Hem-Onc pathology Flashcards
Immune thrombocytopenic purpura (ITP)
Spleen produces anti-GpIIb/IIIa antibodies and consumes platelet/antibody complex.
Acute form arises after viral infection/immunization
Chronic form may arise secondary to SLE
Normal PT/PTT
Tx: corticosteroids, splenectomy
Microangiopathic hemolytic anemia
Platelets are consumed in production of platelet microthrombi within small vessels
Shearing of RBCs by microthrombi produce schistocytes
- Thrombotic thrombocytopenic purpura - decreased ADAMTS13 (vWF metalloprotease) leads to platelet adhesion to large vWF multimers; CNS abnormalities
- Hemolytic uremic syndrome - E. coli verotoxin damages endothelial cells resulting in platelet microthrombi; renal insufficiency
Tx: plasmapharesis, corticosteroids
Bernad-Soulier syndrome
Genetic GPIb deficiency impairs platelet adhesion to vWF
Mild thrombocytopenia and enlarged platelets
Glanzmann thrombasthenia
Genetic GPIIb/IIIa deficiency impairs platelet-to-platelet aggregation (via fibrinogen)
No platelet clumping seen on blood smear
Hemophilia A
X-linked recessive factor VIII deficiency (“A” = 8)
Elevated PTT; normal PT, PC, BT
Hemophilia B
Genetic factor IX deficiency
Elevated PTT; normal PT, PC, BT
von Willebrand disease
Genetic (usually AD) vWF deficiency
Increased BT, Increased PTT (vWF normally stabilized FVIII), normal PT
Abnormal ristocetin test (ristocetin causes vWF to bind platelet GPIb; decreased agglutination is diagnostic)
Tx: desmopressin (ADH analog, increases vWF release from Weibel-Palade bodies of endothelial cells)
Vitamin K deficiency
Vitamin K is normally activated by epoxide reductase in the liver; activated Vitamin K gamma carboxylates factors II, VII, IX, X, and proteins C (shorted t1/2) and S
Deficiency occurs in newborns (lack of GI colonizations), long-term antibiotic thearpy, malabsorption
Disseminated intravascular coagulation
Widespread activation of coagulation cascade, resulting in widespread microthrombi and consumption of platelets and clotting factors
Causes: gram negative sepsis, trauma, obstetric complications, acute pancreatitis, malignancy, nephrotic syndrome, transfusion
Decreased PC, Increased BT, Increased PT/PTT, Microangiopathic hemolytic anemia (schistocytes), Increased fibrin split products (D-dimers), Decreased fibrinogen
Fibrinolysis disorders
Normally, tissue plasminogen activator (tPA) converts plasminogen to plasmin
Plasmin cleaves fibrin and serum fibrinogen, destroys coagulation factors, and blocks platelet aggregation
alph2-antiplasmin inactivates plasmin
Plasmin overactivity results in increased BT, normal PC, increased PT/PTT, and increased fibrinogen split products (no D-dimers, unlike DIC)
Tx: aminocaproic acid (blocks plasminogen activation)
Causes of endothelial cell damage
- Atherosclerosis
- Vasculitis
- Hyperhomocystenemia:
- Vitamin B12 or folate deficiency
- Cystathionine beta synthase deficiency (vessel thrombosis, mental retardation, lens dislocation, long slender fingers)
Protein C or S deficiency
Autosomal dominant hypercoagulable state
Proteins C and S normally inactivate factors V and VIII
Increased risk for warfarin skin necrosis
Factor V Leiden
Hypercoagulable state due to a mutated form of factor V that lacks the cleavage site for deactivation by proteins C and S
Most common inherited cause of hypercoagulable state
ATIII deficiency
Hypercoagulable state resulting in decreased protective effects of heparin-like molecules produced by the endothelium
In ATIII deficiency, PTT does not rise with standard heparin dosing
May be acquired through nephrotic syndrome
Causes of iron deficiency
- Breast-feeding
- Poor diet
- Peptic ulcer disease
- Menorrhagia/pregnancy
- Colon polyps/carcinoma
- Hookworm (Ancylostoma duodenale, Necator americanus)
- Gastrectomy (acid maintains Fe+2 state, aids in absorption)
Stages of iron deficiency
- Depletion of storage iron (decreased ferritin, increased TIBC)
- Depletion of serum iron (decreased % saturation)
- Normocytic anemia (BM makes fewer but normal-sized RBCs)
- Microcytic, hypochromic anemia
Concomitant normocytic and microcytic anemias increase RDW
Plummer-Vinson syndrome
Iron deficiency anemia with esophageal web and atrophic glossitis
Presents as anemia, dysphagia, and beefy-red tongue
Hepcidin
Acute phase reactant that limits iron transfer from macrophages to erythroid precursors and suppresses EPO production
Important in pathophysiology of anemia of chronic disease
