Primary Extranodal Diffuse Large B-cell Research Articles

Coexpression of MYC and BCL2 oncoproteins in primary nodal versus primary extranodal diffuse large B-cell lymphoma

Objectives: Diffuse large B-cell lymphoma (DLBCL) is a morphologically and molecularly diversified disease with aggressive biological behavior. The double expression of MYC/BCL2 proteins portends a poorer prognosis. This study aims to evaluate the frequency, describe the clinicopathological features of the double-expressor phenotype of DLBCL in primary nodal (PN) versus primary extranodal (PEN) sites, and investigate their associations. Materials and Methods: A total of 48 patients with the double-expressor phenotype of lymphoma (DEPL) in a tertiary care hospital were included over three years. Clinicopathological parameters and associations were investigated based on the primary site. Statistical Analysis: Data were documented and analyzed using appropriate statistical tests. Results: The incidence of DEPL in our study was 28.7%. The median age of all DEPL patients was 56 years, with a predominance of men (69%). DEPL cases were further subcategorized as PN-DEPL (n = 33) and PEN-DEPL (n=15). Males were affected almost equally in both groups. More PN-DEPL patients exhibited B symptoms (82%), elevated lactate dehydrogenase (LDH) levels (73%), III/IV stage disease (71%), and maximum revised international prognostic index (R-IPI) score (64%) compared to PEN-DEPL patients. On the other hand, bone marrow (BM) involvement (87%), activated B-cell-type phenotype (80%), pathologic stage I/II (67%), and Ki67 index >90% (93%) were more common in PEN-DEPL patients. Conclusions: Significant differences were observed between PN-DEPL and PEN-DEPL in terms of B symptoms, LDH levels, stage at presentation, BM involvement, pathological subtype, Ki67 index, and R-IPI score. This study provides an estimate of the burden of this aggressive entity and encourages further prognostic studies and therapeutic trials.

Primary Extranodal Diffuse Large B-cell Lymphoma Presenting in the Lips: A Case Report and Literature Review.

Approximately 30-40% of malignant lymphomas are classified as diffuse large B-cell lymphoma (DLBCL), with 30% of DLBCL cases manifesting as extranodal lymphomas. Among these extranodal DLBCLs, primary DLBCL in oral lesions, particularly in the lips, is rare. While the treatment methods, chemotherapy assessment, and prognosis for nodal and extranodal DLBCLs are generally similar, diagnostic challenges can lead to delayed therapeutic intervention. We herein present a recent case of primary extranodal DLBCL in the lips that was swiftly diagnosed and managed using rituximab-containing chemotherapies. Our experience underscores the important role that hematologists play in identifying the possibility of oral hematological tumors, thereby allowing for a rapid diagnosis and timely intervention.

Первичная экстранодальная диффузная крупноклеточная В-клеточная лимфома: молекулярный ландшафт, противоопухолевое лечение и прогноз

