Goals

1. Goals • Understand the differences between Hodgkin Lymphoma and non-Hodgkin Lymphoma • Clinically and biologically • Understand the differences between aggressive NHL and indolent NHL • Clinically and biologically

2. C Definition of Lymphoma • Heterogeneous group of lymphoproliferative malignancies • Results from clonal expansion of tumor cells derived from B, T, or NK cells • 85%-90% in the US are derived from B cells • Variable clinical presentations • Range from asymptomatic pick up on routine blood work to painless adenopathy to an emergent medical problem • Pain, failure to thrive, organ failure • Characterized by variable natural histories and therapeutic responses

3. Age at Diagnosis for Hodgkin’s andNon-Hodgkin’s Lymphoma ~56,390 NHL cases/y ~7,350 HD cases/y NHL Cases/100,000 Hodgkin’s Age at diagnosis (y) Data for diagnoses from 1997 to 2001. At: http://seer.cancer.gov. Accessed March 23, 2005.

4. Non-Hodgkin’s Lymphoma:Epidemiology Estimated annualincidence ~4% compound annual increase in incidence Year Adapted from Greenlee et al. CA Cancer J Clin. 2001;51:15. Adapted from Jemal et al. CA Cancer J Clin. 2005;55:10.

5. Hodgkin’s Disease

6. Hodgkin Biology • RS is a “crippled” germinal center B cell • does not have normal B cell surface antigens • micromanipulation of single RS followed by PCR demonstrates clonally rearranged, but non functional immunoglobulin genes • somatic mutations result in stop codon (no sIg) • no apoptotic death malignant transformation • unclear how this occurs; ? EBV • unclear how cells end up with RS phenotype

7. Hodgkin’s Disease • Clinical features • Often seen in young adults • Wide variety of presentations • B symptoms (fevers, night sweats, wt loss) • Pruritis • Cough/SOB • Pain • Painless adenopathy

8. Hodgkin’s Disease • Approach to the Patient • staging evaluation • H & P • CBC, diff, plts • ESR, LDH, albumin, LFT’s, Cr • CT scans chest/abd/pelvis • bone marrow evaluation • PET scan in selected cases

9. Ann Arbor Staging System for Hodgkin's Disease and Non-Hodgkin's Lymphoma Stage I Stage II Stage III Stage IV Reprinted with permission. Adapted from Skarin. Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. 1991.

10. Hodgkin’s Disease • Typical staging results • Most often disease is localized to above the diaphragm • Common to have extensive mediastinal disease • Tends to spread to contiguous nodal groups • Unlike NHL

11. Approach to the Patient • Hodgkin’s Disease • approach dictated mainly by where the disease is located rather (results of staging) than the exact histologic subtype • NHL • approach is often dictated more by the histologic subtype than the results of staging

12. Hodgkin Lymphoma: Treatment of limited stage disease

13. Hodgkin Lymphoma: Prognostic Factors

14. Hodgkins Disease Summary • B cell lymphoma • several histologic subtypes • Generally does not affect the approach to the patient • Reed-Sternberg Cells • Tends to occur in young adults • Mediastinal disease common • Spreads to contiguous nodes • Common to have a “localized” presentation • Highly curable with current treatments

15. Non-Hodgkin’s Lymphoma • 30ish histologic subtypes • B cell (85%), T cell, NK cell • Histologic subtype dictates the approach to the patient • Median age at diagnosis 60 • Often widespread disease at diagnosis • Wide variation in outcome • Some cases rapidly fatal • Some cases readily curable • Some cases incurable but patient can live for many years with good quality of life

16. WHO Classification:B-Cell Malignancies Harris NL et al. J Clin Oncol. 1999;17:3835-3849.

17. WHO Classification:T-Cell Malignancies Harris NL et al. J Clin Oncol. 1999;17:3835-3849.

18. Precursor cells Virgin (naïve) B cells Germinal-center and post–germinal-center B cells B-Cell Development Stem cell Immature B cell Follicle-center B cell s-IgM s-IgM/G/A CD79a CD22 CD79a TdT CD22 CD10 CD21 bcl6 CD21 HLA-DR HLA-DR CD20 CD34 HLA-DR CD20 CD19 CD19 Pre-pre–B cell Immunoblast s-IgM/G/A TdTc-CD22c-CD79a CD22 CD79a Mature B cell CD138± c-Ig s-IgM & IgD CD20 CD19 HLA-DR CD79a CD19 HLA-DR MUM1 CD22 CD21 HLA-DR Pre–B cell CD20 CD10 TdTc-CD22c-CD79ac-m CD19 Plasma cell CD20 CD79a CD138 c-Ig CD19 HLA-DR PCA-1 MUM1

