Lymphoproliferative Disorders

Transcription

1 Lymphoproliferative Disorders

2 Learning outcomes Lymphocyte Ontogeny: know types and origin of lymphocytes Function of lymphocytes Lyphoprloifertive Disorders Acute vs Chronic Principles of diagnosis

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4 Definition of Lymphocyte Lymphocytes: defending the body against disease. Lymphocytes are responsible for immune responses. B cells and T cells. The B cells make antibodies that attack bacteria and toxins. T cells attack body cells themselves when they have been taken over by viruses or have become cancerous. Lymphocytes secrete products (lymphokines( lymphokines) ) that modulate the functional activities of many other types of cells and are often present at sites of chronic inflammation.

5 Lymphocytes B Cells. Bone marrow. Mature B cells migrate to secondary lymphoid organs (nodes). Proliferate/ gene rearrangement in germinal centres. Memory or plasma cells T Cells Marrow Circulation- Thymus. T Cell receptors are specific for one antigen gene rearrangement. Auto reactive T cells are removed. CD4 cells help B cells CD8 cells kill virally infected cells.

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11 Lymphoproliferative Disorders Peripheral blood lymphocytosis Normal Value x 10 9 /l Reactive Infection Viral EBV (Infectious Mononucleosis) TB Pertussis Brucellosis Maliganat Chronic Acute

12 Which of the following is true? 1. Most of the lymphocytes in the peripheral blood are B cells. 2. Most of the lymphocytes in the peripheral blood are T cells. Y 3. Most of the lymphocytes in the peripheral blood are NK cells. 4. T cells produce immunoglobulin. 5. B cells are involved in cell mediated immunity

13 For every stage of lymphocyte development, there is a corresponding lymphoid neoplasm i.e Differentiation block: the cells don t grow up!

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16 B Cell Development Bone Marrow Antigen-Independent Periphery Antigen-Dependent Stem Cell Pro-B Cell Pre-B Cell Immature-B Cell Naïve-B Cell Mature-B Cell D H J H Igα/Igß II µ Surrogate Light Chain of Pre-BCR V H D H J H Y II V L J L Y II IgM Y IIY IgM IgM YII Y II Ig IgD Ig gene rearrangement: -ive and +ive selection Pan B Cell Antigens CD19, CD20 CD38 CD22, CD23, CD40 Precursor B-ALL Burkitt s Somatic Hypermutation CLL, Myeloma, Waldenstroms

17 Acute Lymphoblastic leukemia: ALL 10% of all leukemias 85% of childhood leukemia Commonest years Most are B cell

18 Aetiology We don t t know Chemicals/toxins Radiation Viruses Genetics and congenital factors

19 Poor prognostic factors in ALL Age Sex DX. CNS disease <1 or >10yrs Male > 50x10 9 /l Blasts in CSF Immunophenotype Cytogenetics

20 Acute Lymphoblastic Leukaemia

21 Abnormalities seen in at least 90 %of cases Karyotype is of major prognostic significance Used in planning Treatment t(9:22), t(1:19), t(4:11), t(8:14)

22 ALL Symptoms. Vague Sore throat Fatigue Bone pain Infection Signs Bone marrow failure Pale Bleeding Infection Lymphadenopathy

23 Childhood ALL Most Children are cured with chemotherapy! Disease has a predeliction for CNS. Prevention!

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25 ALL in Adults Very few long term cures compared to children

26 Which of the following is true? 1. Acute lymphoblastic leukaemia occurs mostly in adults. 2. Acute lymphoblastic leukaemia occurs montly in children.y 3. Most children with acute lymphoblastic leukaemia die from their disease. 4. Stem clee transplantation is never indicated as treatment for acute lymphoblastic leukaemia. 5. Bone pain is never a presenting feature of acute lymphoblastic leukaemia

27 Chronic Lymphoproliferative diseases Chronic Lymphocytic Leukemia Hodgkin disease Non Hodgkin Lymphoma Multiple Myeloma B Cell EBV?? B or T Cell Plasma cell (B Cell)

28 Chronic Lymphoproliferative diseases CLL Adults/hypogammaglob ulinemia HD NHL /Adults M Myeloma/ Adults Progressive disease/infection Young/curable in most Lymphadenopathy Incurable Lymphadenopathy Incurable/ bony lesions hypogammaglobulinemia

