This study guide was prepared by Fanconi.

SKELETAL SYSTEM AND SOFT TISSUE TUMORS

Bone Tumors

§         Osteoma

®      Skull and facial bones

®      Osteoblastic tumor

®      Comprise local organ function

®      Multiple = Gardner’s syndrome (polyposis)

§         Osteoid Osteoma

®      Small, benign, no malignant potential

®      Radiolucent nidus, highly vascular spindled stroma

®      Peripheral sclerotic bone spicules

®      Pain ­ PGE2 production

§         Osteoblastoma

®      Giant osteoid osteoma

®      Involves spine more frequently

®      Not as painful

®      May transform to osteosarcoma

§         Osteosarcoma

®      Malignant mesenchymal tumor

®      Cells produce bone matrix

®      Bimodal age distribution (<20 and elderly)

®      Only multiple myeloma is more common bone cancer

®      Familial retinoblastoma ­ incidence (radiation exposure)

®      Sporadic = not assoc. with Rb gene, 3 mutations (Li Fraumeni)

®      80-90% arise in metaphyseal ends of long bones

®      Codman triangle = cortical penetration of tumor with periosteal elevation

Cartilage-Forming Tumors

§         Osteochondroma

®      Autosomal dominant, multiple hereditary exostosis (may lead to chondrosarcoma)

®      Displacement of lateral portion of growth plate

®      3 male: 1 female

®      On metaphyses of long bones, mushroom-shaped, lateral projections

®      Benign, but can transform in familial form

§         Chondroma

®      Benign tumors, mature hyaline cartilage

®      Remnants of epiphyseal cartilage left behind

®      Enchondromatosis = Ollier disease (non-familial)

®      Maffucci syndrome = multiple chondromas with hemangiomas

®      With multiple tumors, transformation to sarcoma is common

§         Chrondroblastoma

®      Rare benign tumor, epiphyses of skeletally immature people

®      Polygonal tumor cells, look like embryonic chondroblasts

®      Multinucleated, osteoclast-like giant cells

®      Chicken wire (scan mineralized matrix)

§         Chondromyxoid Fibroma

®      Uncommon

®      X-ray = circumscribed lucency with scattered calcifications

®      Treated by curettage

§         Chondrosarcoma

®      75% arise de novo

®      Middle to later life, central skeleton and around knee

®      Lobulated translucent tumors, necrosis and spotty calcification

®      X-ray may be diagnostic = localized bone destruction with mottled densities

Fibrous and Fibro-osseous Tumors

§         Fibrous Cortical Defect

®      Non-neoplastic, extremely common developmental lesion

®      Does not transform into malignancy, disappear spontaneously

§         Fibrous Dysplasia

®      Chinese figures = trabeculae of woven bone

®      Localized, benign, progressive replacement of bone

®      70% monostotic

®      Polyostotic disease with endocrinopathies, skin pigmentation and precocious sexual development = McCune-Albright syndrome

§         Fibrosarcoma and Malignant Fibrous Histiocytoma

®      Gray-white infiltrative masses

®      De novo or background of Paget disease, bone infarcts, prior radiation

®      Starry pattern with bizarre multinucleated giant cells

§         Ewing Sarcoma and Primitive Neuroectodermal Tumor

®      Malignant small cells

®      t(11;22)

®      Ewing sarcoma is more undifferentiated

®      B>G, blacks rarely affected

®      Homer-Wright pseudorosettes (central fibrillary space)

®      Necrosis, can metastasize

®      Painful, warm enlarging mass (looks like an infection)

®      Onion-skin periosteal reaction

§         Giant Cell Tumor of Bone

®      Locally aggressive neoplasm

®      Most common 20-55

®      X-ray = soap-bubble lesions

®      Multinucleated giant cells = fusion of spindle cells

§         Metastatic Tumors to the Skeleton

®      Adults = prostate, breast, kidney, lung

®      Kids = neuroblastoma, Wilms’ tumor, osteosarcoma….