Sideroblastic anemia
Microcytic anemia caused by defective protoporphyrin synthesis leading to an accumulation of iron in mitochondria
Congenital defect: X-linked defect in aminolevulinic acid synthetase (ALAS) gene (ALAS normally converts succinyl CoA to ALA using vit B6 as a cofactor)
Acquired defects: alcoholism (mitrchondrial poison), lead poisoning (inhibits ALAD and ferrochelatase), vit B6 deficiency (required cofactor for ALAS; side effect of isoniazid tx)
Ringed sideroblasts and lab findings of iron-overloaded state (increased ferritin, decreased TIBC, increased serum iron, increased % saturation)
Lead poisoning
Inhibits ferrochelatase (mitochondrial enzyme that combines protoporphyrin with Fe+2 to produce heme)
Inhibits ALA dehydratase (cytosomal enzyme that converts ALA to prophobilinogen)
Protoporphyrin and ALA accumulate in the blood
Presents as sideroblastic anemia with basophilic stippling (inhibits rRNA degradation), “lead lines” on gingivae (Burton lines) and metaphyses of long bones, encephalopathy, abdominal colic, and wrist/foot drop.
Tx: Dimercaprol, EDTA, Succimer (chelating agents)
Acute intermittent porphyria
Defective porphobilinogen deaminase (cytosomal enzyme that converts porphobilinogen to hydroxymethylbilane)
Porphobilinogen, ALA, and coporphobilinogen accumulate in urine
Presents as “5 P’s”: Painful abdomen, Port wine-colored urine, Polyneuropathy, Psychological disturbances, Precipitated by drugs, alcohol, and starvation
Tx: glucose and heme (inhibit ALA synthase)
Porphyria cutanea tarda
Deficient uroporphyrinogen decarboxylase (cytosomal enzyme that converts uroporphyrinogen III to coproporphyrinogen III)
Uroporphyrin accumulates (tea-colored urine)
Presents as blistering cutaneous photosensitivity.
Most common porphyria
Alpha-thalassemia
Deletion of alpha globin gene
cis deletion prevalent in Asian populations (increased risk of severe thalassemia in offspring)
trans deletion prevalent in African populations
3 allele deletion - beta-chains form tetramers (HbH)
4 allele deletion - gamma-chains form tetramers (Hb barts); lethal in utero (hydrops fetalis)
Beta-thalassemia
Decreased beta-globin synthesis due to point mutations in splice sites and promoter sequences
Prevalant in Mediterranean populations
Beta-thalassemia minor - beta chain is underproduced; increased HbA2
Beta-thalassemia major -beta chain is absent; increased HbF; requires blood transfusion; marrow expansion and extramedullary hematopoiesis
HbS/Beta-thalassemia heterozygote - mild to moderate sickle cell disease
Folate deficiency
Causes: poor diet (alcoholics), increased demand (hemolytic anemia, pregnancy), folate antagonists (methotrexate)
Folate is absorbed in the jejunum
Symptoms: megaloblastic anemia with hypersegmented neutrophils, glossitis, increased serum homocysteine (increased risk for thrombosis), normal methylmalonic acid
Vitamin B12 deficiency
- Pernicious anemia (autoimmune destruction of parietal cells)
- Pancreatic insufficiency (lack of pancreatic proteases result in failure to detach vit B12 from R-binder)
- Damage to terminal ileum (e.g. Crohn disease or Diphyllobothrium latum [fish tapeworm])
- Vegan diet
- Proton pump inhibitors
Symptoms: megaloblastic anemia with hypersegmented neutrophils, glossitis, increased serum homocysteine (increased risk for thrombosis), increased methylmalonic acid (impairs spinal cord myelinization, results in subacute combined degeneration of the spinal cord)
Subacute combined degeneration: poor proprioception and vibratory sensation, and spastic paresis
Orotic aciduria
Megaloblastic anemia caused by autosomal recessive defect in uridine monophosphate (UMP) synthass, resulting in an inability to convert orotic acid to UMP (de novo pyrimidine synthesis pathway)
Tx: UMP, to bypass mutated enzyme
Causes of nonmegaloblastic macrocytic anemias
- Liver disease
- Alcoholism
- Reticulocytosis
- Drugs (5-FU, zidovudine, hydroxyurea)
Characteristics of extravascular hemolysis
RBC destruction by reticuloendothelial system
- Anemia with splenomegaly
- Jaundice due to unconjugated bilirubin
- Increased risk for bilirubin gallstones
- Marrows hyperplasia with corrected retic count >3%
Characteristics of intravascular hemolysis
- Hemoglobinemia
- Hemoglobinuria
- Hemosiderinuria
- Decreased serum haptoglobin
Hereditary spherocytosis
Inherited defect of RBC cytoskeleton-membrane tethering proteins (ankyrin, spectrin, band 3)
Increased MCHC and Increased RDW.