Диффузная крупноклеточная В-клеточная лимфома (ДВКЛ) представляет собой крайне гетерогенное опухолевое заболевание лимфоидной природы и является наиболее распространенным иммуноморфологическим вариантом из группы агрессивных неходжкинских лимфом (НХЛ). Треть ДВКЛ характеризуется первичной экстранодальной локализацией и вариабельным прогнозом в зависимости от зоны поражения. Следует отметить, что именно молекулярные характеристики играют ключевую роль в различиях клинических проявлений, прогнозе опухолевого заболевания и совершенствовании терапевтического подхода с включением новых противоопухолевых агентов. Экстранодальная ДВКЛ молочной железы, кожи, матки, иммунопривелигированных зон, таких как центральная нервная система (ЦНС), и яичка, обладает фенотипом В-клеток постгерминального уровня (non-GCB) и высокой частотой мутаций MYD88/CD79B. В свою очередь для экстранодальной ДВКЛ желудка и щитовидной железы характерно благоприятное течение заболевания с низкой частотой выявляемости non-GCB-фенотипа. Ритуксимаб-содержащая иммунохимиотерапия (ИХТ) служит стандартом не только для нодальных форм заболевания, но и при первичной экстранодальной локализации. В настоящее время оптимизация стратегии терапии в соответствии с клинико-иммуноморфологическими характеристиками и молекулярной гетерогенностью является крайне актуальной проблемой. В данном обзоре рассматриваются ключевые сигнальные пути и новые подходы к противоопухолевой терапии первичной экстранодальной ДВКЛ. Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumour disease of lymphoid nature and is the most common immunomorphological variant from the group of aggressive non-Hodgkin’s lymphomas (NHL). One third of DLBCL is characterised by primary extranodal localization and a variable prognosis depending on the area of the lesion. It should be noted that it is molecular characteristics that play a key role in the differences in clinical manifestations, prognosis of tumour disease and improvement of the therapeutic approach with the inclusion of new antitumour agents. Extranodal DLBCL of the breast, skin, uterus, immunoprivileged areas such as the central nervous system (CNS) and testis have a postgerminal B-cell (non-GCB) phenotype and a high frequency of MYD88/CD79B mutations. In turn, extranodal gastric and thyroid DLBCL is characterised by a favourable disease course with a low incidence of the non-GCB phenotype. Rituximab- containing immunochemotherapy (ICT) is the standard not only for nodal forms of the disease, but also for primary extranodal localisation. Currently, optimizing the therapy strategy according to clinical and immunomorphological characteristics and molecular heterogeneity is a highly relevant problem. In this review, key signalling pathways and new approaches to antitumour therapy of primary extranodal DLBCL are discussed.

Primary extranodal diffuse large B-cell lymphoma in the rituximab era: a single center, retrospective analysis

ABSTRACT Objectives To analyse the clinical characteristics and therapeutic response of Chinese patients with primary extranodal diffuse large B-cell lymphoma DLBCL (PE-DLBCL). Methods We analysed the clinical features and outcomes of 197 patients who were newly diagnosed with PE-DLBCL between January 2015 and December 2020. Results The gastrointestinal tract showed the highest rate of involvement (34%), followed by the central nervous system (CNS) and intraocular system (31.5%). The 3-year overall survival (OS) rate was 81% for the entire group and 79% for those with CNS and vitreoretinal involvement. Ann Arbour stage, lactate dehydrogenase level, International Prognostic Index > 2, and complete remission (CR) were significantly related to the survival of patients with PE-DLBCL. The lack of CR was the only independent adverse prognostic factor for OS. Conclusion The clinical outcomes of patients with PE-DLBCL at our centre were encouraging, especially for patients with CNS and vitreoretinal involvement.

Targetable alterations in primary extranodal diffuse large B-cell lymphoma.

Primary extranodal diffuse large B‐cell lymphoma (PE‐DLBCL) is a heterogeneous subgroup of DLBCL. We investigated the prevalence and prognostic value of surface expression of PD‐L1, PD1, and CD30, copy number of 9p24.1 (PD‐L1 region), and mutations in MYD88, CD79B, CARD11, and BTK in a cohort of 116 patients, localized in the mediastinum (PMBL, n = 12), ear, nose and throat (ENT, n = 28), central nervous system (n = 29), testis (n = 7), breast (n = 4), stomach (n = 10), bone (n = 8), spleen (n = 2), and skin (n = 16). PD‐L1 expression is most frequent in PMBL (92%), followed by lymphomas originating in the stomach (57%), ENT (23%), and skin (18%). PD1 was expressed at low levels in less than 13% of PE‐DLBCL, while CD30 expression was found in 58% of PMBL. Mutation analysis revealed an unexpectedly high frequency of MYD88 and CD79B mutations in ENT lymphomas (46% and 50%, respectively). CARD11 mutations are rare but more frequently found in gastric lymphomas (30%), suggesting BTK resistance. Thirty‐four of 113 (30%) of the lymphomas harbored both MYD88 and CD79B mutations. Lower overall and progression‐free survival rates were found for cases with MYD88, CD79B, and BTK mutations. These data confirm the biologic singularity of PE‐DLBCLs and provide some suggestions for targeted therapies.

