Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, Korea.
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in all countries and all age groups. DLBCL is potentially curable, and the outcome of patients with DLBCL has completely changed with the introduction of therapy involving the monoclonal antibody rituximab in combination with chemotherapy. Nonetheless, relapse is detected after treatment with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone in approximately 30% of patients. It has recently become clear that DLBCL represents a heterogeneous admixture of quite different entities. Gene expression profiling has uncovered DLBCL subtypes that have distinct clinical behaviors and prognoses; however, incorporation of this information into treatment algorithms awaits further investigation. Future approaches to DLBCL treatment will use this new genetic information to identify potential biomarkers for prognosis and targets for treatment.
Department of Hematology, Oncology and Tumor Immunology, Molecular Cancer Research Center, Charité - Universitätsmedizin Berlin, Germany.
MCL1, diffuse large B-cell lymphoma, aCGH, apoptosis, therapy resistance
MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)). Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.Leukemia accepted article preview online, 21 December 2012; doi:10.1038/leu.2012.367.
Genome sequencing reveals mutation unique to Burkitt lymphoma
The first broad genetic landscape map of a Burkitt lymphoma tumor has identified 70 mutations, including several not previously associated with cancer and a new one that is unique to the disease. These findings could be used to develop new drugs or aim existing therapies at mutations known to be susceptible.
Burkitt lymphoma is an aggressive form of lymphoma. This study was the first complete sequence of a Burkitt lymphoma genome, plus genes from 59 additional Burkitt cases and 94 diffuse large B cell lymphomas, which share many of the same characteristics of Burkitt lymphoma. Similarities between the malignancies can often lead to mistaken diagnoses and failed treatments.
Striking differences were found in the gene mutation pattern of Burkitt lymphomas compared with the diffuse large B cell lymphomas.
“It's important that doctors make the right diagnosis for Burkitt lymphoma, which can be cured with the correct therapies,” said Sandeep S. Dave, MD, MBA, MS, associate professor at Duke Medicine and senior author. “But if misdiagnosed and given the standard chemotherapy regimes for diffuse large B cell lymphomas, Burkitt lymphoma patients invariably relapse.”
The analysis identified 70 genes that were frequently mutated in the Burkitt lymphomas, including a number of genes that were identified in cancer for the first time. One of the newly identified gene mutations, ID3, appeared in 34% of the Burkitt cases, but was not evident in any of the diffuse large B cell lymphomas. The mutation has a silencing effect on a gene that suppresses cell growth, enabling cells to multiply.
Dave explained that this alteration alone may not cause cancer, but when it occurs along with the MYC gene mutations that are common in Burkitt lymphoma and other malignancies, it works like an accelerant to fuel tumor growth. That finding could prove helpful for developing a new drug to function like a normal ID3 gene and suppress cancer cell proliferation in lymphomas as well as numerous other cancers.
“If we can find a way to mimic ID3, restoring the function of the gene to slow the growth of tumors, this could provide a new treatment approach,” Dave said. “We have experiments that suggest this is the case, but much more research is needed. This work provides a starting point.”
These findings were published in Nature Genetics (2012; doi:10.1038/ng.2468).
Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study.
Department of Oncology, Oslo University Hospital, Oslo, Norway.
Many patients with aggressive B-cell lymphomas and high clinical risk score still die of lymphoma after conventional R-CHOP chemoimmunotherapy. We hypothesized that intensified chemoimmunotherapy including systemic central nervous system (CNS) prophylaxis improves outcome and reduces the incidence of CNS-related events.Patients and methodsInclusion criteria were age 18-65 years, primary diffuse large B-cell lymphoma or grade III follicular lymphoma without clinical signs of CNS disease and negative cerebrospinal fluid cytology, age-adjusted International Prognostic Index 2-3 and WHO performance score 0-3. Treatment consisted of six courses of R-CHOEP-14 followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Primary end point was failure-free survival (FFS) at 3 years.ResultsA total of 156 eligible patients with a median age of 54 years (range 20-64) were included. Three toxic deaths were observed. Three-year overall survival (OS) and FFS rates (median observation time 52 months for survivors) were 81% and 65%, respectively. Seven patients experienced CNS relapse, all within 6 months.ConclusionsThe results are promising with favorable 3-year OS and FFS rates, a low toxic death rate and a lower than expected number of CNS events. CNS progression might be further reduced by earlier CNS prophylaxis.CinicalTrials.gov. identifierNCT01502982.
Clinicopathological features of aggressive B-cell lymphomas including B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell and Burkitt lymphomas: a study of 44 patients from Argentina.
