The Non-leukaemic Malignant Disorders

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The Non-leukaemic Malignant Disorders

• Ahmad Sh. Silmi
• Msc Haematology, FIBMS

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Definition

• The Non-leukaemic Malignant Disorders are
  originally defined, as an amorphous group of
  malignant disorders which are characterized by
  the uncontrolled clonal proliferation of bone
  marrow derived cells.

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Classification

• 1. The malignant myeloproliferative disorders,
  which include
• Primary proliferative polycythaemia (PPP)
• Primary thrombocythaemia
• Myelofibrosis
• 2. The malignant lymphoproliferative disorders,
  which include
• Multiple myeloma (MM) and related plasma cell
  disorders.
• Hodgkin's disease (HD)
• Non-Hodgkin's lymphomas

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• The Non-leukaemic Myeloproliferative Disorders

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Introduction

• Hemopoietic stem cell disorder
• Clonal
• Characterized by proliferation
• Granulocytic
• Erythroid
• Megakaryocytic
• Interrelationship between
• Polycythaemia
• Essential thrombocythaemia
• myelofibrosis

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Clonal evolutionClonal evolution stepwise
progression to fibrosis, marrow failure or acute
blast phase
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1- Primary Proliferative Polycythaemia

• Primary proliferative polycythaemia is a
  malignant disorder of haemopoietic stem cells,
  which is characterized by absolute erythrocytosis
  and, a moderately increased granulocyte count and
  platelet count.
• It may occur at any age, but is predominantly a
  disease of middle age the median age at
  diagnosis is 55 years. Males are affected
  slightly more commonly than female.

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Polycythaemia vera(Polycythaemia rubra vera)

• Polycythaemia vera is a clonal stem cell disorder
  characterised by increased red cell production
• Abnormal clones behave autonomous
• Same abnormal stem cell give rise to granulocytes
  and platelets
• Disease phase
• Proliferative phase
• Spent post-polycythaemic phase
• Rarely transformed into acute leukemia

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Recognition and classification of the
polycythaemia

• Definition of polycythemia
• Raised packed cell volume (PCV / HCT)
• Male gt 0.51 (50)
• Female gt 0.48 (48)
• Alterations in the PCV can be caused by
• Reduction in plasma volume.
• True increase in red cell numbers.

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Classification

• Absolute
• Primary proliferative polycythaemia
  (polycythaemia vera)
• Secondary polycythaemia
• Idiopathic erythrocytosis
• Apparent
• Plasma volume or red cell mass changes

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Polycythemia

• True / Absolute
• Primary Polycythemia
• Secondary Polycythemia
• Epo dependent
• Hypoxia dependent
• Hypoxia independent
• Epo independent
• Apparent / Relative
• Reduction in plasma volume

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Absolute Polycythaemia

• Causes
• Malignant transformation, which frees the
  haemopoietic stem cells from hormonal control.
• Hypoxic effect.
• Physiologically inappropriate stimulation of
  erythropoietin release.
• Thus the polycythaemias are large and diverse
  group of disorders, only one member of which,
  PPP, is a malignant disorder. However, an
  understanding of all types of polycythaemia is
  essential because recognition of PPP largely is
  based upon exclusion of the other types.

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Causes of secondary polycythemia

• ERYTHROPOIETIN (EPO)-MEDIATED
• Hypoxia-Driven
• Chronic lung disease
• Right-to-left cardiopulmonary vascular shunts
• High-altitude habitat
• Chronic carbon monoxide exposure (e.g., smoking)
• Hypoventilation syndromes including sleep apnea
• Renal artery stenosis or an equivalent renal
  pathology
• Hypoxia-Independent (Pathologic EPO Production)
• Malignant tumors
• Hepatocellular carcinoma
• Renal cell cancer
• Cerebellar hemangioblastoma
• Nonmalignant conditions
• Uterine leiomyomas
• Renal cysts
• Postrenal transplantation
• Adrenal tumors
• EPO RECEPTORMEDIATED

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Secondary polycythaemia

• Polycythaemia due to known causes
• Compensatory increased in EPO
• High altitude
• Pulmonary diseases
• Heart dzs eg- cyanotic heart disease
• Abnormal hemoglobin- High affinity Hb
• Heavy cigarette smoker
• Inappropriate EPO production
• Renal disease-carcinoma, hydronephrosis
• Tumors-fibromyoma and liver carcinoma

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Secondary Polycythaemias

• Causes
• Physiologically appropriate release of
  erythropoietin.
• Physiologically inappropriate release of
  erythropoietin.

