Case Of Large B-cell Lymphoma Research Articles

A case of diffuse large B-cell lymphoma with a large number of multinucleated giant cells

A case of diffuse large B-cell lymphoma with a large number of multinucleated giant cells

Clinicopathologic features and outcomes of diffuse large B-cell lymphoma with extranodal involvement: A retrospective analysis

Background: Extranodal involvement is seen in about 40%–50% of the cases of diffuse large B-cell lymphoma (DLBCL). However, data on the clinicopathological features and outcomes of DLBCL with extranodal involvement, especially in the rituximab era, are scarce from India.Objectives: In this study, we aimed to assess the clinicopathological features and outcomes of DLBCL with extranodal involvement among Indian patients.Materials and Methods: This retrospective study was conducted on patients with DLBCL, registered in the Department of Medical Oncology of the All India Institute of Medical Sciences, Delhi, India, between January 2014 and December 2018. Patients with nodal DLBCL aged more than 18 years, with concomitant extranodal disease in any anatomical site were included. All patients were treated with multiagent chemotherapy with or without rituximab.Results: Median age of the cohort was 50 years (range, 18–86), a male-to-female ratio of 2:1. B-symptoms and bulky disease were seen in 48% and 39% patients, respectively. Bone was the most common site of extranodal involvement observed in 32% patients. Bone marrow involvement was present in 13% patients. Low-risk International Prognostic Index (IPI) was seen in 32% patients and intermediate risk IPI in 38% patients. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-based treatment was used in 80% of the patients and rituximab (R) was used in 73% of the patients. The objective response rate was 76%, with a complete response rate of 65.5%. After a median follow-up of 26 months, the 3-year progression free survival and overall survival (OS) were 65% and 82.7%, respectively. Involvement of the kidney/adrenal gland and central nervous system, high IPI score, and use of non- R-CHOP regimens were associated with a poor OS on the multivariate analysis.Conclusions: The bone is the most common site of extranodal involvement in Indian patients with DLBCL. The outcome of extranodal DLBCL depends on the primary site of disease involvement.

A Case of Diffuse Large B-Cell Lymphoma Successfully Diagnosed Using Multiple Modalities to Evaluate Specimens From Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration

縦隔リンパ節病変の診断に超音波気管支鏡ガイド下針生検（Endobronchial ultrasoundguided transbronchial needle aspiration：EBUS－TBNA）が有用であり，その一助として針洗浄液のセルブロック作成や採取組織のフローサイトメトリーが考慮されるが，両検査の併用はルーティンでは行なわれていない。症例は77歳の女性。X年6月11日に発熱，体動困難，食欲不振にて当院入院。単純CTで石灰化を伴う縦隔リンパ節の腫大，左尿管結石を認めたが明らかな熱源の特定には至らなかった。縦隔リンパ節病変に対してリンパ節結核や悪性リンパ腫を鑑別に挙げEBUS－TBNAを行ない，針洗浄液のセルブロックから悪性リンパ腫を疑った。穿刺針を22Gから19Gに変更し2回目のEBUS－TBNAを行ない，採取組織のフローサイトメトリーの結果を併せてびまん性大細胞型B細胞性リンパ腫（DLBCL）と診断した。縦隔リンパ節結核を疑ったもののEBUS－TBNA検体でセルブロック作成およびフローサイトメトリー検査を行なうことで，DLBCLの診断につながった症例を経験した。

A Case of Diffuse Large B-Cell Lymphoma Showing Poor Prognosis Markers Successfully Treated with Combined Modality Therapy Including Surgical Resection of Cutaneous Tumor on the Cheek

A Case of Diffuse Large B-Cell Lymphoma Showing Poor Prognosis Markers Successfully Treated with Combined Modality Therapy Including Surgical Resection of Cutaneous Tumor on the Cheek

“Double expressor” diffuse large B-cell lymphoma: A case report and literature review

