hemopathology - patho.szote.u
Transcription
hemopathology - patho.szote.u
HEMOPATHOLOGY Adult hemopoietic stem cells • Ability to self-renew and to differentiate into erythroid, myeloid, and megakaryocytic cell lineages • Occur in specialized microenvironments of the bone marrow (stem cell niches) • Travel in the blood from the bone marrow in one bone to another bone; may settle in the liver and spleen (extramedullary hemopoiesis) • Morph.: small cells with a rounded nucleus and lowcytoplasm-to-nucleus ratio; lack of lineage markers; not possible to identify them by conventional LM • HSCs constitute 1:10.000 of cells in myeloid tissue Constituents of bone marrow Stem cell compartment Repopulating stem cells and restricted progenitors Differentiated cell compartment Ba myeloblast Ba gr Eo myeloblast Eo gr Myelo (mono)blast Neu Mo gr Megakaryoblast Pronormoblast Megakaryocyte Erythrocyte Trephine biopsy to investigate the constituents of bone marrow Trephine biopsy: elements of normal hemopoiesis Constituents of bone marrow Stem cell compartment Repopulating stem cells and restricted progenitors Differentiated cell compartment Ba myeloblast Ba gr Eo myeloblast Eo gr Myelo (mono)blast Neu Mo gr Megakaryoblast Pronormoblast Megakaryocyte Erythrocyte Peripheral blood From bone marrow: granulocytes, thrombocytes, RBCs; from lymphoid tissues: lymphocytes, NK cells ANEMIA A decrease in the RBC mass and the hemoglobin content in the blood All anemia evaluations should include • Erythrocyte count • Hemoglobin level (normal: 7.4-11.2 mmol/L)) • Hematocrit (normal: 36%-49%) • Mean corpuscular volume (MCV; hematocrit/erythrocyte count) • Peripheral blood smear Anemias according to red cell size •Normocytic (normal) – diverse etiologies •Microcytic (smaller) – disorders of hemoglobin synthesis •Macrocytic (larger) – abnormalities in bone marrow erythroid precursor maturation Normocytic anemia Smear: normal RBC morph.; MCV: 80 -100 fL Common causes • Decreased production due to bone marrow failure (aplastic anemia, myelofibrosis) or tumorous infiltration of bone marrow (leukemia, lymphoma, myeloma, carcinoma metastases) • Increased destruction due to hemolysis (autoimmune hemolytic anaemia, sickle cell anemia, Plasmodium falciparum malaria, etc.) • Decreased stimulation: erythropoietin in bilateral chronic renal disease Evidences of hemolysis Jaundice Serum • Elevation of unconjugated bilirubin • Raised lactic dehydrogenase (LDH) released from ruptured RBCs • Reduced haptoglobin (liberated hemoglobin is initially bound to plasma haptoglobins but these soon become saturated; hemoglobin-haptoglobin complexes are removed from the circulation by the liver) Urine: excess urobilinogen resulting from bilirubin breakdown in the intestine Microcytic anemia Smear: smaller RBCs; MCV < 80 fL Common causes 1. Iron deficiency • Chronic blood loss: GI ulcer/cc, gynecologic disturbances, renal cell cc • Increased requirement: pregnancy • Decreased absorption: sprue, Crohn’s disease 2. Anemia of chronic disease • Increased IL-6 hepatic hepcidin synthesis high levels of plasma hepcidin, which blocks the transfer of iron to erythroid precursors from duodenal epithelium and macrophages. • Collagen-vascular disease, infection, sarcoidosis, etc. Macrocytic anemia Smear: enlarged RBCs; MCV >100 fL Causes • Megaloblastic bone marrow in pernicious anemia: vitamin B12/folate deficiency. Basis of pernicious anemia: autoimmune chronic atrophic gastritis of corpus of stomach loss of intrinsic factor production • Normoblastic bone marrow: chronic alcoholics, liver disease APLASTIC ANEMIA Misleading term applied to a sy of bone marrow failure due to the suppression of trilineage myeloid stem cells pancytopenia Aplastic anemia: suppression of myeloid stem cells Ba myelo blast Ba gr Eo myelo blast Myelo (mono) blast Eo Ne Mo gr gr Megakaryoblast