®      Prostaglandins, interleukins, parathyroid hormone-related protein

®      Prostate and breast CA = osteoblastic activity (osteosclerotic response)

DISEASES OF WHITE CELLS

Neutropenia (agranulocytosis)

§         Inadequate granulopoiesis

®      Infiltrative bone marrow disorders

®      Suppression of precursors (drugs)

o        Dose related (alkylating agents, antimetabolites)

o        Idiosyncratic (chloramphenical, sulfonamides…)

®      Disease states (B-12 deficiency, myelodysplastic syndromes)

®      Rare inherited conditions (Kostmann syndrome)

®      Marrow hypocellularity

§         Accelerated removal or destruction

®      Immunologic disorders, drug exposure

®      Splenic sequestration

®      Increased utilization (bacterial, fungal, rickettsial infections)

®      Marrow hypercellularity

Reactive Proliferations of White Cells and Nodes

§         PMN leukocytosis

®      Acute inflammation

§         Eosinophilic leukocytosis

®      IL-5

®      Allergic disorders, parasitic infections, drug reactions

®      HD, MHL

®      Collagen-vascular disorders

®      Atheroembolic disease transiently

§         Basophilic leukocytosis

®      Myeloproliferative disease (e.g., CML)

§         Monocytosis

®      Chronic infections (TB, SBE, rickettsiosis, malaria)

®      Collagen-vascular disorders (SLE)

®      Inflammatory bowel disease (ulcerative colitis)

§         Lymphocytosis

®      IL-7 and c-kit ligand

®      Accompanies monocytosis in chronic immune stimulation

®      Viral infections

®      Bordetella pertussis

§         Pathogenesis

®      IL-1 and TNF = release from bone marrow storage pool

®      Glucocorticoids = increased demargination and decreased extravasation

§         Toxic changes in neutrophils

®      Toxic granulations

®      Dohle bodies = dilated endoplasmic reticulum

®      Vacuoles

§         Leukemoid reactions

®      Childhood viral infections (can look like ALL)

®      Severe inflammatory states

§         Acute nonspecific lymphadenitis

®      Localized = microbiologic drainage (cervical area = teeth, tonsils)

®      Systemic = viral infections and bacteremia

®      Morphology = Large germinal centers with many mitotic figures

§         Chronic nonspecific lymphadenitis

®      Follicular hyperplasia = activating B cells

o        RA, toxo, early HIV infections

o        How to tell apart from follicular lymphoma:  preservation of lymph node architecture, including T cell zones and sinusoids

