section name header

Info


A. Epidemiology navigator

  1. About 50,000 new cases annually; ~3% of all cancers
  2. >400,000 patients with NHL in USA currently
  3. Male to female ratio ~1.5:1
  4. Risk Factors
    1. Epstein-Barr Virus (EBV) infection
    2. HIV Infection
    3. Hepatitis C virus (HCV) infection [2,13]
    4. Simian virus 40 (SV40, a polyomavirus) DNA found in 42% of NHL [3,4]
    5. SV40 infection associated with 5.4X increased risk of developing NHL [5]
  5. NHL in AIDS [6,7,8]
    1. Overall, ~10% of NHL occur in HIV+ patients
    2. HIV positivity increases risk for NHL by >100X
    3. Majority of NHL IN HIV+ are related to progressive immunosuppression
    4. ~50% of HIV+ cases are related to EBV infection
    5. increased risk of all NHL in HIV infection
    6. Essentially all NHL of the CNS are EBV related (even in HIV negative persons)
    7. Rate of SV40+ NHL similar in HIV and non-HIV infected patients [3]
  6. T cell NHL discussed separately

B. Tumor Biologynavigator

  1. NHL are a Family of Different Types and Subtypes
    1. Most are B cell tumors in adults
    2. In children, ~30% are T cell tumors (see below)
    3. Immunoglobulin (Ig) and T cell receptor (TCR) rearrangements most useful to distinguish
    4. Surface markers may be used for diagnosis and as targets for therapy
    5. In immunosuppressed patients, often associated with EBV infection
    6. Most CNS lymphomas are of the NHL type [46,54]
  2. Surface Markers and Cytogenetics [1,9]
    1. Most NHL are derived from B lymphocytes
    2. NHL thought be arise from B lymphocytes with abberrant immunglobulin rearrangements
    3. NHL can be classified as derived from pre-germinal or germinal center B cells
    4. Most NHL are derived from germinal center (rearranged Ig genes) B cells
    5. Hodgkin's lymphomas are also derived from B lymphocytes, mainly germinal center
  3. Classification by Immunological Status [1]
    1. Foreign Antigen Independent - arise from bone marrow cells
    2. Foreign Antigen Depedendent - arise from peripheral lymphoid tissue cells
    3. Terminal Differentiation - multiple myeloma, plasmacytoma
  4. Tumor Spread
    1. Hematogenous spread allows diffuse seeding
    2. Usually disseminated to lymph nodes (LN) when discovered
    3. Spleen rarely involved (compare with Hodgkin's Lymphoma)
  5. Endothelial cells in most NHL contain similar genetic mutations to the tumor cells [53]
  6. Relation to Leukemia
    1. Several diseases can exist as lymphoma, leukemia variants, or both
    2. Acute T lymphoblastic leukemia (ALL-T) and lymphoblastic lymphoma
    3. Acute B lymphoblastic leukemia (ALL-B) and diffuse small non-cleaved cell lymphoma
    4. Chronic lymphocytic leukemia (CLL) and diffuse small lymphocytic lymphoma
  7. HTLV-1 Disease
    1. Adult T cell leukemia and lymphoma (ATLL) - mixed tumors
    2. Incidence is higher in Japanese
    3. Incidence of hypercalcemia is increased due to bone invasion
  8. Tumor-Infiltrating Immune Cells [22]
    1. Host-immune response to lymphoma may play a role in outcomes
    2. Gene expression profiling of tumor infiltrating immune cells has independent prognostic features
    3. Interaction of tumor with normal immune cells may play pivotal role in outcome
  9. May produce parathyroid hormone related peptide causing hypercalcemia [10]

C. Histologic Classificationnavigator

  1. Newer classification uses indolent (low grade) versus aggressive types of NHL
  2. Indolent (Low Grade)
    1. Diffuse small lymphocytic (CLL lymphoma variant, plasmacytoid)
    2. Follicular, Small Cleaved Cell
    3. Follicular, Mixed Small Cleaved and Large Cell
    4. Mantle Cell - now considered an aggressive tumor (poor prognosis)
    5. Mucosal associated lymphoid tissue (MALT) Lymphoma
  3. Aggressive (Formerly Intermediate Grade)
    1. Follicular, Large Cell
    2. Diffuse, Small Cleaved Cell
    3. Diffuse, Mixed Small and Large Cell
    4. Diffuse, Large Cell (Cleaved or Non-Cleaved)
  4. Aggressive (Formerly High Grade)
    1. Large Cell, Immunoblastic
    2. Lymphoblastic
    3. Small Non-Cleaved Cell (Burkitt's)
  5. Molecular diagnosis, prognosis and therapy selection is increasingly based on molecular (surface and internal) markers and genomic profiles [27]

