Leukemia (1) PDF - Hematological Malignancies

Hematological Malignancies By: Haftu A. 1/25/2025  Outline Learning Objectives  Introduction  Classification of leukemias  Acute leukemias  Chronic leukemias  Lymphomas  Myelodysplastic syndromes  Myeloproliferative disorder...

Hematological Malignancies By: Haftu A. 1/25/2025  Outline Learning Objectives  Introduction  Classification of leukemias  Acute leukemias  Chronic leukemias  Lymphomas  Myelodysplastic syndromes  Myeloproliferative disorder 1/25/2025  Learning 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  Describe myeloproliferative disorders  Define malignant lymphoma  Characterize multiple myeloma 1/25/2025  Introduction Blood cell development 4 1/25/2025  WBC Proliferative Disorder Reactive Neoplastic Proliferativ proliferativ e e Leukemoi Myeloid Lymphoid Leukocytosi Proliferativ d Proliferativ s e Reaction e AML MDS MPD Peripheral Peripheral Pre B Pre T-cell B cell T-cell/NK Myelo- cell-ALL ALL/NK CML PCV Neoplasia Neoplasia ET Fibrosis 5 1/25/2025  Reactive proliferation  When WBCs increase in peripheral circulation in response to some trauma, infection, and inflammation.  Leukocytosis  Leukemoid reaction 1/25/2025  Leukocytosis (Mild-moderate)  When there is mild to moderate leukocytosis occurs.  In this type, we can find the following subtypes of WBCs out of proportion. For example;  The pyogenic infection leads to Neutrophilic leukocytosis or Neutrophilia.  The parasitic infection leads to Eosinophilic leukocytosis or Eosinophilia.  Allergy, drug reactions, or specific neoplasia produce Basophilic leukocytosis.  Chronic inflammation and infections produce Monocytosis 1/25/2025  Leukemoid Reaction  When there is severe leukocytosis occurs (>30,000 cells/nl)  When there is severe or prolonged stress(inflammation, infection, trauma, surgery), the following changes occur which eventually lead to increase WBCs in the circulation:  Bone marrow storage pool of WBCs can be mobilized  The marginated pool of WBCs  Overstimulation of production house, i.e., Bone marrow  The leukemoid reaction can be differentiated from CML  As there is a high leukocyte alkaline phosphatase score (LAP score) in Leukemoid reaction  The leukemoid reaction can be differentiated from AML  As the blast cells in peripheral circulation or bone marrow almost never go more than 20% in leukemoid reaction 1/25/2025 Leukemoid Reaction vs Leukemia 1/25/2025  Neoplastic proliferation of White Blood Cells  Neoplastic proliferation are clonal proliferations of malignant leukocytes that arise initially in the bone marrow before disseminating to the peripheral blood, lymph nodes, and other organs.  They are broadly classified into three categories  Lymphoid neoplasms  Myeloid neoplasms  Histiocytic neoplasms  1/25/202  Malignancies  A tumor that is malignant or cancerous  That can invade and destroy nearby tissue  That may spread (metastasize) to other parts of the body.  Malignant cells tend to have fast, uncontrolled growth and do not die normally due to changes in their genetic makeup.  Hematological malignancies are clonal diseases that derive from a single cell in the marrow or peripheral lymphoid tissue which has undergone a genetic alteration  Most hematological malignancies are sporadic and not attributable to identifiable genetic or environmental risk factors. 1/25/202  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 as oncogene and Tumour suppressor genes Oncogene 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 1/25/202  Malignant transformation con’……..  Tumor suppressor genes  May acquire loss-of-function point mutation leading to malignant transformation  Tumor-suppressor genes commonly act as components of control mechanisms which regulate cell growth.  The most significant TSG in human cancer is p53 which is mutated or inactivated in over 50% of cases of malignant disease, including many haemopoietic tumor. 