29 Hodgkins disease

30 Chronic Lymphoproliferative diseases Majority have acquired cytogenetic/molecular lesions

31 Lymphoma Classification B cell Precursor B cell neoplasm Precursor B lymphoblastic leukemia/lymphoma (precursor B cell acute lymphoblastic leukemia) Mature (peripheral) B cell neoplasms B cell chronic lymphocytic leukemia/small lymphocytic lymphoma B cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B cell lymphoma (± villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B cell lymphoma of MALT type Mantle cell lymphoma Follicular lymphoma Nodal marginal zone B cell lymphoma (± monocytoid B cells) Diffuse large B cell lymphoma Burkitt's lymphoma/burkitt cell leukemia T cell Precursor T cell neoplasm Precursor T lymphoblastic lymphoma/leukemia (precursor T cell acute lymphoblastic leukemia) Mature (peripheral) T cell neoplasms T cell prolymphocytic leukemia T cell granular lymphocytic leukemia Aggressive NK cell leukemia Adult T cell lymphoma/leukemia (HTLV-I+) Extranodal NK/T cell lymphoma, nasal type Enteropathy-type T cell lymphoma Hepatosplenic T cell lymphoma Subcutaneous panniculitis-like T cell lymphoma Mycosis fungoides/sézary syndrome Anaplastic large cell lymphoma, primary cutaneous type Peripheral T cell lymphoma, not otherwise specified (NOS) Angioimmunoblastic T cell lymphoma Anaplastic large cell lymphoma, primary systemic type

32 Which of the following is true? 1. Chronic Lymphocytic leukaemia is a T cell disease. 2. In chronic lymphocytic leukaemia the lymphocyte count in the blood is normal. 3. Chronic lymphocytic leukaemia occurs mainly in children 4. In chronic lymphocytic leukaemia the immunoglobulin levels are usually normal. 5. In chronic lymphocytic leukaemia the immunoglobulin levels are usually decreased. Y

33 Learning outcomes Lymphocyte Ontogeny: know types and origin of lymphocytes Function of lymphocytes Lyphoprloifertive Disorders Acute vs Chronic Principles of diagnosis

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35 Acute vs. Chronic leukemia Acute leukemias: young, immature, blast cells more fulminant presentation more aggressive course

36 Acute vs. Chronic leukemia Chronic leukemias: accumulation of mature, differentiated cells often subclinical or incidental presentation in general, more indolent course Frequently splenomegaly accumulation of cells

37 leukemia vs lymphoma Reasonably straightforward: leukemia = increased WBC in blood and marrow leukemias can be myeloid or lymphoid: lymphocytosis, neutrophilia,, blasts of either origin lymphoma is always of a lymphoid origin B cell lymphoma (85%) T and NK cell lymphoma (15%)

38 leukemia vs Lymphoma most lymphoid diseases can enter a leukemic phase if advanced enough high tumor burden, spills out into blood BUT myeloid diseases very rarely present in lymph nodes

39 Lymphoma Classification complicated, getting worse now able to distinguish subtle differences in cells better than ever before broadly, Hodgkin s vs non-hodgkin Hodgkin s

40 leukemia vs Lymphoma other common example: chronic lymphocytic leukemia and small lymphocytic lymphoma the two best examples: called leukemia vs lymphoma depending on mode of presentation

41 leukemia vs Lymphoma A few specific entities can present as either lymphoblastic lymphoma and acute lymphoblastic leukemia are the same disease, but named depending on mode of presentation nodal or leukemic

42 leukemia vs Lymphoma leukemia presents in blood and marrow lymphoma most often presents primarily with lymphadenopathy however: one caveat

43 leukemia vs Lymphoma lymphoma of two general types: Hodgkin s s lymphoma B B cell origin Reed-Sternberg cells Non-Hodgkin Hodgkin s s lymphoma all others B, T and NK

44 Leukaemia Acute Chronic Myeloid (AML) 46% Lymphoblastic (ALL) 11% Myeloid (CML) 14% Lymphocytic (CLL) 29%

45 Acute vs. Chronic leukemia leukemias are classified according to cell of origin: lymphoid cells ALL - lymphoblasts CLL mature appearing lymphocytes myeloid cells AML myeloblasts CML mature appearing neutrophils

46 Acute vs. Chronic leukemia Acute leukemia = blasts in marrow and often blood Chronic leukemia = mature appearing cells in marrow and blood

47 Lymphoma Classification Newer classification: REAL, WHO Take into account cell type (B vs. T) disease biology immunophenotype Cytogenetics

48 Lymphoma Classification Old classification: Working Formulation Classified according to clinical behaviour Low Grade Intermediate Grade High Grade

