LYMPHOPROLIFERATIVE DISORDERS. Dr Mere Kende MBBS, MMED (Path), MACTM, MACRRM, MAACB Lecturer: SMHS, UPNG

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1 LYMPHOPROLIFERATIVE DISORDERS Dr Mere Kende MBBS, MMED (Path), MACTM, MACRRM, MAACB Lecturer: SMHS, UPNG

2 Outline What are lymphoproliferative Disorders? Examples of LPD Classification Causes Clinical Features Investigation Principles of Treatment Complications Prognosis References

3 What are Lympho-proliferative Disorders Diseases resulting from abnormal division, development, proliferation or differentiation of lymphocyte cell series (B-cells & T-cells) Immunodeficiency and Growth of Cancer Cells (lymphomas & some leukaemias

4 Hemopoiesis

Granulocyte-CSF SDF-1= Stromal cell-derived factor-1 FLT-3 ligand= FMS-like

5 Normal Hemopoiesis SCF= Stem Cell Factor Tpo= Thrombopoietin Epo= Erythropoietin IL= Interleukin GM-CSF= Granulocyte Macrophage-CSF M-CSF= Macrophage-CSF G-CSF= Granulocyte-CSF SDF-1= Stromal cell-derived factor-1 FLT-3 ligand= FMS-like tyrosine kinase 3 ligand TNF-a = Tumour necrosis factoralpha TGFβ = Transforming GF beta

6 Examples of Lympho-Proliferative Disorders / Diseases Lymphomas (Hodgkins, Non-Hodgkin s) Leukaemias (ALL/CLL) Paraproteinaemias (multiple myeloma) Autoimmune LPD Hypergammaglobulinemia

7 Classification Historically, LYMPHOMA - Rappaport, Kiel, or Working Formulation systems; ACUTE LEUKAEMIA - French-American-British (FAB) system; HODGKIN S DISEASE - Rye classification. WHO CLASSIFICATION - brings together all lymphoid neoplasms into a single framework. All these are limited value clinically Classification based on clinical manifestations and natural history of diseases is more clinically useful (next Table).

8 Clinical Classification - Lymphoid Neoplasm CLL (mainly B-cells) ALL (mainly T-cell) Hodgkin s Disease (B-cells) Indolent lymphomas (mainly B-cells, (NHL) Aggressive Lymphomas (B & T cell, NHL) Plasma Cell Disorders (100% B-cells) Harrison s Manual of Medicine 17 th Edition

9 Relative Frequencies of Lymphoid Malignancies Harrison s Manual of Medicine 17 th Edition

10 LPD-Malignancy Malignancy of cells of lymphoid or immune cell origins include lymphomas and leukaemias Neoplasms of lymphocytes usually represent malignant counterparts of cells at discrete stages of normal lymphocyte differentiation. Lymphoid Leukaemia (leukaemia): Bone Marrow & Peripheral blood involvement dominate the clinical picture Lymphoma: Lymph nodes and other extranodal sites involved predominantly.

11 Some lymphoid malignancies can only present as leukemia, while others almost always present as lymphomas. Others can present as either leukemia or lymphoma. Clinical pattern can change over the course of the illness. Eg lymphoma can subsequently develop into leukemia over the course of the illness.

12 The distinction between lymphoma and leukemia is sometimes blurred; eg: Small lymphocytic lymphoma and CLL are tumors of the same cell type; if the absolute number of peripheral blood lymphocytes is >5 109/L, then its called leukemia.

13 Aetiology Unknown (majority) Inherited risk factors SCID, Wiskott-Aldrich syndrome, Ataxia telangiectasis, & Chediak- Higashi Syndrome Genetic /Chromosomal abnormalities Translocations: - t(8;14) in Burkitt s lymphoma, t(14;18) in follicular lymphoma, t(11;14) in mantle cell lymphoma, t(2;5) in anaplastic large cell lymphoma Mutations: bcl-6 on 3q27 in diffuse large cell lymphoma, and others

14 Aetiology Acquired Infections (HIV, EBV) Drugs (immunosupressants) Infective/Viruses: Epstein-Barr virus (EBV),Human herpesvirus 8 (HHV-8) (both herpes family viruses), and human T-lymphotropic virus type I (HTLV-I, a retrovirus) may cause some lymphoid tumors.