Diffuse large B-cell lymphoma, not otherwise specified, is the most common type of non-Hodgkin lymphoma worldwide, accounting for 30-40% of all lymphomas. It represents a collection of morphologically, genetically and clinically different diseases. Therefore, it can be subdivided into morphological variants, phenotypic subtypes, and molecular or genetic categories. More recently, diffuse large B-cell lymphoma has witnessed advances in molecular profiling and treatment of patients with refractory and relapsed disease. The optimal management requires integrated morphological and immunophenotypic analysis of cell and tissue, along with chromosome and molecular analyses. Double-expressor lymphoma, defined as overexpression of MYC and BCL2 proteins not related to underlying chromosomal rearrangements, accounts for 20% to 30% of Diffuse large B-cell lymphoma cases. In the latest, 5th edition of the World Health Organization Classification of Hematolymphoid Tumors-lymphoid neoplasms, double-expressor lymphoma is not defined as an independent entity, but it has been proven to be a marker for poor outcome in diffuse large B-cell lymphoma. However, the degree of adverse prognosis is lesser than in double-hit lymphomas. Although double-expressor lymphoma feature is confirmed as adverse prognostic marker for diffuse large B-cell lymphoma patients, currently no sufficient data is available to support treatment intensification over standard rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone regimen. Well-designed randomized clinical trials are mandatory in order to properly respond to this substantial clinical dispute.

A case of primary breast diffuse large B cell lymphoma

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin’s lymphoma with limited data. We here report a case of primary breast diffuse large B-cell lymphoma mimicking breast cancer. A 52-year-old woman had a painless mass in her right breast. Fine needle aspiration cytology and core biopsy were performed which suggested malignant features but could not confirm the specific subtype. Excisional biopsy then was conducted revealing non-Hodgkin lymphoma, which was subsequently confirmed with histopathology and diagnosed as diffuse large B-cell lymphoma (DLBCL). A chest computed tomography scan revealed a 3.5 cm sized breast mass with skin thickening and modest lymphadenopathy in the ipsilateral axilla. The patient received six courses of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab) chemotherapy, then whole breast radiation (30Gy in 15 fractions). At 12 months of follow-up, the patient survives with no evidence of disease. No morbidities occurred in this patient during the follow-up period. We briefly review the current practice pattern in patients with primary breast diffuse large B-cell lymphoma.

90Y-ibritumomab Tiuxetan in B-cell Non-Hodgkin Lymphomas: Real-world Data From the United Arab Emirates

PurposeB-cell non-Hodgkin lymphomas (NHLs) are significant contributors to cancer-related mortality. In this single-arm, retrospective cohort study, we aimed to examine the outcomes of a radioimmunotherapeutic modality, 90Y-labeled ibritumomab tiuxetan (90YIT) in B-cell NHLs. Methods and MaterialsWe conducted this study based on data from the United Arab Emirates lymphoma registry. All patients with NHL subjected to 90YIT were eligible for inclusion. The country of research lacked a national autologous stem cell transplantation (ASCT) center, but many ASCT-eligible patients received 90YIT. We investigated overall survival (OS) and event-free survival (EFS), as well as safety outcomes. ResultsBetween 2004 and 2008, 54 of 111 patients with B-cell NHL received radioimmunotherapy. The therapy was applied as first-line treatment in 18 cases (33.3%) and second- or later-line treatment in 36 cases (66.7%). All patients were evaluable for response. The first-line group consisted mainly of follicular lymphoma cases, and 3 of 18 patients died (16.7%) during the follow-up (range, 22-67 months). Median OS was not reached. No progression occurred after treatment (median EFS, 36.5 months [Q1-Q3 range, 30.5-44 months]). The second- or later-line group consisted mainly of diffuse large B-cell lymphoma cases, and 3 of 36 patients died (8.3%) during the follow-up (range, 4-68 months). Median OS was not reached. One case of progression was registered (median EFS: 33 months [Q1-Q3 range, 30.5-44 months]). 90YIT had acceptable short- and long-term safety profiles. ConclusionsThe findings suggest that patients with NHL may benefit from 90YIT as salvage treatment if ASCT is not available; however, this should be validated in randomized studies.