o        Marked variation in shape and size of nodules

o        Frequent mitotic figures

®      Paracortical lymphoid hyperplasia

o        Reactive changes in T cell areas

o        Dilantin reactions

o        Infectious mononucleosis

o        Vaccination against certain viral diseases

®      Sinus histiocytosis

o        Reticular hyperplasia

o        Lymph nodes draining cancers

o        Immunologic response to cancer antigens

Neoplastic Proliferations of White Cells

§         Lymphoid neoplasms

§         Myeloid neoplasms

§         Histiocytoses

Lymphoid Neoplasms

§         Tumors of Precursor B Lymphocytes

®      Precursor B cell acute lymphoblastic leukemia/lymphoma

o        Immature TdT + B cells that is most common in childhood

o        Genetically heterogenous

§         Tumors of Precursor T Lymphocytes

®      Precursor T cell acute lymphoblastic leukemia/lymphoma

o        TdT + T cells most common in adolescent boys

o        Mediastinal mass

o        Genetically heterogenous

§         Tumors of Mature B cells

®      Small lymphocytic lymphoma/chronic lymphocytic leukemia

o        Indolent CD5+/CD23+ B cell tumor of older adults

o        Nodal and splenic enlargement

®      Mantle cell lymphoma

o        Moderately aggressive CD5+/CD23-

o        Older adults within lymph nodes or extranodal

o        BCL1 gene

®      Follicular lymphoma

o        CD10+ B cell tumor of older adults

o        Presents in lymph nodes

o        BCL2 regarrangement

®      Burkitt lymphoma

o        Aggressive B cell tumor of adolescents

o        Extranodal

o        C-myc gene rearrangement

®      Diffuse large B cell lymphoma

o        Aggressive, most common in adults

o        Extranodal or within LN

o        Genetically heterogenous

®      Marginal zone lymphoma

o        CD5-/CD10-

o        Adults

o        Extranodal

o        Chronic inflammatory, autoimmune reactions

®      Hairy cell leukemia

o        CD5-/CD10-

o        Bone marrow and spleen

o        Older patients, serum hyperviscosity

®      Lymphoplasmacytic lymphoma

o        CD5-/CD10-, partial differentiation to IgM-producing plasma cells

o        Marrow, liver, spleen

o        Hyperviscosity

®      Multiple myeloma/solitary plasmacytoma

o        Plasma cells, destructive bony lesions

o        Secrete partial or complete Ig

o        Poor prognosis

§         Tumors of Mature T cells and NK cells

®      Peripheral T-cell lymphoma

o        Histologically, genetically heterogenous

o        Aggressive course

®      Adult T-cell lymphoma/leukemia

o        CD4+ mature T cells, assoc. with HTLV-1

o        Poor prognosis

®      Mycosis fungoides/Sezary syndrome

o        CD4+ epidermotropic mature T cells

o        Generally indolent course

®      Large granular lymphocytic leukemia

o        Indolent tumor of mature T cells or NK cells (less common)

o        Marrow, peripheral blood involvement

o        Anemia, neutropenia

®      Angiocentric lymphoma

o        Locally destructive

o        Sinonasal area

o        NK cell markers and EBV genomes

o        Aggressive

Specific Entities within the REAL Classification

§         ALL

®      95% TdT +

®      Pre-B = CD19

®      Pre-T = CD1a

®      Good prognosis = hyperdiploidy, t(12;21)

®      Bad prognosis = t(9;22) Philadelphia, 11q23 (MLL gene)

®      Abrupt stormy onset, symptoms of depression of normal marrow function, bone pain and tenderness, generized lymphadeopathy, splenomegaly, and hepatomegaly, CNS manifestations.

®      Bad prognosis = < 2 years old (MLL gene), presentation in adolescence or adulthood, Philadelphia chromosome

§         CLL

®      Pan-B cell markers CD19 and CD20, some CD5 and sIg (IgM)

®      Trisomy 12 and deletions of 11q = bad prognosis

®      Presents age >50, 2M:1F, generalized lymphadeopathy

®      Prolymphocytic transformation

®      Transformation to diffuse large B cell lymphoma (Richter syndrome) = rapidly enlarging mass within a LN

§         Follicular lymphoma

®      45% of adult lymphomas (most common)

®      Centrocytes = small cleaved cells

®      Centroblasts = several nucleoli = blocks apoptosis

®      BCL2 expression, t(14;18)

®      B cell markers = CD19, CD20, CD10, sIg

§         Diffuse large B cell lymphoma

®      B cell markers CD19, CD20

®      30% have t(14;18)

®      30% have BCL-6 translocation, zinc-finger transcription factor normally expressed in germinal centers (better prognosis)

®      Bad prognosis = p53 mutation

®      HHV8 = body cavity lymphoma

§         Burkitt Lymphoma

®      Endemic = African, young

®      Sporadic = elderly

®      Starry sky appearance

®      Mature B cell markers, surface IgM, monotypic kappa or lambda light chain, CD19, CD20, and CD10

§         Multiple Myeloma

®      Plasma cell tumor with lytic bone lesions at multiple sites

®      IL-1b, IL-6 = osteoclast-activating factors

®      Balanced translocation of FGFR3 (fibroblast growth factor receptor 3) under control of IgH promoter