15 Infective Cause EBV & Burkitt s lymphoma HHV-8 causes a rare entity, body cavity lymphoma, mainly in pts with AIDS. HTLV-I is associated with adult T cell leukemia/ lymphoma (Japanese). Immune Deficiency- Inherited or acquired : Lymphoma is 17 times more common in HIV infected than in HIVnoninfected people.

16 Helicobacter pylori infection & MALT Lymphomas- Gastric mucosa-associated lymphoid tissue (MALT) lymphoma Treated infection produces durable remissions in about half of pts with gastric MALT lymphoma. MALT lymphomas of other sites are associated with either infection (ocular adnexae, Chlamydia psittaci; small intestine, Campylobacter jejuni; skin, Borrelia) or autoimmunity (salivary gland, Sjogren s syndrome; thyroid gland, Hashimoto s thyroiditis).

17 Drugs Drugs Immunosupressants (tacrolimus) Anti-transplant Rejection Drugs (cyclosporin) HIV Drugs Other causes Lymphoma occurs with increased incidence in farmers and meat workers; Hodgkin s disease is increased in wood worker

18 Clinical Features of LPDs Incidental lymphocytosis (CLL) Non-specific complaints (night sweats/fever/weight loss Lymphadenopathy (lymphoma) Hepatomeglay & Splenomegaly (CML) Recurrent Infections Anaemia (leukaemia/lymphoma/myeloma) Thrombocytopenia Autoimmune hemolysis (CLL) Kidney Failure/Bone Fractures (Multiple Myeloma) Hypercalcemia (MM)

19 Neck Lymphoma

20 Burkitt s Lymphoma

21 Chest Lymphoma

22 Multiple Myeloma- Skull punched out lesions Skull/Lumbar spine

23 CML Severe Splenomegaly

24 Microangipathic Hemolysis Red cell fragmentation

25 Hemoglobinuria

26 Lymphomas Hodgkin s (Disease) Lymphomas Non-Hodgkins Lymphomas

27 Hodgkin s Disease Hodgkin's disease is a group of cancers characterized by Reed Sternberg cells in an appropriate reactive cellular background. The malignant cell is derived from B lymphocytes of germinal center origin

28 Hodgkin s Disease RSC is present near the center of the field; large cell -bilobed nucleus, prominent nucleoli giving an "owl's eyes" appearance. Rest are normal lymphocytes, neutrophils, and eosinophils that form a pleiomorphic cellular infiltrate.

29 Reedsternberg Giant Cells

30 Hodgkin s Lymphoma-Subtypes; nodular sclerosis (75% ) mixed cellularity (20%), & lymphocyte depletion (5%) lymphocyte predominance

31 Nodular Sclerosing Type RSG cells, with characteristic background infiltrate composed of eosinophils, lymphocytes, plasma cells, and histiocytes. Variable degree of fibrosis is also present

32 Mixed Cellularity Type Mixed Cellularity type accounts for 20% to 25% of cases of Classical Hodgkin s Lymphoma. Reed- Sternberg cells are present in a background of eosinophils, plasma cells, lymphocytes, and atypical mononuclear cells. Fibrosis is usually absent

33 Lymphocyte depleted A Reed-Sternberg cell is seen in a background of eosinophils, lymphocytes, and macrophages. Lymphocytedepleted is the most aggressive type of Hodgkin s lymphoma, commonly associated with advanced stages at presentation

Lymphocyte Predominant (nodular) In Nodular Lymphocytepredominant Hodgkin s Lymphoma, classic Reed- Sternberg cells, eosinophils, plasma cells, and

34 Lymphocyte Predominant (nodular) In Nodular Lymphocytepredominant Hodgkin s Lymphoma, classic Reed- Sternberg cells, eosinophils, plasma cells, and areas of fibrosis are absent. Instead, numerous L&H cells with multilobed, folded nucleus with small nucleoli are present in a background rich in lymphocytes

35 Clinical Findings 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Hodgkin s Lymphoma Bimodal Peak Age Age in Years

36 Clinical Findings Whites > blacks B-cell origin Common presentation: a painless mass in the neck Constitutional symptoms such as fever, weight loss, or drenching night sweats, or because of generalized pruritus. Arises within single lymph node areas and spread in an orderly fashion to nearby lymph glands. Later vascular invasion widespread hematogenous dissemination. DDx : reactive lymphocytosis (EBV, cat-scratch disease, or drug reactions (eg, phenytoin).