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

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

PRIMARY DIFFUSE LARGE B-CELL LYMPHOMA OF THE MANDIBLE: A RARE CASE REPORT

Diffuse large B-cell lymphoma is a malignant neoplasm of the lymphoid system and represents the majority cases of non-Hodgkin lymphomas. Nevertheless, it is a low-rate event in the head and neck region, especially as a primary occurrence. This is a case report of a primary extranodal diffuse large B-cell lymphoma in the mandible of a 52-year-old male patient who had no previous neoplasm history. Clinical examination and image examinations evidenced an asymptomatic singular intraosseous lesion in the mandibular bone measuring 5 cm, presenting one-and-a-half-year evolution. Odontogenic myxoma was clinical diagnostic hypothesis, and an incisional biopsy was performed. Microscopy was compatible with malignant neoplasm and immunohistochemical analysis was positive for CD20, PAX5, CD3, CD4, and CD10 markers, concluding the diagnosis of diffuse large B-cell lymphoma. The patient was treated with 4 cycles of rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone chemotherapy protocol. He responded very positively to the treatment and is still under follow-up. Diffuse large B-cell lymphoma is a malignant neoplasm of the lymphoid system and represents the majority cases of non-Hodgkin lymphomas. Nevertheless, it is a low-rate event in the head and neck region, especially as a primary occurrence. This is a case report of a primary extranodal diffuse large B-cell lymphoma in the mandible of a 52-year-old male patient who had no previous neoplasm history. Clinical examination and image examinations evidenced an asymptomatic singular intraosseous lesion in the mandibular bone measuring 5 cm, presenting one-and-a-half-year evolution. Odontogenic myxoma was clinical diagnostic hypothesis, and an incisional biopsy was performed. Microscopy was compatible with malignant neoplasm and immunohistochemical analysis was positive for CD20, PAX5, CD3, CD4, and CD10 markers, concluding the diagnosis of diffuse large B-cell lymphoma. The patient was treated with 4 cycles of rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone chemotherapy protocol. He responded very positively to the treatment and is still under follow-up.

Primary Extranodal Diffuse Large B-Cell Lymphomas Are Enriched for Mutations in MYD88 and CD79B.

Introduction: Diffuse large B-cell lymphomas (DLBCLs) with mutations in MYD88 and CD79B are a distinct molecular subentity according to recent analysis (“MCD-type” according to R. Schmitz et al., N Engl J Med 2018; and partially “cluster 5” according to B. Chapuy et al., Nature Medicine 2018). Both mutations were found particularly in specific anatomical localizations.Methods: To evaluate the incidence of MYD88 and CD79B mutations in primary extranodal DLBCL, we analyzed 111 tumor specimens of 99 patients. We performed targeted resequencing analysis to detect MYD88, CD79B, CARD11 and BTK mutations.Results:MYD88 mutations were frequently found in primary CNS lymphoma (67%), lymphoma of Waldeyer´s ring and paranasal sinuses (ENT) (44%), breast (75%), testicular (60%) and cutaneous (50%); the majority of mutations (89%) were located on L265P. CD79B mutations were frequent in CNS lymphoma (57%), lymphoma of ENT (52%) and breast lymphoma (50%). Both mutations occur simultaneously in CNS lymphoma (48%) and ENT lymphoma (33%). CARD11 mutations were frequently found in CNS lymphoma (33%) and in ENT lymphoma (26%). BTK mutations were found rarely, with the highest frequency (11%) in ENT lymphoma.Conclusion: Both, mutations in CD79B and MYD88 are frequent in primary extranodal lymphoma particularly in CNS lymphoma, lymphoma of Waldeyer's ring and paranasal sinuses, testicular, cutaneous and breast lymphoma. These findings may contribute to establish targeted therapeutic intervention of B-cell signaling in this subentity. [Display omitted] DisclosuresWeissinger:Bristol-Myers Squibb: Research Funding. Viardot:BMS: Consultancy, Honoraria; Gilead Kite: Consultancy, Honoraria; Amgen: Consultancy; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Primary extranodal diffuse large B-cell lymphomas: Many sites, many entities? Clinico-pathological, immunohistochemical and cytogenetic study of 106 cases