D. Low Grade NHL (~40% of NHL) navigator

  1. Often present as stage IV
    1. Bone marrow and organ involvement
    2. 50% death rate in 7 years
    3. 60% death by 10 years
  2. Often transform to high grade lymphomas
    1. Appears to be dependent on genetic mutations
    2. Chromosome 7 or 17 abnormalities common in transformation
  3. 15% of tumors are localized at presentation
    1. Often no treatment is indicated
    2. Radiation may be used
    3. Systemic chemotherapy is indicated for symptomatic disease only
    4. Bone marrow transplantation has not improved survival
  4. Follicular Lymphomas (22% of NHL overall)
    1. Arise from germinal center B cells, likely early stage
    2. Hypermutated Ig genes are found
    3. Bcl-2 gene translocations to IgH are found in essentially all of these tumors: t(14;18)
    4. Translocations involve the 5' end of Ig J and D regions
    5. Follicular lymphomas probably arise from mistakes in V(D)J recombination
    6. Formerly called centrocytic or centroblastic lymphomas
  5. Small lymphocytic: slowly progressive lymphoma, usually adults >60 years
  6. Mantle Cell Lymphoma (now classified as aggressive; ~6% of NHL overall)
    1. More aggressive than usual low grade NHL with very poor prognosis
    2. Relatively rare cell type (~8% of NHL)
    3. Deregulation of Bcl-1 gene (Cyclin D1) due to translocations to IgH locus: t(11;14)
    4. Cells are derived from pre-germinal center B cells
    5. Prognosis based on molecular signature (proliferation genes) is more accurate than clinical variables [11]
    6. CHOP is standard but prognosis is generally poor, even with high dose chemotherapy (HDC)
    7. Response rates in the 30% range with rapid recurrence
    8. Bortezomib (Velcade®), a proteasome inhibitor induces responses in ~33% of cases
  7. Gastric MALT Lymphomas [12]
    1. These tumors are called mucosa-associated lymphoid tissue (MALT) lymphomas
    2. Gastric MALT lymphomas of the stomach are related to Helicobacter pylori infection
    3. Chronic inflammation induced by H. pylori thought to promote lymphomagenesis
    4. Lymphomas are often oligoclonal and have been shown to be present in early lesions
    5. Chronic gastritis is therefore linked to gastric mucosal lymphomas through infection
  8. HCV Infection [13,17]
    1. Associated with ~3.5X risk of immunocytomas overall
    2. Overall, HCV is found in ~37% of patients with NHL B cell lymphomas; 9% of controls
    3. Associated with mixed cryoglobulinemia and B cell NHL lymphomas
    4. HCV infection does not appear to affect prognosis of NHL B cell lyhmphomas
    5. HCV associated with 3X risk of Waldenstrom Macroglobulinemia [13]
    6. HCV is not associated with MALT (mucosa-associated lymphoid tissue) lymphomas
    7. Associated with splenic lymphoma with villous lymphocytes [18]
    8. Treatment of HCV+ splenic lymphoma with interferon ± ribavirin can lead to complete remissions [18]
  9. Progression to Intermediate or High Grade NHL [19]
    1. Occurs in ~25% of low grade NHL patients overall
    2. Most commonly from follicular small cleaved progressing to diffuse large cell lymphoma
    3. Triggers and genetic mechanisms for progression are not known

