Part1 by wuyunyi


									Chicago Medical School
Session 1
Review for shelf exam and
          Part I
  Arthur S. Schneider, M.D.
  Kimiko Suzue, M.D., Ph.D.

   Department of Pathology
              Part 1:
Cellular Reaction to Injury
Inflammation and Repair
Hemodynamic Dysfunction
Genetic and Metabolic Mechanisms of
Immune Mechanisms of Injury
Environmental Pathology and Physical and
Chemical Injury
         A. Adaptive Changes

   Hypertrophy
       myocardium in hypertension
       uterus in pregnancy (along with hyperplasia)
       increased protein synthesis
       can be compensatory hypertrophy, such as
        enlargement of a remaining kidney following
        nephrectomy of the contralateral kidney
         A. Adaptive Changes

   Hyperplasia
       increased mitosis
       increased protein synthesis
        A. Adaptive Changes
   Atrophy
       lipofuscin (from membrane peroxidation)
       autophagic granules containing intracellular
       causes: ischemia, prolonged
        immobilization, aging
       brown atrophy of heart
          elderly persons
          small heart with paranuclear lipofuscin deposits
         A. Adaptive Changes

   Metaplasia
       squamous metaplasia in bronchi with long-
        term tobacco use
        B. Hypoxic Cell Injury

   Initial cellular lesion is diminished
    oxidative phosphorylation in mitochondria
    leading to decreased ATP
       leads to pump failure and increased cell Na+
        and water, decreased K+
            increased water  cellular swelling
       leads to increased glycolysis  increased
        lactic acid  decreased pH
        B. Hypoxic Cell Injury

   "Point of no return"
       damage to cell membranes (irreversible injury
        with loss of membrane phospholipids) 
        massive calcium influx with calcification of
   Cerebellar Purkinje cells most susceptible
    to anoxia, next cerebral cortical neurons
  C. Free Radicals, Oxygen
Toxicity, Carbon Tetrachloride
   Free radical injury
       formation of free radicals
            ionizing radiation, UV light, reperfusion after
             hypoxia, oxygen toxicity, carbon tetrachloride
       degradation of free radicals
            glutathione peroxidase, superoxide dismutase,
             ascorbate, beta-carotene, selenium, ceruloplasmin,
  C. Free Radicals, Oxygen
Toxicity, Carbon Tetrachloride
   Examples of free radical injury
       peroxidation of lipid membranes
       oxygen toxicity in newborn  retrolental
        fibroplasia (retinopathy of prematurity) and
        blindness in premature infants; characterized
        by vessel proliferation in retina with
        penetration into vitreous
       damage to alveolar endothelial cells with
        hyaline membrane formation
       carbon tetrachloride poisoning  fatty change
        and cell necrosis in hepatocytes
          D. Reversible and
         Irreversible Injury,
        Coagulative Necrosis
   Reversible
       cell swelling with water retention
       fatty change (steatosis); reversible if cause
        is removed
       squamous metaplasia
   Irreversible
       mitochondrial damage
       cell membrane damage with influx of Ca++
       necrosis
  D. Reversible and
 Irreversible Injury,
Coagulative Necrosis
   necrosis (cont.)
      coagulative necrosis
         most frequent cause: interrupted blood
          supply with local hypoxia; example is
          myocardial infarct
             increase in serum enzymes due to
              increased membrane permeability
         morphologic features: pyknosis,
          karyolysis, karyorrhexis
         target organs: heart, kidney
      D. Reversible and
     Irreversible Injury,
    Coagulative Necrosis
   necrosis (cont.)
        liquefactivenecrosis
        target organ: brain

     caseous necrosis: tuberculosis,
      manifestation of partial immunity
        caused by interaction of CD4+
         lymphocytes, macrophages, and
         probably cytokines derived from these
    E. Cellular Accumulations

   Milk-alkali syndrome
       metastatic calcification caused by milk and
        antacid therapy for peptic ulcer
       in kidney, manifest as nephrocalcinosis and
        renal stones
    E. Cellular Accumulations

