43fae8fa-a754-47e3-85a9-fe210cabf9a2.pptx

leukemia pathology

1. Leukemia

2. NEOPLASTIC PROLIFERATIONS OF WHITE CELLS Malignant neoplasms of white cells, though less frequent than the reactive proliferations, are the most important from clinical point of view.

3. Myeloid Neoplasms They form a heterogeneous group of neoplasms, which arise from early hematopoietic progenitor cells. These neoplasms primarily involve the bone marrow and to a lesser extent the secondary hematopoietic organs (the spleen, liver, and lymph nodes). They usually present with symptoms related to altered hematopoiesis. They can be broadly categorized as: • Acute myeloid leukemias : They are characterized by accumulation of immature progenitor cells in the bone marrow, which suppresses the normal hematopoiesis.

4. Myelodysplastic syndromes (MDS): These syndromes are associated with ineffective hematopoiesis which leads to peripheral blood cytopenias . Myeloproliferative neoplasms (MPN): The characteristic feature of these neoplasms is increased production of one or more terminally differentiated myeloid elements. They usually produce elevated peripheral blood counts. • Myelodysplastic / myeloproliferative neoplasms: These neoplasms present the clinical, laboratory and morphological features that overlap both MDS and MPN.

5. Lymphoid Neoplasms These include a diverse group of neoplasms of B cell, T cell, and NK cell origin. They can be sub divided into two categories. • Lymphocytic/lymphoid leukemias : These neoplasms present with widespread involvement of the bone marrow and usually (but not always) the peripheral blood. • Lymphoma: They represent lymphoid proliferations which present as tissue masses. These are categorized into two main groups namely: Non-Hodgkin and Hodgkin lymphoma

6. Histiocytic and Dendritic Cell Neoplasms These are uncommon proliferative lesions of macrophages and dendritic cells. Langerhans cell is a special type of immature dendritic cell which can produce a spectrum of neoplastic disorders known as Langerhans cell histiocytosis . Both myeloid and lymphoid neoplasms can present as acute and chronic leukemias . Though acute lymphoid and myeloid leukemias are distinct ( immunophenotypically and genotypically ), they usually have certain features in common

7. ACUTE LEUKEMIA Leukemia is defined as a group of malignant stem cell neoplasms characterized by: • Diffuse replacement of bone marrow with proliferating leukocyte precursors (blast cells) • Abnormal numbers and forms of immature white blood cells in circulation. • In acute leukemia the immature, neoplastic leukemic ‘blast’ cells proliferate and accumulate, but fail to mature. The blasts diffusely replace the normal bone marrow and a variable number of these accumulate in the peripheral blood.

8. Acute leukemia should be diagnosed when the blast cells constitute more than 20% of the nucleated cells in the marrow (normally blast cells are less than 5%). In some patients there may be very few /no blasts in the peripheral blood and is termed as aleukemic / subleukemic leukemia. • Infiltration of the marrow by leukemic cells finally results in bone marrow failure resulting in cytopenias . Most patients present with consequences of cytopenias (anemia, neutropenia and thrombocytopenia) particularly in the acute leukemias .

9. Risk Factors Environmental factors • Ionizing radiation: Exposure to ionizing radiation and X-rays are associated with increased risk of leukemias . The evidences for this association are:  Survivors of atomic bomb explosions in Hiroshima and Nagasaki, who had high incidence of acute myelogenous leukemia (AML) and chronic myeloid leukemia (CML).  Increased risk of AML (secondary) in patients with malignancies/ neoplasms treated by radiation.

10. Drugs : Drugs can cause secondary hematopoietic neoplasms.  Leukemia develops in patients who have been administered alkylating agents for neoplasms like Hodgkin lymphoma. The various drugs include nitrogen mustard, chlorambucil , etc.  AML occurs in myeloma patients treated with melphalan .  Leukemia follows chemotherapy of lung and ovarian cancer. Some anticancer drugs induce myelodysplastic changes with certain chromosomal abnormalities and subsequently develop AML

11. Chemicals: Benzene (used in paint industry, plastic glues, etc ) causes chromosomal abnormalities resulting in higher incidence of acute leukemia, myelodysplastic syndrome and aplastic anemia. Genetic disorders A few genetic disorders may be associated with acute leukemias , e.g. Down syndrome (ALL or AML), Fanconi anemia (AML), ataxia telangiectasia (ALL, NHL).

12. Acquired Disorders • Acquired stem cell disorders like PNH and aplastic anemia may transform into acute leukemia. • AML may develop de novo or secondary to myelodysplastic syndrome (MDS).

