Hema II Chapter 5 Hematological Malignancies PDF

CHAPTER 5 HEMATOLOGICAL MALIGNANCIES 1 Objectives At the end of this chapter, the student shall be able to:  Define hematological malignancies  Explain the mechanisms of malignant transformation  Describe the classification of leukemia  Explain the diagnostic methodo...

CHAPTER 5 HEMATOLOGICAL MALIGNANCIES 1 Objectives At the end of this chapter, the student shall be able to:  Define hematological malignancies  Explain the mechanisms of malignant transformation  Describe the classification of leukemia  Explain the diagnostic methodologies of leukemia  Describe myelodysplastic syndromes  Define malignant lymphoma  Characterize multiple myeloma  Describe myeloproliferative disorders 2  Introduction  Haematological malignancies are clonal diseases that derive from a single cell in the marrow or peripheral lymphoid tissue which has undergone a genetic alteration  A combination of genetic and environmental factors determine the risk of developing malignancy: Inherited factors – genetic diseases increase the incidence of leukemia Down’s syndrome, Bloom’s syndrome, Fanconi’s anemia, ataxia telangiectasis Environmental influences Chemicals, drugs, radiation, infection 3 The genetics of malignant transformation  Malignant transformation - accumulation of genetic mutations in cellular genes  The genes involved in the development of cancer are divided broadly into two groups:  Oncogenes Arise because of gain-of-function mutations in normal cellular genes called proto-oncogenes Oncogenic versions are generated when the activity of proto- oncogenes is increased or they acquire a novel function through: Translocation Mutation Duplication  Tumour suppressor genes May acquire loss-of-function point mutation or deletion leading to malignant transformation 4 Leukemia  The leukemias are a group of disorders characterized by the accumulation of abnormal white cells in the bone marrow  These abnormal cells may cause: Bone marrow failure A raised circulating white cell count Infiltration of organs  Thus common but not essential features include: Abnormal white cells in the peripheral blood A raised total white cell count Evidence of bone marrow failure (i.e., anemia, neutropenia, thrombocytopenia) in the acute leukemias Involvement of other organs (e.g., liver, spleen, lymph nodes, meninges, brain, skin or testes) 5  Leukemia cont’d  Although viruses cause several forms of leukemia in animals, their role in humans is uncertain Only two viral associations are identified Epstein-Barr virus, a DNA virus, associated with Burkitt's lymphoma Human T-cell lymphotropic virus type I, called human T- cell leukemia/lymphoma virus, an RNA retrovirus, associated with some T-cell leukemias and lymphomas  Exposure to ionizing radiation and certain chemicals (e.g., benzene, some anti-neoplastic drugs) is associated with an increased risk of leukemia 6  Leukemia cont’d  Some genetic defects (e.g., Down syndrome, Fanconi's anemia) also predispose to leukemia Classification of leukemia  The main classification is into acute and chronic leukemia  On the basis of morphology and cytochemistry, acute leukemia is further subdivided into:  Acute myeloid (myeloblastic/myelogenous) leukemia (AML) Acute lymphoblastic (lymphocytic) leukemia (ALL)  AML is further subdivided into eight variants on a morphological basis according to the French-American- British (FAB) scheme (M0 – M7) 7  Classification of Leukemia cont’d  ALL is subdivided on a morphological basis according to the French-American-British (FAB) classification into L1, L2, and L3  The chronic leukemias comprise two main types: Chronic myeloid leukemia (CML) Chronic lymphocytic (lymphatic) leukemia (CLL)  Other chronic types include: Hairy cell leukemia Prolymphocytic leukemia Various leukemia/lymphoma syndromes 8  The Acute Leukemias  The leukemic cell population in ALL and AML probably result from clonal proliferation by successive divisions form a single abnormal stem or progenitor cell  There are over 50% myeloblasts or lymphoblasts in the bone marrow at clinical presentation, and these blast cells fail to differentiate normally but are capable of further divisions Replacement of the normal hemopoietic precursor cells of the bone marrow by myeloblasts or lymphoblasts and, ultimately in bone marrow failure 9  The Acute Leukemias cont’d  The clinical condition of the patient can be correlated with the total number of leukemic cells in the body When the abnormal cell number approaches 1012 the patient is usually gravely ill with severe bone marrow failure  Peripheral blood involvement by the leukemic cells and infiltration of organs such as the spleen, liver and lymph nodes may not occur until the leukemic cell population