Pronormoblast Mega- Erythkaryo- rocyte cyte Granulopenia, thrombopenia, anemia Pathogenesis • Idiopathic - 65%: T-cell mediated autoimmune suppression of stem cells; intrinsic abnormality of stem cells; defective hemopoietic microenvironment • Secondary to cytotoxic drugs, chemicals (benzene, insecticides), viral infections (hepatitis, HIV, EBV, CMV), whole body irradiation Gross: yellow fatty marrow at sites of red bone marrow (top: femur, bottom: sternum) LM of bone marrow: hypocellular; composed of fat cells and a few ly-s; hemopoietic cells are rare or absent Clinical features May occur at any age Gradual onset of anemia progressive weakness, cutaneous and conjunctival pallor, and dyspnoea; thrombopenia spontaneous bleedings: petechiae, ecchymoses, gingival haemorrhages; granulopenia bacterial infections: ulcerative gingivitis/pharyngitis, pneumonias, colitis, cystitis No splenomegaly Prognosis: variable, bone marrow Tx or immunosuppressive th may be beneficial Diff. dg.: from other causes of pancytopenia • • • • Acute aleukemic leukemia Myelodysplastic sy Lymphoma in bone marrow spaces Cc metastases in bone marrow spaces (lung, breast, prostate) Prostate carcinoma metastases in spine and femur (bottom: normal trabecular structure after formol fixation) MYELOID NEOPLASIAS General features • Malignant clonal disorders of hemopoietic stem cell/restricted progenitors • Arise in the bone marrow and involve the sec. hemopoietic organs (spleen, liver, lymph nodes) • The symptoms are related to the suppression of normal hemopoiesis (e.g., anemia, infection and/or bleeding) • May produce neoplastic leukocytosis in the blood Classification 1) Acute myeloid leukemia 3) Chronic myeloproliferative disorders 3) Myelodysplastic syndromes ACUTE MYELOID LEUKEMIA (AML) • In any age; affects primarily adults • Peak: 60 years of age • Highly malignant Pathogenesis • Hemopoietic stem cell/restricted progenitors gain oncogenic mutations which interfere with transcription factor activities required for normal myeloid cell differentiation • E.g.,: in acute promyelocytic leukemia, a t(15;17;) translocation results in the fusion of the retinoic acid receptor-α gene (RARA) on chromosome 17 to the promyelocytic leukemia (PML) gene on chromosome 15 the fusion product blocks myeloid cell differentiation • Gradual replacement of bone marrow cells with immature leukemic myeloblasts These blasts • suffer additional mutations • spill over into the blood leukemic blood picture • suppress non-mutated stem cells declining normal hemopoiesis Morphology Gross Long bones: yellow blood marrow is replaced by tumorous red bone marrow LM Bone marrow Diagnostic criterion: more than 20% blasts. • The cytoplasm of the blasts contain myeloperoxidase-positive granules • The blasts may exhibit myelomonocytic, monocytic, erythroid or megakaryocytic maturation Grossly, the sites of yellow bone marrow are infiltrated by tumorous red bone marrow. Top: in AML, the diaphysis is replaced by leukemic red bone marrow. Bottom: normally, the diaphysis of femur is filled with yellow fatty bone marrow. AML: leukemic myeloblasts among cells of normal hemopoiesis AML: the marrow is massively infiltrated by myeloperoxidase-positive myeloblasts (Giemsa) Peripheral blood • 10.000 to 100.000 WBCs/ul (smear: the majority are myeloblasts) • On occasion, the patient may have pancytopenia, and the smear does not contain any blasts (aleukemic leukemia; marrow biopsy is required for the dg) AML; blood smear: the majority of nucleated cells are immature myeloblasts Clinical features • Most patients are presented with consequences of anemia, granulopenia, and thrombopenia + mild leukemic infiltration of liver (hepatomegaly), spleen (splenomegaly) + lymph nodes (lymphadenomegaly) • Procoagulants released by leukemic cells can produce DIC – feature of AML with promyelocytic