We analyzed the clinicopathological, immunohistochemical and cytogenetic features of 106 extranodal (EN) diffuse large B-cell lymphomas (DLBCLs) from stomach (34 cases), intestine (10), cervico-cephalic region (11), central nervous system (13), testes (21), skin (8), and miscellaneous sites (9).Hans’ algorithm and the immunohistochemical double expressor score (DES) for MYC and BCL2 were applied to all cases. A subset of fifty-eight cases were analyzed with fluorescent in situ hybridization (FISH) with specific break apart probes for BCL6, MYC, BCL2, CCND1, BCL10 and MALT1 genes. Clinical records were available for all patients.The immunohistochemical study showed that, in our series of EN-DLBCLs, the Hans’ subgroup and the DES differed significantly according to the site of origin. At FISH analysis, BCL6 and BCL2 were the most commonly rearranged genes in non-GC and in GC cases, respectively. Gastrointestinal lymphomas displayed the highest rate of gene rearrangements, often with MYC involvement. One testicular DLBCL showed BCL2/MYC double hit. At survival analysis, cerebral and testicular origin was associated with poor prognosis. In addition, Hans’ subgroup and other immunohistochemical markers influenced patients’ outcome.In conclusion, our data suggest that immunophenotypic, genetic and survival characteristics of EN-DLBCL are related to the specific primary site of the disease.

Primary extra-nodal diffuse large B-cell lymphoma: A prognostic analysis of 141 patients.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma. Approximately 40% of DBLCL originates from extra-nodal sites, but the diversity of clinical presentations and the genetic and molecular alterations indicate that extra-nodal DLBCLs may be distinct disease entities. The aim of the present study was to highlight the various aspects of primary extra-nodal DLBCL (PE-DLBCL) based on a single center cohort. The data from 141 patients with PE-DLBCL treated at Peking Union Medical College Hospital were retrospectively evaluated. The primary extra-nodal sites involved were the gastrointestinal tract (n=42), central nervous system (CNS; n=38), breast (n=19), adrenal gland (n=15), female genital system (FGS; n=12), thyroid (n=8) and bone (n=7). The median overall survival rate was 28 months (range, 1–116). Multivariate analysis demonstrated that an International Prognostic Index (IPI) ≤2 (P=0.049), complete remission (CR) achieved following first-line therapy (P=0.001) and chemotherapy combined with rituximab (P<0.001) were positive prognostic factors. Patients with DLBCL with primary adrenal gland or female genital system (FGS) involvement exhibited a significantly higher risk of CNS recurrence (P<0.05). Rituximab treatment may have reduced the likelihood of CNS recurrence (P=0.005), whereas prophylaxis with intrathecal injection alone was not sufficient for prevention (P>0.05). In conclusion, IPI >2 and the lack of a CR following first-line therapy were independent prognostic risk factors for PE-DLBCL. Patients with primary adrenal gland or FGS involvement exhibited a higher risk of CNS relapse. Rituximab had a positive impact on the survival of patients with PE-DLBCL, also reducing the likelihood of CNS relapse.

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.

Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large b-cell lymphomas of the thyroid – A study of 21 cases

Context: Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored. Objective: Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations. Design: A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data. Results: Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups....

Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B-cell lymphomas of the thyroid--a study of 21 cases.

Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored. Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations. A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data. Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups. Statistically significant deviations were detected at 20q13.33 and 21q11.2. These specific alterations do not seem to occur in thyroid carcinomas or other DLBCL, according to previously published literature. Analysis of BRAF and NRAS showed mutation frequencies of 4.8 and 9.5%, respectively. No MYD88 mutations could be detected in any of the analyzed cases. Fluorescence in situ hybridization demonstrated breakage events involving the BCL2, BCL6, and cMYC locus in 14.3, 9.5, and 9.5%, respectively. Our study revealed ptDLBCL to be predominantly composed of the GCB type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. Additionally, array comparative genomic hybridization showed no overlapping alterations between ptDLBCL and thyroid carcinomas or other nodal or extranodal DLBCL.

