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1. Sarah Lawrence and Oscar Swift

2.  Brief overview of the haematological system  Leukaemias  Lymphomas  Myelomas and other paraproteinaemias  SBAs

4.  Patients present with pancytopaenia  Symptoms of anaemia  Infections  Bleeding  NB AML M3 presents with DIC!  Diagnosis to death 6-12 weeks if untreated  Chemosensitive  Best initial test is blood smear  Blast cells present  WCC can be low, normal or high

6.  Patients present more insidiously  SBA tip – if patient presents at a ‘routine check-up’ answer is much more likely to be chronic leukaemia  Less likely to present with pancytopaenia  Diagnosis to death 6-12 years if untreated  Less chemosensitive  Best initial test is full blood count  WCC always high  Look at white cell differential  ‘Smudge’ cells in CLL on smear

9. Classification of leukaemia •Acute lymphoblastic leukaemia (ALL) •Chronic lymphoblastic leukaemia (CLL) •Acute myeloid leukaemia (AML) •Chronic myeloid leukaemia (CML)

10. Classification of leukaemia •Acute lymphoblastic leukaemia (ALL) •Chronic lymphoblastic leukaemia (CLL) •Acute myeloid leukaemia (AML) •Chronic myeloid leukaemia (CML) By onset and progression

11. Classification of leukaemia •Acute lymphoblastic leukaemia (ALL) •Chronic lymphoblastic leukaemia (CLL) •Acute myeloid leukaemia (AML) •Chronic myeloid leukaemia (CML) By cell type

12. Classification of leukaemia ALL/CLLAML/CML

13. Proliferation of progenitor cells in the bone marrow results in replacement of normal haematopoeitic cells and bone marrow failure.

17. Risk factors •Acquired -Cytotoxic chemotherapy -Haematological e.g. myelodysplasia (AML) •Inherited -DNA repair defects, immune defects -Other e.g. Down syndrome

18. Investigations in leukaemia •History and examination •Bloods -FBC (anaemia, thrombocytopenia, hyperleukocytosis, neutropenia) -Smear (blasts, dysplastic neutrophils (2º AML)) -U&Es (hyperuricaemia) -LDH -Clotting screen -LFTs, BUN/creatinine ratio -Septic screen (if infection suspected)

19. •Imaging -CXR, CT (pneumonia, mediastinal mass, lytic bone lesions) •BM biopsy -Flow cytometry, cytogenetics and immunohistochemistry ->30% blasts

20. Also known as ‘lymphocytic’. Epidemiology •Incidence = 1/50,000. Slight male predominance. •Commonest type of childhood leukaemia (70%) •Peak age 2-5 years, but later increase >50.

21. Pathophysiology Formation of fusion genes  dysregulation of proto-oncogene e.g. TEL-AML1 (25%). 85% are derived from B-cell precursors.

22. Findings specific for ALL •Examination -Lymphadenopathy -Splenomegaly (10-20% presentation) -CNS signs- more likely •Bloods -Anaemia- usually severe, signs present -WBCs- variable, usually neutropenia -Smear- smallish basophilic blasts, few granules, hand-mirror cells -Clotting- 10% ALL presents with DIC •Imaging -Mediastinal mass in some T cell ALL

23. Small basophilic blasts with few granules Hand mirror cells

24. Also known as ‘myelogenous’. Epidemiology •Incidence = 3.7/100,000. Slight male predominance. •Commonest type of adult leukaemia (90%) •Can occur at any age but median is 70 years

25. Pathophysiology Two classes of mutations may be required, similar to ALL:

26. Findings specific for AML •Examination -Lymphadenopathy unusual -Leukaemia cutis (10%), chloroma (rare) •Bloods -Anaemia- usually severe, signs present -WBCs- variable, usually neutropenia -Smear- Auer rods in large hypergranular myeloblasts -Hypokalaemia in monocytic leukaemia -Clotting- DIC commoner in acute promyelocytic leukaemia (M3)

27. Auer rods, oddly shaped, increased N:C

28. Treatment of acute leukaemia Supportive: Problem Anaemia Thrombocytopenia DIC Infection Tumour lysis syndrome CNS prophylaxis Treatment Packed RBCs Platelets (if <10) FFP, cyroprecipitate Antibiotics, reverse barrier nursing Allopurinol/uricase Intrathecal chemo e.g. methotrexate, cytarabine

30. Definitive Chemotherapy: •Induction 4-6w •Consolidation •Maintenance (ALL only) 1-2y -Longer in boys Other •Add in all-trans-retinoic-acid (ATRA) in PML during induction •Monoclonal Ab •CNS radiotherapy •BM transplantation