E. Aggressive NHL (>50% of NHL) navigator

  1. Initially more responsive to chemotherapy than low grade NHL
  2. Overal prognosis slightly improved over low grade disease
    1. Intermediate grade have 2 year 50% mortality
    2. High grade have 1 year 50% mortality
    3. Overall 10 year mortality is ~80%
    4. Molecular signatures are better predictors of outcomes than clinical variables [11,27]
  3. Unlike low grade tumors, some patients are cured (>10 year survival)
  4. Lymphoblastic lymphoma is a varient of ALL (leukemia)
  5. Diffuse Large Cell Lymphoma (DLCL) [10,11,20]
    1. Overall 33% of all NHL with specific subtypes
    2. Germinal center-like (~50%) and activated B cell-like (~30%) are most common subtypes
    3. Third subtype of DLCL also identified with distinct molecular (genomic) profile
    4. Molecular signatures correlate poorly with histopathology but well with outcomes
    5. EBV infection in HIV+ patients grealy increases risk of B-type DLCL
    6. A subset of DLCL are probably Burkitt's lymphoma with high level c-myc [36,37]
    7. BCL6 transcriptional deregulation in ~35% overall
    8. Poor prognostic factors: Stage (III/IV), high LDH levels, low performance status, AIDS
    9. IL-6 levels showed best corrrelation with survival and response of all markers
    10. IL-6 levels are elevated in Hodgkin's Disease and Large Cell Lymphoma
    11. May invade any organ, including CNS, causing neurological symtoms, coma
    12. May present as bilateral adrenal masses [24] or as cardiac lymphoma [8]
    13. Primary mediastinal lymphoma, breast and/or ovarian involvement, CNS disease occurs [47]
  6. Germinal Center-Like DLCL [11]
    1. Likely derived from follicular B cells undergoing development in germinal center
    2. Elevated Bcl-2 expression in ~30% of DLCL overall, likely only in follicular DLCL
    3. Bcl-2 rearrangements t(14;18) identified in this form by molecular profiling [20]
    4. Bcl-6 and c-rel overexpression also found [20]
    5. Translocation t(3;14) involving zinc finger protein bcl-6 found in ~33%
    6. Five year survival after anthracycline based therapy 60% [20]
  7. Activated B Cell-Like DLCL
    1. High expression of c-myc and other growth regulation genes
    2. High levels of NF-kB expression (correlates with chemotherapy resistance)
    3. Five year survival after anthracycline based therapy 35% [20]
  8. Primary Mediastinal Large-B-Cell Lymphoma [55]
    1. Age 20-40 years, F > M
    2. Disease limited to mediastinum
    3. Cells express TRAF-1 which is not found in DLCL
  9. Burkitt's Lymphoma (~2%)
    1. B cell neoplasm
    2. M:F 1.4:1
    3. AIDS represents 10% of cases
    4. C-myc proto-oncogene translocation (chromosome 8) in >99% of cases
    5. Most common variant is t(8;14) with c-myc translocation to IgH chain locus
    6. Variants t(2;8) or t(22;8) to L chain (kappa on chrom 2, lambda on chrom 22) loci
    7. Distinct molecular signature compared with all other NHL subtypes
    8. High level c-myc, low level MHC-I and NF-kB target genes [36,37]
    9. Outside of USA, majority of tumors are associated with Epstein-Barr Virus (EBV)
  10. CNS Lymphoma [26,47]
    1. May present with parenchymal or intravascular disease (usually not both)
    2. Most cases are B cell lymphomas, usually in AIDS and organ transplant patients
    3. 60% present with multiple (versus solitary) lesions
    4. Typically of diffuse large cell or immunoblastic histology
    5. Most patients develop symptoms and signs of increased intracranial pressure
    6. Mass effects with potential herniation may also occur
    7. Cerebellar lesions may be present with ataxia and dysequilibrium [26]
    8. Diffuse neurolymphomatosis may occur, including cauda equina syndrome
    9. Intravascular disease (lymphomatosis) can occur and affects nerves and skin
    10. Essentially all CNS NHL are EBV+ in HIV+ and HIV negative persons [8]
    11. Risk for CNS involvement: LDH, multiple extranodal disease sites, breast involvement
    12. High dose methotrexate is often used, but prognosis is poor
    13. High dose methotrexate is used to prevent CNS spread [47]
  11. Intravascular Lymphoma [28]
    1. Rare condition with <200 reports in English literature
    2. Lymphoma with predominant distribution within blood vessels
    3. CNS vessels are often affected causing neurological symptoms
    4. Weakness, confusion, seizures and motor dysfunction may occur
    5. Skin is also affected with macular or papular rash
    6. Pulmonary intravascular NHL causes fevers, often with minimal lung symptoms [29]
    7. Systemic symptoms including fever of unknown origin and weight loss can occur
    8. Lymphadenopathy and splenomegaly are rare
    9. Endocrine disorders can occur
    10. Diagnosis is difficult and tissue including blood vessels is required
    11. Involved skin may be biopsied but is often histologically normal except for vessels
    12. Diagnosis is usually delayed and patients have diffuse disease