   Hemochromatosis
       caused by abnormal accumulation of
        hemosiderin iron
       increased serum iron, decreased total iron
        binding capacity (TIBC, transferrin)
       protein synthesis
    E. Cellular Accumulations

   Amyloidosis
       amorphous eosinophilic material, often
       positive Congo red stain
       prominent cause of nephrotic syndrome
    E. Cellular Accumulations

   Causes of fatty change
       increased supply of free fatty acids
       lack of apolipoproteins secondary to
        decreased protein synthesis
     A. Acute Inflammation
   Leukocytosis initially due to accelerated
    release of cells from bone marrow
    postmitotic reserve pool
       leukemoid reaction
          exaggeration of leukocytosis in response to
           acute inflammation
          often has leukemia-like increase of immature
    A. Acute Inflammation
   Abscess formation
       more likely with staphylococcus than with
        A. Acute Inflammation

   Pseudomembranous inflammation
       surface epithelial necrosis (tonsils, small
        bowel, colon) overlaid by adherent
        inflammatory membrane (pseudomembrane)
       organisms (e.g., Clostridium difficile) usually
        not deeply invasive, secrete destructive
        B. Inflammatory Cells
   Neutrophils
       acute inflammation, bacteria; first cells to
        appear in acute inflammation; appear in
        wounds and areas of acute injury within first
        24 hours
       immediate release of neutrophils and bands
        in response to acute inflammation is a
        release of cells from postmitotic bone
        marrow reserve pool
     B. Inflammatory Cells
   Lymphocytes, plasma cells, macrophages:
    chronic inflammation (along with scar
    tissue formation), viruses, fungi
        B. Inflammatory Cells

   Macrophages: replace neutrophils after
    about 3 days of acute inflammation, divide
    in tissues
       products: acid hydrolases, prostaglandins,
        cytokines, interferons
   Mast cells and basophils: sources of
          C. Chemotaxis and
          Chemotactic Factors
   Chemotaxis can be assessed in vitro using
    migration in a Boyden chamber
   Chemotactic factors
       neutrophils: C5a, HETE, LTB4, kallikrein
       fibroblasts: fibronectin
       monocytes: platelet-derived growth factor
   Acute phase reaction
       elicited by IL-1 (and IL-6) and TNF-alpha (and
          D. Phagocytosis and
            Bacterial Killing
   Opsonins include IgG and C3b
   Bacterial killing within leukocytes
       defensins (cytotoxic peptides in leukocyte
       oxygen metabolites within phagolysosomes
       myeloperoxidase halide (Cl- or I-) system of
     E. Vasoactive Mediators