13. Classification Depending on microscopic appearance of the involved cell and the course of leukemias , they were initially classified as: Acute Acute myelogenous / myeloblastic / myelocytic /myeloid leukemia (AML) Acute lymphoblastic/lymphocytic leukemia (ALL) • Chronic Chronic myeloid leukemia (CML) Chronic lymphocytic leukemia (CLL) Differentiation of two broad groups of ALL and AML from each other is important, because of difference in the treatment, course and prognosis.

14. Diagnosis of Acute Leukemia Presently the diagnosis of acute leukemia requires the presence of 20% or more blasts in the bone marrow (WHO criteria). The sub classification of acute leukemia is based on: (1) morphology,(2) cytochemistry , (3) immunophenotyping , (4) cytogenetics (e.g. karyotyping) and (5) molecular genetics.

15. Clinical Presentation of Acute Leukemia Though ALL and AML are distinct ( immunophenotypically and genotypically ), they usually have similar clinical presentation; Bone marrow failure : Most often leukemic patients present with signs and symptoms of bone marrow failure due to replacement of normal marrow hematopoietic cells by leukemic blast cells. All or any of the three cell lines are decreased, which results in anemia, neutropenia and thrombocytopenia.

16. Anemia causes fatigue, weakness and hypermetabolic state which is directly related to the degree of anemia. Neutropenia results in life-threatening infections by bacteria or opportunistic fungi, Pseudomonas and commensals. The infection may develop in the oral cavity, skin, lungs, kidneys, urinary bladder and colon. The common presentations include respiratory infections (pneumonia), cellulitis or sepsis.

17. Thrombocytopenia presents as bleeding manifestations in the form of petechiae , atraumatic ecchymoses gum bleeding, epistaxis, urinary tract and fundal hemorrhages. Marrow expansion and infiltration of the subperiosteum causes bone pain (more common in ALL) and sternal tenderness.

18. Leukostasis : Stasis of blood flow may develop when the blast count in the peripheral blood is above 50 × 10 9 (50,000/cu mm). Leukostasis is more common in AML than ALL because myeloblast is larger and expresses adhesive proteins. Most of the patients have leukocytosis and is responsible for the following symptoms:  Cerebral leukostasis may cause headache, confusion and visual disturbances.  Pulmonary leukostasis can cause dyspnea at rest and tachypnea.

19. Coagulopathy: Both disseminated intravascular coagulation (DIC) and primary fibrinolysis may lead to hemorrhagic diathesis in addition to that due to thrombocytopenia. Extramedullary infiltration: Leukemic blasts may infiltrate organs like lymphnodes , spleen,gingiva , skin (leukemia cutis) and meninges. Hepatosplenomegaly : Splenomegaly and hepatomegaly may be found and is more common in AML.  Lymphadenopathy: It is found occasionally in ALL and is rare in AML.

20. Tumor lysis syndrome (TLS): It is a group of metabolic complications that can occur after treatment of leukemias (also in lymphomas) and is caused by the breakdown products of dying tumor cells. The killed tumor cells release intracellular ions and large amounts metabolic byproducts (includes potassium, phosphate and nucleic acids) into the systemic circulation. They result in metabolic abnormalities like hyperkalemia, hyperphosphatemia,hyperuricemia , hyperuricosuria , hypocalcemia , and consequent acute uric acid nephropathy and renal failure.

21. Acute Lymphoblastic Leukemia Acute lymphoblastic leukemia/lymphoma (ALL) is a group of neoplasms consisting of immature, precursor B (pre-B) or T (pre-T) lymphocytes known as lymphoblasts . Morphologically it is difficult to distinguish malignant pre-B and pre-T lymphoblasts . It requires immunophenotyping for subclassification of ALL.

22. Leukemia vs. Lymphoma: • Leukemia: Proliferations of lymphoblasts in the bone marrow and peripheral blood are termed as lymphoblastic leukemia. • Lymphoma: Primary involvement of lymphnodes or extranodal sites by lymphoblasts is referred to as lymphoblastic lymphoma

23. About 85% of ALLs are tumors of precursor B cells which are primarily seen in childhood and present as acute leukemias . Remaining 15% of ALLs are derived from precursor T cells and present in adolescent males as lymphomas , often with involvement of mediastinum (thymus).

24. Clinical Features Age and Sex : ALL is the most common hematological malignancy of children. Most commonly found between 1 to 5 years of age and second peak in adults is found between 30 to 40 years. There is a slight male preponderance.

25. Onset: Abrupt. Symptoms: They are related to depressed marrow function due to infiltration by blasts. This includes symptoms due to anemia, neutropenia and thrombocytopenia. Testicular enlargement .