comprised 60% or more of the marrow cell total 10  The Acute Leukemias cont’d  The disease may be recognized by conventional morphology only when blast (leukemic) cells in the marrow exceed 5% of the cell total (unless the blast cells have some particular abnormal feature, e.g., Auer rods in myeloblasts) This corresponds to a total cell count in excess of 108  The clinical presentation and mortality in acute leukemia arises mainly from: Neutropenia Thrombocytopenia, and Anemia because of bone marrow failure Organ infiltration, e.g., Brain, kidney, liver,… 11 Auer rods 12  The Acute Leukemias cont’d  The acute leukemias comprise over half of the leukemias seen in clinical practice  ALL is the common form in children Its incidence is highest at 3-4 years Falls off by 10 years There is a lower frequency of ALL after 10 years of age with a secondary rise after the age of 40  AML occurs in all age groups It is the common form of acute leukemia in adults including the elderly 13  Laboratory features in Acute Leukemias  A normochromic normocytic anemia  The total white cell count may be decreased, normal or increased up to 200x109/l or more  Thrombocytopenia in most cases, often extreme in AML  Blood film examination typically shows variable numbers of blast cells In AML, the blasts my contain Auer rods and other abnormal cells may be present, e.g., promyelocytes, myelocytes, agranular neutrophils, or myelomonocytic cells  ALL must be differenpseudo-Pelger cells tiated from infectious mononucleosis and other causes of lymphocytosis 14 Laboratory features of Acute Leukemias cont’d  In AML M6 (erythroleukemia) many erythroblasts may be found and these may also be seen in smaller numbers in other forms  The bone marrow is hypercellular with a marked proliferation of leukemic blast cells which amount to over 50% and typically over 75% of the marrow cell total  In ALL the marrow may be difficult to aspirate because of increased reticulin fiber  In AML M7 the patient typically has an acute onset of Pancytopenia with marrow fibrosis 15 L1 ALL 16 L2 ALL 17 L3 ALL 18 AML M0 19 AML M1 20 AML M2 21 AML M3 22 AML M4 23 AML M5 24 AML M6 25 AML M7 26  Acute Plasmacytic Leukemia It is the uncontrolled proliferation of plasma cells in the blood and bone marrow. It is considered a rare and advanced form of multiple myeloma, with distinct. A condition marked by high levels of abnormal plasma cells in the peripheral blood, typically exceeding 2.0 × 10^9/L or comprising more than 20% of the total white blood cell count 27 Acute Plasmacytic Leukemia 28  Differentiation of ALL from AML  In most cases, the clinical features and morphology on routine staining separate ALL from AML In ALL the blasts show no differentiation (with the exception of B-ALL) In AML some evidence of differentiation to granulocytes or monocytes is seen in the blasts or their progeny  Special test (e.g., cytochemistry, gene rearrangement studies and chromosome analysis) are needed when the cells are undifferentiated to: Confirm the diagnosis of AML or ALL, and Subdivide cases of AML or ALL into their different subtypes 29 Differentiation of ALL from AML cont’d PAS POSITIVE L1 PAS POSITIVE L2 ALL PEROXIDASE NEGATIVE L1 ALL ALL 30 AML M2 PEROXIDASE 31 The Chronic Leukemias Chronic Myeloid Leukemia (CML)  Comprises 50x109/l and sometimes > 500x109/l A complete spectrum of myeloid cells is seen in the peripheral blood The levels of neutrophils and myelocytes exceed those of blast cells and promyelocytes 36  Laboratory findings in CML cont’d  Philadelphia (Ph) chromosome on cytogenetic analysis of blood or bone marrow  Hypercellular bone marrow with granulopoietic predominance  Neutrophil alkaline phosphatase score is invariably low  Increased circulating basophils  Normochromic, normocytic anemia is usual  Platelet count may be increased (most frequently), normal or decreased  Serum vitamin B12 and vitamin B12-binding capacity are increased  Serum uric acid is usually raised 37  Chronic lymphocytic leukemia  It accounts for 25% or more of the leukemias seen in clinical practice  It occurs in older subjects and is rare before 40 years  The male to female ratio is 2:1  The accumulation of large numbers of lymphocytes to 50-100 times the normal lymphoid mass in the blood, bone marrow, spleen, lymph nodes and liver may be related to immunological non-reactivity and excessive lifespan The cells are a monoclonal population of B lymphocytes  With advanced CLL: Bone marrow failure A tumorous syndrome with generalized discrete lymphadenopathy Soft tissue lymphoid masses 38  Chronic lymphocytic leukemia cont’d  Immunological failure results from reduced humoral and cellular immune processes with a tendency to infection Laboratory findings in CLL  Lymphocytosis