F. Related Conditionsnavigator

  1. Lymphomas and Immunosuppression
    1. Transplant recipients are at high risk for post-transplant lymphoproliferative disease (PTLD) which is usually but not always due to EBV reactivation [59]
    2. Overall risk is 1-2.5% for various types of solid-organ transplants
    3. PTLD occurs in ~5% of pediatric heart transplant patients [23]
    4. HIV-associated NHL is usually EBV associated but has very poor prognosis
    5. Usually treated with reduced immunosuppression, antivirals, and/or chemotherapy
    6. Reduction of cyclosporin A doses in kidney transplants reduces lymphoma incidence
  2. Lymphomatoid Granulomatosis [57,58]
    1. Continuum of abnormal lymphocyte diseases from benign to malignant
    2. Strongly associated with Epstein Barr Virus (EBV) transformation of B lymphocytes
    3. Reactive T lymphocytes ± eosinophils may be present in large numbers
    4. Necrotic granulomas of lungs, skin, CNS, and kidneys
    5. May act as benign diseases or as highly malignant lymphomas
    6. Strong male predisposition
    7. Multiple lung nodules and cavitary lesions frequently occur
    8. Lymphadopathy not usually seen; may be mistaken for sarcoidosis
    9. Minority will spontaneously resolve; most progress to aggressive lymphomas
    10. Combination chemotherapy for severe and aggressive disease, usually with rituximab
    11. Rituximab (Rituxan®), anti-CD20 mAb, has shown good efficacy
    12. Interferon alpha (IFNa) has shown efficacy ~67% in moderate to severe disease
  3. Celiac Disease (Sprue) [30]
    1. Increased risk for NHL at any site ~3X
    2. Primary site usually in the gut (very high incresaed risk)
    3. Approximately equal risk of B cell and T cell NHL
  4. Immunoproliferative Small Intestine Disease [31]
    1. Uncommon immunoproliferative disease resembling MALT lymphomas
    2. Originally called alpha chain disease
    3. Abnormal plasma cells with truncated Ig alpha heavy chain without light chain
    4. Infiltration of bowel wall with plasma cells - autoreactive B cell clone driven by T cells
    5. More common in Middle East, Far East, Africa
    6. Cases recently linked to infection with Campylobacter jejuni [44]
    7. Malabsorption and protein losing enteropathy
    8. May respond to antibiotics
  5. Sjogren's Syndrome
    1. ~10% of patients developed lymphoma over 4 years
    2. SS carries ~44X increased risk of developing lymphoma compared to controls
  6. Rheumatoid Arthritis
    1. Increased risk of NHL ~5X
    2. Mainly NHL of T cell type, large granular morphology, CD3+, CD57+
    3. Large granular T lymphocytic leukemias similar to lymphomas
  7. May present with dermatomyositis [56]

G. Staging Evaluation navigator

  1. Similar to Hodgkin's Lymphoma
  2. Complete Blood Count, Coagulation parameters
  3. Electrolytes, renal function, uric acid, calcium, albumin, phosphate
  4. Liver Function Tests (LFT), Lactate Dehydrogenase (LDH)
  5. Bone marrow biopsy
  6. Chest Radiograph (and/or CT Scan), Abdominal CT Scan
  7. Optional
    1. Bone Scan
    2. Gastrointestinal Studies
    3. Gallium Scan or Positron Emission Tomography [32]
  8. Evaluate for HCV (± HIV) infection [17]