1/25/202  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: o Bone marrow failure o A raised circulating white cell count o Infiltration of organs 1/25/202  Leukemia Cont’d…  Thus common 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) 1/25/202 1/25/2025  General: General: b Gender: men are more likely to develop CML, CLL and AML than women Age: the risk of most leukemias, with the exception of ALL, typically increases with age Genetics Genetics: and Immunological Factors Family history: most leukemias have no familial link. However, first degree relatives of CLL patients, or having an identical twin who has or had AML or ALL, may at an increased risk for developing the disease Mutations in a single gene are found in many cases of leukemia; larger changes in one or more chromosomes are also common. Several types of chromosomal changes may be found: Translocations:  Are the most common type of DNA change that can lead to leukemia. A translocation means that a part of one chromosome breaks off and becomes attached to a different chromosome.  The point at which the break occurs can affect nearby genes: eg, it can turn on oncogenes or turn off genes that would normally help a cell to mature. Deletions: Occur when part of a chromosome is lost. This may result in the cell losing a gene that helped keep its growth in check, for example, a tumor suppressor gene. Inversions: Occur when part of a chromosome gets turned around, so it is now in reverse order. This can Addition: result  It isinan the losschromosome extra of a gene (oror genes) because part of the cell can a chromosome no longer is gained. read This canitslead instructions in to too many protein copies translation. of certain genes within the cell. This can be a problem if one or more of these genes are oncogenes. 1/25/2025 Genetics and Immunological Factors ………  Cancers can be caused by DNA mutations that turn on oncogenes or turn off tumor suppressor genes.  For example, changes in certain genes such as FLT3, c-KIT, and RAS are commonly found in acute myelogenous leukemias (AMLs). Genetic disease: Dawns syndrome may play a role in development of leukemia Lifestyle: Life style Smoking: although smoking may not be a direct cause of leukemia, smoking cigarettes does increase the risk of developing AML Previous Exposure Exposures: Exposure to high-energy radiation (atomic bomb explosions) and intense exposure to low-energy radiation from electromagnetic fields (power lines) Long-term exposure to certain pesticides or industrial chemicals like benzene is considered to be a risk for leukemia Previous Treatment Previous cancer treatment: certain types of chemotherapy and radiation therapy for other cancers are considered leukemia risk factors 1/25/2025 1/25/2025 20 1/25/2025 21 1/25/202 5 22 1/25/2025 1/25/2025 1/25/2025  Classification of Leukemia  Generally leukemia is classified into two: Acute leukemia Chronic leukemia  Acute leukemia is further subdivided into: Acute myeloid (myeloblastic/myelogenous) leukemia (AML) Acute lymphoblastic (lymphocytic) leukemia (ALL)  The chronic leukemias comprise two main types: Chronic myeloid leukemia (CML) (type of MPD) Chronic lymphocytic (lymphatic) leukemia (CLL)  Other chronic types include: Hairy cell leukemia Prolymphocytic leukemia 1/25/202  Acute vs Chronic Comparison of acute and chronic leukemias Characteristics Acute Chronic Age all ages Usually adults Clinical onset Sudden insidious Course (untreated) 6 mo. or less 2-6 years Leukemic cells Immature >30% More mature cells blasts Anemia Prominent Mild Thrombocytopenia Prominent Mild WBC count Variable Increased Lymphadenopathy Mild present; often prominent Splenomegaly Mild present; often prominent 1/25/202  The Acute leukemias  In acute leukemias or aggressive lymphomas, maturation arrest occurs early (near the lymphoblast cells), proliferation continues  In chronic leukemias or less aggressive lymphomas, maturation arrest occurs late (near the mature cells), less proliferation occurs 1/25/2025 The Acute leukemias Con’d…  The leukemic cell population in ALL and AML probably result from clonal proliferation by successive divisions from 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 1/25/2025 The Acute leukemias Con’d…  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  The disease may be recognized by conventional morphology only when blast (leukemic) cells in the marrow exceed 5% of the cell total.  