The absolute lymphocyte count is >5 x 109/l and may be up to 300x109/l or more Between 70% and 99% of white cells in the blood film  appear as small lymphocytes Smudge or smear cells are also present  39 Smudge or smear cells 40  Laboratory findings in CLL  Normocytic normocytic anemia is present in later states due to marrow infiltration or hypersplenism Autoimmune hemolysis may also occur  Thrombocytopenia occurs in many patients  Bone marrow aspiration shows lymphocytic replacement of normal marrow elements Lymphocytes comprise 25-95% of all the cells  Reduced concentrations of serum immunoglobulins More marked with advanced disease Rarely a paraprotien is present 41  Hairy Cell Leukemia  Also known as leukemic reticuloendotheliosis  It is a slow growing leukemia  It is most common in older white males  It is an unusual disease of peak age 40-60 years  Men are affected nearly four times as frequently as women  It is a type of chronic lymphoid leukemia  The disease is characterized clinically by features of Pancytopenia  The spleen may be moderately enlarged 42  Hairy Cell Leukemia cont’d  There is a monoclonal proliferation of cells with an irregular cytoplasmic outline (‘hairy’ cells, a type of B lymphocyte) in: The peripheral blood Bone marrow Liver and other organs  The number of hairy cells in the peripheral blood is variable  The bone marrow trephine shows a characteristic appearance of mild fibrosis and a diffuse cellular infiltrate  A serum paraprotein may be present and patients may have arthritis, serositis or vasculitis 43 Hairy Cell Leukemia Hairy Cell Leukemia (HCL) is a rare form of blood cancer characterized by the proliferation of abnormal B lymphocytes, which have distinctive "hairy" projections visible under a microscope. 44 CML 45 CLL 46 CMML (Chronic Myelomonocytic Leukemia) It primarily affects older adults and is associated with an overproduction of monocytes 47 Prolymphocytic Leukemia (PLL) Prolymphocytic Leukemia (PLL) is a rare and aggressive form of leukemia characterized by the proliferation of prolymphocytes, There are two main subtypes: B-cell prolymphocytic leukemia (B- PLL) and T-cell prolymphocytic leukemia (T-PLL). Differentiation by immunophenotyping 48  Myelodysplastic Syndromes (MDS)/Myelodysplasia  A heterogeneous group of disease states that usually present as peripheral blood cytopenias with a hypercellular bone marrow  Most common in the elderly and males are more commonly affected  There is a tendency to progress to acute myeloid leukemia, although death often occurs before this develops  The fundamental disorder is the clonal proliferation of stem cells that produce progeny that fail to mature normally The maturation defect is more subtle; mature forms develop but they are often morphologically atypical (“dysplastic”) and frequently dysfunctional as well 49 Myelodysplastic Syndromes (Myelodysplasia) cont’d  The MDS are classified into five subgroups: Refractory anemia (RA) RA with ring sideroblasts (RARS) RA with excess blasts (RAEB) RAEB in transformation (RAEB-t) Chronic myelomonocytic leukemia (CMML) 50  Myelodysplastic Syndromes (Myelodysplasia) cont’d Laboratory features of MDS  Peripheral blood Pancytopenia is a frequent finding The red cells are usually macrocytic or dimorphic but occasionally hypochromic; normoblasts may be present The reticulocyte count is low Granulocytes are often reduced Show lack of granulation Their chemotactic, phagocytic and adhesive functions are impaired 51  Laboratory features cont’d  The Pelger abnormality (single or bilobed nucleus in neutrophils)) is often present  In CMML, monocytes are >1.0x109/l in the blood  The total white blood count may be >100x109/l  The platelets may be unduly large or small and are usually decreased in number but in 10% of cases are elevated  Variable numbers of myeloblasts in blood indicate poor prognosis blood 52 Laboratory features cont’d Bone marrow  The cellularity is usually increased  Ring sideroblasts may occur in all five FAB types  Multinucleate normoblasts and other dyserythropoietic features are seen  The granulocyte precursors Show defective primary and secondary granulation, and Cells which are difficult to identify as either agranular myelocytes, monocytes or promonocytes are frequent  Megakaryocytes are abnormal with micro-, small binuclear or polynuclear forms  Bone marrow biopsy shows fibrosis in 10% of cases 53  Malignant Lymphomas  This group of diseases is divided into: Hodgkin’s disease, and Non-Hodgkin’s lymphomas  In both, there is replacement of normal lymphoid structure by collections of abnormal cells Hodgkin’s disease is characterized by the presence of Reed-Sternberg (RS) cells and The non-Hodgkin’s lymphomas are characterized by diffuse or nodular collections of abnormal lymphocytes or, rarely, histiocytes 54  Hodgkin’s disease  It is a type of lymphoma characterized by the presence of Reed- Sternberg cells  In many patients, the disease is localized initially to a single peripheral lymph node region and its subsequent progression is by contiguity within the lymphatic system  RS cells and the associated abnormal and smaller mononuclear cells are neoplastic and the associated inflammatory cells represent a hypersensitivity response by the host  After a variable period of containment within the lymph nodes, the natural progression of the disease is to disseminate to involve non-lymphatic tissue 55 Hodgkin’s disease cont’d  The disease can present at any age but is rare in children  It has bimodal age incidence First peak in young adults (age 20-30 years) A second after the age of 50  In developed counties the ratio of young adults to child cases and of nodular sclerosing disease to other types is increased  There is an almost 2:1 male predominance 56  Laboratory findings in Hodgkin’s disease  Normochromic, normocytic anemias is most common  One-third of patients have a leucocytosis due to a neutrophil increase  Eosinophilia is frequent  Advanced disease is associated with lymphopenia  The platelet count is normal or increased during early disease, and reduced in later stages  The ESR is usually raised and is useful in monitoring disease progress 57  Laboratory findings in Hodgkin’s disease cont’d  Bone marrow involvement is unusual in early disease It may be demonstrated by trephine biopsy, usually in patients with disease at many sites  There is progressive loss of immunologically competent T lymphocytes with reduced cell-mediated immune reactions  Infections are common, particularly: Herpes zoster Cytomegalovirus Fungal, e.g., Cryptococcus and Candida Tuberculosis may occur 58  Laboratory findings in Hodgkin’s disease cont’d  Patients with bone disease may show: Hypercalcaemia Hypophosphataemia Increased levels of serum alkaline phosphatase  Serum lactate dehydrogenase (LDH) is raised initially in 30-40% of cases an indicates a poor prognosis  Elevated levels of serum transaminases may indicate liver involvement  Serum bilirubin may be raised due to biliary obstruction caused by large lymph nodes at the portal hepatitis  Hyperuricaemia may occur 59 Reed-Sternberg cells are large, abnormal lymphocytes (a type of white blood cell) that may contain more than one nucleus 60  Non-Hodgkin’s lymphomas  The clinical presentation and natural history of these malignant lymphomas are more variable than in Hodgkin’s disease  Pattern of spread is not regular  A greater proportion of patients present with extra nodal disease or leukemic manifestations Laboratory findings in Non-Hodgkin’s lymphoma  A normochromic normocytic anemia is usual but auto-immune hemolytic anemia may also occur  In advance disease with marrow involvement there may be neutropenia, thrombocytopenia (especially if the spleen is enlarged) or leuco-erythroblastic features 61 Laboratory findings in non-Hodgkin’s lymphomas cont’d  Lymphoma cells (‘cleaved follicular lymphoma’ or ‘blast’ cells) with variable nuclear abnormalities may be found in the peripheral blood in some patients  Trephine biopsy of marrow shows focal involvement, usually paratrabecular, in 20% of cases  Elevation of serum uric acid may occur Abnormal liver function tests suggest disseminate disease  The serum LDH level is raised in more rapidly proliferating and extensive disease and may be used as a prognostic marker 62  Multiple Myeloma  It is a neoplastic monoclonal proliferation of bone marrow plasma cells characterized by: Lytic bone lesions Plasma cell accumulation in the bone marrow, and The presence of monoclonal protein in the serum and urine  98% of cases occur over the age of 40 with a peak incidence in the seventh decade 63 Laboratory finding in multiple myeloma  In 98% of patients monoclonal protein occurs in the serum or urine or both The serum paraprotein is IgG in two-thirds IgA in one-third Rare IgM or IgD or mixed cases Normal serum immunoglobulins (IgG, IgA and IgM) are depressed  The urine contains Bence-Jones protein in two-thirds of cases  The bone marrow shows increased plasma cells often with abnormal forms – ‘myeloma cells’ Immunological testing shows these cells to be monoclonal B cells Express the same immunoglobulin heavy and light chains as the serum monoclonal protein 64  Laboratory finding in multiple myeloma cont’d  There is usually a normochromic, normocytic or macrocytic anemia  Rouleaux formation is marked in most cases  Neutropenia and thrombocytopenia occur in advanced disease  Abnormal plasma cells appear in the blood film in 15% of patients  Leuco-erythroblastic changes