HAEMATOLOGICAL MALIGNANCY Benjamin Smeeton (Year 4)
• In an adult, all blood cells are produced in the red marrow.• Restricted to the bones of the axial skeleton (vertebrae, ribs, sternum, skull, sacrum, pelvis and femur).• In fetal life, the major haemopoietic tissues are: • Yolk sac (before 6 weeks). • Liver and spleen (6 weeks to 6-7 months).• In disease, the liver and spleen can again become haemopoietic, even in adult life (extramedullary haemopoiesis).
• The same basic pathological mechanism underpins a large number of haematological malignancies.• Essentially, a haemopoietic stem cell in the BM acquires genetic mutations which disrupt the normal differentiation and maturation of its progeny.• The resulting disease depends on how these mutations affect the differentiation pathway.
Undifferentiated Differentiated Normal Abnormaldifferentiation differentiation Lymphomas
• Characterised by the presence of large numbers of undifferentiated blood cells (blasts) in the BM.• These immature cells rapidly overwhelm the normal developing blood cells and spill out into the peripheral blood.• Clinical features reﬂect the consequences of bone marrow failure.• Highly aggressive and rapidly fatal without treatment (6-12 weeks). • Sudden onset of marrow failure• Types: (pancytopenia). - Fatigue and lethargy (↓RBCs) • ALL - acute lymphoblastic leukaemia - Infections (↓WBCs) • AML - acute myeloid leukaemia - Bleeding, bruising and purpura (↓Plts) • Bone pain (esp. in children)• Diagnosis requires the presence of > 20% blasts in • Lymphadenopathy the blood or bone marrow. • Splenomegaly
• ALL (acute lymphoblastic leukaemia): • Commonest childhood cancer (peak incidence at age 2-4 years) • Modern treatment has improved prognosis signiﬁcantly (4 stages - induction, consolidation, CNS prophylaxis, and maintenance) • Male gender and age > 10 years represent negative prognostic factors.• AML (acute myeloid leukaemia): • Sudden onset of marrow failure • May occur at any age, but becomes increasingly (pancytopenia). common in older people. - Fatigue and lethargy (↓RBCs) • Down’s syndrome = 400x greater incidence. - Infections (↓WBCs) - Bleeding, bruising and purpura (↓Plts) • Poor prognosis, patients over the age of 70 • Bone pain (esp. in children) rarely survive beyond 1 year. • Lymphadenopathy • Splenomegaly
• Commonest leukemia in adults.• Characterised by the accumulation of small mature B lymphocytes in the BM and peripheral blood (smear cells).• Unknown aetiology.• Peak incidence 60-80 years; male 2:1 female.• A watch and wait policy is usually appropriate for many patients.• Around 10% develop a high-grade non-Hodgkin • Slow and indolent, many asymptomatic at diagnosis lymphoma, which is refractory to treatment and • Isolated lymphocytosis (↑WBCs) carries a very poor prognosis (Richter’s syndrome). • Anaemia (tiredness and fatigue) • Recurrent infections • Autoimmune phenomena (AIHA, ITP) • Lymphadenopathy (late) • Bone marrow failure (late)
• A group of neoplastic disorders characterised by the overproduction of normal myeloid cells.• Occur mostly in the elderly.• Caused by a genetic abnormality which bestows a proliferation advantage to one or more myeloid cell lineages.• Types: • Chronic myeloid leukaemia (↑neutrophils) • Polycythaemia vera (↑RBCs) • Essential thrombocythaemia (↑Plts) • Primary myeloﬁbrosis (↑Megakaryocytes)• Diagnosis is difﬁcult as blood cell overproduction can often be a normal physiological response.
• CML is the most common myeloproliferative disorder.• Very rare in children; incidence increases with age.• Examination of the peripheral blood reveals large numbers of neutrophils and neutrophil precursors.• Associated with the Philadelphia chromosome. • 95% possess the t(9;22) translocation. • The translocation produces an abnormal fusion gene, BCR-ABL, which generates a protein with • Pallor excessive tyrosine kinase growth signaling • Night sweats properties. • Fatigue, weight loss and anorexia. • Massive splenomegaly• Tx. imatinib (tyrosine kinase inhibitor - not curative). • Begins with a ‘chronic’ phase (5 years) which then spontaneously transforms into a ‘blast’ crisis with fulminant bone marrow failure.
• Increased production of RBCs.• Excess proliferation of other myeloid lineages is usually seen (↑neu ↑plts).• Rarely presents before age 40.• 90% of cases associated with a mutation in the erythropoietin signaling pathway (JAK-2).• The key to diagnosis is the exclusion of a secondary physiological erythrocytosis. • Chronic hypoxia (e.g. lung disease) • Plethora (red face) • Erythromelalgia (burning red skin) • ↑EPO secretion (e.g. RCC, PCKD) • Pruritus (particularly after hot baths)• Thrombosis is a serious risk. • Hepatosplenomegaly • Headache, dizziness and stroke (↑• With treatment (venesection), patients often survive blood viscosity). 10 years; most die from thrombosis / haemorrhage. • Mesenteric, portal or splenic vein thrombosis.