The clinical presentation and mortality in acute leukemia arises mainly from: Neutropenia Thrombocytopenia, and Anemia because of bone marrow failure Organ infiltration 1/25/2025 The Acute leukemias Con’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 1/25/2025  FAB Classification of Acute leukemias  In 1976, a group of seven French, American, and British hematologists proposed a system of nomenclature, the French-American-British (FAB) cooperative classification system.  This FAB classification is based on the  Morphological characteristics cells in peripheral blood or bone marrow  Cytochemical staining of blasts.  The FAB system groups AMLs into subtypes (M0 through M7); ALL into three categories (L1 through L3).  This system is based on the type of cell from which the leukemia developed and the maturity of cells.  In a revision of the original criteria, more than 30% blasts in the marrow for 1/25/2025 the diagnosis of acute leukemia in any of the categories.  WHO Classification of Acute leukemias  The underlying rationale behind the WHO classification uses all available information-  Morphology  Cytochemistry  Immunophenotype  Genetics, and clinical features 1/25/2025  Acute Myeloid Leukemia (AML)  AML is a genetically heterogeneous clonal disorder characterized by a maturation block and the accumulation of acquired genetic alterations in hematopoietic progenitor cells that alter:  Normal mechanisms of self- renewal  Proliferation  Differentiation.  In AML, malignant transformation and uncontrolled proliferation of an abnormally differentiated, long-lived myeloid progenitor cell results  In high circulating numbers of immature blood cells  Replacement of normal marrow by malignant cells.  The WHO classification of myeloid neoplasms is complex but it does continue to include categories that resemble the previous FAB classifications of AML 1/25/2025 Pathophysiology of AML  Acute myeloid leukemia is caused by a series of acquired genetic aberrations.  Abnormal proliferation, clonal expansion, aberrant differentiation, and diminished apoptosis lead to replacement of normal blood elements.  Leukemic cell infiltration of other organ systems tends to be less common in AML than in ALL, however:  Infiltration can enlarge the liver, spleen, and lymph nodes.  Bone marrow and periosteal infiltration may cause bone and joint pain. 1/25/2025 Classification of AML with their cytogenetic abnormalities FAB Subtype Common Name Chromosomal Abnormality M0 Acute undifferentiated leukemia M1 AML with minimally differentiated M2 AML with maturation t (8;21), t (6;9) M3 Acute promyelocytic leukemia t (15;17) M4 Acute myelomonocytic leukemia inv (16), del(16q) M4eo Acute myelomonocytic leukemia with inv (16), t (16;16) BM Eo M5a and M5b Acute monocytic leukemia  Type a: 80% monoblasts del(11q), t (9;11). t(11,19)  Type b: >20% promonocytes Acute erythroleukemia M6 M6a: erythro leukemia M6b: very rare pure erythroid leukemia M7 Acute megakaryoblastic leukemia t(1;22) 1/25/2025 WHO Classification of AML  Acute myeloid leukemia has a number of subtypes and precursor neoplasms that are distinguished from each other by  Morphology  Immunophenotype  Cytochemistry  Genetic abnormalities  Seven classes are described based on WHO classification, including  AML with recurrent genetic abnormalities  AML with myelodysplasia-related changes (AML-MRC)  Therapy-related AML (t-AML)  AML, not otherwise specified (NOS)  Myeloid sarcoma  Myeloid proliferations related to Down syndrome Less common  Blastic plasmacytoid dendritic cell neoplasm 1/25/2025  AML with recurrent genetic abnormalities  AML with t(8;21): RUNX1-RUNX1T1  AML with t(9;11): MLLT3-KMT2A  APL with PML-RARA  AML with inv(16) or t(16;16): CBFB-MYH11  AML with t(6;9);DEK-NUP214  AML with inv(3) or t(3;3): GATA2, MECOM  AML (megakaryoblastic) with t(1;22): RBM15-MKL1 1/25/2025  AML with myelodysplasia-related changes  AML-MRC as acute leukemia with ≥20% blasts in the PB or BM with morphological features of myelodysplasia.  