are occasionally seen  High ESR  Serum calcium elevation occurs in 45% of patients 65  Laboratory finding in multiple myeloma cont’d  The blood urea is raised above 14mmol/l and serum creatinine raised in 20% of cases  Proteinaceous deposits from heavy Bence-Jones proteinuria, hypercalcaemia, uric acid, amyloid and pyelonephritis may all contribute to renal failure  A low serum album occurs with advance disease  Serum β2-microglobulin (the light chain of the HLA class 1 antigens) is a useful indicator of prognosis It partly reflects renal function Levels less than 4mg/l imply a relatively good prognosis 66 Myeloproliferative Disorders  A group of conditions characterized by clonal proliferation of one or more hemopoietic components in the bone marrow and, in many cases, the liver and spleen Polycythemia vera (PV) Essential thrombocythemia Myelofibrosis 67  Polycythemia vera (PV)  Also referred to as erythrocytosis  Refers to a pattern of blood cell changes that includes: An increase in hemoglobin above 17.5g/dl in adult males and 15.5g/dl in females An accompanying rise in red cell count (above 6.0 x 1012/l in males and 5.5x1012/l in females) Hematocrit (above 55% in males and 47% in females)  The increase in red cell volume is caused by endogenous myeloproliferation  The stem cell origin of the defect is shown in many patients by an over-production of granulocytes and platelets as well as of red cells  This is a disease of older subjects with an equal sex incidence. 68  Laboratory findings in PV  The hemoglobin, hematocrit and red cell count are increased  A neutrophil leucocytosis is seen in over half the patients, and some have increased circulating basophils  A raised platelet count is present in about half the patients  The neutrophil alkaline phosphatase score is usually increased above normal  Increased serum vitamin B12 and vitamin B12-binding capacity due to an increase in transcobalamin I 69 Laboratory findings in PV cont’d  The bone marrow is hypercellular with prominent megakaryocytes Best assessed by a trephine biopsy Clonal cytogenetic abnormalities may occur, but there is no single characteristic change  Blood viscosity is increased  Plasma urate is often increased  Circulating erythroid progenitors are increased and grow in vitro independently of added erythropoietin 70  Essential thrombocythemia  Megakaryocyte proliferation and overproduction of platelets is the dominant feature of this condition  There is sustained increase in platelet count above normal (400x109/l)  Recurrent hemorrhage and thrombosis are the principal clinical features  Splenic enlargement is frequent in the early phase but splenic atrophy due to platelets blocking the splenic mirocirculation is seen in some patients  There may be anemia due to: Iron deficiency from chronic gastrointestinal or uterine hemorrhage The marrow disorder itself 71 Laboratory findings in Essential thrombocythemia  Abnormal large platelets and megakaryocyte fragments may be seen in the blood film  The bone marrow is similar to that in PV  Platelet function tests are consistently abnormal 72 Myelofibrosis  There is the gradual replacement of the bone marrow by connective tissue  A prime feature is extramedullary hematopoieis  Patients will typically have an enlarged spleen and liver  Typically affects patients more than 50 years old Laboratory findings in myelofibrosis  Anemia is usual but a normal or increased hemoglobin level may be found in some patients  The white cell and platelet counts are frequently high at the time of presentation Later in the disease leucopenia and thrombocytopenia are common 73 Laboratory findings in myelofibrosis cont’d  A leuco-erythroblastic blood film is found The red cells show characteristic ‘tear-drop’ poikilocytes  Bone marrow is usually unobtainable by aspiration Trephine biopsy may show a hypercellular marrow with an increase in reticulin-fibre pattern  Low serum and red cell folate, raised serum vitamin B12 and vitamin B12-binding capacity, and an increased neutrophil alkaline phosphatase score are usual  High serum urate, LDH and hydroxybutyrate dehydrogenase levels reflect the increased but largely ineffective turnover of hemopoietic cells  Transformation to acute myeloid leukemia occurs in 10-20% of patients 74 Discussion 1. Briefly describe the classification of leukemia and causes 2. Acute leukemia (ALL,AML) 3. Chronic Leukemia(CML,CLL) 4. Define myelodysplastic syndrome 5. What are the features of malignant lymphoma 6. What are the characteristics multiple myeloma 7. Describe myeloproliferative disorders 75  Assignment Hematology of Pregnancy Hematology of Geriatric Hematology of Newborn Hematology of HIV AIDS Cytogenetics of major leukemia types Cytochemistry 76 Thank you !!! 77