Servicio de Patología, Hospital Privado de Córdoba. Córdoba, Argentina.
Aggressive B-cell lymphomas incorporate a wide spectrum of lymphomas that pose challenges in diagnosis as well as treatment. We evaluated the clinicopathological features of 44 patients with aggressive B-cell lymphomas which were classified into 3 groups based on the World Health Organization 2008 classification as follows: including 30 cases of diffuse large B-cell lymphoma (DLBCL), 8 cases of Burkitt lymphoma (BL) and 6 cases of B-cell lymphoma, unclassifiable, with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma (BCLU). Male predominance was observed in BL and BCLU groups and the mean age varied from 29 years in BL, 61 years in DLBCL and 70 years in BCLU. Patients with BCLU presented at more advanced stages and had a higher international prognostic index. By immunohistochemistry, they shared characteristics of both BL (including more frequent expression of SOX11) and DLBCL. FISH analyses showed three cases with more than one rearrangement: one MYC/BCL2 and two BCL2/BCL6, in addition to which one case with BCL2/IGH translocation and another with MYC rearrangement were also detected. The mean follow-up survival time of BCLU was 6.6 months, which was significantly shorter in comparison to DLBCL (31 months) and BL (30 months), respectively. The importance of recognizing this BCLU group relies on its different clinical course, poor prognosis and shorter survival than DLBCL and BL. An accurate diagnosis is critical for risk stratification and to improve therapeutic approaches and outcomes.
Department of Radiation Oncology, Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, P. R. China.
The value of intensity-modulated radiation therapy (IMRT) after doxorubicin-based chemotherapy in primary mediastinal large B-cell lymphoma (PMBCL) is unknown. We assessed the dosimetric parameters, treatment outcomes, and toxicity of IMRT in PMBCL.
METHODS AND MATERIALS:
Forty-one PMBCL patients underwent mediastinal IMRT after doxorubicin-based chemotherapy. Thirty-eight patients had stage I-II disease, and 3 patients had stage III-IV disease. Most patients presented with bulky mediastinal disease (65.9%) and local invasion (82.9%). The dose-volume histograms of the target volume and critical normal structures were evaluated.
The average planning target volume (PTV) mean dose was 39 Gy. Only 0.5% and 1.4% of the PTV received <90% and <95% of the prescribed dose, respectively, indicating excellent target coverage. The median mean lung dose and percentage lung volume receiving 20 Gy (V20) were 16.3 Gy and 30.6%. The 5-year overall survival (OS) and local control (LC) were 95.1% and 89.8%. After chemotherapy, consolidation radiation therapy in patients with complete/partial response resulted in significantly better survival than salvage radiation therapy in patients with stable/progressive disease (3-year OS 100% vs 75%; 3-year LC 96.6% vs 62.5%). No grade 4 or 5 acute or late toxicities occurred.
Mediastinal IMRT after doxorubicin-based chemotherapy can be safely and efficiently delivered, and it provides favorable outcomes in PMBCL patients with a large target volume and high-risk features.
Hematology and Oncology Department, Hôpital Saint-Louis, AP-HP and IUH, INSERM U728, University Paris VII, 75010 Paris, France.
Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma (NHL) in adults. Even if the natural history of DLBCL has been improved with the advent of immunochemotherapy, the survival results obtained with current treatment options clearly indicate that new agents or novel approaches are needed. Lenalidomide (Revlimid, Celgene Corporation, Summit, NJ, USA), an analogue of thalidomide, is an immunomodulatory drug with pleiotropic mechanisms of action potentially adding to immunochemotherapy. We present here the biological rational for the use of lenalidomide in DLBCL in light of recent advances in the pathophysiology of the disease and the therapeutic results of the most recent trials published in literature or reported in meetings in relapsed/refractory situations as well as in first-line treatment.
1Hospital Saint Louis, Paris Diderot University, Paris, France.
Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard of treatment for chemosensitive relapses in diffuse large B-cell lymphoma. The addition of rituximab to chemotherapy has improved the response rate and failure-free survival after first-line treatment and relapses. Fewer relapses are expected, although there is no consensus on the best salvage regimen. The intergroup Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) set the limits for this standard of treatment after first comparing 2 salvage regimens: rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) and rituximab, dexamethasone, aracytine, and cisplatin (R-DHAP). There was no difference in response rates or survivals between these salvage regimens. Several factors affected survival: prior treatment with rituximab, early relapse (< 12 months), and a secondary International Prognostic Index score of 2-3. For patients with 2 factors, the response rate to salvage was only 46%, which identified easily a group with poor outcome. Moreover, patients with an ABC subtype or c-MYC translocation responded poorly to treatment. More than 70% of patients will not benefit from standard salvage therapy, and continued progress is needed. Studies evaluating immunotherapy after transplantation, including allotransplantation, new conditioning regimens with radioimmunotherapy and other combinations of chemotherapy based on diffuse large B-cell lymphoma subtype, are discussed herein. Early relapses and/or patients refractory to upfront rituximab-based chemotherapy have a poor response rate and prognosis. A better biological understanding of these patients and new approaches are warranted.