or occurring in patients with a prior history of MDS and/MPN, with MDS related cytogenetic abnormalities.  Absence of specific genetic abnormalities like, AML with recurrent genetic abnormalities.  Therefore, there are three main criteria when patients are classified in this category: (i) those with the presence of dysplasia; (ii) those with MDS related cytogenetic abnormalities (iii) those with a prior history of MDS and MDS/MPN. 1/25/2025  AML with myelodysplasia-related changes  Blasts 20% or more  Dysplasia in > 50% of the cells in 2 or more lineages  Dyserythropoietic:  Dysgranulopoiesis:  Dysmegakaryopoiesis: 1/25/2025  Therapy-related myeloid neoplasms  Is a subtype of AML caused by prior treatment with certain antineoplastic drugs (alkylating agents, hydroxyurea, and topoisomerase II inhibitors).  Most t-AMLs occur 3 to 10 years after initial therapy.  Alkylating agents cause chromosomal deletions and unbalanced translocations.  Hydroxyurea causes del(17)p and also inhibits P53 activation.  Topoisomerase II inhibitors lead to balanced chromosomal translocations. 1/25/2025  AML, NOS  This includes cases of AML that don’t fall into one of the above groups, and is similar to the FAB classification.  AML with minimal differentiation (FAB M0)  AML without maturation(FAB M1)  AML with maturation (FAB M2)  Acute myelomonocytic leukemia (FAB M4)  Acute monoblastic/monocytic leukemia (FAB M5)  Pure erythroid leukemia (FAB M6)  Acute megakaryoblastic leukemia (FAB M7)  Acute basophilic leukemia 1/25/2025  Myeloid sarcoma  (also known as granulocytic sarcoma or chloroma)  Is characterized by extramedullary myeloblastic infiltration of skin (leukemia cutis), gingiva, and other mucosal surfaces. 1/25/2025  Myeloid proliferations related to Down syndrome  Acute myeloid leukemia of Down syndrome (AML-DS) are disorders associated with trisomy 21.  These conditions almost always develop before the age of 5 years.  In individuals with Down syndrome (DS), the risk of developing AML-DS is increased 150 to 500 fold, compared to a 30-fold increase of developing ALL.  Approximately 1%-2% of children with DS develop acute myeloid leukemia, with a large majority of cases (70%) being acute megakaryoblastic leukemia (AML French-American-British [FAB] classification: M7). 1/25/2025  Lymphoid Neoplasms  In acute leukemias or aggressive lymphomas, maturation arrest occurs early (near the lymphoblast cells), proliferation continues  In chronic leukemias or less aggressive lymphomas, maturation arrest occurs late (near the mature cells), less proliferation occurs  Lymphoid neoplasms are classified as follows  Precursor B-cells neoplasia (Pre B-ALL)  Peripheral B-cells neoplasia (CLL/SCL, hairy cell leukemias, Burkitt lymphoma)  Precursor T-cells neoplasia (Pre T-ALL) or Precursor NK-cells neoplasia (Pre NK-ALL)  Peripheral T-cells neoplasia or Peripheral NK-cells neoplasia 1/25/2025  Acute lymphoblastic leukemia (ALL)  Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer of lymphocyte blood cells.  It is a rapidly progressing form of leukemia.  ALL begins in the bone marrow produces too many abnormal and immature lymphocytes known as lymphoblasts. Normally, lymphoblasts develop into mature cells, which then help the body fight off infections.  People with ALL, however, the lymphoblasts are abnormal they do not develop into mature healthy lymphocytes, nor are they capable of effectively fighting off infections.  These abnormal lymphoblasts enter the bloodstream and can spread to other parts of the body such as the brain and spinal cord, spleen, liver, testicles, skin, and lymph nodes, among others. 