differentiation • Gingival and skin infiltration (leukemia cutis) – feature of AML with monocytic differentiation Outcome • Variable, depends on AML subtype, rapidly fatal if left untreated • Overall 5-y-survival rate ranges between 15%-30% • Death from thrombopenic hemorrhages (CNS, lungs, GI) or from bacterial or fungal infections In promyelocytic leukemia, the PML/RARA fusion protein can be blocked with all-trans retinoic acid (ATRA) + arsenic trioxide producing cure in the majority of patients CHRONIC MYELOPROLIFERATIVE DISEASES • • • • Chronic myeloid leukemia Polycythemia vera Essential thrombocytosis Myelofibrosis Common features • Mutation of stem cell leading to the presence of constitutively active tyrosine kinases that induce growth-factor independent proliferation and survival of marrow progenitors which retain maturation capacity • The neoplastic stem cells infiltrate the marrow and suppress the stem cells of normal hemopoiesis • The neoplastic stem cells settle down in the sec. hemopoietic organs and produce extramedullary hemopoiesis, particularly in the spleen(splenomegaly) • MPDs may progress over time to AML or terminate in a spent phase bone marrow fibrosis and pancytopenia Chronic myeloid leukemia (CML) • Malignant neoplasm of hemopoietic stem cell leading to preferential proliferation of granulocytic progenitors • Disease primarily of adults; peak: between 50-60 ys Pathogenesis • Translocation involving the BCR (Breakpoint cluster Region) gene on chromosome 22 and the ABL (Abelson leukemia virus) gene on chromosome 9 • • The BCR-ABL fusion gene directs the synthesis of a protein with tyrosine kinase activity: increased proliferation and decreased apoptosis of maturing granulocytic progenitors • t[9.22] translocation: designated as Philadelphia chromosome Translocation involving the BCR gene on chrom. 22 and the ABL gene on chrom. 9. The BCR-ABL fusion gene directs the synthesis of a protein with tyrosine kinase activity Kumar et al. Pathologic Basis of Disease, Elsevier, 2005 Morphology • Bone marrow: hypercellular, no fat cells; granulopoiesis predominates • Blood: up to 300000 WBC/ul (ng-s, metamyelocytes, myelocytes, and <10% myeloblasts), anemia • Neoplastic extramedullary hemopoiesis: massive splenomegaly, hepatomegaly, + lymphadenomegaly Clinical course • Chronic phase (lasts for years): weight loss, fatigue, malaise, fever, and sweating; splenomegaly (up to 3000 grams; fills the abdominal cavity and extends into the pelvis + infarcts) left upper quadrant pain • Accelerated phase: increasing severity of anemia and thrombopenia; myeloblasts start to in the bone marrow and blood • Fatal blast crisis phase: features of AML; death: from infections or thrombopenic hemorrhage Tyrosin kinase inhibitor imatinib markedly decreases (but does not eliminate) the number of BCR-ABLpositive cells and yields sustained remission in 90% of patients if administered in the chronic phase Polycythemia vera (PV) Pathogenesis • Increased marrow production of erythrocytes, granulocytes, and platelets because of activating point mutations in the JAK2 tyrosine kinase that participates in JAK/STAT signaling pathways. • The in red cell mass is responsible for most of the clinical symptoms Morphology • Bone marrow: proliferation of erythroid, granulocytic and megakaryocytic elements • Pancytosis in the blood: erythrocytosis (polycythemia; hematocrit > 60%), granulocytosis, thrombocytosis Clinical features • • • • Onset: around 60 ys Skin: plethoric and cyanotic; itching High blood viscosity: headache, dizziness Risk of thrombotic episodes (deep veins, sinuses of the brain, coronaries) • Splenomegaly • Hypertension in most patients • Epistaxis and bleeding gums because of platelet dysfunction Outcome • Phlebotomy to normalize the hematocrit results in median survival of 10 ys • Transformation to AML: infrequent • Left-sided heart failure because of blood hyperviscosity Essential thrombocytosis (ET) Pathogenesis • In majority of patients: activating point mutations in JAK2 • In minority of patients: activating point mutations in MPL, a tyrosine kinase that is normaly activated by thrombopoietin • These mutations induce the hyperproliferation of the megakaryocytic lineage Morphology • Bone marrow: significantly increased number of megakaryocytes, often abnormally large • Blood: thrombocytosis, abnormally large platelets, mild leukocytosis Trephine biopsy in ET: abnormal megakaryocytes Clinical features • Asymptomatic for several years, indolent course • Erythromelalgia: throbbing and burning of hands and feet caused by occlusion of small arteries by platelet aggregates • Paradoxical hemorrhagic complications • Progression to myelofibrosis or transformation to AML: infrequent MYELOFIBROSIS (MF) Development of obliterative marrow fibrosis diminished hemopoiesis cytopenias in the blood + extensive extramedullary hemopoiesis Pathogenesis Two subsets: Primary MF: • JAK2 mutations or MPL mutations (in minority of patients); release of PDGF and/or TGF-beta from neoplastic megakaryocytes marrow fibrosis • Secondary MF: spent phase of PV or ET Morphology • Trephine biopsy: variable cellularity with increased reticulin, progressing to massive deposition of collagen • Late in the course, the fibrotic marrow space can convert to bone (osteosclerosis) bone marrow cannot be aspirated! • Hemopoiesis is displaced to the spleen and liver (myeloid metaplasia) massive splenomegaly (more than 4000 g) and hepatomegaly Myelofibrosis: accumulation of reticulin fibers in marrow spaces Myelofibrosis: the bone trabeculae are thickened, the marrow spaces are narrowed and display fibrosis Myelofibrosis (right): osteosclerosis of the marrow spaces of sternum. Right: normal sternum Myelofibrosis. Note extreme splenomegaly induced by extramedullary hemopoiesis (myeloid metaplasia). The arrow indicates spontaneous infarction of the spleen parenchyma. Liver The patient died of consequences of transformation to acute myeloid leukemia. Spleen Stomach Blood • Anemia, tear-drop erythrocytes (dacrocytes) • Normal or reduced WC count • (quali: presence of granulocytic and erythroid precursors [leukoerythroblastosis]) • Large platelets, later thrombopenia Clinical features of primary MF • Insidious onset in individuals older than 60 ys • With blood transfusions, survival is often a few years MYELODYSPLASTIC SYNDROME (MDS) Hemopoietic stem cell neoplasm characterized by ineffective hemopoiesis manifesting as cytopenia(s), morphologically dysplastic hemopoietic cells, and a high risk of transformation to AML. Pathogenesis Not fully understood • The bone marrow is partly or wholly replaced by the clonal progeny of a mutant multipotent stem cell that retains the capacity to differentiate into red cells, granulocytes, and platelets. • However, the differentiation process is ineffective and disordered. • Bone marrow stromal cells induce increased apoptosis in more mature hemopoietic precursors, accounting for the cytopenia(s). Classification • Primary MDS: affects people above 50 ys, insidious development • Therapy-related (t-MDS): complication of myelosuppressive drug or radiation therapy; 2-8 ys after exposure Morphology Bone marrow: hypercellular or normocellular Dysplasia affecting all three lineages: - ringed sideroblasts (erythroid progenitors with ironladen mitochondria [blue granules in Prussian blue stain]) - neutrophils with little granulation and abnormal nuclear features - hypolobated or hyperlobated megakaryocytes Blood: cytopenia(s) Clinical features • Pancytopenia-related weakness, infections, haemorrhages • Progression to AML in 10-40% of patients; some die of bleeding or infection • Median survival in primary MDS: 9 to 29 mo, in tMDS: 4 to 8 mo