37 Staging Nomenclature (Ann Arbor) : stage I, one lymph node region involved; (neck/throat/thymus) stage II, involvement of two lymph node areas on one side of the diaphragm; (neck, mediastinal & hilar) stage III, stage IV, lymph node regions involved on both sides of the diaphragm; and (chest & abdomen) disseminated disease with bone marrow or liver involvement.

38 Sub-classified Stage A--no constitutional symptoms Asymptomatic eg IA, IIB, IIIB etc Stage B---eg IB, IIB symptomatic 10% weight loss over 6 months, fever, or night sweats are present.

39 Hodgkins Lymphomas Essentials of Diagnosis Painless lymphadenopathy. Constitutional symptoms may or may not be present. Pathologic diagnosis by lymph node biopsy

40 Diagnosis-Hodgkin s Disease

41 Investigation Biopsy CXR/CT CHEST Abdominal USS Bone Marrow biopsy

42 Histopathology Staging- Cytogenetics-

43 Treatment Radiation therapy - used as initial treatment only for patients with low-risk stage IA and IIA disease. Combination chemotherapy: Most patients with Hodgkin's disease (including all with stage IIIB and IV disease) are best treated with using doxorubicin (Adriamycin), bleomycin, vincristine, and dacarbazine (ABVD). New shorter and more intensive regimens are being studied, but have not yet proved superior to ABVD.

44 Prognosis Stage IA or IIA disease treated by radiotherapy is excellent, with 10-year survival rates in excess of 80%. Patients with disseminated disease (IIIB, IV) have 5-year survival rates of 50 60%. Poorer results - Older patients lymphocyte depletion or mixed cellularity on histologic examination. Better result - lymphocyte-predominant form of the disease with cure seen in > 70% of those with disseminated disease and with limited treatment needed for those with early-stage disease. Relapse- after initial chemotherapy high-dose chemotherapy with autologous stem cell transplantation.

45 Non-Hodgkin s Disease Heterogeneous group of cancers of lymphocytes. Variable clinical presentation and course from indolent to rapidly progressive. Burkitt's lymphoma, Best studied characteristic cytogenetic abnormality of translocation between the long arms of chromosomes 8 and 14 Translocated protooncogene c-myc from its normal position on chromosome 8 to the heavy chain locus on chromosome 14.

46 Burkitts Lymphoma

47 Burkitts Lymphoma

48 Aetiology Unknown Elderly>young Males>females Risk factors: chemicals/organ transplant/hiv infection/inherited immune deficiency

49 Cells committed to B cell differentiation are likely to have enhanced expression of this heavy chain locus, and it is likely that over-expression of c-myc (in its new anomalous position) is related to malignant transformation. Follicular lymphomas, the t(14,18) translocation is characteristic and results in over-expression of bcl- 2, resulting in protection against apoptosis, the usual mechanism of cell death.

51 The normal nodal architecture is effaced by nodular expansions of tumor cells. Nodules vary in size and contain predominantly small lymphocytes with cleaved nuclei along with variable numbers of larger cells with vesicular chromatin and prominent nucleoli. Follicular Lymphoma

52 Diffuse B-cell lymphoma The neoplastic cells are heterogeneous but predominantly large cells with vesicular chromatin and prominent nucleoli.

53 Burkitts Lymphoma Homogenous, Mediumsized B cells, frequent mitotic figures Reactive macrophages - pale cytoplasm in a background of bluestaining tumor cells give the tumor starry sky appearance.