31. Prognosis of acute leukaemia 5 year survival rates •ALL -Children- 75% -Adults- 40% -Worse if <1 or >60, high WBC, >4w to remission •AML -30-50% -Better if BM Tx, children, worse if >60 Prognosis of acute leukaemia 5 year survival rates •ALL -Children- 75% -Adults- 40% -Worse if <1 or >60, high WBC, >4w to remission •AML -30-50% -Better if BM Tx, children, worse if >60

32. Classification of leukaemia ALL/CLLAML/CML

34. Risk factors •Acquired -Radiation (CML) -Immunodeficiency e.g. HIV/AIDS, post-transplant -Pesticides •Inherited -Family history (CLL)

35. 98% develop from B cells. Epidemiology •Incidence = 4.2/100,000. Slight male predominance. •Most common form of leukaemia in the West •Usually >55, median age 72, rare <40.

36. Pathophysiology Largely unknown with no specific genetic abnormalities.

37. Findings specific for CLL Usually asymptomatic! • Examination -Lymphadenopathy/splenomegaly present in late disease. • Bloods -WBCs- extremely high -Smear- lymphocytosis with ‘smudge/basketball cells’ • Other -Richter’s syndrome -Prolymphocytic transformation

38. Smudge cells- destruction of fragile lymphocytes during smear

39. Stepped-up production of granulocytes and their precursors and failed apoptosis leads to insidious progression towards a blast crisis. Epidemiology •Incidence= 0.6-2/100,000 •Can occur at any age but rare in children. Peak incidence at 40-60 •Less common than AML, CLL

40. Pathophysiology 95% involve t(9;22)(q34;q11) translocation, resulting in the Philadelphia chromosome. This forms a fusion gene- BCR-ABL1 with constitutively active tyrosine kinase activity.

41. Findings specific for CML Usually asymptomatic! •Examination -Splenomegaly- may be only feature at latent phase, massive later on •Bloods -Anaemia- mild, worsens with progression -WBCs- extremely high -Smear- leukocytosis with granulocyte left-shift

42. Leukocytosis, increased numbers of banded neutrophils

43. Treatment of chronic leukaemia CLL •Watchful waiting with regular monitoring •Chemotherapy. Indications: -Severe systemic symptoms -Non-pred-responsive AI anaemia/thrombocytopenia -Progressive splenomegaly/lymphadenopathy -Increased WBC/reduced ‘doubling time’ Treatment of chronic leukaemia

44. CML •Imatinib -Tyrosine kinase inhibitor, targets BCR-ABL1. Greatly increases 5 year survival compared to older drug therapies -Initial treatment, continued indefinitely if optimal response.

45. Other: •Monoclonals •Surgery -Splenectomy for splenomegaly or pancytopenia •Radiotherapy -Pallative for bulky LN or splenomegaly

46. Prognosis of chronic leukaemiaPrognosis of chronic leukaemia •CLL -Binet Staging -Median approx. 10 years with terminal progressive phase for 1-2 years •CML -Overall 5 year survival with imatinib now 89% (or more?) BM transplant is the only curative therapy

47. Acute Chronic Lymphocytic Myelocytic Lymphocytic Myelocytic Age Childhood Any Middle/Old Middle Raised WBC +/- +/- ++ ++ Anaemia ++ ++ +/- + Thrombocytopenia + + +/- - Lymphadenopathy + +/- + - Splenomegaly + +/- + ++ Other CNS involvement Maintenance required Hand mirror cells Auer rods APL Leukaemia cutis Haemolytic anaemia Hypogammagl obulinaemia Smudge cells Low ALP Ph chromosom e targeted by imatinib Blast phase

48.  Non leukaemic malignancies  Polycythaemia vera  Essential thrombocythaemia  Mastocytosis  Form part of a spectrum with CML  All are closely related to each other  Associated with JAK2 mutations

51.  Clinical features  Night sweats  Hyperviscosity symptoms  Pruritus after a hot bath  Plethoric face  Splenomegaly  Haemorrhage  Hypertension  Gout

52.  Important lab features  Increased Hb, HCT, Red cell mass  Low serum EPO  JAK2 mutation in 95%  Treatment  Venesection  Cytotoxic myelosuppression  Hydroxyurea  Busulphan

53. Lymphoma

54. What’s the difference between leukaemia and lymphoma?

56. Hodgkin’s lymphoma Originates from B cells in the germinal centres of lymphoid tissue and is characterised by orderly spread from one LN group to another. Epidemiology •Incidence = 2.2/100,000, 30% of all lymphoma •Bimodal distribution with peaks at 15-30 and >50 years •Slight male predominance

57. Risk factors •Acquired -HIV/AIDS- increases with CD4 count -Previous non-Hodgkin’s lymphoma -Autoimmune conditions •Inherited -Immune defects -Family history of H/non-H lymphoma, CLL

58. Pathogenesis Some proliferation of malignant Reed-Sternberg cells (probably of B cell lineage) and abnormal mononucleocytes.