Department of Oncology and Radiotherapy, Edgardo Rebagliati Martins Hospital, Lima, Peru.
We describe the clinical and pathological characteristics of seven patients who were human T-lymphotropic virus type 1 (HTLV-1) carriers and had a pathological diagnosis of de novo diffuse large B-cell lymphoma. Interestingly, three of our cases showed positive expression of Epstein-Barr-virus, (EBV-) encoded RNA within the tumor cells indicating a possible interaction between these two viruses. Furthermore, our three EBV-positive cases presented with similar clinical characteristics such as early clinical stage and low-risk indices. To the best of our knowledge, this is the first case series describing the characteristics of HTLV-1-positive DLBCL patients. The potential relationship between HTLV-1 and EBV should be further explored.
Department of Biostatistics & Epidemiology, School of Public Health, Hamadan University of Medical Sciences, Hamadan, Iran.
The present study was conducted to predict survival time in patients with diffuse large B-cell lymphoma, DLBCL, based on microarray data using Cox regression model combined with seven dimension reduction methods. This historical cohort included 2042 gene expression measurements from 40 patients with DLBCL. In order to predict survival, a combination of Cox regression model was used with seven methods for dimension reduction or shrinkage including univariate selection, forward stepwise selection, principal component regression, supervised principal component regression, partial least squares regression, ridge regression and Losso. The capacity of predictions was examined by three different criteria including log rank test, prognostic index and deviance. MATLAB r2008a and RKWard software were used for data analysis. Based on our findings, performance of ridge regression was better than other methods. Based on ridge regression coefficients and a given cut point value, 16 genes were selected. By using forward stepwise selection method in Cox regression model, it was indicated that the expression of genes GENE3555X and GENE3807X decreased the survival time (P=0.008 and P=0.003, respectively), whereas the genes GENE3228X and GENE1551X increased survival time (P=0.002 and P<0.001, respectively). This study indicated that ridge regression method had higher capacity than other dimension reduction methods for the prediction of survival time in patients with DLBCL. Furthermore, a combination of statistical methods and microarray data could help to detect influential genes in survival.
Department of Medical Oncology, Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland.
To complete the existing treatment guidelines for all tumor types, ESMO organizes consensus conferences to better clarify open issues in each disease. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, immediately after the end of the 11th International Conference on Malignant Lymphoma.The consensus conference convened ∼45 experts from all around Europe and selected six lymphoma entities to be addressed; for each of them three to five open questions were to be discussed by the experts. For each question, a recommendation should be given by the panel, supported by the strength of the recommendation based on the level of evidence.This consensus report focuses on the three most common lymphoproliferative malignancies: diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia. A second report will concentrate on mantle cell lymphoma, marginal zone lymphoma and T-cell lymphomas.
Sheffield Children's Hospital, Sheffield, United Kingdom;
Mediastinal large B-cell lymphoma (MLBL) represents only 2% of mature B-cell non-Hodgkin lymphoma (B-NHL) in patients ≤18 years of age. Gene expression profiling demonstrates that MLBL in adults more closely resembles classical Hodgkinlymphoma than it does diffuse large B-cell lymphoma (DLBCL). We analyzed data from childhood and adolescent patients with Stage III MLBL (N=42) and non MLBL DLBCL (N=69) treated with Group B therapy on the FAB/LMB 96 study. Demographics of MLBL patients: M/F: 26/16; median age 15.7 yrs (12.5-19.7); LDH <2 vs. ≥2 ULN: 23:19. Six MLBL patients (14%) had <20% response to initial COP-therapy. Central pathology classification revealed approximately 50% with classical features of primary mediastinal B-cell lymphoma (PMBL). Five-year event-free survival (EFS) for Stage III MLBL and non-MLBL DLBCL groups were 66% (95% CI: 49-78%) and 85% (95% CI: 71-92%), respectively, p<0.001 (14%). The 5-year overall survival (OS) in the 42 MLBL patients was 73% (95% CI: 56-84%). MLBL in adolescent patients is associated with significantly inferior EFS compared with stage III non-MLBL DLBCL and can be of multiple histologies. Alternate treatment strategies should be investigated in the future taking into account both adult MLBL approaches and more recent biological findings in adult MLBL.