H. Treatment Regimens [33] navigator

  1. CHOP Combination Chemotherapy
    1. CHOP+rituximab is standard for any patients with aggressive NHL [34,47]
    2. Consists of 4 drugs + monoclonal Ab combination given in 3 week cycles (usually 8 cycles):
    3. Cyclophosphamide (Cytoxan®): 750mg/m2 on day 1
    4. Doxorubicin (Adriamycin®): 50mg/m2 on day 1
    5. Vincristine (Oncovin®): 1.4mg/m2 on day 1 (to maximal dose 2.0mg)
    6. Prednisone: 40mg/m2 x 5 days (days 1-5)
    7. Methotrexate (systemic and intrathecal) added for high grade
    8. Induces complete responses (CR) in ~65-70% of aggressive NHL
    9. Five year overall survival is ~50% for aggressive NHL
    10. Addition of rituximab to CHOP improves response rates in young and older patients [34]
    11. Low grade and mantle cell lymphomas are rarely cured with current therapy (see below)
    12. Rituximab + CHOP had improved response rates and overall survival in patients 60-80 years old with DLCL [35]
    13. HDC with stem cell support may be curative (see below)
  2. CHOP versus other Chemotherapy
    1. Overall, no benefit of new regimens versus CHOP therapy
    2. Survival at 3 years ~50% regardless of regimen chosen
    3. Fatal toxic reactions in 1% of CHOP, 3-6% of other groups
    4. CHOP remains standard of care, usually with rituximab
    5. Dose intensified ACVBP had improved event-free and overall survival compared with CHOP plus radiotherapy for localized aggressive NHL (age <61 years) [49]
  3. Radiation Therapy
    1. Frequently used for large masses in combination regimens
    2. Also used as potentially curative for localized disease (which is unusual in NHL)
  4. Overview of Monoclonal Antibody Therapies
    1. Most B cell tumors express CD20, CD22 and/or CD37 cell surface antigens
    2. Anti-CD20 MAb (rituxumab) is a major addition to treatment (see below)
    3. 131-iodine- (Bexxar®) or 90-Yttrium (Zevalin®) tagged anti-CD20 for refractory NHL
    4. Bexxar® has shown excellent responses and duration in first line follicular NHL [21]
  5. Rituximab (Rituxan®) [43]
    1. IgG1 kappa chimeric mouse/human antibody which binds to CD20 antigen
    2. Nearly all low grade B cell NHL express CD20, as do normal B cells
    3. Rituximab depletes all CD20 expressing cells, including normal and malignant B cells
    4. Rituximab may also sensitize B cells to effects of some anticancer agents
    5. Given slowly IV once weekly (375mg/m2) for 4 weeks or every three weeks with CHOP
    6. Median time to response was ~50 days
    7. Partial + complete responses with rituximab alone occurred in ~50% of patients with untreated [38] or relapsed [43] low grade NHL
    8. Combination of rituximab and CHOP produced very good overall responses, 70% CRs [34,35,47]
    9. Some single-agent efficacy in patients with CD20+ aggressive NHL [34]
    10. Adverse effects occurred with initial dose, usually an immediate hypersensitivity
    11. These effects respond to acetaminophen (Tylenol®) and diphenhydramine (Benadryl®)
    12. Thrombocytopenia and/or neutropenia may occur as well
  6. 90-Yttrium-Ibritumomab (Zevalin®) [39]
    1. Anti-CD20 MAb labelled with 90-Yttrium
    2. showed 30% complete and 50% partial responses in rituxumab-naive NHL
    3. Using myeloablative levels of radiolabelled Ab, 15% complete and 59% partial responses were observed in rituxumab refractory NHL
    4. Zevalin® is FDA approved for rituxumab refractory low grade NHL
  7. Iodine-131-Tositumomab (Bexxar®) [40]
    1. Anti-CD20 MAb labelled with 131-Iodine
    2. Approved for use with recurrence after rituximab and refractory to chemotherapy
    3. I-131-CD20 showed 50% complete and 79% partial responses in refractory follicular NHL
    4. I-131-CD20 showed 75% complete and 95% overall responses in first line follicular NHL [21]
  8. Denileukin Difitox (Ontak®) [25]
    1. IL2 fusion with fragment of diphtheria toxin
    2. May be useful for CD25 (IL2 receptor) expressing lymphomas and leukemias
    3. Dose is 9-18µg/kg qd for 5 days every 3 weeks
    4. Vascular leak syndrome may occur
  9. Bortezomib (PS-341, Velcade®) [41,42]
    1. Proteasome inhibitor, reversible
    2. Highly effective in refractor and earlier multiple myeloma
    3. Good responses in relapsed or refractory mantle cell and follicular NHL
  10. Bcl-2 Antisense Therapy [18]
    1. Use of phosphorthiolated antisense oligonucleotides in recurrent NHL
    2. Therapy was well tolerated as a subcutaneous infusion given by pump (4.6mg/m2/day)
    3. Some patients showed stabilization of disease, 1 of 9 had complete response
    4. All patients had overexpression of bcl-2 in lymphoma cells at start of therapy
    5. Some correlation between change in bcl-2 levels and response to therapy
  11. HDC With Stem Cell Suport [45]
    1. Improves survival rates in recurrent disease
    2. This is especially true in high grade lymphomas (such as Burkitt's)
    3. Five year survival rate with recurrent disease is 32% without auto-HDC, 53% with auto-HDC
    4. Superior to chemotherapy (MACOP-B) in high grade lymphomas
    5. Overall survival at 7 years was 81% with HYC, 55% with chemotherapy [45]
    6. Chemotherapy: HiCOM or HyperCVAD type regiment is used
    7. Autologous stem cells preferred due to low incidence of graft versus host disease
    8. Allogeneic transplant with matched sibling donor effective in low grade lymphoma
    9. Allogeneic transplant can lead to cure but is associated with 25-40% mortality
  12. May use PCR detection of lymphoma specific chromosomal translocations to assess relapse
  13. Pamidronate, a bisphosphonate, reduces vertebral fractions in NHL patients receiving chemotherapy [52]

