% vs 22% DSS; HR = 0.37, P < 0.05) and lower frequency of CNS relapse (13% vs 55% cumulative relapse at 2 years; HR = 0.23, P < 0.05). In contrast, LymphGen subgroup was not prognostic in stage I disease. Conclusion Here, we show that there are very few genetic differences comparing testicular DLBCL isolated to the testes to those with stage II-IV disease. The novel observation of truncating mutations in CD58 exclusively in patients with systemic involvement suggests that these mutations contribute to immune evasion thereby promoting disease outside of the immune privileged site of the testes. Genetic subgroups appear to be associated with outcomes in patients with systemic involvement - an observation that requires validation in a larger cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal