Extranodal Diffuse Large B-cell Lymphoma Research Articles

Intravascular Large B-Cell Lymphoma: A Continuing Clinical Enigma

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of extranodal diffuse large B-cell lymphoma characterized by the proliferation of lymphoma cells in the lumen of small blood vessels. Clinical presentation varies among reported cases and diagnosis can be challenging for both clinicians and pathologists. We report a case of a 64-year-old female with a history of prolonged fever. Diagnosis was suspected clinically due to thrombocytopenia and elevated serum lactate dehydrogenase after exhausting work-up for an infectious etiology. IVLBCL was established on post-mortem examination upon finding infiltration of CD20-positive neoplastic cells in several organs in the absence of lymph node involvement.

TREATMENT STRATEGIES AND PROGNOSTIC FACTORS OF PRIMARY GASTRIC DIFFUSE LARGE B CELL LYMPHOMA: A RETROSPECTIVE STUDY OF 303 CASES FROM CHINA LYMPHOMA PATIENT REGISTRY

Introduction: Primary gastric diffuse large B cell lymphoma (PGDLBCL) is the common primary extranodal DLBCL, with higher incidence in Asian than in Western countries. However, the optimal treatment for PGDLBCL remains controversial. We thus conducted a retrospective analysis of 303 cases to evaluate present treatment strategies and prognostic factors of PGDLBCL. Methods: From three centers of the China Lymphoma Patient Registry (CLAP), 303 PGDLBCL cases from January 1994 to December 2015 were retrospectively analyzed. Patients were classified into four groups: chemotherapy (C, 192 cases), surgery (S, 21 cases), chemotherapy + surgery (C + S, 78 cases), and watch and wait (12 cases). Results: The 3-year progression-free survival (PFS) and 3-year overall survival (OS) of the entire cohort were 75.3% and 80.3% (median follow-up time: 42 months). PFS (p = 0.122) and OS (p = 0.451) were similar among the four treatment groups. In the chemotherapy-treated cohort, group C + S had higher PFS than group C (83.7% vs. 71.8%, p = 0.013). Its OS was also relative higher, even without statistical significance (86.6% vs. 78.5%, p = 0.097). The inclusion of radiotherapy during initial treatment (23 cases) in this cohort did not improve PFS (57.9% vs. 76.2%, p = 0.017) or OS (73.7% vs. 81.1%, p = 0.220). Rituximab did not show significant clinical benefit in our study (PFS: 78.1% vs. 71.1%, p = 0.205; OS: 83.9% vs. 75.7%, p = 0.052). Treatment-related complications included gastrointestinal bleeding (22 cases), perforation (4 cases), and obstruction (4 cases), which correlated with poorer outcomes (PFS: 50.7% vs. 78.1%, p = 0.005; OS: 59.2% vs. 83.3%, p < 0.001). Glucocorticoid in chemotherapy increased incidence of complications (p = 0.035). The univariate analysis revealed prognostic factors as age, Lugano stage, ECOG, B symptom, International Prognosis Index, LDH, HGB, ESR, β2-MG, lesion in cardia, prior gastrointestinal bleeding, and complications. The multivariate analysis showed that B symptom (Relative rate (RR) = 2.82, p = 0.016), lesion in cardia (RR = 2.86, p = 0.039), LDH (RR = 4.65, p < 0.001) and gastrointestinal bleeding before treatment (RR = 3.08, p = 0.005) were highly predictive for poor PFS, and the latter two factors also predicted poor OS (RR = 4.08, p = 0.004; RR = 3.18, p = 0.001). Conclusions: Our results indicated that chemotherapy + surgery is a considerable choice to improve the survival of PGDLBCL. The inclusion of radiotherapy during initial treatment did not improve survival in our study. Due to elevated risk of complication, glucocorticoid could be removed from chemotherapy. B symptom, lesion location, LDH, and gastrointestinal bleeding before treatment are independent predictors of poor outcomes. This retrospective, multicenter analysis provides the largest sample size study for PGDLBCL, but the future prospective trial is warranted. Keywords: extranodal lymphomas.

Role of neutrophil to lymphocyte ratio in addition to revised international prognostic index (R-IPI) in patients with extranodal diffuse large B-cell lymphoma of head and neck.

e19032 Background: Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL). One third of DLBCLs cases have a primary extranodal origin and head and neck localization is second most common localization after gastrointestinal tract. The Revised-International Prognostic Index (r-IPI) is commonly used as prognostic tool, but there is growing evidence that neutrophil to lymphocyte ratio (NLR) also has prognostic significance in DLBCL. Methods: We retrospectively reviewed all cases of extranodal DLBCLs diagnosed between 2006 and 2016 at a single academic institution. Collected data included race, gender, primary site, baseline laboratory data, IPI score, pathology, treatment and survival. Results: A total of 33 patient were included, with 18 (54.5%) being females. Median age at diagnosis was 68 (range 28-92). 15% of patients had a r-IPI of 0, 30% a r-IPI of 1-2, 12% a rIPI of 3-5 and 36% a not evaluable (NE) r-IPI. Twelve (36%) patients had germinal center B cell subtype (GCB) and 17 (51%) patients had activated B cell subtype (ABC) by immunohistochemistry. Among all patients, 13 (39%) had pretreatment NLR equal or more than 3.5 and 11 (33%) patients had NLR less than 3.5 and 9 patients had a NE NLR. . Among deceased patients, 5 (56%) of them had NLR of more that 3.5 (p =0.011). Nine (27%) patients had pretreatment monocyte count less than 700/mm3 and 14 (42%) patients had monocyte count at least 700/mm3 (p=0.611). The 2-year overall survival was 77% (95% CI 0.61 - 0.93). Conclusions: (R-IPI) is the most common tool to predict outcome in DLBCL and our study showed that pretreatment NLR can be used as additional poor prognosis marker for patients with extranodal DLBCL of the head and neck. [Table: see text]

Intravascular large B-cell lymphoma mimicking central nervous system vasculitis

Intravascular large B-cell lymphoma (IVBCL) represents a rare subtype of extranodal diffuse large B-cell lymphoma characterized by selective growth of neoplastic cells within the lumen of small and medium-sized vessels. The clinical spectrum is heterogeneous dominated by neurological and skin manifestations. Intra-vitam diagnosis still remains challenging and usually requires brain biopsy since no pathognomonic neuroradiological findings do exist for IVBCL.We report on the case of a 65-year old male patient presenting with multifocal neurological signs and symptoms including cognitive deficits, aphasia and paraparesis as leading features. Imaging findings were suggestive for cerebral vasculitis prompting initiation of steroid treatment. After initial stabilization the patient deteriorated in spite of systemic steroid treatment, developed severe sepsis and finally died from multi-organ failure. Histopathological findings revealed CD20 positive lymphoma cells in small- and middle-sized vessels of the cerebrum, the lungs and the skin diagnostic for IVBCL.This case should raise the alertness for consideration of IVBCL as a differential diagnosis resulting in early brain biopsy, if no etiology for CNS vasculitis is evident.

Expression of the activation markers Blimp1, Foxp1 and pStat3 in extranodal diffuse large B-cell lymphomas.

Different studies have suggested that the expression of biomarkers related to lymphoid cell activation may provide information on the behavior of DLBCL. Most studies have concentrated on nodal or a mixture of nodal and extranodal lymphomas. The differential expression and potential clinical impact of these markers in a homogeneous group of extranodal DLBCLs are not well defined. In this study, we investigated the expression of three activation markers, Blimp1, Foxp1 and pStat3, in a cohort of 35 extranodal DLBCLs homogeneously treated with R-CHOP. Immunohistochemical stains were evaluated using an immunoreactivity score on representative paraffin sections. Blimp1 was positive in 55% (19/35), Foxp1 in 60% (21/35), and pStat3 in 69% (24/35) of our cases. We did not observe any statistical differences in the expression of these markers in GCB and non-GCB tumors or in gastrointestinal and non-gastrointestinal tumors. Blimp1 expression was negatively correlated with overall survival (OS) (p=0.001) in the whole series and in the non-GCB group (Muris algorithm) (p=0.002). Foxp1 positivity and pStat3 positivity had no impact on the outcome of the patients in the global cohort, but they were associated with a better survival in the non-GCB subgroup (p=0.033, p=0.044 respectively). Multivariate analysis showed that Blimp1 expression but not COO was an independent negative prognostic factor for OS (HR=17.5, 95%, CI=2.2-141.1, p=0.007). Our results suggest that these markers are differentially expressed and have different impacts on outcome in extranodal DLBCLs compared to nodal tumors, emphasizing the need to evaluate separately these and probably other markers in these subsets of tumors.

Epidemiology of Extranodal Diffuse Large B Cell Lymphomas in Algeria: A Study of the Algerian Group of Extranodal Lymphomas (GALEG)

Introduction: Primitive extranodal lymphomas are a heterogeneous group of malignant lymphoid hematological developed from the mucosa-associated lymphoid tissue (MATL) or sites that have acquired MALT after repeated stimulation. The particularity of this type of affection reside: the access to diagnosis which is difficult and therapeutic approach which respond to the ATB, antiviral, surgery and RT. They represent 24-48% of lymph node lymphomas and they are increasing. The incidence of lymphoma is growing in the world, it is approximately 16.8 / 105inhabitants. In Algeria in 2012, the incidence of lymph node lymphomas in adults was 2.24 / 100,000. Lymphomas Diffuse large B-cell phenotype (DLBCL) represent 50-60% of lymphomas, it is the most common histological type.Goals of the study:1-analyze the epidemiological characteristics (gender, age, geographical distribution, annual incidence). 2- Identify anatomical sites. 3- Specify the clinical and prognostic featuresPatients and methods: It's is a multicenter, retrospective study over a period between 2010-2014. The study population included all pts over 15 years and having an extranodal DLBCL at 18 hematology centers and 4 cancer centers. Data were collected on data sheets distributed to the various services involved in the study. The diagnosis is made on the histological examination of a biopsy of the affected organ. The clinical, biological and imaging results allowed us to classify and identify prognostic factors for pts.Results: Among 1057 sheets of extranodal lymphomas, the type DLBCL is specified in 562 (53%) cases, distributed in 325 men and 237 women (sex ratio M/F: 1.36). The average age at diagnosis is 51 years (16-88) with a peak in the age group 50-60 years. The overall annual incidence of 0.31/105 inhabitants/year and the specific incidence for patients over 15 years is 0.42 / 105inhabitants/year. PS 0-1: 323 / 543pts (60%). Number of pts (pts) by place of care: Annaba 65, Sétif: 60, CAC Constantine: 53, Tizi Ouzou: 49, Blida Cac: 41, CMPC-hematology: 40, Tlemcen: 30, Beni- Méssous- hematology: 29, CAC CPMC: 24, EHUOran: 23, hematology CAC Batna: 22, CHU Oran: 19, HMRUO: 17, Blida-hematology: 16, HCA:16, SBA: 15, CAC Béni-Messous: 14, EPH Mascara: 10, HMRU Oran: 9, Bejaia: 7, hematology CHU Batna: 2, hematology Cne:1. Number of cases according to anatomical localisation: Stomach: 180, Intestine: 31, Colon 12, Tonsils: 70, Cavum: 31, nasal cavities: 11, Bones: 43, mediastinum: 41, SNC: 29, Skin: 25, Rate / MO :15, Thyroid: 12, soft Parties: 10, Breast: 6, lung / pleural: 5, Liver: 5, Others: 36. The clinical symptomatology is very heterogeneous, specifically of the affected organ. Clinical stage is specified in 549 cases, according to Ann Arbor: SCIE: 272 (49%), SCIIE: 149 (27%), SCIIIE: 31 (6%), SCIV: 97 (18%). The International Prognostic Index adjusted for age (IPIaa) include: for pts less than 60 years: Low (F): 70 (23%), lower intermediate (IF): 130 (43%), intermediate high (IE) : 69 (23%), high (H): 32 (11%); for over 60 years Topics: F: 33 (23%), MI: 53 (37%) IE: 41 (28%), E: 17 (12%).Comments: As with other types of lymphoma, there is a male predominance and a peak incidence in the age group 50-60 years. The higher number of pts in the center and east of the country is probably related to a denser population in these regions. The histological type DLBCL at 53% is in agreement whith what it is conventionally reported. The incidence of 0.31/105inhabitants/year extranodal DLBCL is lower than the overall nodal DLBCL, however, the incidence of extranodal NHL is rarely determined. The number of cases of extranodal lymphomas described in this study is certainly below the actual number because this group of disorders is supported by various specialties related to the location of lymphoma. Extranodal lymphomas has a clinical polymorphism, but it is recognized that gastric and tonsillar locations are the most common, the other despite their rarity, require attention from management. This type of lymphoma is characterized by a preponderance of localized stages unlike ganglion lymphomas where the extended stages predominate. Likewise distribution by IPIaa not exceeding one pejorative factor is more common.Conclusion: Extranodal DLBCL are rare, they are characterized by a diversity clinicopathological that challenges us to homogenization of their treatment in multidisciplinary level. DisclosuresNo relevant conflicts of interest to declare.

EZH2 Upregulation Is Associated with Unfavorable Prognosis in Diffuse Large B-Cell Lymphoma through Potential RUNX3 Downregulation

Introduction: The runt-related transcription factor 3 (RUNX3) is a downstream effector of the transforming growth factor-β (TGF-β) signaling pathway, and has critical roles in apoptosis, angiogenesis, cell migration and invasion. Putative tumor suppressor activity of RUNX3 has been presented extensively in the literature, particularly in solid epithelial tumors and recently in lymphoma with loss of expression favoring tumorigenesis and/or prognosis, but its role in diffuse large B-cell lymphoma (DLBCL) has not been studied. Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been shown to mediate silencing of RUNX3. RUNX3 downregulation due to EZH2 upregulation has been shown in various solid tumors. In the present study, we investigated the EZH2 and RUNX3 RNA expression status in DLBCL and its impact on clinical outcome.Methods: A retrospective chart review was performed and 169 cases of DLBCL treated with chemoimmunotherapy between 2003 and 2013 were included. Immunodeficiency- or EBV-associated and MYC+ LBCL were excluded. Archived formalin-fixed-paraffin-embedded tissue samples were retrieved and RNA was extracted using commercially available kits. We correlated the RNA expression levels for EZH2 and RUNX3 in various sites using quantitative real-time PCR (Taqman assay) and custom designed primers for each gene. Control samples included three benign lymph nodes free of a neoplastic process.Results: We identified 66 cases of DLBCL, including25 nodal DLBCL and 41 extranodal DLBCL, with sufficient RNA extracted. Extranodal locations included testis (n=12), orbit (n=6), primary central nervous system (n=5), bone (n=3), breast (n=2) and viscera (n=13). The median age was 64 years (range 29- 81 years) with a female to male ratio of 0.4 (F=20 and M=46). Median overall survival (OS) was 28 months (1-156 months). Immunophenotypic subtype based on cell-of-origin using Hans algorithm was available in 63 cases; 34 cases were germinal center B-cell (GCB) type while 29 were non-GCB type. Treatment data was available in 63 cases and all patients received R-CHOP as initial therapy except three patients who died shortly after diagnosis. Forty-four cases showed higher expression of EZH2 and RUNX3 when compared to normal lymph nodes (p < 0.05). Nineteen out of 44 cases showed increased EZH2 and decreased RUNX3 expression (Group 1) while EZH2 expression was lower than RUNX3 in the remaining cases (Group 2). The remaining 22 DLBCL cases did not show significant correlation for expression (Group 3). Overall survival was significantly low in Group 1 compared to Group 2 and Group 3 (p =0.030 and p=0.026, respectively). There was no difference for OS between Groups 2 and 3 (p>0.05) (Figure 1).Conclusions: Our results showed that decreased RUNX3 RNA expression is associated with EZH2 overexpression and poses an adverse prognostic factor in DLBCL. Larger studies are needed to establish the prognostic and therapeutic utility of EZH2 and/or RUNX3. [Display omitted] DisclosuresMehta:Pharmacyclics: Research Funding; Merck: Research Funding; Incyte: Research Funding; Medimmune: Research Funding; Roche Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Forero:University of Alabama at Birmingham: Research Funding. Costa:Sanofi: Honoraria, Research Funding.

An Unexpected Diagnosis from ERCP for Ascending Cholangitis and Ampullary Mass: Extranodal Diffuse Large B-Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is a histological subtype of non-Hodgkin lymphoma (NHL) that accounts for approximately 25% of all NHL cases. DLBCL usually presents as an enlarging mass, most commonly as nodal enlargement in the neck or axilla. Systemic B-symptoms are often reported, including severe night sweats, fever, and weight loss. Extranodal disease has been reported in up to 30 percent of cases, and the diagnosis of DLBCL is most commonly made with excisional lymph node biopsy. A 73 y/o F with a PMH of anemia presented with painless jaundice, abdominal pain, and weight loss. Physical was remarkable for jaundice and sclera icterus. Labs were positive for a WBC of 18.4, ALT of 73, AST of 57, ALKP of 786, total bilirubin of 3.7, direct bilirubin of 3.2, LDH of 247, and lipase of 859. US abdomen showed marked intra- and extra-hepatic biliary dilation, gallbladder distention, and abrupt termination of the CBD in the pancreatic head. CT scan confirmed biliary dilation with extensive peritoneal metastases or lymph nodes. A CA 19-9 level was 8894. An ERCP with cytology brushing and ampulla biopsy revealed an ampullary mass, a 1.5 cm dilated intrahepatic biliary tract, and a 5 cm distal and mid-common bile duct stricture beginning at the ampulla. A PET-CT scan was obtained, which showed abnormal uptake in posterior mediastinal, right axillary, right cardiophrenic, mesentery, and retroperitoneum lymph nodes, as well as in the right liver lobe and the pancreatic head and tail. Cytology brushing revealed atypical cells, and ampullary biopsy revealed DLBCL. This case of DLBCL was unique for multiple reasons. The initial symptoms of painless jaundice, abdominal pain, subjective fevers, and recent weight loss are not typical presenting symptoms of DLBCL; no rapidly enlargement mass or nodal enlargement of the neck and axilla was present. Her symptoms could have been explained solely by her ascending cholangitis. It was also remarkable how the clinical presentation resembled pancreatic adenocarcinoma but was actually due to a DLBCL with significant distant metastasis. This less common extranodal presentation would not have been expected given her complaints, as additional symptoms or a diagnosis would have presumably been previously suspected. Lastly, the majority of DLBCL diagnoses are made with excisional lymph node biopsy, but this case's diagnosis was interestingly made from an ampullary mass biopsy from an ERCP for ascending cholangitis.

Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Clinicopathological features of 49 primary gastrointestinal diffuse large B-cell lymphoma cases; comparison with location, cell-of-origin, and frequency of MYD88 L265P.

The gastrointestinal (GI) tract is the most common primary site of extranodal diffuse large B-cell lymphoma (DLBCL), with approximately one-third of extranodal DLBCL occurring in the GI tract. We investigated the clinicopathological features and immunohistochemically-assessed cell-of-origin of 49 GI DLBCL cases (stomach, 24; small intestine, 10; colon, 15) and also examined the presence of MYD88 L265P as recently this mutation has been frequently identified in ABC-like DLBCL, particularly in extranodal sites. Small intestinal DLBCL was characterized by the preponderance of women (P = 0.041) and elevated LDH (P = 0.002) and soluble interleukin-2 receptor (P = 0.033). Small intestinal DLBCL more frequently showed anemia (P = 0.031) and elevated CRP (P = 0.029) than gastric DLBCL. ABC-like phenotype was seen in 71.4% cases (stomach, 79%; small intestine, 70%; colon, 60%). MYD88 L265P was detected in 6.1% cases; all were primary gastric DLBCL with ABC-like phenotype but had no distinct clinicopathological features. In conclusion, GI DLBCL had different clinicopathological features according to the primary site especially in the small intestine. Also, MYD88 L265P had little involvement in GI DLBCL compared with other extranodal DLBCLs, suggesting that its pathogenesis might be different from that of organs with a high frequency of MYD88 L265P.

Clinicopathologic significance of tumor microenvironment CD11c, and FOXP3 expression in diffuse large B-cell lymphoma patients receiving rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy.

Background/AimsCD11c is a dendritic cell marker in humans, which potentially induces a cytotoxic effect on lymphoma cells. Forkhead boxP3 (FOXP3) is a regulator of T lymphocyte in the microenvironment of the lymphoma. The principal objective of this study was to determine whether the tumors’ microenvironment expressions of CD11c and FOXP3 are predictive of clinical outcomes in diffuse large B-cell lymphoma (DLBCL) patients receiving treatment with rituximab, cyclophosphamide, anthracycline, vincristine, and prednisone (R-CHOP) combination chemotherapy.MethodsThe study population consisted of 100 patients with DLBCL. The CD11c and FOXP3 expression in primary tumors’ microenvironment were evaluated using an immunohistochemistry (IHC).ResultsCD11c and FOXP3 expression positivity in microenvironment were 25% and 35%, respectively. Each one counted for 1 point. In CD11c and FOXP3 stain, positive was counted as 0 and negative was 1. The points were separated into low risk (0 to 1) and high risk (2) groups. Only the extranodal DLBCL patient group analysis conveyed significant differences of progression-free survival (p = 0.019) and overall survival (p = 0.039) between the two groups.ConclusionsWe can achieve possible clinical significance of lymphoma tumor microenvironments through CD11c and FOXP3 IHC stains in extranodal DLBCL patients receiving R-CHOP therapy.

Clinical manifestation and treatment of extranodal diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) accounts for 30-40% of all lymphoma subtypes. More than half of DLBCLs are estimated to arise from extranodal sites, and are called extranodal DLBCLs. Generally, the outcomes of extranodal DLBCL are not different from those of nodal DLBCL. To our knowledge, this report is the first to discuss the concept and the cell of origin of extranodal DLBCL, with the significance of the presence/absence of each involvement site in determining the outcome. Second, the evidence of clinical manifestation and outcomes of several extranodal DLBCLs requiring treatments other than R-CHOP, which is the current standard therapy for this malignancy, are discussed. Most primary central nervous system (CNS) and testicular lymphomas are histologically DLBCLs. Moreover, primary mediastinal and intravascular large B-cell lymphomas are subtypes of DLBCL by definition. Hence, the evidence of high-risk sites for CNS involvement is also described.

Intravascular Large B-Cell Lymphoma Mimicking Central Nervous System Vasculitis

Intravascular large B-cell lymphoma (IVBCL) represents a rare subtype of extranodal diffuse large B-cell lymphoma characterized by selective growth of neoplastic cells within the lumen of small and medium-sized vessels. The clinical spectrum is heterogeneous dominated by neurological and skin manifestations. Intra-vitam diagnosis still remains challenging and usually requires brain biopsy since no pathognomonic neuroradiological findings do exist for IVBCL. We report on the case of a 65-year old male patient presenting with multifocal neurological signs and symptoms including cognitive deficits, aphasia and paraparesis as leading features. Imaging findings were suggestive for cerebral vasculitis prompting initiation of steroid treatment. After initial stabilization the patient deteriorated in spite of systemic steroid treatment, developed severe sepsis and finally died from multi-organ failure. Histopathological findings revealed CD20 positive lymphoma cells in small- and middle-sized vessels of the cerebrum, the lungs and the skin diagnostic for IVBCL. This case should raise the alertness for consideration of IVBCL as a differential diagnosis resulting in early brain biopsy, if no etiology for CNS vasculitis is evident.

The Presence of M Protein Is Strongly Associated with Very Poor Prognosis in Patients with Extranodal Diffuse Large B-Cell Lymphoma

IntroductionSeveral studies concerning extranodal diffuse large B-cell lymphoma (DLBCL) have been reported sporadically. However, no new, valuable prognostic factors have been reported since several risk factors, such as a high international prognostic index (IPI) score, elevated lactate dehydrogenase (LDH) level, poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), advanced stage, and extranodal sites ≥2, were identified.MethodsTo identify new and valuable prognostic factors, we reviewed the medical records of patients with nodal and extranodal DLBCL who were newly diagnosed at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from February 2005 to September 2014, and retrospectively analyzed the data of a total of 463 consecutive DLBCL patients. The cases were nodal DLBCL in 237 patients and extranodal DLBCL in 226 patients. We investigated the relationships between overall survival (OS), progression-free survival (PFS), and age, gender, LDH level, beta-2 microglobulin level (b2MG), performance status (PS), stage, extranodal sites ≥2, Ki-67 index, and M protein in serum protein fraction electrophoresis at diagnosis. Univariate and multivariate analyses of estimated risk factors for OS and PFS in extranodal DLBCL patients were performed using the log-rank test and Cox proportional hazard regression analysis.ResultsIn patients with extranodal DLBCL, the median age was 67 years (range, 20-89 years). The median follow-up was 41 months (range, 1-115 months). A serum electrophoresis study detected M protein in 7 patients (3.1%). To adjust the impact of age, gender, LDH level, b2MG, PS, stage, extranodal sites ≥2, Ki-67 index, and the presence of M protein in serum protein fraction electrophoresis at diagnosis for other significant factors for OS, we identified the following risk factors in extranodal DLBCL by univariate analysis: elevated LDH level, elevated b2MG level, stage ≥3, extranodal sites ≥2, and the presence of M protein. Then, we performed multivariate analyses by using all of these factors in the Cox proportional hazard model. M protein (HR 6.78, 95% CI 2.19-20.96, P<0.001) and extranodal sites ≥2 (HR 3.71, 95% CI 1.77-7.80, P<0.001) were identified as independent significant prognostic factors for OS in extranodal DLBCL. Furthermore, we also identified M protein (HR 3.81, 95% CI 1.25-11.60, P=0.019) and extranodal sites ≥2 (HR 2.98, 95% CI 1.45-6.14, P=0.003) as independent significant prognostic factors for PFS by multivariate analysis. Four out of seven patients with M protein died due to lymphoma progression. Median overall survival in patients with extranodal DLBCL with M protein was 12 months (range, 2-114 months) compared with 44 months without M protein (range, 1-115 months, P=0.0038). On the other hand, in patients with nodal DLBCL, M protein (n=10) was not significantly associated with poor OS and PFS.ConclusionsThese results suggest that the presence of M protein in serum protein fraction electrophoresis is significantly associated with very poor OS and PFS in patients with extranodal DLBCL, but not nodal DLBCL. Extranodal DLBCL with M protein is a rare and very poor prognostic subset of DLBCL. [Display omitted] DisclosuresYokoyama:Chugai Pharmaceutical CO., LTD.: Consultancy. Mishima:Chugai Pharmaceutical CO., LTD.: Consultancy. Nishimura:Chugai Pharmaceutical CO., LTD.: Consultancy. Hatake:Chugai Pharmaceutical CO., LTD.: Other: lecture speaking.

Clinical Characteristics and Outcomes of Limited-Stage Primary Extranodal Versus Nodal Diffuse Large B-Cell Lymphoma (DLBCL) in Thailand: A Nationwide Multi-Institutional Registry of 920 Cases in Thailand

IntroductionThe difference in origin between nodal and extranodal DLBCL may contribute to the distinct clinical outcomes and prognoses. Previous studies including patients with both limited and advanced diseases showed various clinical results. The purpose is to study the clinical characteristics, and outcomes of patients with limited stage DLBCL according to the primary site of lymphoma.MethodsFrom the 4,371 patients in a multi-institutional registry of newly diagnosed lymphoma in Thailand between 2007-2014, there were 920 patients with limited stage DLBCL, excluding those with primary central nervous system lymphoma. The baseline patient characteristics and clinical outcomes were analyzed according to the primary site of diseases.ResultsMajority of patients had extranodal diseases (n= 535, 58.2%) while the other 385 cases (41.8%) had nodal DLBCL. The five most common primary sites of extranodal disease were Waldeyer ring (12.2%), stomach (7.3%), intestine (6.8%), sinonasal cavity (6.7%) and breast (2.8%) (Figure 1). Baseline characteristics, treatment and responses were well balanced between the two groups except for a slightly higher proportion of stage I disease in extranodal DLBCL (36.8% vs 28.8%, P =0.01) (Table 1). Two-third of patients received CHOP chemotherapy while the others were treated with R-CHOP. Radiotherapy (RT) was delivered to one-fifth of the patients in each group. Overall response rates were comparable between patients with nodal and extranodal diseases (68.6% vs 66.7%). With a median follow up of 52 months, there were no significant differences of progression free (PFS) (57.6 vs. 60.8%, P =0.46) and overall survival (OS) (63.1% vs. 65.6%, P =0.20) between patients with extranodal and nodal diseases. Among patients with extranodal manifestations, those with primary lymphoma at pancreas & gall bladder, pleura & lung, adrenal gland & kidney and intestine had the worst 4-year OS (33.3%, 39.3%, 53.3%, and 53.7%, respectively) (Figure 2). RT improved PFS (71.7% vs. 54.5%, P =0.03) and OS (74.7% vs. 62.9%, P =0.02) only in primary nodal DLBCL. The two prognostic factors for survivals were being treated with R-CHOP (HR for PFS 0.84, 95%CI: 0.74-0.96; HR for OS 0.70, 95%CI: 0.55-0.91) and the IPI scores (HR for PFS 1.49, 95%CI: 1.24-1.80; HR for OS 1.86, 95%CI: 1.37-2.51).ConclusionAmong limited stage DLBCL in Thailand, primary extranodal disease was more common than the nodal manifestations. Primary sites of origins did not affect baseline characteristics as well as the outcomes. Patients with unusual site lymphomas, however, had an inferior survivals warranted a further investigational therapy.Table 1The clinical characteristics of limited stage DLBCL according to disease of originClinical characteristicsNodal DLBCL(n = 385)Extranodal DLBCL(n = 535)p-valueMale205 (53.2%)294 (55%)0.60Median age (years)54.956.20.23Stage Stage I Stage II111 (28.8%) 274 (71.2%)197 (36.8%) 338 (63.2%)0.01HIV seropositivity11 (3.4%)19 (4.3%)0.53Age ≥ 60164 (42.6%)230 (43%)0.90High serum LDH183 (47.5%)230 (43%)0.17ECOG ≥ 246 (11.9%)60 (11.2%)0.73IPI Low (IPI = 0-1) Low-intermediate (IPI =2) High-intermediate (IPI = 3)285 (74.0%) 81 (21.0%) 19 (4.9%)406 (75.9%) 108 (20.2%) 21 (3.9%)0.82Chemotherapy regimens R-CHOP CHOP98 (29.0%) 227 (67.2%)160 (33.7%) 286 (60.2%)0.25Radiotherapy94 (24.9%)120 (22.8%)0.46Response Overall response Complete response261 (68.6%) 227 (59.7%)352 (66.7%) 322 (61%)0.24*IPI: International prognostic index [Display omitted] [Display omitted] DisclosuresKhuhapinant:Roche: Honoraria.

Extranodal diffuse large B-cell lymphoma with monoclonal gammopathy: an aggressive and primary refractory disease responding to an immunomodulatory agent

BackgroundAlthough the clinical outcome of patients with diffuse large B cell lymphoma (DLBCL) has been improved by the addition of rituximab to standard chemotherapy, almost one-third fails or relapses after first line treatment. The presence of monoclonal gammopathy (MG) is a known adverse prognostic factor for DLBCL. Because this subset of patients does not benefit from R-CHOP, new therapeutic options are required. Herein, we report the first case of extranodal DBCL of the lung with a concomitant MG who achieved a long lasting complete remission with lenalidomide.Case presentationThe 73-year-old male patient presented with lateral cervical lymphadenopathy, B symptoms, lactate dehydrogenase and beta2-microglobulin elevation. Computed tomography (CT) showed mediastinal lymphadenopathy and bilateral lung involvement. Biopsy of both disease locations revealed the presence of DLBCL. Successive bone marrow trephine biopsy proved the presence of concordant DLBCL involvement. At the time of diagnosis, a MG was present as well. The patient did not respond to the standard treatments, and subsequently underwent lenalidomide 25 mg/m2 days 1–21 q28 plus dexamethasone 40 mg days 1–4, 9–12 e 17–20. This therapeutic regimen was efficacious and safe as salvage therapy in extranodal DBCL with a MG. Furthermore, we observed a close association between DLBCL response to therapy and MG levels, suggesting that the amount of M-protein might be a surrogate marker of disease response.ConclusionAlthough DLBCL associated with MG does not respond properly to the standard treatments, it is highly sensitive to lenalidomide, which is why we endorse its role as treatment of choice in this subset of patients. In addition, MG levels appear to correlate with tumor burden, suggesting that it might be a useful marker of disease response. Prospective trials to validate these observations are warranted.

Clinicopathologic Profile and Outcome of Extranodal Diffuse Large B-Cell NHL: Egyptian National Cancer Institute Experience

Abstract Background: Primary extranodal diffuse large B-Cell lymphoma (PE-DLBCL) accounts for about one-third of all cases of DLBCL. We reviewed the clinical and pathological characteristics of cases with PE-DLBCL presented to NCI, Egypt. Patients and methods: We retrospectively studied patients with pathologically documented PE-DLBCL presented to the National Cancer Institute between January 2008 and December 2010. Revision of histopathology and sub-classification of patients to germinal centre (GC) DLBCL and non-GC-DLBCL through immunostaining of CD10, BCL-6 and MUM-1 were done. Cases that were CD10+/BCL-6±/ MUM-1- were categorised as GC-DLBCL, while cases that were CD10-/BCL-6±/MUM-1+ were categorised as non-GC-DLBCL. Clinical data regarding baseline characteristics, chemotherapy given and the response to chemotherapy was collected. Results: A total of 57 patients of PE-DLBCL were included in the study. Mean age was 48.9 years (range 21-78), and 32 patients (56.1%) were females. Most frequent locations were gastrointestinal and liver (29.9% and 22.9 %; respectively). Forty-two patients (73.7%) were sub-classified as non-GC-DLBCL. The patients who were stage III/IV were more common (52.6%). Fifty-two patients received CHOP, 5 received CVP, and 6 patients received radiotherapy after finishing chemotherapy. Complete response rate (CR) was 64.9%, there was no difference in the CR (66.7%, 64.3%) and Overall Survival (53.3%, 52.4%) in GC-DLBCL group in comparison to non-GC-DLBCL group (p = 0.24 and 0.6; respectively). The CR and OS for patients with low international prognostic index (IPI) were significantly better than patients with intermediate or high IPI (p = 0.008 and 0.08, respectively). Conclusion: Non-GC-DLBCL is more common than GC-DLBCL in PE-DLBCL in Egyptian population. The most affected sites are gastrointestinal and liver reflecting the association between high frequency of hepatitis B and C and hepatic non-Hodgkin’s lymphoma (NHL). Stage of the disease and IPI remains the most important prognostic factor for PE-DLBCL.

Abstract 3896: Recurrent TERT promoter mutations in primary central nervous system lymphoma

Abstract Primary central nervous system lymphoma (PCNSL) is a rare extranodal diffuse large B-cell lymphoma (DLBCL) restricted to the CNS and associated with a poor prognosis. Despite a notable effort contributing to better characterize the genomic basis of these tumors, few molecular abnormalities were proposed as predictive or prognostic biomarkers. Recently, two hotspot mutations, C228T and C250T, and the polymorphism rs2853669, located within TERT core promoter region have known a growing interest due to their prognostic value in a wide range of tumors, including melanoma, hepatocellular carcinoma or glioblastoma. Forty-one PCNSL tumor samples of newly diagnosed PCNSL were sequenced for C228T and C250T TERT somatic mutations. TERT promoter mutations status was correlated with clinical outcome and rs2853669 genotype. We identified C228T and C250T mutations and rs2853669 genotype in 20%, 9.4% and 50%, respectively. No case with co-occurrence of C228T and C250T mutations was identified. C228T mutations, but not C250T, were significantly associated with shorter overall survival (OS) (median OS = 4.5 months vs 33 months for non-mutated, p = 0.0048) and progression free survival (PFS) (median PFS = 3 months vs 11.5 months for non-mutated, p = 0.0260). We found no association between TERT promoter mutations and the rs2853669 genotype. To our knowledge, we showed the presence of TERT promoter mutations in PCNSL for the first time. In addition, C228T promoter mutation was associated with a poor outcome. Considering that these mutations are known to confer enhanced TERT promoter activity, we speculate that an increased telomerase activity could play a role in PCNSL aggressiveness. This work was granted by the LOC study group network (réseau national de centres experts des lymphomes primitifs du SNC, INCa), the Ligue contre le Cancer (Comité du Val d’Oise), the Fondation pour la Recherche Médicale (FDT20140930968), the APHP-CRIC 2013 (assistance publique - hôpitaux de Paris), and the Association pour la Recherche sur les Tumeurs Cérébrales. Citation Format: Aurélie Bruno, Mailys Daniau, Karima Mokhtari, Amithys Rahimian, Marc Polivka, Anne Jouvet, Clovis Adam, Dominique Figarella-Branger, Catherine Miquel, Sandrine Eimer, Caroline Houillier, Carole Soussain, Agusti Alentorn, Khê Hoang-Xuan. Recurrent TERT promoter mutations in primary central nervous system lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3896. doi:10.1158/1538-7445.AM2015-3896

IX. Is it only about MYC? How to approach the diagnosis of diffuse large B-cell lymphomas.

Keywords: diffuse large B-cell lymphoma; cell of origin; genetic alterations; double hit; double expresser; MYC; BCL2; BCLU

DUSP4 deficiency caused by promoter hypermethylation drives JNK signaling and tumor cell survival in diffuse large B cell lymphoma.

The epigenetic dysregulation of tumor suppressor genes is an important driver of human carcinogenesis. We have combined genome-wide DNA methylation analyses and gene expression profiling after pharmacological DNA demethylation with functional screening to identify novel tumor suppressors in diffuse large B cell lymphoma (DLBCL). We find that a CpG island in the promoter of the dual-specificity phosphatase DUSP4 is aberrantly methylated in nodal and extranodal DLBCL, irrespective of ABC or GCB subtype, resulting in loss of DUSP4 expression in 75% of >200 examined cases. The DUSP4 genomic locus is further deleted in up to 13% of aggressive B cell lymphomas, and the lack of DUSP4 is a negative prognostic factor in three independent cohorts of DLBCL patients. Ectopic expression of wild-type DUSP4, but not of a phosphatase-deficient mutant, dephosphorylates c-JUN N-terminal kinase (JNK) and induces apoptosis in DLBCL cells. Pharmacological or dominant-negative JNK inhibition restricts DLBCL survival in vitro and in vivo and synergizes strongly with the Bruton's tyrosine kinase inhibitor ibrutinib. Our results indicate that DLBCL cells depend on JNK signaling for survival. This finding provides a mechanistic basis for the clinical development of JNK inhibitors in DLBCL, ideally in synthetic lethal combinations with inhibitors of chronic active B cell receptor signaling.