59. Presentation •Painless non-tender rubbery enlarged LN -Cervical involvement in 60-70%, axillary in 10- 15%, inguinal in 6-12% -May increase/decrease in size spontaneously -May become ‘matted’ and non-mobile -Contiguous progression to nearby groups -Alcohol-induced pain •Systemic symptoms -Especially fever (30%), may be cyclic -And severe pruritis (25%) •Other -Early satiety due to splenomegaly

60. Investigations •FBC -Exclude leukaemia, mononucleosis •ESR/CRP •LFTs •U&Es •CXR -Lymphadenopathy, mediastinal expansion •CT -Thorax, abdomen for staging •BM biopsy •Other -HIV, Monospot, LDH, thoracentesis, PET, LP, MRI

61. •Lymph node USS and excision biopsy Important to see the architecture of the LN!

63. Ann-Arbour staging Automatic stage IV if extranodal involvement. Systemic symptoms = B, extranodal = E, >10cm = X, splenic involvement = S

64. Treatment Supportive •Fertility •Cardiac function •Respiratory function •Tumour lysis syndrome •Others, as indicated (see leukaemias slide)

65. Treatment Definitive •IA/IIA -Radiotherapy alone- affected nodes and prophylatically -Chemo with radiotherapy of affected nodes •IB/IIB/III/IV -Chemo •BM transplant -If still progressive despite chemo or after induction of remission after relapse

66. Non-Hodgkin’s lymphoma A heterogeneous group of lymphoid tumours, mostly of B cell origin. Characterised by irregular pattern of spread and common extranodal disease, they vary in their aggressiveness. Epidemiology •Incidence = 17/100,000 •Median age is >50 •Diffuse large B cell and follicular commonest

67. Risk factors •Acquired -Infection e.g. EBV (Burkitt’s, sinonasal), HTLV-1 (T cell), HCV, HHV8 (Kaposi’s), H. pylori (gastric MALT) -Previous chemotherapy/Hodgkin’s -Autoimmune disorders e.g. Sjogren’s, Hashimoto’s -Immunodeficiency e.g. post-transplant, HIV/AIDS •Inherited

68. Pathogenesis

69. Presentation •Painless non-tender rubbery enlarged LN -Non-contiguous progression •Systemic symptoms -Commoner in high-grade •Rash -Cutaneous involvement e.g. mycosis fungoides, anaplastic large- cell etc. •Abdominal pain, early satiety -Splenomegaly but unusual as rarely massive -Hepatomegaly •Mass -Testicular -GI, symptoms of obstruction •Shortness of breath, pleuritic chest pain, SVC syndrome -Mediastinal mass in high grade •Neurological -Primary CNS lymphoma, commoner in immunosuppressed

70. Investigations •FBC -Anaemia, thrombocytopenia, neutropenia -Thrombocytosis, lymphocytosis may occur •ESR/CRP •LFTs •U&Es -Obstructive nephropathy, hypercalcaemia •Serology -HIV, HTLV-1, HCV •Imaging -CXR-Intrathoracic lymphadenopathy, mediastinal expansion -CT-Thorax, abdomen for staging -Bone scan -PET -MRI- Brain, cord -USS- Scrotum •BM biopsy -Should always be carried out

71. •Lymph node USS and excision biopsy

72. Treatment •Low grade -Localised (rare)- radiotherapy, surgery -Disseminated- watch and wait or chemo when symptomatic/organ dysfunction -Gastric MALT- associated with H pylori, antibiotic therapy curative in 90% •High grade -Aggressive chemo e.g. CHOP -Maintenance not needed -Allogenic stem cell transplantation -CNS prophylaxis in very high grade e.g. Burkitt’s

73. Prognosis of lymphoma 5 year survival rates •Hodgkin’s- highly curable -I/II- 90% -IV- 65% -Long-term sequelae of treatment •Non-Hodgkin’s- vary widely (see IPI) -Overall 63% -Indolent follicular lymphoma I/II- 91% but may not be curable -DLBLC- curable with aggressive chemo