®      Protein casts in kidneys

®      Metastatic calcifications secondary to hypercalcemia

®      Nonamyloid light-chain deposition in kidneys (does not stain with Congo red)

®      Bence Jones proteins in urine

®      M protein in serum is IgG, usually

®      Suppression of normal humoral immunity

®      Recurrent infections with bacteria

®      Hyperviscosity syndrome

®      Renal insufficiency

§         Plasmacytoma

®      Solitary bony lesions

§         Lymphoplasmacytic Lymphoma

®      B-cell neoplasm that secretes monoclonal IgM, hyperviscocity = Waldenstrom macroglobulinemia

®      Visual impairment

®      Neurologic problems

®      Cryoglobulinemia (Raynaud phenomenon)

®      Plasmapheresis

§         Mantle Cell Lymphoma

®      CD5+ B-cell neoplasm

®      Overexpression of cyclin D1 (progression from G1 to S)

®      Cytogenetics:  t(11;14) puts BCL-1 under control of IgH promoter

§         Marginal Zone Lymphoma

®      Chronic autoimmune reactions (Sjorgren) or infections (H. pylori)

®      Stepwise progression from a polyclonal immune reaction to monoclonal neoplasm

®      Good prognosis (e.g., treat gastritis)

§         Hairy Cell Leukemia

®      B cell neoplasm

®      CD11c, CD25 (IL-2 receptor), PCA-1

®      Splenic red pulp infiltrated, obliteration of white pulp

®      Hepatic portral triads infiltrated

§         Peripheral T cell Lymphoma

®      Lack TdT and CD1

®      Express Pan-T cell markers Cd2, Cd3, and T cell alpha-beta or delta-gamma receptors

®      Generalized lymphadenopathy, eosinophilia, pruritis, fever, weight loss

§         Adult T cell Lekuemia/Lymphoma

®      HTLV-1 infection

®      Southern Japan, Caribbean

®      Cells with multilobar nuclei (cloverleaf or flower cells)

®      Skin involvement

®      Gen. Lymphadenopathy, hepatosplenomegaly

®      Lymphocytosis

®      Hypercalcemia

§         Mycosis Fungoides and Sezary Syndrome

®      T cell tumors of the skin

®      Cerebriform nucleus of T cells (infolding of nucleus)

®      CD4+ T cells

§         Large Granular Lymphocytic Leukemia

®      T cell tumors that express CD3 and CD8

®      NK tumors express CD16 and CD56

®      Neutropenia, pure red cell aplasia, increased incidence of rheumatologic disorders

®      Felty’s syndrome = RA, splenomegaly, neutropenia

®      Splenic red pulp and hepatic sinusoids infiltrated

®      Azurophilic granules

§         Angiocentric Lymphoma

®      Destructive midline mass of oropharynx

®      NK cell origin

®      EBV infection

Hodgkin Disease

§         Immunophenotype of Reed-Sternberg Cells and Variants

®      Classic, mononuclear, and lacunar variants are negative for B and T cell markers, but positive for CD15 and CD30

®      L+H cells are positive for pan-B cell markers, CD20, and negative for CD15 and CD30

§         HD, Nodular Sclerosis Type

®      Most common

®      Lacunar cell

®      Collagen bands divide tissue into nodules

®      Only form of HD that is more common in women

§         HD, Mixed Cellularity Type

®      Diffuse effacement of lymph nodes

®      Classic R-S cells and mononuclear variants

®      Men, B symptoms, older age, advanced stage

§         HD, Lymphocyte Predominance Type

®      L+H R-S cells

§         Pathogenesis

®      R-S cells make IL-5 ® eosinophilia (mixed cellularity and nodular sclerosis types)

®      TGF-b is a fibrogenic cytokine, nodular sclerosis, secreted by eosinophils

®      EBV transcripts are NOT found in lymphocyte predominance type HD

®      EBV-infected cells express latent membrane protein-1 = transforming activity