Epstein–Barr-virus-positive large B-cell lymphoma associated with breast implants: an analysis of eight patients suggesting a possible pathogenetic relationship

Breast implant anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm arising around textured breast implants that was recognized recently as a distinct entity by the World Health Organization. Rarely, other types of lymphoma have been reported in patients with breast implants, raising the possibility of a pathogenetic relationship between breast implants and other types of lymphoma. We report eight cases of Epstein–Barr virus (EBV)-positive large B-cell lymphoma associated with breast implants. One of these cases was invasive, and the other seven neoplasms were noninvasive and showed morphologic overlap with breast implant ALCL. All eight cases expressed B-cell markers, had a non-germinal center B-cell immunophenotype, and were EBV+ with a latency type III pattern of infection. We compared the noninvasive EBV+ large B-cell lymphoma cases with a cohort of breast implant ALCL cases matched for clinical and pathologic stage. The EBV+ large B-cell lymphoma cases more frequently showed a thicker capsule, and more often were associated with calcification and prominent lymphoid aggregates outside of the capsule. The EBV+ B-cell lymphoma cells were more often arranged within necrotic fibrinoid material in a layered pattern. We believe that this case series highlights many morphologic similarities between EBV+ large B-cell lymphoma and breast implant ALCL. The data presented suggest a pathogenetic role for breast implants (as well as EBV) in the pathogenesis of EBV+ large B-cell lymphoma. We also provide some histologic findings useful for distinguishing EBV+ large B-cell lymphoma from breast implant ALCL in this clinical setting.

Molecular and Genetic Characterization of Tumor Samples from Patients with Relapsed or Refractory Follicular Lymphoma Identifies Factors Influencing Response to Tazemetostat

Molecular and Genetic Characterization of Tumor Samples from Patients with Relapsed or Refractory Follicular Lymphoma Identifies Factors Influencing Response to Tazemetostat

Primary diffuse large B-cell lymphoma of the prostate: a case report and\xa0review of the\xa0literature

BackgroundPrimary lymphoma of the prostate is an exceedingly rare disease, with diffuse large B-cell lymphoma being the most common known subtype in a small number of reported cases. Due to its low prevalence, there has been a chronic lack of targeted diagnostic guidelines and treatment procedures.Case presentationIn this article, we report a case of primary diffuse large B-cell lymphoma of the prostate in a 70-year-old Asian man who presented with symptoms of urinary tract obstruction. Histological and immunocytochemical studies of transurethral biopsy of the prostate showed diffuse large B-cell lymphoma. The patient was managed by a combination of eight courses of chemotherapy with a regimen including rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone and radiotherapy. Post-chemotherapy computed tomography scans showed complete remission. He remained disease free, until now, 15 months after the end of therapy. We also reviewed and analyzed relevant literature to illustrate the diagnosis, treatment, and prognosis of this disease.ConclusionDiffuse large B-cell non-Hodgkin’s lymphoma originating in the prostate is a rare and highly aggressive disease that lacks specificity in its clinical presentation and is easily misdiagnosed. This disease should be considered clinically in patients with significant prostate enlargement and insignificant prostate-specific antigen elevation. The diagnosis can be clarified with a prostate puncture biopsy. Chemotherapy is the main treatment for patients and may be supplemented with surgical treatment and radiotherapy.

Epstein-Barr Virus-Positive Adrenal Diffuse Large B-Cell Lymphoma after Treatment for Angioimmunoblastic T-Cell Lymphoma.

We report a case of EBV-positive B-cell lymphoma of the adrenal gland after treatment for angioimmunoblastic T-cell lymphoma (AITL)When patients present with signs and symptoms suggestive of relapse after AITL treatment, another biopsy should be performed for the accurate determination of whether these lesions indicate AITL relapse or new-onset of EBV-positive B-cell lymphoma.The involvement of extranodal sites may indicate a poor prognosis of EBV-positive B-cell lymphoma after AITL treatment.

Large B-cell lymphoma with IRF4 rearrangement

Introduction. Large B-cell lymphoma with IRF4 rearrangement is rare disease, recently described in WHO 2017, arising in children and young adults, presenting with enlarged lymph nodes of the head and neck and/or Waldeyer ring. It is characterized by strong expression of MUM1 protein with IRF4 rearrangement.Aim — to present a clinical case of large B-cell lymphoma with IRF4 rearrangement and characterize its clinical, morphological, and cytogenetic features.Main findings. An observation of a patient with a rare case of large B-cell lymphoma with IRF4 rearrangement is presented.In-depth morphological, immunohistochemical analysis, and additional research methods made it possible to establish a correct diagnosis. Features of the case were the predominantly diffuse growth of large tumor cells in the lymph node biopsy with the indolent clinical course, and the presence of aberrations in both homologues of chromosome 6: IRF4 rearrangement and deletion 6p25. Treatment with 4 R-CHOP-21 courses allowed for the achievement of disease remission, which continued 26 months post treatment.

Revised International Prognostic Index and genetic alterations are associated with early failure to R-CHOP in patients with diffuse large B-cell lymphoma.

Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) cases have a poor outcome. Here we analysed clinico-biological features in 373 DLBCL patients homogeneously treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP), in order to identify variables associated with early failure to treatment (EF), defined as primary refractoriness or relapse within 12months from diagnosis. In addition to clinical features, mutational status of 106 genes was studied by targeted next-generation sequencing in 111 cases, copy number alterations in 87, and gene expression profile (GEP) in 39. Ninety-seven cases (26%) were identified as EF and showed significantly shorter overall survival (OS). Patients with B symptoms, advanced stage, high levels of serum lactate dehydrogenase (LDH) or β2-microglobulin, low lymphocyte/monocyte ratio and higher Revised International Prognostic Index (R-IPI) scores, as well as those with BCL2 rearrangements more frequently showed EF, with R-IPI being the most important in logistic regression. Mutations in NOTCH2, gains in 5p15·33 (TERT), 12q13 (CDK2), 12q14·1 (CDK4) and 12q15 (MDM2) showed predictive importance for EF independently from R-IPI. GEP studies showed that EF cases were significantly enriched in sets related to cell cycle regulation and inflammatory response, while cases in response showed over-representation of gene sets related to extra-cellular matrix and tumour microenvironment.

Clinicopathological features and prognosis of primary mediastinal large B-cell lymphoma: a series of sixty cases

Objective: To investigate the clinicopathological features and prognostic factors of primary mediastinal large B-cell lymphoma (PMBL). Methods: The clinical data of 60 patients with PMBL including 44 biopsy cases and 16 consultation cases from September 2000 to November 2019 in the Department of Pathology, China-Japan Friendship Hospital (14 cases) and Peking Union Medical College Hospital (46 cases) were enrolled. Pathologic features, immunophenotype, immunoglobulin (Ig) gene rearrangement and microRNA expression profile were retrospectively studied. Results: Of the 60 patients, 23 were males and 37 were females, age ranged from 15 to 64 years (median 28 years). Immunohistochemical staining showed that the tumor cells were positive for pan-B cell antigens, CD30 (77.4%, 24/31), CD23 (73.1%, 19/26), MUM1 (45.8%, 11/24), Ki-67 index ≥70 % (90.6%, 29/32). EBER in situ hybridization was analyzed in 21 PMBL, only one case (4.8%) was positive. Ig gene rearrangement was performed in 20 cases, and seven were positive (35.0%). MicroRNA gene expression profiles were analyzed in seven cases of PMBL and nine cases of diffuse large B-cell lymphoma, and there were 33 microRNAs with significant difference (P<0.05). Univariate analysis indicated that the poor prognostic factors included serum lactate dehydrogenase (LDH) level,International Prognostic Index (IPI) score ≥3, stages Ⅲ-Ⅳ, chemotherapy not combined with rituximab and MUM1 positivity (P<0.05). Multivariate analysis showed that the treatment combined with rituximab was independently related to prognosis (P<0.05). Conclusions: PMBL is different from diffuse large B-cell lymphoma in clinicopathologic features, immunophenotypic presentation and molecular features. The prognostic factors, molecular genetics and immunological characteristics reveal that this study has enriched our understanding of the biology of PMBL, thus providing evidence and strategies for treatment.