1/25/2025  Pathophysiology of ALL  ALL is caused by a series of acquired genetic aberrations.  Abnormal proliferation, clonal expansion, aberrant differentiation, and diminished apoptosis (programmed cell death) lead to replacement of normal blood elements with malignant cells.  Disease can manifest as leukemia when neoplastic cells (lymphoblasts) involve blood and bone marrow (defined as > 20% bone marrow blasts) or as lymphoma when blasts infiltrate mainly extramedullary tissue. 1/25/2025 1/25/2025  L1- ALL  L1 – Around 25 to 30% of adult cases and 85% of childhood cases of ALL.  In this type small cells are seen with: Regular nuclear shape Homogeneous chromatin Small or absent nucleolus Scanty cytoplasm 1/25/2025  L2-ALL  L2 – Around 70% of adult cases and 14% of childhood cases.  The cells are large and or varied shapes with: Irregular nuclear shape Heterogeneous chromatin Large nucleolus 1/25/2025  Burkitt’s lymphoma type  L3 – This is a rarer subtype with only 1 to 2% cases.  Cells are large and uniform with vacuoles (bubble like features) in the cytoplasm overlying the nucleus 1/25/2025 1/25/2025 Laboratory Diagnosis of Acute Leukemias Complete blood count (CBC) and peripheral blood smear Bone marrow Examination Cytochemistry studies Cytogenetics Immunophenotyping Molecular studies 1/25/2025  Laboratory diagnosis….  A diagnosis of acute leukemia is made when myeloid/ lymphoid blast cells are  ≥ 20% of marrow nucleated cells  or at any myeloid blast or lymphoblast percentage in the presence of recurrent cytogenetic abnormalities [t(8;21), t(15;17), inv(16) or t(16;16)].  Diagnosis can be made by the same criteria using peripheral blood. 1/25/2025  CBC and peripheral smear  are the first tests done; pancytopenia and peripheral blasts suggest acute leukemia.  Blast cells in the peripheral smear may approach 90% of the WBC count. Aplastic anemia, viral infections such as infectious mononucleosis, and vitamin B12 deficiency, and folate deficiency should be considered in the differential diagnosis of severe pancytopenia.  A normocytic normochromic anemia  Variable total white cell count, May be decreased, normal or increased up to 200x109/l or more The degree of peripheral blood involvement determines classification: Increased WBCs due to blasts Blasts without increased WBCs  Thrombocytopenia (Decreased platelets) in most cases, often extreme in 1/25/2025  CBC and peripheral smear  Auer rods (linear azurophilic inclusions in the cytoplasm of blast cells) are the hallmark of acute myeloblastic leukemia.  Unlike in AML, Auer rods (linear azurophilic inclusions in the cytoplasm of blast cells) are never present in acute lymphoblastic leukemia.  Leukemoid reactions (marked granulocytic leukocytosis [WBC > 30 × 109/L] produced by normal bone marrow) to infectious disease never manifest with high blast counts. 1/25/2025  Blast cells of Acute leukemias AML : the myeloblast is a large blast ALL: in contrast to the myeloblast, with a moderate amount of cytoplasm, the lymphoblast is a small blast with fine lacey chromatin, and prominent scant cytoplasm, dense chromatin, nucleoli. indistinct nucleoli, and no auer rods 10-40% of myeloblasts contain auer rods. 56 1/25/2025  Bone marrow examination  BM examination (aspiration and needle biopsy) is routinely done. Blast cells in the bone marrow are typically between 50 and 75% in patients with AML or ALL. 1/25/2025  Bone marrow examination  The bone marrow is hypercellular with a marked proliferation of leukemic blast cells to over 50% -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 1/25/2025  Cytochemical staining  Help distinguish the blasts of AML from those of ALL or other disease processes.  Include staining for myeloperoxidase, which is positive in cells of myeloid origin.  Cytochemical studies include staining for terminal deoxynucleotidyl transferase (TdT), which is positive in cells of lymphoid origin. 1/25/2025  Immunophenotyping  Detection of specific immunophenotypic markers (CD13, CD33, CD34, CD117) is essential in classifying the AML.  