Leukemias Notes

NOTES NOTES LEUKEMIAS GENERALLY, WHAT ARE THEY? PATHOLOGY & CAUSES ▪ Malignant neoplastic monoclonal proliferation of hematopoietic blood cells ▪ Abnormal blood cells/precursors accumulate in bone marrow → physical suppression → prevent maturation TYPES Acute ▪ Acute lymphoid leukemia ▪ Acute myeloid leukemia Chronic ▪ Chronic lymphoid leukemia ▪ Chronic myeloid leukemia RISK FACTORS ▪ Numerical, structural chromosomal aberrations ▪ Ionizing radiation, chemotherapy ▪ Benzene exposure COMPLICATIONS ▪ Infections, bleeding → death SIGNS & SYMPTOMS Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis ▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis 394 OSMOSIS.ORG Neoplastic infiltration ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ Blood count Blood smear Bone marrow smear Immunophenotyping TREATMENT MEDICATIONS ▪ Chemotherapy SURGERY ▪ Bone marrow transplantation OTHER INTERVENTIONS ▪ Radiation therapy

Chapter 48 Leukemias ACUTE LYMPHOID LEUKEMIA (ALL) osms.it/acute-lymphoid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of lymphoid stem cells (lymphoblasts) in bone marrow ▪ Immature lymphoblasts accumulate in bone marrow → physical suppression → prevent maturation TYPES B cell acute lymphoblastic leukemia (B-ALL) ▪ Most common (85%) ▪ Origin ▫ Pre-B cells of bone marrow ▪ Associated with translocations t(12,21), t(9,22) T cell acute lymphoblastic leukemia (T-ALL) ▪ Origin ▫ Pre-T cells in thymus ▪ Associated with NOTCH1 mutation RISK FACTORS ▪ Young age (most common leukemia in children) ▫ B-ALL: peak incidence at three years old ▫ T-ALL: peak incidence at 15–20 years old ▪ Down syndrome (after age five) ▪ Radiation exposure SIGNS & SYMPTOMS ▪ Abrupt onset Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis ▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis Neoplastic infiltration ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity DIAGNOSIS LAB RESULTS Blood count, smear of peripheral blood ▪ ↑ lymphoblasts ▪ ↑ white blood cells Bone marrow smear ▪ Hypercellular bone marrow, lymphoblast domination (> 20%) ▪ T-ALL ▫ “Starry sky” pattern produced by phagocytosing macrophages ▪ Mitotic figures Immunophenotyping ▪ Terminal deoxynucleotidyl transferase (TdT) ▫ Positive nuclear staining, distinguish from acute myeloid leukemia (AML) ▪ B-ALL ▫ Express tumor markers CD10, CD19, CD20 ▪ T-ALL ▫ Express tumor markers CD1, CD2, CD5, CD7, CDH OSMOSIS.ORG 395

TREATMENT MEDICATIONS ▪ Aggressive chemotherapy with prophylactic injections to scrotum, cerebrospinal fluid (CSF) ▫ 95% complete remission, 75% cure rate ▫ More successful in children > two years old ▪ If spread to brain ▫ Intrathecal chemotherapy/radiation therapy ▪ Tyrosine-kinase inhibitors MNEMONIC: ABCDE Characteristics of Acute leukemias Acute: Blasts predominate Children Drastic course Elderly Few WBC’s (+ Fevers) Figure 48.1 A bone marrow film from an individual with acute lymphoid leukemia. ACUTE MYELOID LEUKEMIA (AML) osms.it/acute-myeloid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of myelogenous stem cells (myeloblasts) in bone marrow ▪ Immature myeloblasts accumulate in bone marrow → physical suppression → prevents maturation TYPES Acute promyelocytic leukemia ▪ Associated with translocation t(15,17) → disruption of retinoic acid receptor → promyelocytes accumulate Acute monocytic leukemia 396 OSMOSIS.ORG Acute megakaryocytic leukemia RISK FACTORS ▪ ▪ ▪ ▪ Adults age; peak at 60 Radiation, chemotherapy Myeloproliferative disorders Down syndrome (before age five) COMPLICATIONS ▪ Disseminated intravascular coagulation (DIC) SIGNS & SYMPTOMS ▪ Abrupt onset

Chapter 48 Leukemias Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis ▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis Neoplastic infiltration ▪ Symptoms less common in AML than ALL ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity Neoplastic infiltration ▪ Symptoms more common in AML than ALL ▪ Skin ▫ Leukemia cutis ▪ Gums ▫ Swelling (classic) SURGERY ▪ Bone marrow transplantation Figure 48.2 The histological appearance of a myeloid sarcoma, also known as a chloroma. The tumor is an extramedullary manifestation of acute myeloid leukemia. DIAGNOSIS LAB RESULTS Blood count, blood smear ▪ ↑ leukocytes, anemia Bone marrow smear ▪ ↑ myeloblasts > 20% ▪ Myeloblasts containing Auer rods (aggregates of myeloperoxidase) TREATMENT MEDICATIONS Figure 48.3 A CT scan of the head in the axial plane demonstrating a myeloid sarcoma, or chloroma, of the occiput. The tumor is extradural and destroying the overlying bone. ▪ Chemotherapy ▪ All-trans retinoic acid treatment ▫ For promyelocytic leukemia OSMOSIS.ORG 397