The Rare Face of an Infrequent Lymphoma Diagnosed by an Exquisite Method: Case Report with Review of Literature

AbstractLarge B-cell lymphomas include both the commonly encountered, as well as not so frequent entities. We report a rare case of hepatic intravascular large B-cell lymphoma (IVLBCL). These cases usually pose a major challenge to timely diagnosis due to the limited clinical exposure and nonspecific symptoms; however, timely diagnosis is possible with awareness of this entity and close coordination between radiology and pathology. The patient presented with pain abdomen, fever, edema, hepatomegaly but no lymphadenopathy or cutaneous lesions were identified. Blood investigations revealed pancytopenia, high lactate dehydrogenase (LDH) levels and bone marrow investigations were not helpful. Left-sided portal hypertension, coagulopathy, and hypoalbuminemia raised a clinical suspicion of chronic liver disease with high LDH levels and liver biopsy was challenging in view of very low platelet counts. The uniquely explored transjugular biopsy helped in obtaining liver tissue which showed sinusoidal large atypical lymphoid cells positive for CD20 rendering a diagnosis of IVLBCL. After administration of the R-miniCHOP chemotherapy, there was evident clinical and radiological response. This case highlights the importance of considering transjugular liver biopsy in scenarios where the clinical presentation is unusual. At the same time, a meticulous histological examination is needed to diagnose a rare yet potentially treatable large B cell lymphoma.

Probability calibration-based prediction of recurrence rate in patients with diffuse large B-cell lymphoma

BackgroundAlthough many patients receive good prognoses with standard therapy, 30–50% of diffuse large B-cell lymphoma (DLBCL) cases may relapse after treatment. Statistical or computational intelligent models are powerful tools for assessing prognoses; however, many cannot generate accurate risk (probability) estimates. Thus, probability calibration-based versions of traditional machine learning algorithms are developed in this paper to predict the risk of relapse in patients with DLBCL.MethodsFive machine learning algorithms were assessed, namely, naïve Bayes (NB), logistic regression (LR), random forest (RF), support vector machine (SVM) and feedforward neural network (FFNN), and three methods were used to develop probability calibration-based versions of each of the above algorithms, namely, Platt scaling (Platt), isotonic regression (IsoReg) and shape-restricted polynomial regression (RPR). Performance comparisons were based on the average results of the stratified hold-out test, which was repeated 500 times. We used the AUC to evaluate the discrimination ability (i.e., classification ability) of the model and assessed the model calibration (i.e., risk prediction accuracy) using the H-L goodness-of-fit test, ECE, MCE and BS.ResultsSex, stage, IPI, KPS, GCB, CD10 and rituximab were significant factors predicting the 3-year recurrence rate of patients with DLBCL. For the 5 uncalibrated algorithms, the LR (ECE = 8.517, MCE = 20.100, BS = 0.188) and FFNN (ECE = 8.238, MCE = 20.150, BS = 0.184) models were well-calibrated. The errors of the initial risk estimate of the NB (ECE = 15.711, MCE = 34.350, BS = 0.212), RF (ECE = 12.740, MCE = 27.200, BS = 0.201) and SVM (ECE = 9.872, MCE = 23.800, BS = 0.194) models were large. With probability calibration, the biased NB, RF and SVM models were well-corrected. The calibration errors of the LR and FFNN models were not further improved regardless of the probability calibration method. Among the 3 calibration methods, RPR achieved the best calibration for both the RF and SVM models. The power of IsoReg was not obvious for the NB, RF or SVM models.ConclusionsAlthough these algorithms all have good classification ability, several cannot generate accurate risk estimates. Probability calibration is an effective method of improving the accuracy of these poorly calibrated algorithms. Our risk model of DLBCL demonstrates good discrimination and calibration ability and has the potential to help clinicians make optimal therapeutic decisions to achieve precision medicine.