CD3 (for lymphoid cells of T cell origin) and CD19, CD20, and CD22(for lymphoid cells of B cell origin) is essential in classifying the ALL. Diagnosis of AML using immunophenotyping Precursor stage: CD34, CD38, CD117, CD133 Granulocytic markers: CD13, CD15, CD16, CD33, CD65, cytoplasmic myeloperoxidase (cMPO) Monocytic markers: Non-specific esterase (NSE), CD11c, CD14, CD64, lysozyme, CD11b, CD36 Megakaryocytic markers: CD41, CD42, CD 63 Erythroid marker CD235a (glycophorin A) 1/25/2025 Cytogenetic Studies  Commonly observed cytogenetic abnormalities in AML and ALL are listed as follows: Commonly cytogenetic abnormalities in Common cytogenetic abnormalities in AML ALL t(9;22)/BCR-ABL1; (Philadelphia t(15;17) /PML-RARA chromosome positive or Ph+) High hyper diploidy (51–65 t(16;16) or inv(16)/CBFB-MYH11 chromosomes in leukemia cells) Hypodiploidy (< 46 chromosomes in t(8;21)//RUNX1-RUNX1T1 leukemia cells) t(12;21)/ ETV6-RUNX1 Trisomy 8 1/25/2025  Differentiation of ALL from AML  In most cases, the clinical features and morphology on routine staining separate ALL from AML  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 62 1/25/2025  Chronic Myeloid Leukemia (CML)  CML is a myeloproliferative disorder resulting from the clonal expansion of a transformed multipotent hematopoietic stem cell.  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  Philadelphia (Ph) chromosome on cytogenetic analysis of blood or bone marrow  Hypercellular bone marrow with granulopoietic predominance  Neutrophil alkaline phosphatase score is low  Increased circulating basophils  Normochromic, normocytic anemia is usual  Platelet count may be increased (most frequently), normal or 68 decreased 1/25/2025  Chronic lymphocytic leukemia (CLL)  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 69 1/25/2025 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 smashed cells are also present  Normocytic normochromic anemia is present in later states due to marrow infiltration or hypersplenism  Autoimmune hemolysis may also occur  Thrombocytopenia may occurs in patients  Bone marrow aspiration shows lymphocytic replacement of normal marrow elements 70 Lymphocytes comprise 25-95% of all the cells 1/25/2025  CLL Smudge Cells 71 1/25/2025  Hairy Cell Leukemia Cont’d….  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 72 1/25/2025  Hairy Cell Leukemia  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 73 1/25/2025  Myelodysplastic Syndromes (MDS)  A heterogeneous group of disease states that usually present as peripheral blood cytopenia's with a hypercellular bone marrow  Elderly and males are more commonly affected  There is a tendency to progress to acute myeloblast leukemia, although death often occurs before this develops  The fundamental disorder is the clonal proliferation of stem cells 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 74 1/25/2025  Myelodysplastic Syndromes (MDS)  The MDS are classified into five subgroups:  Refractory anemia (RA)  RA with ring sideroblasts (RARS)  RA with excess blasts (RAEB) Reading  RAEB in transformation (RAEB-t) Assignment  Chronic myelomonocytic leukemia (CMML) 75 1/25/2025  Laboratory features of MDS  Peripheral blood  Pancytopenia is a frequent finding  The red cells are usually macrocytic or dimorphic but occasionally hypochromic.  The reticulocyte count is low  Granulocytes are often reduced  Bone marrow  The cellularity is usually increased  Ring sideroblasts may occur in all five FAB types  Megakaryocytes are abnormal with micro-, small binuclear or polynuclear forms  Bone marrow biopsy shows fibrosis in 10% of cases 76 1/25/2025  Malignant Lymphomas  Lymphoma is Abnormal proliferation of cells within the lymphatic tissue or lymph nodes, results in a solid tumor (cohesive mass)  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  The non-Hodgkin’s lymphomas are characterized by diffuse or nodular collections of abnormal lymphocytes or, rarely, histiocytes 