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non-hodgkin’s-lymphoma
- 1. Non-Hodgkin’s Lymphoma Epidemiology, Disease and Staging
- 2. chronic myeloid leukaemia (CML) Haematopoietic Malignancies Polycythemia vera (PV) Idiopathic myelofibrosis (MF) Essential thrombocythemia (ET) Acute myeloid leukaemia (AML) Chronic myeloid leukaemia (CML) Acute lymphatic leukaemia (ALL) Chronic lymphatic leukaemia (CLL) hairy cell leukaemia (HCL) Hodgkin’s lymphoma Burkitt's lymphoma cutaneous T-cell lymphoma (CTCL) Non-hodgkin’s lymphoma (NHL) Myeloproliferative diseases Leukaemias Malignant lymphomas
- 4. Haematopoietic Malignancies Family of chronic neoplastic diseases Due to a clonal disorder arising at the level of the pluripotent stem cell Characterised by abnormal proliferation of 1 or more blood cell lines Neoplastic disease of a haematopoietic precursor cell Characterised by replacement of normal bone marrow Often infiltration into other organs Malignant clones suppress normal cell formation Neoplastic disease of lymphatic tissue Originates in lymph node or spleen Hodgkin’s (15%) non-Hodgkin’s (85%) Myeloproliferative diseases Malignant lymphomas Leukaemias
- 6. Lymphatic Tissue Lymph nodes, spleen, liver, skin and the respiratory, GI and GTU tract Lymphocytes undergo further proliferation and differentiation in lymphoid tissue – B-lymphocytes tend to reside in lymph nodes & spleen – T-lymphocytes tend to circulate throughout the lymphatic system
- 7. Lymph Node - normal histology afferent lymphatic vessel capsule follicle (mainly B- cells) - germinal centre - mantle zone C cortex medulla paracortex efferent lymphatic vessel artery vein
- 8. Hodgkin’s Lymphoma 15% of lymphomas First described by Thomas Hodgkin in 1832 Originally had a very poor prognosis (<10% survival at 5 years) Improved staging techniques and understanding of the pattern of spread helps direct management Now curable in over 70% of cases through the use of radiotherapy and chemotherapy
- 9. Non-Hodgkin’s Lymphoma (NHL): Definition and Indication A heterogeneous group of B- and T-cell malignancies that are diverse in cellular origin, morphology, cytogenetic abnormalities, response to treatment, and prognosis
- 10. Non-Hodgkin’s Lymphoma (NHL) 85% of lymphomas 6th major cause of cancer deaths yearly Heterogeneous group of malignant diseases arising from lymphoid tissue – lymph nodes, spleen Various immune cell types – principally B-cells derivation (>85%) – T-cells derivation – Histiocytes (very rarely) – Various stages of differentiation and maturation
- 11. NHL Incidence Incidence of 13.3/100,000 per year (Aust) Predominates in the 40-70 years age group – most common neoplasm in the 20-40 age group Incidence is rising – 150% growth over the past 30 years – increasing by 4% annually since 1970’s Mortality rate is also rising – 2% rise per year – third highest rise, exceeded only by lung cancer in women and malignant melanoma
- 12. Increases with age – implications Slight male predominance overall Striking male predominance for several subtypes Incidence of certain subtypes varies greatly around the world – Burkitt’s Lymphoma in African children – T-cell type more common in Japan NHL Incidence
- 13. Estimated Incidence of NHL in the Year 2000 (Worldwide) 0 10,000 20,000 30,000 40,000 50,000 60,000 Micronesia Melanesia Caribbean Australia/New Zealand Northern Africa Western Africa Northern Europe Southeast Asia Eastern Europe South Central Asia North America
- 14. Adapted from Greenlee et al. CA Cancer J Clin. 2001;51:15. EstimatedAnnualIncidence Year ~4% compound annual increase in incidence Estimated Incidence of NHL (US) 0 15,000 30,000 45,000 60,000 1980 1985 1990 1995 2000