74.  Multiple Myeloma  MGUS  Waldenstrom’s macroglobulinaemia  (Non-Hodgkin lymphoma)  (CLL)

75.  Presdisposing factors  Radiation  Benzene  Pesticides  Epidemiology  4 per 100,000 per year  Median age 66 years  Pathophysiology  Post germinal centre B cell proliferation  Monoclonal antibody

77.  Hypercalcaemia  Renal impairment  Anaemia  Bone disease  Hyperviscosity  Amyloidosis (AL)  Infection (recurrent)

84.  Amyloid L – Ig light chains  paraproteinaemias  Amyloid A – Protein A  Chronic inflammation  Amyloid TTR – Transthyretin  Transthyretin abnormality  Polyneuropathy,  Restrictive cardiomyopathy  Amyloid B2M – Beta 2 microglobulin  Occurs in dialysis  Carpal tunnel

86.  Hypercalcaemia  Renal impairment  Anaemia  Bone disease  Hyperviscosity  Amyloidosis (AL)  Infection (recurrent)

87.  FBC and film  ESR  Urine dipstick  24 hour urine collection  U&Es  Urate  Albumin, calcium, phosphate, ALP  Serum and urinary electrophoresis  Serum Ig  X-ray 

88. 1. Production of a single monoclonal antibody (paraprotein)  ‘M’ band in γglobulin region on serum/ urine electrophoresis 2.Increased clonal plasma cells in the bone marrow  >20% monoclonal plasma cells on bone marrow biopsy 3. Evidence of organ damage (‘CRAB HAI’)

90.  Prognosis  MM remains an incurable disease  Mean survival 3-4 yrs from diagnosis  Treatment  Specific  Supportive

91.  Intensive or non intensive  Intensive if <65  Non intensive if >65  Intensive  4-6 cycles chemotherapy  Cyclophosphamide, dexamethasone, thalidomide  THEN autologous stem cell collection and transplant  Non-intensive  Chemo: Melphalan and cyclophosphamide

92.  Renal disease  rehydration – 3L/day  Bone disease  Bisphosphonates  Radiotherapy to bony lesions  Corticosteroids  Anaemia  Transfusion/ EPO  Hyperviscosity  Plasmapheresis  Infection

93.  Post germinal centre B cell proliferation  Monoclonal antibody/ paraprotein production  M Band  BJP  >20% monoclonal plasma cells in BM  ‘CRAB HAI’  Specific and supportive treatment  Outcome still poor

94.  Often discovered incidentally in elderly  Benign  Characterised by:  Low levels of paraprotein, normal levels of Ig  <10% plasma cells in bone marrow  Absence of lytic bone lesions  Absent/minimal urinary BJP  Absence of end organ damage associated with MM  1% per year develop MM

95.  Lymphoplasmacytoid proliferation  Similarities with CLL  IgM paraprotein  Plasma viscosity  Organomegaly and lymphadenopathy more common than in MM  No end organ damage (cf MM)

97. A 66 year old man has a FBC done whilst being tested for hypercholesterolaemia and was found to have a WBC of 15.4x109 /L with the rest of the count otherwise normal. The most likely diagnosis is: a)Infectious mononucleosis b)CMV infection c)ALL d)Pertussis e)Chronic lymphocytic leukaemia e)

98. A 46 year old woman presents with weight loss and abdominal enlargement. She has also noticed she is sweating more than normal and her temperature is 38C. She is found to have hepatosplenomegaly (liver 2cm below RCM, spleen 6cm below LCM). Lymph nodes are not enlarged. FBC shows: WBC 98x109 /L, Hb 8.3g/L, Plts 504x109 /L. A blood smear was performed.

100. The blood smear shows increased numbers of neutrophils, eosinophils and basophils. In addition, there are increased numbers of promyelocytes (but infrequent blast cells). What is the optimum treatment for this patient? a)Allogenic stem cell transplantation b)Combination chemo c)Imatinib d)Blood transfusion to relieve symptoms e)Rifampicin and isoniazid c) (CML)

102. Which ONE of these is the most likely clinical presentation of a child with acute lymphoblastic leukaemia? a) A 6 month history of fatigue and repeated upper respiratory tract infection b) Poor appetite and abdominal pain resulting from swollen spleen c) Swollen gums in the mouth d) Recent history of bruising and tiredness e) None- incidental finding d) Anaemia and thrombocytopenia common