Addition of rituximab to the CHOP regimen has no benefit in patients with primary extranodal diffuse large B-cell lymphoma

BackgroundThe addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy (R-CHOP) has significantly improved clinical outcomes for patients with diffuse large B-cell lymphoma (DLBCL). However, new predictors of patient response to R-CHOP have not been established. We aimed to evaluate the impact of R-CHOP compared with CHOP in patients with DLBCL and to establish clinical predictors of better outcomes in these patients.MethodsWe retrospectively identified 177 patients diagnosed with CD20-positive DLBCL and treated with CHOP (N=82) or R-CHOP (N=95). The response rate, event-free survival (EFS), and overall survival (OS) rates were compared between the 2 treatment groups. All patients were classified into primary extranodal lymphoma (PENL) or nodal lymphoma (NL) subgroups, and the clinical parameters of each subgroup were analyzed.ResultsThe overall response rate was higher in R-CHOP group (95% vs. 84%, P=0.07). The 3-year EFS rate was significantly higher in R-CHOP group (71% vs. 52%, P=0.013), but the OS rate was comparable between the 2 groups (79% vs. 69%, P=0.23). A significant survival benefit was seen with R-CHOP compared to CHOP therapy in NL patients (P=0.002 for EFS and 0.04 for OS). Multivariate analyses confirmed that R-CHOP therapy is an independent prognostic factor for EFS (hazard ratio of 0.32 [0.17-0.62], P=0.001) and OS (hazard ratio of 0.4 [0.18-0.87], P=0.02) in NL patients.ConclusionPatients in the PENL group did not benefit from R-CHOP chemotherapy.

A controversial conclusion regarding primary extranodal diffuse large B-cell lymphoma

TO THE EDITOR: Recently, primary extranodal non-Hodgkin's lymphoma (NHL) has gained considerable attention. Many controversies are associated with primary extranodal NHL, mainly due to inadequate and contradictory literatures, and lack of uniformity in definition, clinicopathological characteristics, and clinical outcomes according to the involved sites. Jang et al. put forth prospects for further research to evaluate primary extranodal DLBCL [1]. Although they concluded that rituximab had no role in the treatment of primary extranodal DLBCL, their report included several limitations that were obstacles to achieve conclusive results. The diversity in clinical presentation, morphology, immunophenotype, and genetic alterations strongly suggest that DLBCL belongs to a heterogeneous group of aggressive B-cell lymphomas. Extranodal disease is the predominant disease manifestation (incidence, about 40%) among DLBCL patients. Even in patients with stage I disease, 56% had extranodal DLBCL [2]. On the basis of the results of routine staging, the authors defined PENL (primary extranodal lymphoma) as a lymphoma with no or minor nodal involvement, along with a clinically dominant extranodal component. The definition of extranodal disease has been controversial, particularly in the presence of both nodal and extranodal manifestations. The designation of stage III and IV lymphomas as PENLs is debatable, since many clinicians consider only stage I and II presentations as primary extranodal disease [3]. For patients in the advanced stage of disease, this diagnostic approach may be inappropriate, because many extranodal lymphomas can disseminate and vice versa. In the above study, patients with stage III or IV disease constituted more than 50% of all subjects. Therefore, this definition for PENL inevitably introduces a selection bias. The second controversial issue is the different prognosis according to the involved site. Lopez-Guillermo et al. [4] reported that the clinical characteristics of nodal and extranodal DLBCLs were heterogeneous. Lymphomas arising from two specific sites [Waldeyer's ring (nodal) and gastrointestinal region (extranodal)] showed very favorable characteristics at diagnosis (e.g., early stage, absence of bone marrow involvement, normal serum LDH level, and low-risk IPI), whereas DLBCLs arising in the remaining areas (lymph nodes or other extranodal sites) presented with poorer diagnostic characteristics. In terms of response to therapy, risk of relapse and overall survival, both Waldeyer's ring and gastrointestinal lymphomas showed notably better outcomes than those shown by the other groups [4, 5]. Thus, not only the nodal or extranodal presentation, but also involvement of specific sites may be related to particular clinicobiological characteristics and disease outcomes. The authors did not provide detailed information about the involved sites and differences in patient's characteristics between the extranodal and nodal disease groups. Primary extranodal DLBCLs, according to the involved site, may be considered as different entities with different natural histories, therefore, inference from figures should be dealt with caution. Therefore, further research using population-based studies is needed to achieve conclusive results for the diagnosis of primary extranodal DLBCL. Furthermore, the study of unresolved issues, including ambiguous definition, different clinicobiological characteristics, and gene profiles of primary extranodal DLBCL arising from different sites is warranted.