I. Therapy By NHL Typenavigator

  1. Watch and wait with asympatomic low grade NHL and age >70 years may be appropriate [50]
  2. Follicular Low Grade Lymphoma
    1. Localized disease (unusual) may be cured by radiotherapy
    2. Most patients have disseminated disease and should receive systemic chemotherapy
    3. Oral chlorambucil ± glucocorticoids or CVP for 6 months
    4. CVP is cyclophosphamide, vincristine, prednisone
    5. Fludarabine alone or anthracycline containing regimens are alternatives
    6. CHOP therapy may be used initially or for relapse after chlorambucil
    7. Rituximab (anti-CD20 monoclonal antibody, MAb) is best tolerated, especially in elderly
    8. Initial treatment with CHOP+rituxumab is probably the most effective regimen
    9. Radiolabelle
    10. Combination chemotherapy and MAbs for recurrent disease
    11. Radiolabelled anti-CD20 MAbs (see below) are effective for recurrent disease
  3. Small Lymphocytic Lymphoma
    1. Similar treatment as follicular low grade lymphoma
    2. Recurrent disease often responds to fludarabine or cladribine (similar to CLL)
  4. Mantle Cell Lymphoma
    1. CHOP treatment first line provides good response, but disease recurs
    2. Overall survival with current therapies is ~3 years
    3. HDC with stem cell rescue has shown some response in recurrent disease
    4. Rituxumab added to chemotherapy may be beneficial
    5. Bortezomib (Velcade®), a proteasome inhibitor, has induced good responses in Phase II
  5. Diffuse Large B Cell Lymphoma (DLCL)
    1. Good prognosis Stage I-II disease treated with CHOP often with targeted radiation therapy
    2. Advanced disease best treated with high dose chemotherapy and stem cell rescue [51]
    3. High dose chemotherapy with stem cell rescue improves outcomes primarily for DLCL
    4. Addition of rituximab to CHOP improves response rates and probability of survival in high-intermediate and high risk NHL patients (versus intermediate and low risk) [51]
    5. CHOP is reasonable in patients >65 years or who cannot tolerate high dose chemotherapy
  6. Burkitt's Lymphoma
    1. Intensive chemotherapy with intrathecal treatments
    2. Survival ~80%
  7. Lymphoblastic Lymphoma
    1. Very aggressive, similar to ALL (see above)
    2. Treatment similar to ALL including intrathecal chemotherapy
  8. Gastric MALT Lymphomas
    1. H. pylori eradication leads to regression or cures of tumors in ~75% of cases [14]
    2. Multiple cycles of H. pylori eradication therapy are required for treatment of tumors
    3. Resistance of MALT NHL to H. pylori eradication associated with t(11;18) in neoplasm [15]
    4. The t(11;18, q21;q21) translocation involves API2 and MLT genes
    5. This fusion is believed to provide a survival advantage to MALT NHL
    6. Minimal residual low-grade MALT after H. pylori eradication does not require treatment with chemotherapy, but should be monitored closely [16]
    7. Transformation to large B-cell lymphoma can occur
  9. CNS Lymphomas
    1. Usually aggressive diffuse large B-cell type tumor
    2. Radiation + high dose methotrexate based regimens provides best responses
    3. Median survival approaches 5 years with current regimens

J. Prognostic Factorsnavigator

  1. Molecular profiling will likely replace current clinical risk factor predictors [11]
  2. Risk Stratification (1 point for each higher risk category)
    1. Age: <60 lower risk versus >60 (higher risk)
    2. Tumor Stage: I or II versus III or IV
    3. Serum LDH: normal versus >1X normal
    4. "Performance Status" (comorbid conditions, functional status, others): low versus high risk
    5. Extranodal involvement: 0-1 site versus 2 or more sites
  3. Overall 5 year Survivors
    1. Low Risk (score 0 or 1 risk factor; 35% of patients) 73%
    2. Low intermediate (score 2; 27% of patients) 51%
    3. High intermediate (score 3; 22% of patients) 43%
    4. High Risk (score 4 or 5; 16% of patients) 26%
  4. "International index" based on above factors more predictive than earlier indices
    1. Predicts complete response and relapse rate
    2. All of these patients had received doxorubicin based chemotherapy
  5. Transformation from low grade to high grade disease is an independent poor risk factor

