Lymphoma

1. Lymphoma Farjah Hassan AlGahtani Assistant Professor, Consultant Hematology Director of Transfusion Medicine and Blood Bank

2. Overview • Concepts, classification, biology • Epidemiology • Clinical presentation • Diagnosis • Staging • Three important types of lymphoma

3. Conceptualizing lymphoma • neoplasms of lymphoid origin, typically causing lymphadenopathy • leukemia vs lymphoma • lymphomas as clonal expansions of cells at certain developmental stages

4. ALL CLL Lymphomas MM Neutrophils AML Myeloproliferative disorders Myeloid progenitor Eosinophils Hematopoietic stem cell Basophils Monocytes Platelets Red cells naïve germinal center B-lymphocytes Plasma cells Lymphoid progenitor T-lymphocytes

5. CLL MM ALL DLBCL, FL, HL B-cell development memory B-cell germinal center B-cell stem cell mature naive B-cell lymphoid progenitor progenitor-B pre-B immature B-cell plasma cell Bone marrow Lymphoid tissue

6. Clinically useful classification Biologically rational classification • Diseases that have distinct • morphology • immunophenotype • genetic features • clinical features • Diseases that have distinct • clinical features • natural history • prognosis • treatment Classification

7. Lymphoma classification(2001 WHO) • B-cell neoplasms • precursor • mature • T-cell & NK-cell neoplasms • precursor • mature • Hodgkin lymphoma Non- Hodgkin Lymphomas

8. Category Survival of untreated patients Curability To treat or not to treat Non-Hodgkin lymphoma Indolent Years Generally not curable Generally defer Rx if asymptomatic Aggressive Months Curable in some Treat Very aggressive Weeks Curable in some Treat Hodgkin lymphoma All types Variable – months to years Curable in most Treat A practical way to think of lymphoma

9. Mechanisms of lymphomagenesis • Genetic alterations • Infection • Antigen stimulation • Immunosuppression

10. Epidemiology of lymphomas • 5th most frequently diagnosed cancer in both sexes • males > females • incidence • NHL increasing • Hodgkin lymphoma stable

11. Incidence of lymphomas in comparison with other cancers in Canada

12. Age distribution of new NHL cases in Canada

13. Age distribution of new Hodgkin lymphoma cases in Canada

14. Risk factors for NHL • immunosuppression or immunodeficiency • connective tissue disease • family history of lymphoma • infectious agents • ionizing radiation

15. Clinical manifestations • Variable • severity: asymptomatic to extremely ill • time course: evolution over weeks, months, or years • Systemic manifestations • fever, night sweats, weight loss, anorexia, pruritis • Local manifestations • lymphadenopathy, splenomegaly most common • any tissue potentially can be infiltrated

16. Other complications of lymphoma • bone marrow failure (infiltration) • CNS infiltration • immune hemolysis or thrombocytopenia • compression of structures (eg spinal cord, ureters) • pleural/pericardial effusions, ascites

17. Diagnosis requires an adequate biopsy • Diagnosis should be biopsy-proven before treatment is initiated • Need enough tissue to assess cells and architecture • open bx vs core needle bx vs FNA

18. Stage I Stage II Stage III Stage IV Staging of lymphoma A: absence of B symptoms B: fever, night sweats, weight loss

19. Three common lymphomas • Follicular lymphoma • Diffuse large B-cell lymphoma • Hodgkin lymphoma

20. Relative frequencies of different lymphomas Non-Hodgkin Lymphomas Diffuse large B-cell Hodgkin lymphoma NHL Follicular Other NHL ~85% of NHL are B-lineage

21. Follicular lymphoma • most common type of “indolent” lymphoma • usually widespread at presentation • often asymptomatic • not curable (some exceptions) • associated with BCL-2 gene rearrangement [t(14;18)] • cell of origin: germinal center B-cell

22. defer treatment if asymptomatic (“watch-and-wait”) • several chemotherapy options if symptomatic • median survival: years • despite “indolent” label, morbidity and mortality can be considerable • transformation to aggressive lymphoma can occur

23. Diffuse large B-cell lymphoma • most common type of “aggressive” lymphoma • usually symptomatic • extranodal involvement is common • cell of origin: germinal center B-cell • treatment should be offered • curable in ~ 40%

24. Hodgkin lymphoma Thomas Hodgkin (1798-1866)

25. Epidemiology • ~ 20 000 new cases in North America and Europe every year • Annual incidence 2.7/100 000 per year • Annual mortality only 0.5/100 000 per year • North American lifetime risk – 1/250 to 1/300 • Young adults • 90% in adults 16-65 • Median Age 35 • Slight male predominance • Much less frequent in eastern Asian populations

26. Associated (etiological?) factors • EBV infection • smaller family size • higher socio-economic status • caucasian > non-caucasian • possible genetic predisposition • other: HIV? occupation? herbicides?