- 15. Revised European-American Lymphoma (REAL) Classification: B-Cell Neoplasms Hiddemann. Blood. 1996;88:4085. Indolent Aggressive Very Aggressive CLL/SLL Lymphoplasmacytic/ IMC/WM HCL Splenic marginal zone lymphoma MZL - Extranodal (MALT) - Nodal Follicle center lymphoma, follicular, grade I-II PLL Plasmacytoma/ Multiple myeloma MCL Follicle centre lymphoma, follicular, grade III DLCL Primary mediastinal large B-cell lymphoma High-grade B-cell lymphoma/Burkitt’s- like Precursor B-lymphoblastic lymphoma/ Leukemia Burkitt’s lymphoma/ B-cell acute leukemia Plasma cell leukemia
- 16. World Health Organization (WHO) Classification of Lymphoid Neoplasms: B-Cell Neoplasms Jaffe et al. Ann Oncol. 1998;9 (suppl 5):S25. Precursor B-cell neoplasm – Precursor B-lymphoblastic leukemia/lymphoma (precursor B- cell acute lymphoblastic leukemia) Mature (peripheral) B-cell neoplasms – B-cell CLL/SLL – B-cell PLL – Lymphoplasmacytic lymphoma – Plasmacytoma, plasma cell myeloma – HCL Marginal zone B-cell lymphoma – Marginal zone B-cell lymphoma of MALT – Nodal marginal zone lymphoma (+/- monocytoid B-cells) – Splenic marginal zone B-cell lymphoma FL – Grade 1, 0-5 centroblasts/hpf – Grade 2, 6-15 centroblasts/hpf – Grade 3, >15 centroblasts/hpf 3a, >15 centroblasts, but centrocytes still present 3b, centroblasts from solid sheets with no residual centrocytes – Variants Cutaneous follicle center MCL DLCL – Mediastinal (thymic) large B-cell lymphoma – Intravascular lymphoma – Primary effusion lymphoma Burkitt’s lymphoma/Burkitt cell leukemia
- 17. The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982;49:2112. Modified Ann Arbor Staging of NHL Stage I Involvement of a single lymph node region Stage II Involvement of ≥2 lymph node regions on the same side of the diaphragm Stage III Involvement of lymph node regions on both sides of the diaphragm Stage IV Multifocal involvement of ≥1 extralymphatic sites ± associated lymph nodes or isolated extralymphatic organ involvement with distant nodal involvement
- 18. Staging of NHL
- 19. Staging of NHL
- 21. Follicular non-Hodgkin’s Lymphoma Classification and survival
- 22. Classification of Indolent NHL: International Working Formulation (IWF) A. Small lymphocytic 3.6 5.8 B. Follicular, predominantly small cleaved cell 22.5 7.2 C. Follicular, mixed small and large cell 7.7 5.1 D. Follicular, predominantly large cell 3.8 3.0 The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer. 1982;49:2112. % of NHL Median Class Patients Survival (y)
- 23. Adapted from Horning. Semin Oncol. 1993;20(5 suppl 5):75. Patients(%) Year 1987-1996 1976-1986 1960-1975 100 60 40 20 0 80 0 5 10 15 20 25 30 Survival of Patients with Indolent Lymphoma: The Stanford Experience, 1960-1996
- 24. SWOG Finding: New treatment options have changed the natural history of follicular lymphoma1 0 25 50 75 100 1974-1978 CHOP + non-specific immunostimulants 1988-1994 ProMACE – MOPP + Interferon 1998-2000 CHOP + monoclonal antibody therapy 69% 79% 91%Overallsurvival(%) Impact of new treatment options on the natural history of follicular lymphoma determined by SWOG via retrospective analysis of three sequential treatment approaches. 1:Fisher et al Blood 2004;104 Abstract 583 Adapted from ref 1
- 25. Follicular Lymphoma: Overall Survival Adapted from Armitage and Weisenburger. J Clin Oncol. 1998;16:2780. Year 8 IPI 0/1 IPI 2/3 IPI 4/5 100 OverallSurvival(%) 0 2 5 6 73 41 P<0.001 60 40 20 0 80
- 26. Aggressive non-Hodgkin’s Lymphoma Classification and Survival
- 27. National High-Priority Lymphoma Study: Overall survival for aggressive lymphoma Fisher et al. N Engl J Med. 1993;328:1002. Patients(%) Years After Radomization 100 80 60 40 20 0 0 1 2 3 4 5 6 CHOP m-BACOD ProMACE-CytaBOM MACOP-B
- 28. International Prognostic Index (IPI) Patients of all ages Risk Factors Age >60 years PS 2-4 LDH level Elevated Extranodal involvement >1 site Stage (Ann Arbor) III-IV Patients ≤60 years (age-adjusted) PS 2-4 LDH Elevated Stage III-IV Shipp. N Engl J Med. 1993;329:987.