   Bradykinin: a 9-carbon peptide, a
    mediator of pain and increased vascular
   Histamine: released by degranulation of
    basophils and mast cells, increases
    capillary permeability
     E. Vasoactive Mediators
   Complement components
       C5a: chemotaxis, along with leukotriene B4
        and bacterial products
       C5b-9: cytolysis
       C3a, C5a (anaphylatoxins): degranulation of
        basophils and mast cells, causing release of
        histamine as well as increased vascular
       C3b: opsonization (along with IgG)
     F. Cytokines and Acute
   Interleukin-1 (and TNF): acute phase
    reactions (fever, phase proteins,
    leukocytosis, synthesis of adhesion
    molecules), macrophage and neutrophil
   Gamma interferon (produced by T cells
    and NK cells) activates monocytes
           G. Arachidonic Acid
   Phospholipase A: liberation of arachidonic
    acid from membrane
   Cyclooxygenase (cyclic endoperoxide)
       prostacyclin (PGI2) in endothelial cells:
        vasodilator and platelet antiaggregant
       thromboxane A2 (TxA2) in platelets:
        vasoconstrictor and platelet aggregant
           G. Arachidonic Acid
   Lipoxygenase pathway
       leukotriene B4: chemotactic for neutrophils
       LTC4, LTD4, LTE4: vasoconstrictors
           H. Impaired Acute
        Inflammatory Response
   Cancer chemotherapy: increased bacterial
    infections because of neutropenia
   Chronic granulomatous disease of
    childhood: failure of oxidative burst,
    catalase-positive organisms (such as
    Staphylococcus aureus) ingested but not
       defect in NADPH (NADP+) oxidase
        H. Impaired Acute
     Inflammatory Response
   Diabetes mellitus, acute leukemia,
    hereditary complement deficiencies
   Chédiak-Higashi syndrome: impaired
    chemotaxis and migration
          I. Granulomatous
   Involves activated macrophages and T
    cells, related to poorly soluble materials
    such as bacterial lipids
   Epithelioid cells and giant cells derived
    from monocytes/macrophages
         I. Granulomatous
   Causes include foreign bodies such as
    suture material, infectious agents such as
    mycobacteria which replicate within
   Etiologic agents include foreign bodies,
    tuberculosis, Coccidioides immitis,
    Histoplasma capsulatum, sarcoid, leprosy,
    cat-scratch disease, syphilis
           I. Granulomatous
   Killing of mycobacterial-laden
    macrophages by CD8+ suppressor T cells
     caseous necrosis
   Noncaseating granulomas
       most common cause is sarcoidosis
J. Tissue Regeneration and
   Repair, Wound Healing
   Stable cells
       can regenerate from G0 cells when needed;
        e.g., hepatocytes, renal tubular cells are
        both replaced rapidly after loss
J. Tissue Regeneration and
   Repair, Wound Healing
   Primary and secondary healing (healing
    by first and second intention)
       more fibrovascular (granulation tissue)
        reaction, more intense inflammatory
        reaction, and much more wound
        contraction in secondary
J. Tissue Regeneration and
   Repair, Wound Healing
   Tissue regeneration and repair
       lymphocytes and plasma cells not involved
        in wound healing (or in fibrous repair of
       complete restoration of structure: hepatitis
        A, acute tubular necrosis, acute erosive
        gastritis, mucosal ulcerations of colon
       granulation tissue: young fibroblasts and
        new capillary growth
J. Tissue Regeneration and
   Repair, Wound Healing

   Tissue regeneration and repair (cont.)
       healing with scarring (connective tissue
        repair): myocardial infarction, full-thickness
        burns, skin wounds, abscesses
       fibroblastic proliferation after injury begins
        in 3-10 days
       last event in scar formation is collagen
       keloids: abnormal scar tissue, more
        common in persons of African descent
J. Tissue Regeneration and
   Repair, Wound Healing

   Tissue regeneration and repair (cont.)
       delayed wound healing: ascorbate deficiency,
        infection, foreign bodies, obesity
       perivenular fibrosis in alcoholic hepatitis is
             A. Infarction
   Venous obstruction is cause of bowel
    infarction in volvulus, incarcerated hernia,
    adhesions, etc.
               A. Infarction
   Pulmonary infarcts
       classically hemorrhagic, wedge-shaped, and
        subpleural (although hemorrhagic, are also
        examples of coagulative necrosis)
       postoperative state is a major risk factor
       diagnosis facilitated by ventilation-perfusion
       usual source is deep venous thrombosis (DVT)
        of lower extremities
             A. Infarction

   Release of intracellular enzymes into
    circulation due to increased membrane
                B. Thrombosis

   Deficiencies of antithrombin III, protein C
    and protein S, factor V Leiden (hereditary
    resistance to activated protein C)
   Hageman factor (factor XII)
       in addition to activating intrinsic pathway of
        coagulation, also activates kinin and
        fibrinolytic systems; fibrinolytic system in turn
        activates complement system
                B. Thrombosis

   Reduced blood flow and stasis, endothelial
    injury, hyperviscosity, platelet aggregation
       platelet aggregants: collagen, thromboxane
       thromboxane from platelets is platelet
        aggregant and vasoconstrictor
       prostacyclin from endothelial cells is platelet
        antiaggregant and vasodilator
       fibrin degradation products are
             B. Thrombosis
   Risks for thrombogenesis: polycythemia,
    congestive failure, SS disease, cancer, oral
   Risks for venous thrombosis:
    postoperative state, visceral malignancy
   Trousseau syndrome: migratory venous
    thrombosis in association with visceral
    malignancy (pancreas or lung most
                 C. Embolism
   Fat embolism
       life-threatening target sites, lungs and brain
       associated with multiple fractures
       fat embolism syndrome: pulmonary
        insufficiency, petechial rash, and neurologic
   Air (gas) embolism, decompression
       deep sea diving
       increased risk with obesity
                 C. Embolism
   Paradoxical embolism
       right-sided emboli pass to arterial circulation
        through right-to-left cardiac shunt
   Middle cerebral artery most frequent
    intracranial site of arrest of arterial emboli
   Left-sided (arterial) emboli (to kidneys,
    brain, etc.)
       often from mural thrombus in heart
        (myocardial infarction or mitral stenosis)
                  C. Embolism