Synchronous gastric cancer and primary lymphoma of right adrenal gland: a case report

This report presents an extremely rare case of synchronous gastric cancer and primary adrenal diffuse large B-cell lymphoma (DLBCL). An 82-year-old man underwent computed tomography, which revealed a heterogeneous appearing and hypodense adrenal mass and a gastric mass with no enlarged lymph nodes in the neck, mediastinum, abdomen, and inguinal region. Upper gastrointestinal endoscopy revealed a protruding gastric tumor. The specimens obtained from endoscopic biopsy were histologically confirmed to be adenocarcinoma. The hormonal findings eliminated functional adrenal tumor. The patient underwent distal gastrectomy with regional lymph node resection for gastric cancer and incisional biopsy of the adrenal mass. Based on the pathological findings, diagnoses of mixed mucinous and tubular adenocarcinomas of the stomach and adrenal DLBCL were confirmed. Postoperation, the patient received rituximab combined with low-dose doxorubicin, cyclophosphamide, vincristine, and prednisone (R-miniCHOP). Six courses of R-miniCHOP were planned, but were completed in only one course at the patient’s request. The patient died 2 months after surgery.

Diffuse Large B-Cell Lymphoma With a Background of Extensive Granulomatous Inflammation: A Potential Pitfall for Misdiagnosis

Granulomatous inflammation has been reported to be associated with Hodgkin and non-Hodgkin lymphomas. Here, we report a case of recurrent diffuse large B-cell lymphoma (DLBCL) with extensive granulomatous inflammation that was initially misdiagnosed as granulomatous lymphadenitis. In 2019, a 75-year-old Caucasian male presented to our hospital with an enlarged right supraclavicular lymph node. He had a medical history of prostate cancer (in 2004), DLBCL (initially diagnosed in 2009), and rectal adenocarcinoma (in 2017), all of which responded well to treatment. In 2018, the patient had experienced right axillary adenopathy, weight loss, and intermittent night sweats. An excisional biopsy of a right axillary lymph node, performed at another institution, was diagnosed as granulomatous lymphadenitis. In 2019, at our hospital, an excisional biopsy of a right supraclavicular lymph node showed DLBCL in a background of granulomatous inflammation. A review of the prior right axillary lymph node biopsy also showed DLBCL with a background of extensive granulomatous inflammation. Chemotherapy was initiated and the patient’s follow-up showed a good response. We report this case to raise awareness that granulomatous inflammation may obscure the diagnosis of some neoplasms, such as DLBCL, which are less commonly known to have granulomatous inflammation. This may result in delayed treatment and may ultimately affect outcomes.