49 Staging Ann Arbor staging system 1974 I Involvement of single lymph node region (I) or of single extralymphatic organ or site (Ie( Ie) II Involvement of 2 or more lymph node regions on the same side of the diaphragm alone (II) or with involvement of limited, contiguous extralymphatic organ or tissue (IIe( IIe) III Involvement of lymph node regions on both sides of the diaphragm (III) which may include the spleen (IIIs( IIIs) ) or limited, contiguous extralymphatic organ or site (IIIe( IIIe) ) or both (IIIes( IIIes) IV Diffuse or disseminated foci of involvement of one or more extralymphatic organs or tissues, with or without associated lymphatic involvement

50 Etiology Chance Genetic Modifiers Environmental exposures MHC/Immune Sx. Carcinogen metabolism DNA Repair Inherited mutated alleles Stem cells Chance Genotoxic Ionizing Radiation Solvents Proliferative Stress Infection Toxins Diet Transforming viruses Mutations dominant clone Chance Acquired Modifiers Diet Infection Immunosuppression Leukaemia Chance Greaves, Lancet

51 Presentation Acute leukemia is always serious and life threatening Anemia: Pallor, lethargy, dyspnoea Leucopenia: Infection - mouth, skin, perianal region Thrombocytopenia: -bruising, menorrhagia, gum bleeding Hepatosplenomegaly is common Gum hypertrophy, skin infiltration

52 Differential Diagnosis Lymphadenopathy Hepatosplenomegaly Pancytopenia Infectious mono. or other viral infections, Lymphoma, Myelo or Lymphoproliferative disorders Autoimmune, Metabolic, storage disorders Aplastic anemia, Drug related, Hypersplenism, Myelodysplasia

53 Investigations: General FBC: Usually shows HB and platelets (maybe <20) WCC can vary <1.0 - > 200 x 10 9 /l, Abnormal differential, Film: Blasts Coag. Screening: Chemistry: Maybe abnormal LDH reflects tumor burden, renal failure, hyperuricemia Others: Chest x-ray, USD, Virology, LP, Blood C/S Initial evaluations are not only directed towards diagnosis but to initiate supportive measures for patients with advanced disease (Large mediastinal mass, Renal Failure, Very high WCC)

54 Investigations: Specific Morphology Immunophenotype Cytogenetics Molecular genetics

55 Immunophenotyping: Flowcytometery TdT HLA-DR CD34 Stem cell compartment CD7 CD3 CD19 CD22 CD13 CD33 T-ALL B-ALL AML

56 Treatment Supportive Care Red cell transfusion for anaemia Platelets transfusion for thrombocytopenia Vigorous treatment of infection Social and psychological support Hydration and treatment for hyperuricemia

57 Principles of therapy in ALL Remission induction Consolidation CNS prophylaxis Allogeneic BMT for high risk groups Maintenance

58 Treatment Outcome The most important factor to influence treatment outcome is AGE Continuous decline in CR from 95% in children to 40-60% in pts older than 60 Cytogenetics Overall CR in adults: 75% (63-86) leukemia Free Survival: 31% (13-44)

59 Childhood ALL

60 Chronic Lymphocytic leukemia Commonest leukemia in the western world Clonal proliferation of the B-LymphocytesB Disease of the elderly Younger patients now seen M:F ratio, 2:1 CLL is highly variable disorder 75% cases, diagnosis by chance on a routine blood test

61 Aetiology Cause unknown Not associated with radiation or exposure to occupational hazards Among the leukemias, CLL has the strongest tendency for familial incidence

62 Clinical Findings Asymptomatic: incidental finding Anaemia & thrombocytopenia Infections Weight loss, Night sweats, Fever (B Symptoms) Lymphadenopathy Splenomegaly AIHA (Auto immune haemolytic anaemia)

63 Binet system A: <3 lymphoid sites involved, Hb>10, Plts> 100 B: >3 lymphoid sites, Hb>10, Plts>100 C: Hb< 10, Plts <100, independent of lymph site involvement

64 Prognosis Late stage patients have usually progressive disease Highly Variable for early stage patients Significant subset of early stage eventually progress Refractory to treatment Infectious Complications Autoimmune complications

65 Treatment Watchful waiting First do no harm Single agents Alkylators: Chlorambucil, Cyclophosphamide Purine analogues: Fludarabine Monoclonal antibodies Rituximab (Anti CD20 antibody) Campath (Anti CD52 antibody) Combination Chemoimmunotherapy FCR Stem Cell Transplant

66 Hodgkin s s disease Incidence: 70/million pop Peak Incidence: years M>F: 1.4 Ethnic: 90% Caucasians Association with EB virus (NS)