77 1/25/2025  Hodgkin’s disease  It is a type of lymphoma characterized by the presence of Reed-Sternberg cells  A cancer of the immune system that develops from abnormal B-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  After a variable period of containment within the lymph nodes, the natural progression of the disease is to disseminate to involve non-lymphatic tissue 78 1/25/2025  Reed-Sternberg (RS) 79 1/25/2025  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  There is an almost 2:1 male predominance 80 1/25/2025 Laboratory findings in Hodgkin’s disease  Normochromic, normocytic anemias is most common  One-third of patients have a leukocytosis 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 81 1/25/2025  Non-Hodgkin’s lymphomas  Characterized by diffuse or nodular collection of abnormal Lymphocyte  Diffuse large B-cell lymphoma and follicular lymphoma are among the most common subtypes.  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 1/25/2025 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 83 1/25/2025  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 84 1/25/2025  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 There is usually a normochromic normocytic or macrocytic anemia 85 1/25/2025  Laboratory finding in multiple myeloma cont’d…  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 86 1/25/2025 Myeloproliferative Disorders (MPD)  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  Myeloproliferative disorder include:  Polycythemia vera (PV)  Essential thrombocythemia  Myelofibrosis 87 1/25/2025  Polycythemia Vera (PV)  Also referred to as erythrocytosis  Refers to a pattern of blood cell changes that includes:  An increase in hemoglobin above 18g/dl in adult males and 16g/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 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 88 1/25/2025  Laboratory findings in PV The hemoglobin, hematocrit and red cell count are increased  A neutrophil leukocytosis 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  The bone marrow is hypercellular with prominent megakaryocytes  Blood viscosity is increased  Plasma urate is often increased  Circulating erythroid progenitors are increased 89 1/25/2025  Essential thrombocythemia  A condition with Megakaryocyte proliferation and overproduction of platelets is x-zed by sustained increase in platelet count above normal (400x109/l)  Clinical feature  Recurrent hemorrhage and thrombus  Splenomegaly  splenic atrophy due to platelets blocking the splenic microcirculation is seen in some patients 90 1/25/2025  Essential thrombocythemia  Abnormal large platelets and megakaryocyte fragments may be seen in the blood film The bone marrow is hypercellular megakaryocyte Abnormal Platelet function tests 91 1/25/2025  Myelofibrosis  There is the gradual replacement of the bone marrow by connective tissue/fat acid  A prime feature is extramedullary hematopoiesis  Patients will typically have an enlarged spleen and liver  Typically affects patients more than 50 years old  Transformation to acute myeloid leukemia occurs in 10-20% of patients 92 1/25/2025  Laboratory findings in myelofibrosis  Anemia is usual but a normal or increased hemoglobin level may be found in some patients  Leukocytosis and Thrombocytosis at the time of presentation  Later in the disease leucopenia and thrombocytopenia are common  A leuco-erythroblastic blood film is found  The red cells show characteristic ‘tear-drop’ poikilocytoses  Bone marrow trephine biopsy may show a hypercellular marrow with an increase in reticulin-fiber pattern 93 1/25/2025  Review Questions 1. Briefly describe the classification of leukemia 2. Explain the laboratory diagnosis of different form of leukemia 3. Define myelodysplastic syndrome and indicate the hematological findings 4. What are the features of malignant lymphoma? 5. What are the characteristics multiple myeloma? 6. Describe myeloproliferative disorders 94 1/25/2025  Any questions? 95 1/25/2025