19. WM MM ALL MCL, CLL Burkitts, FL, DLBCL Stem cell Pre-B Early B Mature B Activated B Plasmacytoid B Plasma Germinal center • Type of B cell lymphoma is a function of: • Where the cell was in development/maturation when it went “bad” • What molecular derangement occurred Antigen Expression in B-Cell Lineage Jaffe. In: Non-Hodgkin’s Lymphoma. 1997:84.

20. Models of Chromosomal Translocations in NHL REG REG REG REG CODING CODING CODING CODING Proto-oncogene Proto-oncogene TRANSLOCATION TRANSLOCATION REG REG COD ING CODING TRANSCRIPTIONALDEREGULATION FUSIONPROTEIN REG = regulatory sequence. Harris NL et al. Hematology (Am Soc Hematol Educ Program). 2001:194-220.

21. Chromosomal Translocations Commonly Associated With Activation in B-Cell Malignancies National Comprehensive Cancer Network. Practice Guidelines in Oncology. v.1.2005.

22. Lymphoma Biology • Aggressive NHL • short natural history (patients die within months if untreated) • disease of rapid cellular proliferation • Potentially curable with chemotherapy • Indolent NHL • long natural history (patients can live for many years untreated) • disease of slow cellular accumulation • Generally incurable with chemotherapy

23. NHL: Presentation and Staging • Aggressive NHL • Patients likely to present with symptoms • Indolent NHL • Patients likely to present with painless adenopathy • Initial workup similar to Hodgkin Lymphoma

24. NHL: Approach to the Patient • Approach dictated mainly by histology • reliable hematopathology crucial • Aggressive NHL • Cure is often the goal • Indolent NHL • Cure is rarely the goal • Control is the goal

25. Most Common NHLs Armitage JO, Weisenburger DD. J Clin Oncol. 1998;16:2780-2795.

26. Follicular Lymphoma

27. Approach to Indolent NHL • Indolent NHL: guiding treatment principle • immediate treatment does not prolong overall survival for many patients • When to treat? • constitutional symptoms • compromise of a vital organ by compression or infiltration, particularly the bone marrow • bulky adenopathy • rapid progression • evidence of transformation • Will often begin with relatively non-toxic treatments and escalate the intensity of the therapy

29. Diffuse Large B Cell Lymphoma

30. Approach to Aggressive NHL • Patients have the potential to be cured • Administer most effective therapy (no matter how harsh) at diagnosis • If not cured, patients typically die within a few years of diagnosis

32. International Prognostic Index for Age-Adjusted The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993;329:987-994.

33. DLBCL: Subtypes Revealed by Expression Array 1.0 Germinal-centerB-cell–like 0.8 0.6 Probability ActivatedB-cell–like 0.4 0.2 P = 7.9 E-6 0.0 0 2 4 6 8 10 Overall survival (years) Single histology with multiple molecular subtypes …with different outcomes Alizadeh AA et al. Nature. 2000;403:503-511.

34. Summary • NHL incidence increasing • Hodgkin incidence stable or decreasing • Hodgkin Lymphoma • Characterized by the Reed-Sternberg Cells • Stage more important that histologic subtype • Often limited stage (stage I or II) • Spreads to contiguous nodes • Often affects younger patients • Very responsive to therapy • Cure rate quite high

35. Summary • NHL cure rate mediocre • Many histologic subtypes • Often more important that the stage • indolent vs. aggressive • Function of underlying biology • indolent: • Often asymptomatic • Treatment: Less is more • aggressive: • Often symptomatic • require aggressive treatment ASAP to achieve cure