Uncertainty and discordance in the staging and prognosis of diffuse large B‐cell lymphoma with isolated bilateral testicular involvement

American Journal of HematologyVolume 84, Issue 11 p. 762-763 LetterFree Access Uncertainty and discordance in the staging and prognosis of diffuse large B-cell lymphoma with isolated bilateral testicular involvement† Ronald S. Go, Corresponding Author Ronald S. Go [email protected] Center for Cancer and Blood Disorders, Gundersen Lutheran Health System, La Crosse, WisconsinCenter for Cancer and Blood Disorders, Gundersen Lutheran Health System, Mail Stop: EB2-001, 1900 South Avenue, La Crosse 54601, WI 54601Search for more papers by this authorJacob D. Gundrum, Jacob D. Gundrum Department of Medical Research, Gundersen Lutheran Medical Foundation, La Crosse, WisconsinSearch for more papers by this author Ronald S. Go, Corresponding Author Ronald S. Go [email protected] Center for Cancer and Blood Disorders, Gundersen Lutheran Health System, La Crosse, WisconsinCenter for Cancer and Blood Disorders, Gundersen Lutheran Health System, Mail Stop: EB2-001, 1900 South Avenue, La Crosse 54601, WI 54601Search for more papers by this authorJacob D. Gundrum, Jacob D. Gundrum Department of Medical Research, Gundersen Lutheran Medical Foundation, La Crosse, WisconsinSearch for more papers by this author First published: 10 August 2009 https://doi.org/10.1002/ajh.21522Citations: 4 † Conflict of interest: Nothing to report. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Carbone PP,Kaplan HS,Musshoff K, et al. Report of the committee on Hodgkin's disease staging classification. Cancer Res 1971; 31: 1860– 1861. 2 Gospodarowicz M. Individuality versus conformity. Is perfection necessary in staging and prognostic classifications of specific primary extranodal lymphomas? Ann Oncol 1999; 10: 1405– 1407. 3 Armitage JO. Staging non-Hodgkin lymphoma. CA Cancer J Clin 2005; 55: 368– 376. 4 Zucca E,Conconi A,Mughal TI, et al. Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the international extranodal lymphoma study group. J Clin Oncol 2003; 21: 20– 27. 5 Bentley RC,Devlin B,Kaufman RE, et al. Genotypic divergence precedes clinical dissemination in a case of synchronous bilateral B-cell malignant lymphoma of the testes. Hum Pathol 1993; 24: 675– 678. 6 Salvatore JR,Ross RS. Primary bilateral adrenal lymphoma. Leuk Lymphoma 1999; 34: 111– 117. 7 Ryan G,Martinelli G,Kuper-Hommel M, et al. Primary diffuse large B-cell lymphoma of the breast: Prognostic factors and outcomes of a study by the international extranodal lymphoma study group. Ann Oncol 2008; 19: 233– 241. 8 Hoffman PM,McKelvie P,Hall AJ, et al. Intraocular lymphoma: A series of 14 patients with clinicopathological features and treatment outcomes. Eye 2003; 17: 513– 521. 9 Kojima M,Shimizu K,Nishikawa M, et al. Primary salivary gland lymphoma among Japanese: A clinicopathological study of 30 cases. Leuk Lymphoma 2007; 48: 1793– 1798. 10 Decaudin D,de Cremoux P,Vincent-Salomon A, et al. Ocular adnexal lymphoma: A review of clinicopathologic features and treatment options. Blood 2006; 108: 1451– 1460. 11 Cordier JF,Chailleux E,Lauque D, et al. Primary pulmonary lymphomas. A clinical study of 70 cases in nonimmunocompromised patients. Chest 1993; 103: 201– 208. 12 Cortelazzo S,Mian M,Rossi A, et al. Primary extranodal diffuse large B-cell lymphomas (DLBCL) arising in distinct sites of head and neck have different clinical characteristics and outcome. Haematologica 2007; 92 (s1). Abstract 0863. 13 Rohatiner A,d'Amore F,Coiffier B, et al. Report on a workshop convened to discuss the pathological and staging classifications of gastrointestinal tract lymphoma. Ann Oncol 1994; 5: 397– 400. 14Surveillance, Epidemiology, and End Results. Available at: http://seer.cancer.gov/Accessed on July 2, 2009. Citing Literature Volume84, Issue11November 2009Pages 762-763 ReferencesRelatedInformation