• Increased production of platelets (megakaryocyte cell line).• Platelet count > 600 x 109/L (normal = 150-400)• Difﬁcult to differentiate from reactive causes of thrombocytosis (e.g. infection, malignancy).• 50% possess JAK-2 mutation.• Usually affects older patients; presents with thrombotic or bleeding complications.• An indolent condition with a median survival of • Many asymptomatic (25%) • Erythromelalgia and digital ischaemia 12-15 years. (intense burning and pain)• Rarely transforms into an acute leukaemia. • Stroke • Recurrent abortions and fetal growth retardation • Hepatic and portal vein thrombosis (e.g. Budd-Chiari syndrome)
• Overproliferation of megakaryocytes which release ﬁbroblast-stimulating factors (e.g. platelet-derived growth factor).• Usually presents age 50+• These factors stimulate marrow stromal cells to lay down ﬁbrous tissue in the BM.• The marrow space becomes obliterated resulting in extramedullary haematopoiesis.• Immature nucleated RBCs and neutrophils enter the • Hepatosplenomegaly and pallor peripheral blood (leukoerythroblastosis). • Splenic pain • Constitutional symptoms (weight• Distorted RBCs (teardrop cells) and a ‘dry tap’ on loss, night sweats, fever) trephine needle biopsy are typical. • Anaemia symptoms (SOB, fatigue, palpitations)• Very poor prognosis, 3-5 years. • Gout (increased cell turnover = hyperuricaemia)
• A malignant disease of plasma cells in the BM.• Unknown aetiology.• Generalised BM involvement; although areas of greatest haematopoietic activity (vertebrae, ribs and skull) are predominantly affected.• Malignant plasma cells produce a single non- functioning monoclonal immunoglobulin (paraprotein) in large quantities.• The abnormal plasma cells also produce free immunoglobulin light chains, which are readily ﬁltered and excreted by the kidneys (Bence-Jones protein).
• Clinical features: • Bony destruction: proliferating plasma cells stimulate osteoclast activity (lytic lesions). • Immunosuppression: production of normal immunoglobulins is impaired, leading to immune paresis (recurrent infections). • Renal failure: free light chains produced by the malignant cells become trapped in the renal tubules resulting in kidney damage.• Diagnosis: • Peak age 50-60 years. • Bone destruction / pain • Serum electrophoresis (serum paraprotein) • Renal failure • Urine electrophoresis (Bence-Jones protein) • Bone marrow failure • Bone marrow aspirate (demonstrates plasma cell • Immunodeﬁciency inﬁltration). • Hypercalcaemia • Amyloidosis (peripheral neuropathy, cardiomyopathy etc)
• The same basic pathological mechanism underpins a large number of haematological malignancies.• Using knowledge of haematopoiesis, the haematological malignancies can be categorised into: • Acute leukaemias • Chronic leukaemias • Myeloproliferative disorders • Others (e.g. myeloma)• In part two of this series, we will be covering the topic of lymphoma.
(1)A 63 year old female presents to her GP with general fatigue and lethargy of 6 months duration. She suffers from HTN, but is otherwise well. A FBC reveals ↑WBCs and ↓Hb (iron, B12 and folate are normal). The doctor orders a blood ﬁlm. Examination of the blood ﬁlm reveals large reticulocytes and damaged red cells. The presence of characteristic smear cells is also noted. What is the most likely diagnosis?a) Acute myeloid leukaemiab) Multiple myelomac) Iron deﬁciency anaemiad) Chronic lymphocytic leukaemiae) Essential thrombocythaemia
(2)A 4 year old boy presents with his mother. His mother explains he has had a widespread rash for 7 days and that he has been ‘somewhat lethargic’ for the last 2 weeks. O/E: he is pale, with a widespread purpuric rash but there is no fever or meningism; generalised non- tender lymphadenopathy and splenomegaly are also noted. A FBC reveals ↓WCC, ↓Hb, ↓Plts and a blood ﬁlm is ordered. Examination of the blood ﬁlm reveals blast cells. What is the most likely diagnosis?a) Bacterial meningitisb) Acute myeloid leukaemiac) Acute lymphoblastic leukaemiad) Chronic lymphocytic leukaemiae) Essential thrombocythaemia
(3)A 65 year old man presents to his GP with intermittent headache and dizziness of 6 months duration. He has also noted an unpleasant burning sensation in his hands and feet, especially when he is in the shower. O/E: both his big and ﬁrst toes of his right foot are dusky in colour and tender to touch. What single pathological process is most likely to account for his symptoms?a) Bone marrow failureb) Plasma cell proliferationc) Chronic haemolysisd) Chronic lymphocytic leukaemiae) Myeloproliferation
(4)A 58 year old farmer presents with severe upper arm pain having suffered a trivial fall at home. He also complains of lower back pain and signiﬁcant lethargy for the last 6 months. O/E: he is notably pale with a pulse of 120 bpm, with a visibly inﬂamed and painful upper left arm. He is also considerably kyphotic. Urinalysis is +++ for protein. What is the most likely haematological diagnosis?a) Multiple myelomab) Grave’s diseasec) Chronic lymphocytic leukaemiad) Primary myeloﬁbrosise) Essential thrombocythaemia