§         Clinical features

®      Painless enlargement of LN

®      4 stages

®      increased incidence of MDS, AML, NHL, solid tumors

Myeloid Neoplasms

§         AML

§         Myelodysplastic syndromes

§         Chronic myeloproliferative disorders

Acute Myelogenous Leukemia

§         M0

®      Minimally differentiated AML

®      Myeloperoxidase negative

®      Myeloid lineage antigens

§         M1

®      AML without differentiation

®      Immature but perixodase positive

®      Few granules or Auer rods

§         M2

®      AML with maturation

®      Most common

®      Auer rods

®      Favorable prognosis with t(8;21)

§         M3

®      Acute promyelocytic leukemia

®      Auer rods, DIC, t(15;17), patients are younger (35-40)

§         M4

®      Acute myelomonocytic leukemia

®      Chromosome 16 abnormalities

®      Myelocytes and monocytes

®      Marrow eosinphilia

®      Good prognosis

§         M5

®      Acute monocytic leukemia

®      M5a = monoblasts, M5b = monocytes

®      Tissue infiltration

§         M6

®      Acute erythroleukemia

®      Dysplastic erythroid precursors

®      20% of therapy-related AML

§         M7

®      Acute megakaryocytic leukemia

®      Blasts react with platelet-specific antibodies directed against Gp IIb/IIIa or vWF, myelofibrosis or increased marrow reticulin

§         Chromosomal abnormalities

®      AML that follows MDP often involves loss of chromosome 5 or 7

®      De novo AML usually involves balanced translocations

®      Treatment-induced AML usually involves MLL gene at 11q23 (etoposide)

®      M3 involves fusion of a truncated retinoic acid receptor-a, blocking differentiation (give ATRA)

Myelodysplastic Syndromes

§         Stem cell damage

§         Monosomy 5 or 7

§         Trisomy 8

§         Deletions of 20q

§         Morphology

®      Erythroid

o        Ringed sideroblasts

o        Megaloblastoid maturation

o        Nuclear budding abnormalities

®      Granulocytic

o        PMNs with toxic granules or Dohle bodies

o        Pseudo-Pelger-Huet anomaly (PMNs with two nuclear lobes)

®      Megakaryocytic

o        MKs with single nuclear lobes or multiple separate nuclei

®      Peripheral Blood

o        Pseudo-Pelger-Huet cells, giant platelets, macrocytes, poikilocytes, monocytosis

§         Prognosis

®      Poor prognosis = development after cytotoxic therapy, increased blasts, chromosomal abnormalities, severe thrombocytopenia

Chronic Myeloproliferative Disorders

§         CML

§         PV

§         ET

§         Myelofibrosis with myeloid metaplasia

Chronic Myelogenous Leukemia

§         Philadelphia t(9;22)

®      BCR-ABL fusion gene, p210, increased protein kinase activity

®      No leukocyte alkaline phosphatase

o        Stable phase

o        Accelerated phase

o        Blast phase

®      70% has morphology of blasts

®      30% express TdT, Cd10, CD19

§         Patients may profess to a phase of diffuse marrow fibrosis

Polycythemia Vera

§         Trilineage stem cell disorder

®      Absolute increase in stem cell mass

®      Bone marrow hyercellularity

®      Peripheral basophilia and neutrophilia (left shift)

®      Giant platelets

®      Mild organomegaly

§         Marrow fibrosis, can transform into AML

§         Pruritis after hot shower

Essential Thrombocytopenia

§         Megakaryocytes have diminished need for growth factors

®      Platelet dysfunction = bleeding and thrombosis

®      Erythromelalgia = throbbing and burning of hands and feet

Myelofibrosis with Myeloid Metaplasia

§         Collagen deposition in marrow by non-neoplastic fibroblasts

®      PDGF, TGF-b from neoplastic megakaryocytes

§         Leukoerythroblastosis = immature cells released from bone marrow

®      Tear drop erythrocytes

®      Increased basophils

®      Enlarged platelets

®      High cell turnover, hyperuricemia and gout may complicate the picture

Langerhans Cell Histiocytosis

§         Clonal proliferation of antigen presenting dendritic cells

®      Abundant vacuolated cytoplasm

®      Overpexression of HLA-DR, Fc recptors, and CD1a

®      HX bodies = Birbeck granules ® looks like a tennis racket (electron microscope)