104.  A 67 year old lady is found to have an Hb of 18.9g/dL. Her erythropoeitin level is markedly raised. Which of the following is the least likely diagnosis?  A) COPD  B) Eisenmenger’s syndrome  C) Polycythaemia vera  D) Renal cell carcinoma  E) Nepalese woman living at high altitude

105.  A 67 year old lady is found to have an Hb of 18.9g/dL. Her erythropoeitin level is markedly raised. Which of the following is the least likely diagnosis?  A) COPD  B) Eisenmenger’s syndrome  C) Polycythaemia vera  D) Renal cell carcinoma  E) Nepalese woman living at high altitude

106. Which ONE of these is NOT TRUE regarding the Reed-Sternberg cell in Hodgkin’s lymphoma? a) It is thought to be of B cell lineage‐ b) It is multinucleate c) It represents the majority of cells in a lymph node of Hodgkin's lymphoma d) It usually expresses CD15 and CD30 e) Their absence has a high negative predictive value c) Near-pathogonomic but in the minority of cells

107. A 6 year old boy from Kenya develops swelling of the jaw. The mass responds rapidly to chemotherapy. What is the most likely diagnosis? a) Burkitt's lymphoma b) Follicular lymphoma c) Mycosis fungoides d) Lymphoblastic lymphoma e) Enteropathy-associated T cell lymphoma a) Burkitt’s lymphoma occurs in the context of chronic malaria infection causing reduced immunity to EBV. Also associated with AIDS.

108.  A 59 year old man receiving chemotherapy for Non Hodgkin’s Lymphoma develops painful haematuria. Which of the following is the most likely cause of his symptoms?  A) Rituximab  B) Cyclophosphamide  C) Adriamycin (doxorubicin/ hydroxydaunarubicin)  D) Vincristine (oncovin)  E) Prednisolone

109.  A 59 year old man receiving chemotherapy for Non Hodgkin’s Lymphoma develops painful haematuria. Which of the following is the most likely cause of his symptoms?  A) Rituximab  B) Cyclophosphamide  C) Adriamycin (doxorubicin/ hydroxydaunarubicin)  D) Vincristine (oncovin)  E) Prednisolone

110. Pulmonary fibrosis  Busulfan  Bleomycin  Cardiotoxicity  Adriamycin (doxorubicin)  Haemorrhagic cystitis  Cyclophosphamide  Peripheral neuropathy  Vincristine (oncovin)  Vinblastine

111.  A 63 year old woman is about to commence chemotherapy for treatment of MM. Which of the following medications should she be started on prior to chemotherapy?  A) Colchicine  B) Dexamethasone  C) Diclofenac  D) Allopurinol  E) Hydroxychloroquine

112.  A 63 year old woman is about to commence chemotherapy for treatment of MM. Which of the following medications should she be started on prior to chemotherapy?  A) Colchicine  B) Dexamethasone  C) Diclofenac  D) Allopurinol  E) Hydroxychloroquine

113.  Malignant cells release intracellular contents after the first dose of chemotherapy  Hyperkalaemia  Hyperuricaemia  Renal failure  Allopurinol inhibits xanthine oxidase and prevents hyperuricaemia  Large volumes of fluid should be given pre-chemo to prevent renal failure

114.  Which one of the following is not consistent with a diagnosis of MGUS?  A) normal urinalysis  B) normal renal function  C) 20% plasma cells in bone marrow  D) Normochromic, normocytic anaemia with Rouleaux formations  E) Absence of lytic bone lesions

115.  Which one of the following is not consistent with a diagnosis of MGUS?  A) normal urinalysis  B) normal renal function  C) 20% plasma cells in bone marrow  D) Normochromic, normocytic anaemia with Rouleaux formations  E) Absence of lytic bone lesions

116.  A patient has a sharp M band on serum electrophoresis. Which of the following is least consistent with this result?  A) IgG MM  B) Waldenstrom’ macroglobulinaemia  C) AA amyloidosis  D) MGUS  E) CLL

117.  A patient has a sharp M band on serum electrophoresis. Which of the following is least consistent with this result?  A) IgG MM  B) Waldenstrom’ macroglobulinaemia  C) AA amyloidosis  D) MGUS  E) CLL

118.  Brief overview of the haematological system  Leukaemias  Lymphomas  Myelomas and other paraproteinaemias  SBAs

119.  http://www.med- ed.virginia.edu/courses/path/innes/wcd/lym pleuk.cfm  http://www.umm.edu/patiented/articles/ly mphomas_non-hodgkins_000084.htm  http://www.essentialhaematology6.com  http://www.youtube.com/watch? v=xWf8gvTF6hw&feature=related  Watch from ~20 mins onwards

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