- 29. IPI Risk Strata All ages Low (L) 0-1 Low-intermediate (LI) 2 High-intermediate (HI) 3 High (H) 4-5 Age-adjusted L 0 LI 1 HI 2 H 3 Risk FactorsRisk Group Shipp. Blood. 1994;83:1165.
- 30. IPI: Overall Survival by Risk Strata Adapted from Shipp. N Engl J Med. 1993;329:987. 100 75 50 25 0 0 2 4 6 8 10 H HI LI L Patients(%) Year
Notas del editor
- Defining non-Hodgkin’s lymphoma (NHL) has been a consistent challenge for clinicians. 51,83 NHL describes a heterogeneous group of malignancies of B or T lymphocytes that generally originate in the lymph nodes. Lymphomas are differentiated by a range of cellular, morphologic, and molecular features. NHL is the sixth most frequent malignancy in the United Kingdom. The incidence of NHL is increasing at a rate of 5% to 8% per year.
- With 60,000 new cases, North America had the highest estimated incidence of lymphoma in the world for the year 2000.
- NHL is a heterogeneous group of B- and T-cell malignancies with diverse growth patterns and responses to therapy. Although some types of NHL are among the most common childhood cancers, more than 95% of cases occur in adults. 40 The annual report of cancer statistics, issued by the American Cancer Society, estimates that 56,200 new cases of NHL will be diagnosed in the United States in the year 2001. 40 NHL currently ranks fifth and sixth for newly diagnosed cancers among men and women, respectively, and it accounts for 5% of all cancer-related deaths in the United States. The incidence of NHL in the United States and worldwide over the last 15 years has increased by approximately 4% annually, despite the decline in age-adjusted incidence rates for all cancers combined. 40 NHL is one of the most rapidly rising cancers; its incidence has doubled since the early 1970s. Potential explanations for the increased incidence of NHL include infectious agents, congenital and acquired immunodeficiency syndromes, environmental exposure, and genetic factors.
- Since Gall and Mallory proposed the first lymphoma classification in 1942, several systems have emerged as potentially more effective tools for diagnostic and prognostic purposes. 82 In the last 10 years, increased understanding about NHL resulted in the recognition of new entities and refinement of previously recognized disease categories. A new clinical classification system was needed to accommodate these changes (eg, MCL and MALT lymphoma). In 1994, the International Lymphoma Study Group proposed a new classification of hematologic malignancies, widely known as the Revised European American Lymphoma (REAL) Classification. 51 CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; IMC = immunocytoma; WM = Waldenström’s macroglobulinemia; HCL = hairy cell leukemia; MZL = marginal zone lymphoma; MALT = mucosa-associated lymphoid tissue; PLL = prolymphocytic leukemia; MCL = mantle cell lymphoma; DLCL = diffuse large B-cell lymphoma. MZL = marginal zone lymphoma.
- The REAL classification was updated by the World Health Organization (WHO) in 1998. 88 The modified REAL classification is based on morphology and cell lineage, and it includes B-cell neoplasms, T-cell neoplasms, and Hodgkin’s disease. Within each category, disorders are defined as indolent, aggressive, or very aggressive, based on the clinical course of each disease entity. 57 FL = follicular lymphoma; CLL = chronic lymphocytic leukemia; SLL = small lymphocytic lymphoma; HCL = hairy cell leukemia; MALT = mucosa-associated lymphoid tissue; PLL = prolymphocytic leukemia; MCL = mantle cell lymphoma; DLCL = diffuse large B-cell lymphoma.