Location Matters in Nodal Diffuse Large B-Cell Lymphoma

▪Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma in the United States. The introduction of rituximab has significantly improved outcomes in the treatment of DLBCL. However, relapsed and refractory cases still pose a challenge. More recently, our understanding of the biology of DLBCL has evolved such that assessment of molecular risk through evaluation of the cell of origin and specific genetic mutations are being incorporated into prognostication and treatment decisions. The location of extranodal involvement has been implicated in the prognosis, but the prognostic relevance of the location of lymphadenopathy has not been extensively investigated.MethodsWe used the Surveillance, Epidemiology, and End Results (SEER) database to extract cases of nodal DLBCL from 1983 to 2014. The SEER database considers spleen and Waldeyer's Ring (WR) as nodal, so they were included in the extraction. A total of 71,132 cases were identified. Cases without follow-up, with unknown Ann-Arbor stage (extranodal involvement is not included in the database), with more than one primary tumor, without histologic confirmation of the disease, and with an unspecified location or lymph nodes in multiple regions, were excluded. Age was categorized into the following groups: 20-39,40-59, 60-75, and >75 years. Treatment characteristics for included patients were extracted and cases were dichotomized based on the year of diagnosis; 2000 was used as a cut-off because the first landmark study evaluating R-CHOP was presented at the American Society of Hematology (ASH) meeting in December of that year. Survival curves were estimated by the Kaplan-Meier method and were compared using the log-rank test. A Cox proportional hazard model was constructed to identify the hazard ratios (HR) for each location. ANOVA was used to adjust for age, stage, gender, race, year of diagnosis, administration of chemotherapy, administration of radiation, and cancer-directed surgery. A chi-square test was utilized to compare categorical variables. Proportionality was tested with Schoenfeld residuals. Statistical analysis was performed with R statistics.ResultsA total of 18,870 cases were included in the analysis. The majority of these cases were located in the head/face neck (28%) and abdomen/retroperitoneum (27%).The overall 5-year DLBCL-specific survival (DSS) was 65%. The location of lymphadenopathy was predictive of outcome after adjusting for all other factors (p<.001). In the total cohort, involvement of WR was associated with better survival (79%) and involvement of the abdomen with the poorest survival (51%). Similar results were produced by the Cox model with WR having the best survival (referent) whereas the abdomen had the worst (hazard ratio 1.92, 95% CI 1.69-2.18). When comparing the pre-rituximab and post-rituximab data, the survival of patients from all locations improved, apart from patients who had pelvic lymphadenopathy (HR 0.77, 95% CI 0.55-1.08, p= 0.12). WR and abdomen retained the best and the worst survival, respectively, in both eras. Kaplan-Meier curves for all cases since 1983 are presented in Figure A, whereas the results of the Cox model are presented in Table B . Patients who were diagnosed with DLBCL in the thorax were much younger than all other patients combined (39% vs 8% in 20-39 years, p < .001).ConclusionsThis is the first large study demonstrating a statistically significant difference in survival for patients with nodal DLBCL depending on the primary location of their disease. One possible explanation is that patients with intrathoracic or intraabdominal disease are more vulnerable to vital organ compromise. WR cases probably include cases of large B-cell lymphoma with IRF4 rearrangement, which have a better prognosis. In addition, primary mediastinal B-cell lymphoma was a separate entity in SEER after 2001, so many cases of thoracic DLBCL prior to that date could actually be the former. Further investigation and validation in other cohorts incorporating molecular studies is warranted before this information can be incorporated into prognostic tools. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Immune Checkpoint Receptors PD-1, PD-L1, TIM-3 and LAG-3 in Lymphoma: Tumor Cell and Tumor Infiltrating Lymphocyte (TIL) Expression, Patient Prognostication, and Identification of Rational Therapeutic Targets