K. Non-Hodgkin's Lymphoma in AIDS [6,7] navigator

  1. About 3% of patients with AIDS present with NHL
    1. Overall, 5-20% of HIV+ develop NHL in their lifetimes
    2. Numbers of NHL-HIV patients is increasing (likely due to better infection treatment)
  2. Non-CNS and CNS associated NHL, nearly all B cell types
  3. ~50% Epstein Barr Virus associated, high grade
  4. Types
    1. Centroblastic (45%)
    2. Immunoblastic (13%)
    3. Burkitt Type (40%) - both classical and plasmacytic differentiation
    4. T cell or Null Cell (2%)
    5. Primary central nervous system (CNS) lymphoma (usually CD20+ B cell)
  5. Chemotherapy Usually indicated
    1. Reduced dose M-BACOD is probably as effective as standard dose
    2. CHOP therapy has similar outcomes in HIV+ as M-BACOD
    3. Etoposide, vincristine, doxorubicin (EPOCH) is well tolerated and active [6]
    4. Hydroxyurea (400-700mg/m2) daily was effective in EBV+ primary CNS lymphoma [48]
  6. Patients with CD4>200/µL may do as well with chemotherapy as HIV negative persons

L. Non-Hodgkin's Lymphoma in Childhood [14]navigator

  1. 500 cases annually in USA
  2. ~13% of all childhood cancers
  3. Frequency of histological types differ in children and adults
  4. Histological Types in Children
    1. Small non-cleaved cell (Burkitt's) - 34% of cases, B cells (c-MYC gene associated)
    2. T Cell Lymphoblastic - 29% (Tal1, RHOMB, HOX11, LYL1, MYC, LCK genes associated)
    3. Large Cell - 27% of cases; B, T, or null cell types (NPM-ALK genes associated)
  5. Most NHL in children are rapidly growing
  6. Staging is similar to that used for adults
  7. Chemotherapy is also similar, with CHOP or CHVP, and HiCOM for Burkitt's Lymphoma
  8. Current overall survival is ~75% at 10 years