- Although it was originally designed for staging Hodgkin’s disease, the modified Ann Arbor staging system is also commonly used to define the extent of disease in NHL. 83 However, this system does not address certain prognostic or therapeutic issues known to be important in NHL, such as bulky disease (lesion >10 cm in diameter). Each of the stages is further subdivided “ A” – patients without B symptoms “ B” – patients with B symptoms (unexplained weight loss, sweats, high fever, or pruritis) “ E” – extranodal lymphoid malignancies; a symbol for the specific site may also be used: nodes (N), spleen (S), liver (H), pleura (P), lung (L), bone (O), bone marrow (M), skin (D)
- According to the International Working Formulation (IWF), there are 3 classes of indolent NHL (A, B, and C). 82 These classes of indolent NHL are commonly grouped with follicular, predominantly large cell lymphoma (IWF class D) as “indolent lymphomas” due to similarities in disease characteristics and prognosis. The median survival rate of patients with indolent lymphoma ranges from 3 to 7+ years. As is shown in the slide, the majority of patients with indolent lymphoma have follicular, predominantly small cleaved cell NHL. Follicular, mixed small and large cell NHL is the next most common class. Follicular, predominantly large cell NHL and small lymphocytic NHL are less common.
- Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use of single-agent or multiagent chemotherapy or combined modality therapy has not had a significant impact on the natural course of the disease. 54
- A retrospective evaluation of the REAL classification was conducted by the International Lymphoma Study Group. Nine institutions provided 200 consecutive cases of previously untreated patients with NHL that were representative of the region during the period between January 1, 1988, and December 31, 1990. In total, 1403 cases were examined. 3 The International Prognostic Index (IPI) was used to stratify patients, and outcome was measured using failure-free survival and OS. For patients with FL, overall rates were distinctly different among the various IPI risk groups. Five-year OS rates ranged from ~12% in the high-risk group (IPI 4–5) to ~87% in the low-risk group (IPI 0–1). 3
- The efficacy of CHOP, a first-generation combination chemotherapy regimen, was demonstrated for lymphoma in the 1970s and 1980s. Patients achieved high response (45%–53%) and long-term survival rates (30%–37% 5 years). 28 Single-institution studies conducted in the 1980s suggested that 55%–65% of patients with intermediate- or high-grade NHL might be cured by more complex, third-generation regimens. 28 In the 1980s, the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) conducted a prospective, randomized, phase III trial (NHPLS) to compare the relative efficacy of CHOP and several third-generation combination chemotherapy regimens in patients with aggressive NHL. 28 Eligible patients (N=899) were stratified by prognostic factors and randomized into 4 treatment groups to receive CHOP, m-BACOD, ProMACE-CytaBOM, or MACOP-B. At 3 years post-treatment, 44% of all patients were alive and disease-free without significant differences among the 4 treatment arms. Patients treated with CHOP, however, had fewer fatal toxic reactions ( P =0.09). 26 These results established CHOP as the standard of care for patients with aggressive NHL.
- To identify prognostic factors for survival, an international study involving >2000 patients with aggressive NHL was conducted between the years 1982 and 1987. 56 Objective characteristics independently associated with survival included age, PS, serum LDH level, number of extranodal disease sites, and disease stage (Ann Arbor). For younger patients ( 60 years), clinical features predictive of survival were PS, LDH, and stage.
- Because the relative risk associated with each prognostic factor is similar, the survival probability is simply calculated by adding the number of prognostic factors present at diagnosis. The relative risk for death in patients with each possible number of prognostic factors was determined, and patients with similar relative risk (low [L], low-intermediate [LI], high-intermediate [HI], or high [H] risk) were identified. 107 An age-adjusted model was also developed because of significant differences in treatment options and clinical outcomes for younger ( 60) vs older (>60) patients.
- Each of the 4 risk groups in the International NHL Prognostic Factors Project exhibited a distinct 5-year survival pattern ranging from 26% in the high-risk group to 73% in the low-risk group. 56