Premature removal of RBCs by spleen –> splenomegaly and risk of aplastic crisis (parvovirus B19)
Dx: osmotic fragility test, eosin-5-maleimide binding test
Tx: splenectomy
Sickle cell anemia
Autosomal recessive point mutation (valine replaces glutamate in beta chain)
Increased risk of sickling with hypoxemia, dehydration, and acidosis
Complications: extramedullary hematopoiesis, increased risk of aplastic crisis (parvovirus B19), dactylitis (common presenting sign in infants), autosplenectomy (infection with encapsulated organism most common cause of death in children), salmonella osteomyelitis, acute chest syndrome (msot common cause of death in adults), pain crisis, renal papillary necrosis, renal medullary infarcts
Dx: metabisulfite screen, Hb electrophoresis
Tx: hydroxyurea (increases HbF)
Hemoglobin C
Autosomal recessive point mutation (lysine replaces glutamate in beta chain) “lyCine”
Formation of characteristic HbC crystals
Causes of aplastic anemia
- Radiation
- Drugs (benzene, choramphenicol, alkylating agents, antimetabolites)
- Viruses (parvovirus B19, EBV, HIV, HCV)
- Fanconi anemia (DNA repair defect)
- Idiopathic (may follow acute hepatitis)
Paroxysmal nocturnal hemoglobinuria
Acquired defect in myeloid stem cells resulting in absent glycosylphosphatidylinositol (GPI), which normally secures decay accelerating factor (DAF, CD55) to cell membrane; loss of DAF renders cells susceptible to complement destruction
Sleep –> mild respiratory acidosis –> activation of complement –> lysis of RBCs, WBCs, and platelets
Complications: thrombosis (hepatic, portal, cerebral veins), iron deficiency anemia (due to hemoglobinuria), acute myeloid leukemia (AML)
Tx: eculizumab (inhibit complement system)
G6PD deficiency
X-linked recessive disorder resulting in reduced half-life of G6PD, which renders cells susceptible to oxidative stress
African variant is less severe than the Mediterranean variant
Causes of oxidative stress: infection, drugs (primaquine, sulfa drugs, dapsone), fava beans
Heinz bodies (denatured Hgb) and bite cells
Presents with hemoglobinuria and back pain after exposure to oxidative stress
Autoimmune hemolytic anemia
Extravascular hemolysis resulting in spherocytes
- IgG (warm agglutinin) - SLE, CLL, penicillin (IgG attaches to pencillin/membrane complex), alpha-methyldopa (induces production of IgA autoantibodies)
- IgM (cold agglutinin) - fixes complement to membrane and residual C3b serves as opsonin for splenic macrophages; Myoplasma pneumonia, infectious mono
Coombs positive
Direct Coombs test
Anti-Ig antibody (Coombs reagent) is added to patient’s blood. RBCs agglutinate if RBCs are coated with Ig
Indirect Coombs test
Normal RBCs are added to patient’s serum. If serum has anti-RBC surface Ig, RBCs agglutinate when anti-Ig antibodies (Coombs reagent) is added.