27. The EBV Association • 3x increased risk Hodgkins with serologically confirmed infectious mononucleosis • EBV genomes detected in ~ 1/3 of Hodgkin lymphoma tissues (developed countries) • Highest proportion mixed cellularity • Population study showed high pre-diagnostic titres of EBV in patients later diagnosed with Hodgkin’s • ?causative – especially in younger patients

28. Pathology • B cell neoplasm • Unique due to the relative paucity of clonal malignant cells in a background of reactive inflammatory cells • 2 distinct entities • Nodular Lymphocyte predominant HL • L&H cell “popcorn cell” • Classical HL • Reed Sternberg cell • 4 subtypes

29. Classical Hodgkin Lymphoma

30. Hodgkin lymphoma • cell of origin: germinal centre B-cell • Reed-Sternberg cells (or RS variants) in the affected tissues • most cells in affected lymph node are polyclonal reactive lymphoid cells, not neoplastic cells

31. Reed-Sternberg cell

32. Reed Sternberg Cell • “owl’s eye” • 2 nuclear lobes with large inclusion like nucleoli (eosinophilic) • Clear halo around nucleolus (chromatin condensed to nuclear membrane) • Abundant cytoplasm – usually eosinophilic • Lymphocytic and Histiocytic Cell • “popcorn cell” • Polylobated nucleus • Lack of prominent eosinophilic nucleoli • Lack of halo

33. RS cell and variants classic RS cell lacunar cell popcorn cell (lymphocyte predominance) (mixed cellularity) (nodular sclerosis)

34. A possible model of pathogenesis loss of apoptosis transforming event(s) EBV? cytokines germinal centre B cell RS cell inflammatory response

36. Nodular Lymphocyte Predominant Hodgkin’s Lymphoma • 5-10% of patients • “popcorn cell” • Positive for CD 45 • express B-cell associated antigens CD19, CD20, CD22, CD79a, EMA • lack CD15 and CD30 • Background of primarily B lymphocytes +/- histiocytes • Commonly presents early stage (~80%) • 4:1 M:F • slightly higher risk of development of NHL (2% to 5%) • Usually DLBCL • Some treatment differences compared with classical Hodgkin’s

37. Classical Hodgkin’s Lymphoma • Nodular Sclerosis • Mixed Cellularity • Lymphocyte-depleted • Lymphocyte-rich • CD 15 and CD 30 positive +/- CD 20

38. Nodular Sclerosis • partially nodular pattern with fibrous bands separating the nodules • lacunar type RS cells - multilobated nuclei and small nucleoli with abundant pale cytoplasm that retracts in formalin-fixed sections producing an empty space • 40%-70% of patients • Commonly present early stage (~70%) • Often confined above the diaphragm • Slight female predominance • Commonly adolescents and young adults

40. Mixed Cellularity • Classic RS cells common • Background of lymphocytes, eosinophils, plasma cells and histiocytes • 30%-50% of patients • More commonly presents with advanced stage disease, B symptoms • Pediatric and older patients

41. Lymphocyte-depleted • Classic RS cells with hypocellular fibrotic or reticular background • Presents more commonly in older patients • Commonly advanced stage • Less common involvement of peripheral nodes and mediastinum • Lymphocye-rich • Similar to NLPHL but has classical immunophenotype

42. Clinical Presentation • Painless lymphadenopathy • Contiguous spread between lymphoid regions • Usually begins supra diaphragmatically • Regional sub diaphragmatic disease < 10% • Symptoms associated with compressive effect • *mediastinal mass • Abdominal/inguinal • “B symptoms” • Wt loss > 10% over 6 months • Persistent fever >38.2 • Drenching night sweats • Puritis

43. Weird and wonderful… • Alcohol induced pain • Nephrotic syndrome • paraneoplastic secondary to lymphokines • Dermatologic • ichthyosis, acrokeratosis (Bazex syndrome), urticaria, erythema multiforme, erythema nodosum, necrotizing lesions, hyperpigmentation, and skin infiltration

44. Neurologic • cerebellar degeneration, chorea, neuromyotonia, limbic encephalitis, subacute sensory neuronopathy, subacute lower motor neuronopathy, and the stiff man syndrome • Cholestatic liver disease • Hypercalcemia

45. Modified Ann Arbour Staging System • I • Single lymph node region (I) • or one extralymphatic site (IE) • II • Two or more lymph node regions, same side of the diaphragm (II) • or local extralymphatic extension plus one or more lymph node regions same side of the diaphragm (IIE)

46. III • Lymph node regions on both sides of the diaphragm (III) • Which may be accompanied by local extralymphatic extension (IIIE) • IV • Diffuse involvement of one or more extralymphatic organs or sites

47. A = no B symptoms • B = atleast one of • Unexplained weight loss > 10% during preceding 6 months • Recurrent unexplained fever > 38 • Recurrent night sweats • Bulky disease • Single mass > 10 cm largest diameter

49. Staging Evaluation • Pathology Review • History looking for B symptoms or other symptoms suggesting systemic disease • Physical for lymphadenopathy and organomegaly • CBC and ESR • Cr, ALP, LDH, bili, Ca, AST, albumin, SPEP • CXR – PA and lat • CT neck, thorax, abdomen and pelvis

50. Bone marrow aspirate and biopsy if • B symptoms • WBC < 4 • Hgb <120 (women) 130 (men) • Platelets < 125 • ENT examination if • Stage IA or IIA disease with upper cervical lymph node involvement (supra-hyoid)