§         Unifocal = usually affects skeletal system of children

§         Multifocal = Children with fever, diffuse eruptions (otitis media, URI)

®      Hand-Schuller-Christian triad

o        Calvarial bone defects

o        Diabetes insipidus

o        Exophthalmos

§         Disseminated = Letterer-Siwe disease

®      Occurs before age 2

®      Anemia with destrutive bony lesions

®      Rapidly fatal in untreated

®      With chemo, 5-yr survival = 50%

DISEASES OF RED CELLS

Anemias

§         Anemias of blood loss

®      Acute blood loss, incr. reticulocytes

®      Chronic blood loss = iron deficiency anemia

§         Hemolytic anemias

®      Premature destruction of red cells

®      Accumulation of hemoglobin catabolism (bilirubin)

®      Increased reticulocytosis

®      Intravascular hemolysis

o         Microangiopathic or complement-mediated lysis

o         Hemoglobinemia, hemoglobinuria

o         Hemosiderinuria

o         Jaundice

o         Reduction in serum haptoglobin

®      Extravascular hemolysis

o         Mononuclear phagocytes of spleen, other organs

o         No hemoglobinemia, hemoglobinuria

§         Hereditary spherocytosis

®      75% autosomal dominant

®      Deficiency of spectrin = unstable membranes, reduced flexibility

®      Marrow shows normoblastic hyperplasia

®      Asplatic crisis with parvovirus infections

®      Gallstones ®chronic hyperbilirubinemia

®      Increased mean cell hemoglobin concentration (MHC) ® dehydration

§         Glucose-6-phosphate dehydrogenase deficiency

®      Can’t produce glutathione to protect cells from oxidant stress

®      Altered hemoglobin preceipitates = Heinz bodies

®      X-linked

®      G6PD A- = American blacks, progressive loss of G6PD in older red cells, hemolysis with antimalarias.  Younger red cells are not affected.

®      G6PD Mediterranean = levels of G6PD much lower, more severe anemia (cis).  Hemolysis after eating fava beans.

§         Sickle Cell Disease

®      Point mutation of beta globin gene = substitution of valine for glutamic acid at N6.  Transforms HbA to HbS.

®      Amount of HbS and its interaction with other hemoglobin chains is most important factor leading to sickling of red cells.

o         HbF fails to interact with HbS.

o         HbC has a strong tendency to interact with HbS = more severe disease than those with sickle cell trait.

®      MCHC is also important.  Dehydration increases NCHC, facilitates sickling.

®      Coexistence of alpha-thalassemia reduces MCHC and lowers severity of the sickling.

®      Avg. red cell survival shortened by 20 days.

®      Microvascular inclusions ® infarction ® autosplenectomy.

®      Bone marrow shows normoblastic hyperplasia ®resorption of bone can occur.

®      Tendency to develop gallstones.

®      Avascular necrosis of bone can mimic osteomyelitis.

®      Aplastic crises with parvocirus infection or folate deficiency.

®      Susceptibility to Salmonella osteomyelitis and others caused by encapsulated organisms.

§         Thalassemia Syndromes

®      Beta thal = deficient synthesis of beta globin chain.

o         Free alpha chains form highly unstable aggregates that damage cell membrane, leading to a loss of K+ and impaired DNA synthesis.

o         In Bº = total absence of beta globin in homozygous state

o         In B+ = reduced but detectable beta globin chains.

o         Thalassemia major = Patient is transfusion dependent.  Iron overload leads to secondary hemochromatosis.

o         Thalassemia minor = Presence of one normal gene.  Basophilic stippling of RBCs, increase in HbA2.

o         Thalassemia intermedia = in between the two above.

o         Aberrant mRNA splicing = most common defect.