Effects of corticosteroids on WBC count
- Neutrophilia (impairs neutrophil adhesion, leading to release of marginated pool of neutrophils into bloodstream)
- Leukopenia (induce apoptosis)
- Eosinophilia (sequester in lymph nodes)
Infectious mononucleosis
Commonly caused by EBV, less commonly caused by CMV
EBV infects oropharynx (pharyngitis), liver (hepatitis), and B cells
CD8+ T cell response caused generalized LAD (T cell hyperplasia in LN paracortex), splenomegaly (T cell hyperplasia in periarterial lymphatic sheat), and atypical lymphocytosis
Monospot test detects heterophile IgM antibodies (think CMV if monospot is negative)
Complications: splenic rupture, rash if exposed to ampicillin, B-cell lymphoma
Acute lymphoblastic leukemia
TdT+ (nuclear marker of pre-T and pre-B cells)
Children. Associated with Down syndrome after the age of 5
- B-ALL - lymphoblasts express CD10, CD19, CD20; excellent response to chemo but requires prophylaxis to scrotum and CSF
- t(12;21) - good prognosis
- t(9/22) - poor prognosis; more common in adults
- T-ALL - lymphoblasts express CD2-CD8; present in teenagers as a thymic mass
Acute promyelocytic leukemia
Subtype of AML; MPO+ (crystals seen as Auer rods)
t(15;17) translocation of retinoic acid receptor blocks maturation of promyelocytes
Increased risk for DIC
Tx: all-trans-retinoic acid (ATRA) binds altered receptor and forces blasts to mature
Acute monocytic leukemia
Subtype of AML; MPO-
Blasts characteristically infiltrate gums
Acute megakaryoblastic leukemia
Subtype of AML; MPO-
Associated with Down syndrome before the age of 5 (vs. ALL which is associated with Down syndrome after the age of 5)
Myelodysplastic syndrome
Defect in cell maturation of all non-lymphoid lineages. Increased blast production but <20% blasts in bone marrow
Caused by de novo mutations or environmental exposure (radiation, benzene, chemo).
Risk of transformation to AML
Chronic lymphocytic leukemia
Naive B cells that co-express CD5 (normally just on T cells) and CD20
Increased lymphocytes and smudge cells on blood smear
Involvement of lymph nodes –> small lymphocytic lymphoma
Complications: hypogammaglobulinemia (infection), autoimmune hemolytic anemia, transformation to diffuse large B-cell lymphoma (Richter transformation)
Hairy cell leukemia
Mature TRAP+ B cells characterized by hairy cytoplasmic processes
Splenomegaly (accumulation of hairy cells in red pulp) and “dry tap” on bone marrow aspiration (due to fibrosis)
Absent LAD
Tx: 2-CDA (cladribine) - adenosine deaminase inhibitor that accumulates adenosine in neoplastic B cells to toxic levels
Adult T-cell leukemia/lymphoma
Mature CD4+ T cells associated with HTLV-1
Japan, West Africa, and the Caribbean
Rash, generalized LAD with hepatosplenomegaly, and lytic (“punched-out”) bone lesions with hypercalcemia
Don’t confuse with multiple myeloma
Mycosis fungoides
Mature CD4 T cells that form aggregates of neoplastic cells in the epidermis called Pautrier microabscesses
Skin rash, plaques, nodules
Sezary syndrome occurs if cells spread into the blood (characteristic cerebriform nuclei on blood smear)
Chronic myeloid leukemia
Proliferation of mature myeloid cells, especially granulocytes (basophils are characteristic)
t(9;22) Philadelphia chromosome generates a BCR-ABL fusion protein with increased tyrosine kinase activity; blocked by imatinib
Complications: splenomegaly, transformation to AML (2/3) or ALL (1/3) since mutation is in pluripotent stem cells
Differentiated from leukemoid rxn by negative LAP stain, increased basophils, and t(9;22)
Polycythemia vera
Proliferaiton of mature myeloid cells, especially RBCs
JAK2 kinase mutation (hematopoietic growth factor)
Symptoms: blurry vision, headache, increased risk of venous thrombosis (Budd Chiari syndrome), flushed face, itching after bathing (histamine release from mast cells)
Tx: phlebotomy, hydroxyurea
Essential thrombocythemia
Proliferation of mature myeloid cells, especially platelets
JAK2 kinase mutation
Increased risk of bleeding and/or thrombosis
No significant risk for hyperuricemia
Myelofibrosis