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1- Physiologically appropriate release of
erythropoietin.

• A persistently low atmospheric oxygen tension
• As in high altitude
• Inadequate uptake of atmospheric oxygen as in
• chronic bronchitis
• emphysema
• pulmonary fibrosis,
• pulmonary oedema
• Defective transport of absorbed oxygen from the
  lungs This occurs in the following
  abnormalities
• A variety of inherited and acquired defects of
  haemoglobin function.
• Metabolic defects, which limit the effectiveness
  of oxygen transport, include methaemoglobin
  reductase deficiency and 2,3 DPG deficiency.
• Heavy smoking, which affect the haemoglobin
  function.

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2- Physiologically inappropriate release of
erythropoietin

• A variety of disorders are associated with
  inappropriate release of erythropoietin occurs as
  a rare complication of renal disorders such as
• polycystic kidneys.
• chronic glumerulonephritis.
• Hydronephrosis.
• renal tumours.
• extrarenal tumours such as hepatoma and bronchial
  carcinoma.

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Secondary polycythaemia

• Arterial blood gas
• Hb electrophoresis
• Oxygen dissociation curve
• EPO level
• Ultrasound abdomen
• Chest X ray
• Total red cell volume(51Cr)
• Total plasma volume(125 I-albumin)

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Apparent Polycythaemia

• Apparent polycythaemia is defined as those cases
  where an increased venous PCV is not explained by
  an increased red cell mass (RCM) but by a
  reduction in the plasma volume (PV), or by the
  combination of an RCM towards the upper limit of
  normality and a PV towards the lower limit of
  normality.
• Apparent polycythaemia is by far the most common
  finding where the PCV is only minimally
  increased, accounting for up to 50 of such
  cases.
• Alternative names for this condition include
  relative polycythaemia, pseudopolycythaemia,
  stress polycythaemia and spurious polycythaemia.

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Apparent Polycythaemia

• Causes
• Stress
• Cigarette smoker or alcohol intake
• Dehydration
• Plasma loss- burn injury

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Pathophysiology

• The presenting features of PPP are related to
  hypervolaemia and hyperviscosity, which
  accompanies the absolute increase in red cell
  mass. Typical complaints include
• Headache
• Blurred vision
• Dizziness
• Mental impairment
• Feeling of congestion on the head

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Pathophysiology

• Splenomegaly secondary to extramedullary
  haemopoiesis.
• Hyperviscosity with impairment of blood flow
  contribute to the increased incidence of arterial
  and venous thrombosis.
• Platelet dysfunction with a tendency to bruise
  and bleeding tendency.
• Sever itching particularly after a warm bath, due
  to histamine release from basophile.

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Laboratory findings-1

• Increase Hb, PCV and RBCs
• Increase granulocytes count
• Neutrophil morphology and function are increased
• Platelet increases by about 50, by bizarre
  platelet morphology and dysfunction are common.
• Bone marrow is hypercellular with predominance of
  granulocytes. Erythroid hyperplasia is less
  common.
• Cytogenetic abnormalities are present in about
  15 of cases at presentation.

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Laboratory findings-2
Bone marrow in PV

• Normal Neutrophil Alkaline Phosphatase (NAP).
• Plasma urate high
• Circulation erythroid precursors
• Low serum erythropoietin

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Clinical features

• Majority patients present due to vascular
  complications
• Thrombosis (including portal and splenic vein)
• DVT
• Hypertension
• Headache, poor vision and dizziness
• Skin complications (pruritus, erythromelalgia)
• Haemorrhage (GIT) due to platelet defect

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Polycythaemia vera(Polycythaemia rubra vera)
Erythromelalgia

• Hepatosplenomegaly
• Erythromelalgia
• Increased skin temp
• Burning sensation
• Redness

Liver 40
Spleen 70
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Prognosis

• 25 of PPP transform to chronic myelofibrosis and
  only 1/3 of these progresses to ANLL. The
  treatment with chemotherapy is associated with
  increase transformation to ANLL.

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Treatment

• The main aim is to reduce thrombotic
  complication.
• " Debulking" by removal of RBCs and platelet by
  apheresis or by repeated phlebotomy. The median
  survival may be as long as 15 years.
• Additional treatment may not be needed and is
  controversial(Chemotherapy).