Anatomic Pathology Section, Department of Molecular Pathology, University of Pavia and IRCCSFondazione Policlinico "San Matteo", Pavia, Italy - email@example.com.
Primary cutaneous B-cell lymphoma (PCBCL) is an heterogeneous group of lymphoproliferative disorders, which account for 25-30% of all primary cutaneous lymphoma and include three main histotypes: 1) primary cutaneous marginal zone B-cell lymphoma (PCMZL); 2) primary cutaneous follicular center cell lymphoma (PCFCL); 3) primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type (PCDLBCL-LT). PCMZL and PCFCL are indolent lymphomas, with an excellent prognosis despite an high rate of cutaneous recurrences; in contrast, PCDLBCL-LT is clinically more aggressive and usually requires to be treated with multi-agent chemotherapy and anti-CD20 monoclonal antibodies. PCDLBCL-LT histologically consists of large round cells (centroblasts and immunoblasts), is characterized by strong bcl-2 expression, in the absence of t(14;18) translocation, and resembles the activated B-cell type of nodal DLBCL. Recently, the term primary cutaneous DLBCL-other (PCDLBCL-O) has been proposed to include diffuse lymphomas composed of large transformed B-cells that lack the typical features of PCDLBCL-LT and do not conform to the definition of PCFCL. Some clinical studies suggested that such cases have an indolent clinical course and may be treated in a conservative manner; however, data regarding the actual prognosis and clinical behaviour of these peculiar cases are still too limited. The spectrum of primary cutaneous DLBCL also encompasses some rare morphological variants, such as anaplastic or plasmablastic subtypes and T-cell rich B-cell lymphoma, and some recently described, exceedingly rare DLBCL subtypes, such as intravascular large B-cell lymphoma and EBV-associated large B-cell lymphoma of the elderly, which often present in the skin.
Divisions of Pathological AnatomyDepartment of Critical Care Medicine and SurgeryUniversity of Florence Medical School, Florence, Italy2Division of DermatologyDepartment of Critical Care Medicine and SurgeryUniversity of Florence Medical School, Florence, Italy3Division of HematologyDepartment of Critical Care Medicine and SurgeryUniversity of Florence Medical School, Florence, Italy.
Among primary cutaneous B-cell lymphomas (CBCL), two main clinico-pathologic entities are recognized, i.e. marginal zone lymphoma (MZL), otherwise defined as extranodal MZL, MALT (Mucosa-Associated Lymphoid Tissue) type, and follicle center lymphoma (FCL). They are mostly characterized by indolent course (very limited risk of extracutaneous spread), very good response to non-aggressive treatment (radiotherapy is the gold standard), and excellent prognosis (>90% 5-year survival overall). The clinical presentation of MZL and FCL slightly differ concerning site predilection (trunk and upper limbs in the former, head&neck and trunk in the latter) and frequency of cases with multiple, non-contiguous lesions (higher in MZL). Histologically, MZL and FCL share the multiphasic evolution of lesions, while some distinctive features are clues to diagnosis and differential diagnosis: CD5-/CD10-/bcl2+ phenotype of neoplastic cells, "colonization" of reactive lymphoid follicles by neoplastic cells, lymphoplasmacytoid and plasma cells at the periphery of nodular infiltrates in MZL; CD5-, CD10 +/-, bcl6+, MUM-1 neg, FOX-P1 neg, IRF4 neg, IgM neg phenotype of neoplastic cells (centrocytes), and neoplastic follicles (in early lesions) in FCL.
Am old enough to understand the difference between the Bay of Pigs - and roasting a pig at a epicurian feast. Been thru the hippy, yippie and yuppie years - always remaining who I am.
Very much believe in "Sing your own song - weave your own tapestry"
Am young enough to still know the thrill of new discoveries, the beauty of the evening, to celebrate the joy of another tommorow.
Survived these many decades with a severe medical problems. Sorting out the maze of now having two lymphomas and all their nasty little companions, but I continue.
Besides, being a simple iconoclastic eclectic, have been called many things. An incurable romanticist - with a strong touch of reality. Thinker, intellectual (God, how I hate that term) - been told I am a lion with the heart of the poet.
Know how to wage war and conquer my foes - but would rather be known as one who brings hope and life. To bring hope into anothers life is the ultimate of joys.
Life should be about bringing hope, peace, vision... a sense of purpose beyond yourself.