54 Burkitt s Lymphoma

55 Adult T-cell Lymphoma (leukaemia) Peripheral blood smear showing leukemia cells with typical "flower-shaped" nucleus

56 NHL Indolent Versus Aggressive

57 INDOLENT LYMPHOMAS Median Survival ~ 10years: Median Age: 55 years The majority of pts dying from follicular lymphoma have undergone histological transformation to diffuse large B cell lymphoma.

58 Follicular Lymphoma

59 Aggressive NHL Median Survival ~if untreated 6 months, Nearly all untreated pts are dead within 1 year Diffuse large B cell lymphoma is the most common (35-45%) Aggressive NHL acount for 60% of all lymphoid tumors. 85% are B-cell origin and 15% T cells origin

60 Clinical Findings Symptoms and Signs Painless lymphadenopathy, which may be isolated or widespread. Involved lymph nodes may be present in the retroperitoneum, mesentery, and pelvis. Usually (85%) disseminated at the time of diagnosis, and bone marrow and liver involvement is frequent. Patients with aggressive NHL have more common B or constitutional symptoms such as fever, drenching night sweats, or weight loss. (10-45%) Symptoms: Fever, sweats, weight loss occur more commonly with Hodgkin s Disease

61 Examination Lymphadenopathy: may be isolated, or extranodal sites of disease (skin, gastrointestinal tract) may be found. Patients with Burkitt's lymphoma are noted to have abdominal pain or abdominal fullness because of the predilection of the disease for the abdomen.

62 Staging Once a pathologic diagnosis is established, the patient is staged based on clinical and investigation findings Chest radiograph and CT scan of the abdomen and pelvis, bone marrow biopsy, and In selected cases with high-risk morphology a lumbar puncture are performed.

63 Investigation Peripheral blood: Usually Normal Blood Chemistry: LDH is a useful for prognosis and risk stratification of treatment Bone Marrow: Manifested as paratrabecular lymphoid aggregates/nodule of cleaved lymphocytes is consistent with Follicular NHL. CSF Cytology: Some high-grade lymphomas involve the meninges.

64 Investigation Tissue Biopsy: Needle aspiration may yield suspicious results, but a lymph node biopsy (or biopsy of involved extranodal tissue) is required for diagnosis and staging. Molecular profiling: Exam gene expression; t(14;18) is present in 85% of cases, resulting in the over-expression of bcl-2, a protein involved in prevention of programmed cell death CXR: May show a mediastinal mass in lymphoblastic lymphoma.

65 Treatment Follicular Lymphoma 15% of pts have localized disease- majority curable with radiation therapy 85% Disseminated Chemotherapy (with cyclophosphamide,doxorubicin, vincristine, & prednisone (CHOP) + rituximab). Nucleoside analogues (fludarabine, cladribine), Radiation therapy, Biologic agents [interferon (IFN) α,) monoclonal antibodies (rituximab, anti-cd20] 90% of pts are responsive to treatment; complete responses are seen 50-70%

66 Aggressive Lymphomas Localized four cycles of CHOP combination chemotherapy ± involved-field radiation therapy. About 85% of these pts are cured. CHOP + rituximab appears to be even more effective than CHOP + radiation therapy. More advanced disease- controversial Six cycles of CHOP + rituximab is the treatment of choice for advanced-stage disease.

67 Harrison s Manual of Medicine 17 th Edition

68 Leukaemias Acute lymphoblastic (ALL) Chronic lymphocytic (CLL)

69 Tianem Mountain Road, Huan China

70 References Current Medical Diagnosis & Treatment 2008 Harrison s Principle of Internal Medicine 17 th Edition

Non-Hodgkin lymphomas (NHLs) Hodgkin lymphoma )HL)

Non-Hodgkin lymphomas (NHLs) Hodgkin lymphoma )HL) Lymphoid Neoplasms: 1- non-hodgkin lymphomas (NHLs) 2- Hodgkin lymphoma 3- plasma cell neoplasms Non-Hodgkin lymphomas (NHLs) Acute Lymphoblastic Leukemia/Lymphoma