MNEMONIC: ABCDE Characteristics of Acute leukemias Acute: Blasts predominate Children Drastic course Elderly Few WBC’s (+ Fevers) CHRONIC LYMPHOID LEUKEMIA (CLL) osms.it/chronic-lymphoid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of mature, functionally abnormal B lymphocytes in bone marrow, blood ▪ Mature B lymphocytes accumulate in bone marrow → physical suppression → prevent maturation CAUSES ▪ Chromosomal abnormalities ▪ Mutation of proteins involved in tyrosine kinase pathway (e.g. Bruton’s tyrosine kinase) RISK FACTORS ▪ Adult age; most common leukemia in adults ▪ Family history ▪ Agent Orange exposure COMPLICATIONS ▪ Abnormal Ig secretion ▫ Hypogammaglobulinemia, autoimmunity (e.g. autoimmune hemolytic anemia) ▪ Richter syndrome ▫ Progresses into aggressive lymphoma (e.g diffuse large B cell lymphoma) 398 OSMOSIS.ORG SIGNS & SYMPTOMS ▪ Late onset Cellular maturation absent ▪ Anemia → fatigue, shortness of breath, pallor ▪ Thrombocytopenia → bruising, petechiae, epistaxis ▪ Neutropenia → bacterial infections → fever, pneumonia, sepsis Neoplastic infiltration ▪ Symptoms less common in AML than ALL ▪ Bone marrow ▫ Bone pain ▪ Thymus ▫ Palpable mass, airway compression ▪ Liver and spleen ▫ Hepatosplenomegaly ▪ Lymph nodes ▫ Lymphadenopathy ▪ Meningeal infiltration ▫ Headaches, vomiting, nerve palsies, nuchal rigidity

Chapter 48 Leukemias DIAGNOSIS LAB RESULTS Blood count, blood smear ▪ Lymphocytosis > 5,000 per mm3 ▪ Smudge cells: disruption of fragile cell membranes of abnormal lymphocytes Immunophenotyping ▪ CD5, CD20, CD23 OTHER DIAGNOSTICS Surgery ▪ Lymph node biopsy ▫ ↑ small, round lymphocytes infiltration ▫ Proliferation centers (pathognomic) TREATMENT Figure 48.4 The gross pathological appearance of the spleen in a case of chronic lymphoid leukemia. The lymph nodes at the hilum of the spleen are also involved. MEDICATIONS ▪ Chemotherapy ▪ Immunotherapy SURGERY ▪ Bone marrow transplant OTHER INTERVENTIONS ▪ Radiation therapy Figure 48.5 The histological appearance of chronic lymphocytic leukemia. There is a proliferation centre (also known as a pseudofollicle) composed of malignant lymphocytes with bigger, larger nuclei. This proliferation centre is surrounded by small, darker staining lymphocytes. Figure 48.6 A CT scan in the coronal plane demonstrating splenomegaly as a consequence of chronic lymphoid leukemia. OSMOSIS.ORG 399

CHRONIC MYELOID LEUKEMIA (CML) osms.it/chronic-myeloid PATHOLOGY & CAUSES ▪ Neoplastic monoclonal proliferation of mature granulocytes/precursors ▪ Mature granulocytes accumulate in bone marrow → physical suppression → prevent maturation ▪ Associated with Philadelphia chromosome t(9, 22) → BCR-ABL1 fusion → chimeric protein with strong tyrosine kinase activity (> 90% of individuals) RISK FACTORS ▪ Adult age (> 40 years), radiation exposure, benzene exposure SIGNS & SYMPTOMS ▪ Classified by clinical signs, lab results ▪ Increasing anemia, thrombocytopenia, basophilia ▪ Bone pain, fever ▪ Significant splenomegaly DIAGNOSIS LAB RESULTS Blood count, blood smear ▪ ↑ granulocytes (basophils, eosinophils, neutrophils) Bone marrow biopsy ▪ Hypercellularity (cells of myeloid cell line/ precursors) ▪ Karyotypic analysis ▫ Fluorescent in situ hybridization (FISH), PCR: BCR-ABL1 gene mapping ▪ Mild fibrosis Chronic phase (85% at time of diagnosis) ▪ Leukocytosis (predominantly neutrophils) ▪ Asymptomatic/non-specific symptoms ▫ Fatigue, weight loss, loss of energy, fever Accelerated phase ▪ > 20% basophils in blood/bone marrow ▪ 10–19% myeloblasts in blood/bone marrow ▪ Anemia ▪ Splenomegaly, hepatomegaly, lymphadenopathy ▪ Recurrent infections ▪ Bleeding, petechiae, ecchymoses ▪ Treatment less effective Blast crisis ▪ Terminal phase; rapid progression, low survival rate ▪ > 20% myeloblasts/lymphoblasts in blood/ bone marrow 400 OSMOSIS.ORG Figure 48.7 A bone marrow smear demonstrating a small, hypolobated megakaryocyte, typical of chronic myelogenous leukemia.

Chapter 48 Leukemias TREATMENT MEDICATIONS ▪ Tyrosine kinase inhibitors SURGERY ▪ Bone marrow transplantation OSMOSIS.ORG 401