®      Alpha-thal = reduced synthesis of alpha globin because of deletion of one to all four normally present genes.

o         Unstable non-a aggregates form

o         Silent carrier state = one gene deletion.

o         Alpha-thal trait = two genes absent.  Clinical picture identical to thalassemia minor.

o         HbH disease = Three genes missing.  Excess tetramers of beta globin.

o         Hydrops fetalis = Excess Hb Barts (gamma chains).  Deletion of all four genes.

§         Paroxysmal Nocturnal Hemogloinuria

®      Only hemolytic anemia from a membrane defect that is not inherited.

®      Mutation in glycosylphosphatidylinositol glycan.  Proteins linked to this include delay-accelerating factor (Cd55), membrane inhibitor of reactive lysis (CD59), and C8-binding protein.

®      Spontaneous in vivo activation of the alternate complement pathway.

®      Clonal disorder of multipotent stem cells that sometimes transforms into aplastic anemia or acute leukemia.

§         Immunohemolytic Anemia

®      Warm Antibody Hemolytic Anemia

o         IgG, not complement fixing.

o         Opsonized red cells become spherocytes ® splenomegaly.

o         Hapten-model (penicillin)

o         Autoantibody model (a-methyldopa)

o         Seoncdary to lymphomas, leukemias, SLE

®      Cold Agglutinin Type

o         IgM, fixes completed at warm temps, agglutinates in cool peripheral parts of body.

o         Acute mycoplasma infection, mono, assoc. with lymphomas

®      Cold Hemolysins

o         IgG binds RBCs at low temps, fixes complement, causes hemolysis when temperature is raised to 30 degrees C.

§         Microangiopathic Anemia

®      Trauma to red cells

®      Prosthetic heart valves

®      DIC

®      Burr cells, helmet cells, triangular cells.

Anemias of diminished erythropoiesis

§         Megaloblastic anemia

®      Deficiency of B12 or folate

®      Abnormally large erythroid precursors = megaloblasts

®      Nuclear maturation lags behind cytoplasmic maturation

®      Anisocytosis = variation in cell size

®      Abnormal granulopoeisis = giant metamyelocytes and hypersegmented PMNs.

®      B12 deficiency

o         Achlorhydria = impaired release from protein-bound form

o         Gastrectomy = loss of IF

o         Pernicious anemia = autoimmune dz against parietal cells, chronic atrophic gastritis, CD4+ T cell-mediated attack.

o         Resection of ileum

o         Malabsorption syndromes

o         Increased requirements (pregnancy)

o         Inadequate diet

o         Demyelination of dorsal and lateral tracts

®      Folate deficiency

o         Inadequate intake

o         Malabsorption (sprue)

o         Increased demand (pregnancy, infancy, disseminated cancer)

o         Administration of methotrexate

§         Iron Deficiency Anemia

®      Dietary heme iron enters mucosal cells directly.

®      Non-heme iron enters through Nramp2

®      Negative iron balance

o         Low dietary intake

o         Malabsorption

o         Increased demands

o         Chronic blood loss = most important (GI, GU tracts)

®      Microcytic, hypochromic anemia

®      Marrow shows mild hyperplasia of normoblasts. Loss of sideroblasts and no stainable storage iron in RE cells.

®      Diagnosis

o         Low serum iron and ferritin

o         Increased TIBC

o         Reduced plasma transferring saturation

§         Anemia of Chronic Disease

®      Serum iron levels reduced

®      Low TIBC

®      Abundant storage iron

®      Marrow hypoproliferation due to low EPO from kidney due to IL-1, TNF-a, and interferon-gamma.

®      Administration of EPO corrects anemia.

§         Aplastic Anemia

®      Myelotoxic drugs = most common

®      Benzene, alkylating agents, antimetabolites, vincristine, busulfan, chloramphenicol, chlorpromazine, streptomycin.