Specific expression of miR-17-5p and miR-127 in testicular and central nervous system diffuse large B-cell lymphoma

Recent studies have shown that certain non-coding short RNAs, called miRNAs, play an important role in diffuse large B-cell lymphomas. Patients with diffuse large B-cell lymphoma have great diversity in both clinical characteristics, site of presentation and outcome. The aim of our study is to validate the differential expression in germinal center and non-germinal center diffuse large B-cell lymphoma,s and to study to the extent to which the primary site of differentiation is associated with the miRNA expression profile. We studied 50 cases of de novo diffuse large B-cell lymphoma for the expression of 15 miRNAs (miR-15a, miR-15b, miR-16, miR-17-3p, miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-92, miR-127, miR-155, miR-181a and miR-221). Apart from 19 nodal cases without extranodal dissemination (stages I and II), we selected two groups with unambiguous stages I and II extranodal presentation; 9 cases of primary central nervous system, 11 cases of primary testicular and 11 cases of other primary extranodal diffuse large B-cell lymphomas. All cases were analyzed with qRT-PCR. In situ hybridization for the most differentially expressed miRNAs was performed to show miRNA expression in tumor cells, but not in background cells. MiR-21 and miR-19b showed the highest expression levels. No significant differences were seen between germinal center and non-germinal center diffuse large B-cell lymphomas in either the total or the nodal group for any of the 15 miRNAs. Two miRNAs showed significant differences in expression levels for diffuse large B-cell lymphoma subgroups according to the site of presentation. MiR-17-5p showed a significant higher expression level in the central nervous system compared with testicular and nodal diffuse large B-cell lymphomas (P<0.05). MiR-127 levels were significantly higher in testicular than in central nervous system and in nodal diffuse large B-cell lymphomas (P<0.05). We conclude that the location of diffuse large B-cell lymphoma is an important factor in determining the differential expression of miRNAs.

No Benefit from Rituximab Containing Regimens in Patients with Primary Extranodal Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous category of lymphoid tumors that comprises different clinical forms not fully recognized in the WHO classification. In this regard, extranodal (EN) DLBCLs have particular clinicobiological features and outcome, sometimes related to the specific site where the lymphoma arises. Nowadays, rituximab plus chemotherapy (CT) is the gold-standard in the treatment of DLBCL. However, the superiority of rituximab-CT (R-CT) over CT alone has not been addressed for all the clinical subsets of the disease and, in fact, the clinical role of the new therapies might be different for primary nodal or EN DLBCLs. The aim of this study was to assess the impact of rituximab in patients suffering from nodal or EN DLBCL. Two-hundred and thirty non-immunocompromised patients (112M/118F; median age, 61 years) diagnosed with CD20+DLBCL in a single institution between 1997 and 2006 (five years before and after establishing R-CT as the standard treatment in DLBCL) and treated with adriamycin-containing regimens were the subject of the present study. The series included 148 primary nodal and 82 EN DLBCL. Patients with primary CNS lymphoma were excluded and lymphomas arising at Waldeyer ring were considered as nodal DLBCL. The main EN sites were GI (n=26), bone (n=13), soft tissue (n=13), lung/pleura (n=9), liver (n=9), and other (n=12). Main clinico-biological and evolutive variables were analyzed. One hundred nineteen patients received only CT and 111 R-CT. Eighty-seven cases with available information were assigned to germinal center B-cell-like (GCB) (41%) or non-GCB (59%) groups according to the Hans method (Blood 2004; 103:275–82) based on CD10, BCL6 and MUM1 expression. Main initial features, including the primary nodal or EN origin, international prognostic index (IPI), and GCB/non-GCB categories were similar for CT and R-CT groups. No correlation was observed between the GCB/non-GCB groups and the primary site of the tumor, although nodal lymphomas more frequently expressed MUM1 than EN (69% vs. 31%, respectively; p=0.01). CR rate and 5-year overall survival (OS) according to the treatment arm (CT vs. R-CT) is detailed for the whole series and for the nodal and EN groups in the table and OS curves depicted in the figure. In the whole series, variables predicting poor OS in the multivariate analysis were high-risk IPI (RR 2.5; p<0.001), primary nodal involvement (RR 1.6; p=0.04) and no R-CT treatment (RR 1.9; p=0.002). In the nodal group, IPI and no R-CT maintained the prognostic value, whereas in the primary EN only IPI predicted OS. Moreover, no difference in OS was observed according to the nodal or EN origin in those patients receiving R-CT. Biological subtypes GCB vs. non-GCB did not add predictive information neither in the whole series nor in the nodal or EN groups. In conclusion, patients with primary EN DLBCL seem to have little benefit from the use of R-CT. Nevertheless, this intriguing observation should be confirmed in further prospective studies.Complete response CR (%)5-years OS (%)CTR-CTCTR-CTAll cases (n=230)5979*4670*Primary nodal (n=148)5478*3471*Primary extranodal (n=82)68787069*p<0.002 R-CT vs. CT [Display omitted]