Introduction: Programmed cell death-1 (PD-1) based immunotherapy represents a significant advance in the treatment of hematologic malignancies, including lymphoma. Mechanisms of resistance and potential methods to overcome this treatment paradigm are a critical focus of research. Signaling through additional immune checkpoint receptors, such lymphocyte-activation gene-3 (LAG-3) and T cell immunoglobulin and mucin domain-3 (TIM-3), may lead to T-cell exhaustion and be a mechanism of immune escape for tumors. However, the expression patterns of TIM-3 and LAG-3 in lymphoma, including DLBCL and HL, are largely unknown. Furthermore, potential override of resistance to PD-1 blockade via rational co-targeting of checkpoint receptors represents a novel therapeutic strategy.Methods: Tissue sections (whole sections and tissue microarrays) of newly diagnosed patient cases of diffuse large B-cell lymphoma (DLBCL, n=123) and Hodgkin lymphoma (HL, n=30) were stained with antibodies to PD-L1, PD-1, TIM-3, and LAG-3. Immunohistochemical (IHC) expression of each marker on tumor cells and on tumor infiltrating lymphocytes (TILs) were scored. Staining patterns were correlated with additional pathologic and clinical parameters as well as patient outcome (i.e., progression free survival (PFS) and overall survival (OS)) among n=59 newly diagnosed advanced-stage DLBCL patients treated from 2005 to 2013 with rituximab-CHOP therapy. 4-year survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. Univariate analysis and multivariate regression according to the Cox proportional hazards regression model were used (for International Prognostic Index (IPI) and TIM-3). In addition, the effects of in vitro checkpoint blockade were evaluated using investigational anti-PD-1, anti-TIM-3 or anti-LAG-3 compounds with tumor-primed T cells and Raji or SUDHL10 as target DLBCL cells. Cell viability was assessed using AcellaTox assay and IL-2 release quantified by ELISA.Results: TIM-3 showed strong, membranous staining (H-score >80) on tumor cells in over 1/3 of DLBCL (39%, 48/123) and the majority of HL cases (70%, 21/30). Furthermore, PD-L1 was expressed (>30% cells tumor cells positive) in essentially all HL cases (100%, 30/30) and in a subset of DLBCL cases (15%, 19/126). This is similar to our and others' previously reported data (Xing W et al. O ncotarget 2016). Both PD-1 and LAG-3 in the current study were positive on tumor cells in only a minority of DLBCL cases (8% and 7%, respectively), and rarely in HL tumor cells. Conversely, PD-1 and LAG-3 were widely expressed on the TILs found in DLBCL in 75% and 94% of cases, respectively. With a median follow-up of 44 months (range 5-85), 4-year PFS and OS rates were significantly inferior among DLBCL patients with high vs low/negative TIM-3 expression (i.e., PFS: 23% (95% CI 7% to 46%) vs 60% (95% CI 43% to 74%), respectively, P=0.008; and OS: 30% (95% CI 10% to 53%) vs 74% (95% CI 58% to 85%), respectively, P=0.006) (see Figure 1A/1B). Furthermore, when controlling for the IPI, both survival endpoints remained significant with high TIM-3 predicting increased risk of progression (PFS HR 2.60 (95% CI 1.22-5.53, P=0.013) and OS predicting increased risk of death (OS HR 3.36, 95% CI 1.52-7.42, P=0.003) on multivariate Cox regression analyses. In addition, we examined these checkpoint receptors as potential therapeutic targets. Co-culture of PD-L1 expressing Raji cells with tumor-dendritic cell primed T cells in the presence of anti-LAG-3 induced a potent dose-dependent increase in in vitro cell death with 15nM IC50 and IL-2 secretion (120pg/ml) as determined by AcellaTox & ELISA based assays (see Figure 1C).Conclusions: Altogether, IHC analyses showed strong expression of the TIM-3 immune checkpoint receptor in over 1/3 of DLBCL and in the majority of HL tumors. Furthermore, analysis of patient outcomes identified that DLBCL patients with high TIM-3 expression (i.e., H-score >80) had significantly inferior survival rates. PD-1 and LAG-3 were consistently expressed in the TILs of DLBCL and HL, but were infrequently expressed by tumor cells. Therapeutically, we identified a dose-dependent increase in Raji-targeted cell death and increased T cell activity with a novel anti-LAG-3 compound. Continued examination of mechanistic studies of these immune checkpoint receptors and associated rational treatment studies are warranted. [Display omitted] DisclosuresGhosh:Tesaro: Employment. Evens:Kite Pharma: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Millennium: Consultancy; AbbVie: Consultancy; Affimed: Consultancy; Merck: Consultancy; • Spectrum Pharmaceuticals: Consultancy.