26. ALL may present with: • Lymphadenopathy: It is present in 75% of patients. • Hepatosplenomegaly : Splenomegaly is more common than hepatomegaly. • Mediastinal mass: Mediastinal thymic mass may compress blood vessels and airways in the mediastinum. This is more common in T-ALL. • Central nervous system involvement: It may spread into the meninges and is more common in ALL (pre-B).

27. Laboratory Findings Peripheral Blood • Total WBC count: Total white cell count is markedly raised ranging from 20 × 10 9 /L to 200 × 10 9 /L. In few cases count may be normal or even reduced.  Subleukemic leukemia: It is characterized by a total white cell count lower than 4 × 10 9 /L and peripheral blood shows very few blasts.  Aleukemic leukemia: The term aleukemic leukemia is used when total white cell count is low (< 4 × 10 9 /L) with no blasts in the peripheral blood. The diagnosis in such cases requires bone marrow examination to demonstrate 20% or more blast cells.

28. Hemoglobin: Hemoglobin progressively decreases and may be reduced even to 3 gm/ dL . • Peripheral smear:  RBCs: They show normocytic normochromic type of anemia.  WBCs: Total count is usually markedly increased. Few may present with pancytopenia. Blasts may replace normal myeloid series and can cause neutropenia.

29. Lymphoblasts : The minimum requirement for diagnosis by WHO criteria is 20% blasts or more. The morphologic distinctions between B and T require lymphocyte-specific markers. Platelets: Thrombocytopenia is common and is responsible for bleeding from skin and mucosa.

30. Cytochemistry of lymphoblasts • Periodic Acid Schiff (PAS) positive . • Myeloperoxidase negative. • Sudan Black B negative.

31. Bone Marrow • Cellularity: Bone marrow is markedly hypercellula r due to proliferation of blasts which replace normal hematopoietic cells. • Erythropoiesis and myelopoiesis : Reduced. • Megakaryopoiesis : Megakaryocytes gradually decrease Blasts • They constitute 20–100% of the marrow cells.

32. Biochemical Findings (Refer tumor lysis syndrome) • Hyperuricemia (increased serum uric acid) • Hyperkalemia (increased serum potassium) • Hyperphosphatemia (increased serum phosphate) • Hypocalcemia (decreased serum calcium) due to hyperphosphatemia • LDH is increased due to increased turnover of leukemic cells.

33. Prognosis About 95% of children undergo complete remission and 75 to 85% are cured with currently available chemotherapy.

34. ACUTE MYELOGENOUS LEUKEMIA Definition Acute myelogenous leukemia (AML) is a neoplasm of hematopoietic progenitors due to acquired mutations which hinder its differentiation, resulting in accumulation of immature myeloblasts in the marrow. It is also called as myeloid/ myeloblastic / myelocytic leukemia.

35. Aberrant tyrosine kinase activation is a common feature of AML.Thus mutated tyrosine kinase along with transcription factor aberrations result in development of AML. Clinical Features Age: AML may develop at any age, but is more common in adults. Symptoms: They are related to depressed marrow function due to infiltration by neoplastic blast cells. This includes symptoms due to anemia, neutropenia and thrombocytopenia

36. Laboratory Findings Peripheral Blood The characteristic feature is the presence of blasts in blood and bone marrow with reduction of normal hematopoietic cells. Total WBC Count: It is markedly raised ranging from 20 × 10 9 /L to 100 × 10 9 /L. In few cases count may be normal or even reduced. • Hemoglobin: It is decreased and ranges from 5 to 9 gm/ dL .

37. Total WBC count is usually markedly increased. Leukemic blast cells may replace normal myeloid series in the marrow and can cause neutropenia.

38. Shows more than 20% myeloid blasts. Auer rods: They are distinctive azurophilic needle-like structures of varying length and width. They represent an abnormal alignment and crystallization of azurophilic granules and are peroxidase-positive. Presence of Auer rods is definitive evidence of myeloid differentiation Platelets: They are variably decreased. There is moderate to severe thrombocytopenia and is responsible for bleeding from skin and mucosa.

39. Myeloblasts stain positively with myeloperoxidase (MPO) and Sudan black B. Bone Marrow • Cellularity: Bone marrow is markedly hypercellula r due to proliferation of blasts which replace normal hematopoietic cells. • Erythropoiesis: Markedly suppressed. • Myelopoiesis : It shows suppression of myeloid maturation and myeloblasts constitute more than 20% of marrow cells. • Megakaryopoiesis : Megakaryocytes are gradually decreased .

40. Prognosis It has a fulminant course and has worse prognosis than ALL. Cytogenetic markers are major determinants of prognosis. E N D