Prognostic significance of primary extranodal diffuse large B-cell lymphoma (DLBCL) in patients treated with R-CHOP

8583 Background: Previous studies in the pre-rituximab era have identified important clinical differences between nodal and primary extranodal DLBCL. We have examined the prognostic significance of primary extranodal DLBCL in the post-rituximab era. Methods: Using the Lymphoid Cancer Database of the British Columbia Cancer Agency, all patients ≥18 years of age diagnosed with DLBCL between January 1999 and May 2006 and treated with an R-CHOP regimen were included for analysis. Patients were excluded if they were HIV positive, presented with disease in the testicular or central nervous system, or had known coincident indolent lymphoma. Primary extranodal DLBCL was defined as disease confined to one or more localized extranodal sites, with no or minimal nearby nodal involvement. Results: 513 patients were identified with the following characteristics: median age 62 y (range 19–93), male 59.1%, stage III/IV 53.8%, elevated LDH 49.5%, and performance status ≥2 38.2%. While 350 (68.2%) had at least some degree of extranodal involvement, only 133 (25.9%) had primary extranodal DLBCL. Among patients with primary extranodal disease, 70 (52.6%), 37 (27.8%) and 26 (19.6%) had 1, 2 and ≥3 extranodal sites, respectively. The most commonly involved extranodal sites included bone (33.1%), soft tissue (28.6%), stomach (15.0%), intestine (12.8%), and sinus (10.5%). Thirty-two percent, 20%, 0% and 48% of patients with primary extranodal DLBCL had stage I, II, III, and IV, respectively. This is in contrast to 11%, 34%, 26% and 29% for the nodal DLBCL group. Primary extranodal DLBCL was less commonly associated with an elevated LDH (37.6% vs. 53.7%, p=0.001). The distribution of International Prognostic Index scores was similar between the two groups. With a median follow-up of 2.8 years, no significant difference in overall survival was detected between primary extranodal DLBCL and nodal DLBCL analyzed either as a group or by individual stages. Furthermore, we did not identify any specific primary extranodal sites that confer a worse prognosis. Conclusion: In the post-rituximab era, the previously identified survival difference in primary extranodal DLBCL is no longer observed in this large cohort. No significant financial relationships to disclose.

Diffuse Large B-cell Lymphoma with Infiltration-Associated Peripheral Neuropathy and Paraneoplastic Myopathy with a Prolonged Course Over Seven Years

Rarely lymphoproliferative disorders (LPD) may be associated with peripheral neuropathy, based on different mechanisms of pathogenesis. Here, we report a case of a primary extranodal diffuse large B-cell lymphoma which showed a prolonged course with several recurrences manifesting as neuropathies, and long term remissions achieved by chemotherapy and involved field radiation. Repeated pathohistologic evaluations showed spread of lymphoma growth predominantly along nerve structures, suggesting neurotropism of the lymphoma cells.