®      Irradiation

®      Non-A,B,C,G Hepatitis

®      Inherited diseases (Fanconi’s anemia)

§         Pure Red Cell Aplasia

®      Thymomas

§         Other forms of marrow failure

®      Myelophthsic anemia (metastatic cancer), chronic renal failure, diffuse liver disease

Polycythemia

§         Relative

®      Dehydration

®      Stress

§         Absolute

®      Primary (myeloproliferative syndrome)

®      Secondary

o         Appropriate (COPD, high altitude, cyanotic heart disease)

o         Inappropriate (EPO-secreting tumors = renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)

Bleeding Disorders

§         Increased Vascular Fragility

®      Infections = meningococcemia, rickettsioses

®      Drug reactions = deposition of immune complexes

®      Poor vascular support = Ehlers-Danlos, scurvy, Cushing syndrome

®      Henoch-Schonlein purpura = purpuric rash, colicky abdominal pain, polyarthralgia, acute glomerulomephritis

o         Vascular and glomerular mesangial deposition of immune complexes

§         Thrombocytopenia

®      Decreased platelet production

o         Aplastic anemia, disseminated cancer, megaloblastic states

®      Decreased platelet survival

o         Immune destruction following drug ingestion (quinine, methyldopa), infections, mechanical injury.

®      Sequestration

o         Splenomegaly

®      Dilutional

o         Massive transfusion

®      HIV-associated

o         Multi-factorial

®      Idiopathic Thrombocytopenic Purpura

o         Acute = kids after rubella, CMV, hepatitis, mono.  Anti-platelet Abs.

o         Chronic = autoantibodies to Gp IIb/IIIa Ib/IX.  Treat with splenectomy.

o         Mucosal bleeding.

®      Thrombotic Thrombocytopenic Purpura and Hemolytic-Uremic Syndrome

o         Transient neurological deficits in TTP (women)

o         Renal failure in HUS (E. coli in kids)

§         Defective Platelet Functions

®      Congenital

o         Defective adhesion

·         Bernard-Soulier = deficiency of platelet receptor Gp Ib/IX, the receptor for vWWF/

o         Defective aggregation

·         Deficiency of Gp IIb/IIIa, which binds to fibronogen.

o         Disorders of platelet secretion

·         Secretion of prostaglandins or ADP impaired.

®      Acquired

o         Aspirin = inhibits COX, no TXA2 produced, which is needed for platelet aggregation

o         Uremia

§         Abnormalities in Clotting Factors

®      Acquired

o         Vit. K deficiency = depressed synthesis of II, VII, IX, X, and   protein C.

o         Parenchymal liver disease

o         DIC

®      Hereditary

o         Von Willebrand Disease

§         Type 1 and Type 3 = reduced quantity.

§         Type 2 = assembly of vWF multimer is bad

o         Factor VIII deficiency = Hemophilia A

§         X-linked recessive

§         Spontaneous hemarthroses

§         No petechiae

§         Prolonged PTT

o         Factor IX deficiency = Hemophilia B

§         Clinically indistinguishable from above.

§         Disseminated Intravascular Coagulation

®      Release of tissue factor or thromboplastic substances into circulation

o         Placenta

o         Granules of leukemic cells in M3 AML

o         Gram-negative sepsis

®      Widespread injury to endothelial cells

o         Ag-Ab complexes (SLE)

o         Temperature extremes (heat stroke, burns)

o         Microorganisms (meningococcus, rickettsia)

®      Morphology

o         Kidneys = thrombi in glomeruli

o         Lungs = microthrombi in alveolar capillaries, ARDS

o         Brain = microinfacts and fresh hemorrhages

o         Adrenals = Waterhouse-Friedrichsen syndrome from massive hemorrhages

o         Placenta = widespread thrombi

®      Treatment

o         Heparin

o         Antithrombin III

o         Fresh-frozen plasma

o         Depends on underlying disorder