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2- Primary Thrombocythaemia

• Primary thrombocythaemia is a malignant clonal
  disorder, which is characterized by
  megakaryocytic hyperplasia and a markedly
  increased circulating platelet count.
• Alternative names for this disorder include
  essential thrombocythaemia, idiopathic
  thrombocythaemia and primary haemorrhagic
  thrombocythaemia.

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Incidence

• Rare in children and young adult.
• Median age is 60 years.
• Men and women appear to be affected with equal
  frequency.

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Pathophysiology

• Increase thromboembolism due to increase in
  platelet count.
• Increase haemorrhage due to platelet dysfunction.
• Splenomegaly in more than 80 of patients.
• Some hepatomegaly.

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Clinical Features

• Increase platelet count for up to 10X106/ m3.
• Platelet clumping with bizarre shape.
• Marked platelet variation.
• Fragment megakaryocytes.
• Increase WBC.
• Normal Hb and RBCs.
• Iron deficiency after chronic haemorrhage.
• 25 transfer to myelofibrosis or PPP or ANLL.

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Blood Film
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Treatment

• Many do not require.
• Platelet apheresis.
• Alkalating agent such as melphelan or busulphan.
• Heparin or Warfarin.
• Aspirin as a prophylactic.

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Prognosis

• Median survival time is 10 years.
• Disease course and prognosis
• 25 develops myelofibrosis
• Acute leukemia transformation
• Death due to cardiovascular complication

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3- Myelofibrosis

• Myelofibrosis predominantly is a disease of the
  middle-aged and elderly.
• It's characterized by
• Progressive collagen fibrosis of the bone marrow.
• Megakaryocytic hyperplasia.
• Splenomegaly due to extramedullary haemopoiesis.
• Myelofibrosis affects men and women equally.

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Pathophysiology

• Lethargy and exercise intolerance secondary to
  anaemia.
• Weight loss and night sweats secondary to
  metabolic disturbances.
• Bruising secondary to platelet dysfunction.
• A feeling of left-sided abdominal fullness
  secondary to massive splenomegaly secondary to
  extramedullary haemopoiesis.
• Extramedullary haemopoiesis in liver may be
  present.
• Greatly increased bone density with narrowing of
  the medullary cavity.

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massive splenomegaly
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Laboratory Findings

• Peripheral blood
• Leukoerythroblastic anaemia with prominent
  polychromasia, anisocytosis and "tear drop"
  poikilocytosis.
• The WBC and platelet count are variable but
  frequently are raised.
• As the disease progresses
• The degree of dysplasia increases.
• The circulating cell counts markedly decreased.
• Increase WBC and RBC turnover leading to increase
  LDH, uric acid and lysozymes and in advanced
  cases, the serum concentrations of hepatic
  enzymes may be abnormal.

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Leucoerythroblastic blood film

• Tear drops red cells
• Increase in NAP score

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Laboratory Findings

• Bone Marrow
• Failure to aspirate bone marrow because of the
  fibrotic overgrowth of marrow space.
• Bone marrow smear reveals large patchy areas of
  hypercellularity, which contain prominent
  clusters of dysplastic megakaryocytes.
• These megakaryocytes die within the marrow space
  and release platelet-derived growth factor (PDGF)
  and platelet factor 4 (PF4).
• PDGF is a fibroblast mitogen.
• PF4 inhibits neutrophil and fibroblast
  collagenase enzymes. The combined effects of
  these two substances rise in collagenous fibrosis
  of the marrow, which characterized this
  condition.

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Bone Marrow, cont.

• Marrow fibrosis thus is a secondary phenomenon in
  myelofibrosis, the primary defect is thought to
  lie in a haemopoietic progenitor cell of CFU-MK
  and CFU-GM.
•  
• The increasing hostility of the marrow
  haemopoietic microenvironment promotes the
  establishment of extramedullary haemopoiesis in
  the foetal sites of the spleen and liver.

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Treatment and Prognosis

• The median survival time is 3 years but some
  cases survive for more than 10 years.
• About 10 of cases progress to ANLL mostly in
  men.
• Splenic irradiation to reduce the size of the
  spleen and to relieve the symptoms of massive
  splenomegaly such as red cell or platelet
  sequestration. Where irradiation is ineffective
  splenectomy may be performed.
• Blood transfusion when required to correct
  anaemia.
• Androgen to correct ineffective haemopoiesis.
• Haematinic therapy if iron or folate deficiency
  is presents.
• Allupurinol to correct hyperuricaemia.
• Where the disease is advancing rapidly,
  chemotherapy can be used with limited success.
• The only hope is bone marrow transplantation in
  young ages.

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Thanks