67 Clinical features: HD Mass: neck, groin (axilla( axilla) Cough, shortness of breath B symptoms: Wt loss>10%, night sweats, pyrexia >38 Pruritus Alcohol induced pain Bone pain due to bone destruction Extreme tiredness

68 Investigations: HD FBC and ESR U&E, LFT, urate,, LDH β2m and CRP C-Tscan thorax and abdomen BMA and trephine (III and IV) ECHO Fertility issues: F and M

69 Stage I and IIA Management: HD (1) Involved field radiotherapy? Role for adjuvant chemotherapy

70 Management: HD (2) Stage IIB, III, IV Gold standard therapy-abvd Anthracycline (doxorubicin) Bleomycin Vinblastine Dacarbazine 6-88 cycles at 28 day intervals Escalated BEACOPP in high risk patients? Involved field radiotherapy for bulky disease

71 Relapsed/refractory HD PBSCT is treatment of choice Salvage rate 50-60% Salvage / priming chemotherapy ESHAP, IEV, VAPEC-B BEAM conditioning +/- DXT at 100 days

72 Low grade lymphoma Incidence: 30-50/million annually 50/million increasing by 4% Peak age: years M>F: 1-55 : 1 Geographical/ethnic variation Pesticide use, hair dyes Caucasian predominance

73 Clinical features: LG-NHL Mass: cervical, axilla,, inguinal Bone marrow failure B-symptoms Abdominal distension Odd presentations bone pain, rash,

74 Investigations: LG-NHL FBC and film Immunophenotype BMAsp and Tx Biochemistry, urate,, LDH Immunoglobulins C-T T scan of abdomen and thorax

75 Incurable: Median OS: Median OS: Management: FCCL after one relapse conventional rx 8-10 years 3 years Stage III/IV disease in >80% Use of molecular testing

76 Management: FCCL Stage I (molecular staging) Local DXT Other stages Watch and wait CVP if concern about bulky disease Rituximab CHOP Minimum therapy to control disease

77 Management: FCCL Patient <60 Allogeneic transplant Conventional vs NST Autologous PBSCT Early versus late harvest Avoid Chlorambucil Role of Rituximab Radioimunetherapy

78 Management: LG-NHL SLL (CLL) and LPL Chlorambucil Fludarabine Fludarabine combination (FCR) Hyperviscosity Immune dysfunction

79 Unanswered questions Role of transplantation Intensification of treatment Many previous re-incarnations! Rituximab at presentation Rituximab combinations

80 High-grade grade NHL Incidence: 50% All age groups, but increases with age CHOP: cure 40% of patients

81 Clinical features: HG-NHL Present with mass Atypical presentations occur Marrow involvement is rare Staging as for LG-NHL

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83 Management: DLCL Gold standard therapy: CHOP: 40% cure rate Gela trial >65 years R-CHOP: CR of 76% (vs( 63%) Stage I (reduced chemo+dxt) Salvage treatment BEAM PBSCT: salvage 40% patients

84 Mantle cell lymphoma 5-10% of NHL Middle aged to elderly males Stage IVB disease Combines worse features of LG and HG-NHL Median OS is 3 years Treat with hyper-cvad or FCR Transplant in first CR/PR

85 Leukaemic type - NHL Rare, <5% of lymphomas Acute Lymphoblastic lymphoma/burkitts Explosive presentation Acute abdomen Rapid onset dyspnoea/mediastinal Mass Common in young people Burkitts often associated with HIV Cure rate of 70% on gold standard therapy

86 Management: Multi-agent chemotherapy CODOX-M M / IVAC UKALL XII HyperCVAD CNS prophylaxis In-patient treatment: 4 months Role of transplantation?

87 Multiple Myeloma Terminally differentiated B cells Malignant plasma cells increasingly infiltrate the bone marrow and produce a monoclonal immunoglobulin Ig (M protein or a Ig chain) Incidence - Accounts for more than 10% of all haematological malignancies Increase in incidence at the rate of 2% per annum for Europe Incurable: : year survival with routine therapy 4-55 year survival with high-dose therapy

88 Investigations FBC U+E, Ca SPEP UPEP (Bence Jones Proteins) Serum Free Light chains Skeletal Survey MRI

89 What Causes Myeloma? Decline in the immune system Increases with age, 40% of patients around 60 yrs Genetic factors Higher incidence in African Americans Occupational exposures Agriculture, petrochemical, rubber & paint industries Radiation

90 Further Reading Case Based Haematology Cases 11, 12, 13, 14, 15