References navigator

  1. Evans LS and Hancock BW. 2003. Lancet. 362(9378):139 abstract
  2. Caligaris-Cappio F. 2001. Lancet. 358(9275):49 abstract
  3. Vilchez RA, Madden CR, Kozinetz CA, et al. 2002. Lancet. 359(9309):817 abstract
  4. Shivapurkar N, Harada K, Reddy J, et al. 2002. Lancet. 359(9309):851 abstract
  5. Vilchez RA, Kozinetz CA, Arrington AS, et al. 2003. Am J Med. 114(8):675 abstract
  6. Little RF, Gutierrez M, Jaffe ES, et al. 2001. JAMA. 285(14):1880 abstract
  7. Gabarre J, Raphael M, Lepage E, et al. 2001. Am J Med. 111(9):704 abstract
  8. Kaplan LD, Afridi NA, Holmvang G, Zukerberg LR. 2003. NEJM. 349(14);1369 (Case Record) abstract
  9. Kuppers R, Klein U, Hansmann ML, Rajewsky K. 1999. NEJM. 341(20):1520 abstract
  10. Erban JK and Tang Z. 2002. NEJM. 347(24):1952 (Case Record) abstract
  11. Staudt LM. 2003. NEJM. 348(18):1777 abstract
  12. Steinbach G, Ford R, Glober G, et al. 1999. Ann Intern Med. 131(2):88 abstract
  13. Giordano TP, Henderson L, Landgren O, et al. 2007. JAMA. 297(18):2010 abstract
  14. Steinbach G, Ford R, Glober G, et al. 1999. Ann Intern Med. 131(2):88 abstract
  15. Liu H, Ruskon-Fournmestraux A, Lavergne-Slove A, et al. 2001. Lancet. 357(9249):39 abstract
  16. Fischbach W, Goebeler-Kolve M, Starostik P, et al. 2002. Lancet. 360(9332):547 abstract
  17. Vallisa D, Berte R, Rocca A, et al. 1999. Am J Med. 106(5):556 abstract
  18. Hermine O, Lefrere F, Bronowicki JP, et al. 2002. NEJM. 347(2):89 abstract
  19. Mintzer D and Bagg A. 2001. Am J Med. 2001. 111(6):480 abstract
  20. Rosenwald A, Wright G, Chan WC, et al. 2002. NEJM. 346(25):1937 abstract
  21. Kaminski MS, Tuck M, Estes J, et al. 2005. NEJM. 352(5):441 abstract
  22. Dave SS, Wright G, Tan B, et al. 2004. NEJM. 351(21):2159 abstract
  23. Webber SA, Naftel DC, Fricker FJ, et al. 2006. Lancet. 367(9506):232 abstract
  24. Udelsman R and Dong HY. 2000. NEJM. 343(20):1477 (Case Record)
  25. Jacobson JO and De Leval L. 2001. NEJM. 345(19):1409 (Case Record)
  26. Alderson LM and Delalle I. 2002. NEJM. 346(13):1009 (Case Record) abstract
  27. Quackenbush J. 2006. NEJM. 354(23):2463 abstract
  28. Kraus MD, Jones D, Bartlett NL. 1999. Am J Med. 107(2):169 abstract
  29. Meyer GS, Hales CA, Amrein PC, et al. 2007. NEJM. 357(8):807 (Case Record) abstract
  30. Catassi C, Fabiani E, Corrao G, et al. 2002. JAMA. 287(11):1413 abstract
  31. Parsonnet J and Isaacson PG. 2004. NEJM. 350(3):213 abstract
  32. Wirth A, Seymour JF, Hicks RJ, et al. 2002. Am J Med. 112(4):262 abstract
  33. Drugs of Choice for Cancer Chemotherapy. 2000. Med Let. 42(1087):83
  34. Kouroukis CT, Browman GP, Esmail R, Meyer RM. 2002. Ann Intern Med. 136(1):144
  35. Coiffier B, Lepage E, Briere J, et al. 2002. NEJM. 346(4):235 abstract
  36. Hummel M, Bentink S, Berer H, et al. 2006. NEJM. 354(23):2419 abstract
  37. Dave SS, Fu K, Wright GW, et al. 2006. NEJM. 354(23):2431 abstract
  38. Hainsworth JD, Burris HA 3rd, Morrissey LH, et al. 2000. Blood. 95:3052 abstract
  39. Ibritumomab. 2002. Med Let. 44(1144):101 abstract
  40. Chatal JF and Hoefnagel CA. 1999. Lancet. 354(9182):931 abstract
  41. Richardson PG, Barlogie B, Berenson J, et al. 2003. NEJM. 348(26):2609 abstract
  42. Kyle RA, Gertz MA, Witzig TE, et al. 2003. Mayo Clin Proc. 78(1):21 abstract
  43. Rituximab. 1998. Med Let. 40(1029):65 abstract
  44. Lecuit M, Abachin E, Martin A, et al. 2004. NEJM. 350(3):239 abstract
  45. Gianni AM, Bregni M, Siena S, et al. 1997. NEJM. 336(18):1290 abstract
  46. Detsky ME, Chiu L, Shandling MR, et al. 2006. NEJM. 355(1):67 (Case Discussion) abstract
  47. Shulman LN, Hitt RA, Ferry JA. 2008. NEJM. 358(5):513 (Case Record) abstract
  48. Slobod KS, Taylor GH, Sandlund JT, et al. 2000. Lancet. 356(9240):1493 abstract
  49. Reyes F, Lepage E, Ganem G, et al. 2005. NEJM. 352(12):1197 abstract
  50. Ardeshna KM, Smith P, Norton A, et al. 2003. Lancet. 362(9383):516 abstract
  51. Milpied N, Deconinck E, Gaillard F, et al. 2004. NEJM. 350(13):1287 abstract
  52. Kim SH, Lim SK, Hahn JS. 2004. Am J Med. 116(8):524 abstract
  53. Streubel B, Chott A, Huber D, et al. 2004. NEJM. 351(3):250 abstract
  54. Batchelor TT, Buchbinder BR, Harris NL. NEJM. 352(2):185 (Case Record) abstract
  55. Shipp MA, Aquino SL, Harris NL. 2005. NEJM. 352(16):1697 (Case Record) abstract
  56. Polisson RP, Crocker JT, Mueller PR, et al. 2005. NEJM. 353(12):1275 (Case Record) abstract
  57. Hochberg EP, Gilman MD, Hasserjian RP. 2006. NEJM. 354(23):2485 (Case Record) abstract
  58. Calfee CS, Shah SJ, Wolters PJ, et al. 2007. NEJM. 356(5):504 (Case Discussion) abstract
  59. Abrahamson JS, Kotton CN, Elias N, et al. 2008. NEJM. 358(11):1176 (Case Record) abstract