Radiation Oncology/NHL/DLBCL

Pathology Morphology - not clinically useful Immunoblastic Centroblastic Anaplastic Multilobated Markers Improved survival Rb (cell cycle) Germinal centre (bcl-6, CD10) Decreased survival CD5 (T-cell lineage) HLA-I, HLA-II (immune) Ki-67 (proliferation) p53+, p21, p27, cyclin D3 (cell cycle) bcl-2, bax, survivin (apoptosis) CD44 (adhesion) Origin Germinal center of activated lymphoid follicle Subclassification Gene profiling identified 3 separate subtypes, with different clinical behavior (5-year OS) Activated B-cell - activation of NFkB - 30% survival Germinal B-cell - hypermutations, REL amplification, bcl-2 translocations - 64% survival Primary Mediastinal B-cell - 59% survival Mediastinal B-cell lymphoma is more closely related to nodular sclerosis subtype of Hodgkin lymphoma (clinically and by gene expression profile), than to the other types of B-cell lymphoma Morphologically, there is also a significant overlap with Burkitt's Lymphoma Charite, 2006 (Germany) 16760442 -- "A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling." (Hummel M, N Engl J Med. 2006 Jun 8;354(23):2419-30.) Gene analysis. 220 mature aggressive B-cell lymphomas. Molecular Burkitt's lymphoma (mBL) signature developed: 58 gene set. Some patients with this signature had morphologic appearance of DLBCL 5-year OS: mBL 75%, GCB-DLBCL 51%, ABC-DLBC 12% Myc locus survival (mBL and DLBCL): breakpoint 15% vs. no breakpoint 44% Conclusion: molecular definition of Burkitt's lymphoma Lymphoma profiling project 2006 16760443 -- "Molecular diagnosis of Burkitt's lymphoma." (Dave SS, N Engl J Med. 2006 Jun 8;354(23):2431-42.) Gene analysis. 303 patients with aggressive lymphomas, 25 pathological Burkitt's. Gene profile developed. 8 samples submitted as DLBCL had molecular profile of Burkitt's Conclusion: Gene-expression profiling is accurate to differentiate BL and DLBCL 2005 16046532 -- "Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction." (Bea S, Blood. 2005 Nov 1;106(9):3183-90.) ABC-DLBCL: trisomy 3, gain of 3q, gain of 18q21-q22, loss of 6q21-q22 GCB-DLBCL: gain of 12q12 PMBCL: gain of 9p21, gain of 2p14-p16 Dana Farber, 2003 12933571 -- "The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma." (Savage KJ, Blood. 2003 Dec 1;102(12):3871-9.) Gene expression profiles compared. Shared survival pathway between MBCL and HL NCI, 2002 12075054 -- "The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma." (Rosenwald A, N Engl J Med. 2002 Jun 20;346(25):1937-47.) Biopsy samples of 240 patients examined with DNA microarrays. 17 gene-set predictor developed Gene array independent predictor to IPS Stanford, 2000 10676951 -- "Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling." (Alizadeh AA, Nature. 2000 Feb 3;403(6769):503-11.) DNA microarrays to conduct a systemic characterization of gene expression Two molecularly distinct types: 1) Germinal Center and 2) Activated B-like OS significantly better for Germinal Center patients Primary Mediastinal Large B-cell Epidemiology: 2% of NHL patients Tends to affect younger women Clinical presentation: Rapidly growing (bulky >10cm) mediastinal mass, often with respiratory symptoms Up to 50% can have symptoms of SVC syndrome (facial edeme, neck vein distension, upper extremity edema Criteria No clear definition for Primary Mediastinal Large B-Cell Lymphoma Various definitions include: Some: restrict only to tumors with sclerosis and clear-cell morphology or only with involved thymic tissue Restricted to low-stage disease or excluding extrathoracic involvement "a [DLBCL] that either presents with disease limited to the mediastinal field or more advanced presentations with the dominant site of disease in the mediastinum" (Rodriguez 1994, 8001905) mediastinal mass of at least 5 cm with no extramediastinal mass larger than that in the mediastinum (Abou-Elella 1999, 10071267) Pathology Believed to arise from thymic B-cells Have bcl-6 translocation, but also gain in Janus kinase (JAK-2), bcl-2 translocation absent Striking clinical, immunologic, and molecular similarities to Hodgkin's disease (NScHL), but cells retain B-cell differentiation markers (eg CD20), and lack Reed-Sternberg cells Treatment Please see the Specific Sites section for more detail Some evidence that dose-intensified therapy (eg MACOP-B, VACOP-B, DA-EPOCH) may be superior to CHOP. Role of Rituxan is unclear, but magnitude of benefit probably similar to DLBCL. Dunleavy article in Specific Sites section suggests the need for radiotherapy is significantly reduced with DA-EPOCH-R. Many patients given consolidative RT for bulky/residual disease, but role of RT somewhat unclear Outcome Somewhat more aggressive course, despite younger age, with similar survival as DLBCL Rarity of relapses past 2 years Reviews JCO 2005 - 16155024 — "State-of-the-Art Therapeutics: Diffuse Large B-Cell Lymphoma." Coiffier B et al. Journal of Clinical Oncology, Vol 23, No 26 (September 10), 2005: pp. 6387-6393. Treatment Please see Aggressive lymphoma treatment section