Proliferation of mature myeloid cells, especially megakaryocytes (produce PDGF causing marrow fibrosis)
JAK2 kinase mutation
Extrameduallary hematopoiesis (splenomegaly)
Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, immature granulocytes)
Increased risk of infection, thrombosis, and bleeding
Follicular lymphoma
Proliferation of small CD20+ B cells that form follicle-like nodules
Presents in late adulthood with painless “waxing and waning” LAD; normal LN architecture is disrupted with no tingible body macrophages in germinal centers; monoclonality
t(14;18) - translocation of heavy-chain Ig (14) and bcl-2 (inhibits apoptosis)
Tx: rituximab (anti-CD20 antibody)
Complications: progression to diffuse large B-cell lymphoma
Mantle cell lymphoma
Progression of small CD20+ B cells that expand mantle zone
Presents in older males with painless LAD
t(11:14) - translocation of heavy-chain Ig (14) and cyclin D1 (promotes G1/S transition)
Marginal zone lymphoma
Proliferation of small CD20+ B cells that expand marginal zone
Associated with chronic inflammatory states (Hashimoto thryoiditis, Sjogren syndrome, H pylori gastritis)
MALToma is marginal zone lymphoma in mucosal sites
Burkitt lymphoma
Proliferation of intermediate-sized CD20+ B cells, classically as an extranodal mass in a child or young adult; associated with EBV
African form usually involves the jaw; sporadic forms usually involves the abdomen
t(8;14) - translocation of heavy-chain Ig (14) and c-myc (promotes cell growth)
High mitotic index and “starry-sky” appearance
Diffuse large B cell lymphoma
Proliferation of large CD20+ B cells that grow diffusely in sheets; most common form of NHL in adults; high grade and clinically aggressive
May arise sporadically or from follicular lymphomas - t(14;18)
Hodgkin lymphoma
Proliferation of Reed-Sternberg cells (CD15/CD30+ large B cells with owl-eyed nuclei); rarely extranodal
RS cells secrete cytokines that recruit lymphocytes, plasma cells, macrophages, and eosinophils, produce “B” symptoms, and may lead to fibrosis
- Nodular sclerosis - most common subtype, affects young female adults, LN divided by sclerosis, RS cells in lake-like spaces (“lacunar cells”)
- Lymphocyte-rich - best prognosis
- Lymphocyte-depleted - worst prognosis; HIV+
- Mixed cellularity - abundant eosinophils
Multiple myeloma
Malignant proliferation of plasma cells in bone marrow; most common primary malignancy of bone; associated with high serum IL-6 (stimulates plasma growth and Ig production)
- Lytic (“punched-out”) skeletal lesions with hypercalcemia (due to activation of RANK receptor on osteoclasts)
- M spike on SPEP, due to monoclonal IgG or IgA
- Increased risk of infection
- Rouleuax formation of RBCs on blood smear
- Free light chains enter blood (primary AL amyloidosis), urine (Bence Jones protein), and kidneys (myeloma kidney)
Monoclonal gammopathy of undetermined significance (MGUS)
M spike on SPEP without other features of MM (lytic bone lesions, hypercalcemia, AL amyloid, Bence Jones proteinuria)
Waldenstrom macroglobulinemia
B-cell lymphoma with monoclonal IgM production
No lytic bone lesions
Large IgM pentamer causes serum hyperviscosity (visual and neurologic deficits, defective platelet aggregation)
Tx: plasmapheresis
Langerhans cell histiocytosis
Langerhans cells are monocyte-derived CD1a+ and S100+ specialized dendritic cells, characterized by Birbeck (tennis racket) granules, found predominantly in skin
- Letterer-Siwe disease - malignant proliferation of Langerhans cells in infants <2 yo; skin rash and cystic skeletal defects; rapidly fatal
- Hand-Schuller-Christian disease - malignant proliferation of Langerhans cells in infants >3yo; scalp rash, lytic skull lesion, diabetes insipidus, exopthalmos
- Eosinophilic granuloma - benign proliferation of Langerhans cells in bone; characteristic pathologic fracture in an adolescent; no skin involvement
Carcinomas that spread hematogenously
- Renal cell carcinoma (invades renal vein)
- Hepatocellular carcinoma (invades hepatic vein)
- Follicular carcinoma of the thyroid
- Choriocarcinoma
Hematogenous spread is also characteristics of sarcomas
