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) PMID 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 PMID 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 PMID 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 PMID 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 PMID 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 PMID 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, PMID 8001905)
    • mediastinal mass of at least 5 cm with no extramediastinal mass larger than that in the mediastinum (Abou-Elella 1999, PMID 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 - PMID 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