   Right-sided (venous) emboli to lung
       most often from deep veins of lower
       lead to pulmonary infarcts
          characteristically hemorrhagic (red infarcts) that
           are wedge-shaped and subpleural in location
          can result in pulmonary hypertension and acute
           right ventricular failure
                D. Shock

   Acute tubular necrosis (shock kidney):
    lesion is reversible
   Other complications include mucosal
    hemorrhages in colon, depletion of
    adrenal cortical lipids, and pulmonary
   Rx hypovolemic shock with whole blood
    and not with packed RBC
       E. Transudates and
   Transudates: low protein, low specific
    gravity (<1.012), pale and yellow,
    glucose normal
       E. Transudates and
   Exudates: high specific gravity
    (>1.020), high protein (>3 gm/dl),
    many neutrophils (and sometimes RBC),
    glucose low
   Cerebrospinal fluid in suppurative
    (pyogenic) meningitis: protein,
    leukocyte count, and pressure are
    increased and glucose is decreased
F. Edema, Congestion, and
   Edema
       injury to capillary endothelium (as in burn
       decreased plasma oncotic pressure (as in
        nephrotic syndrome)
       in congestive heart failure
          increased hydrostatic pressure in small veins
           (passive congestion)
          activation of renin-angiotensin system by
           decreased blood flow to the kidney
F. Edema, Congestion, and
   Hyperemia
       nutmeg liver is sign of chronic passive
        congestion of liver and is associated with right
        ventricular failure
   Hemorrhage
       causes secondary thrombocytosis
    A. Chromosomal Disorders
   Down syndrome
       trisomy 21
       nondisjunction (maternal in 95%)
       can also be caused by robertsonian trans-
        location involving chromosome 21; mating
        with normal gamete causes hereditary trisomy
       mental retardation
       palmar creases, increased susceptibility to
       increased incidence of acute leukemia and
        congenital heart disease
    A. Chromosomal Disorders

   Klinefelter and Turner syndromes
       Klinefelter syndrome
            no mental retardation
            always has X chromosome; can be 47,XXY,
             48,XXXY, etc.
            always has male phenotype with testes
A. Chromosomal Disorders
   Turner syndrome
      45,X(0), no Barr bodies
      short stature, widely spaced nipples, webbing of
      no mental retardation

      coarctation of aorta

      high FSH and LH

   Barr bodies
        one less than number of X chromosomes
    A. Chromosomal Disorders

   Other chromosomal disorders
       XYY karyotype
           severe acne
           no mental retardation
     B. Autosomal Dominant
   Von Hippel-Lindau disease
       multiple tumors, hemangioblastoma or
        cavernous hemangioma of cerebellum, brain
        stem, or retina
       adenomas and cysts of liver, kidney, pancreas
    B. Autosomal Dominant
   Neurofibromatosis (von Recklinghausen
       multiple neurofibromas in skin  can
        become malignant
       schwannomas of VIIIth nerve
       pigmented skin lesions (café au lait spots)
       can lead to other tumors, including
        pheochromocytoma and a variety of
        malignant tumors
       skeletal lesions
     B. Autosomal Dominant
   Marfan syndrome
       tall, thin stature; long, tapering fingers and
        toes; ectopia lentis; cystic medial necrosis;
        can be complicated by dissecting aneurysm
        (dissecting hematoma)
    C. Autosomal Recessive
   Storage diseases due to enzyme
       Tay-Sachs disease
       Hurler syndrome
       most glycogen storage diseases
          glycogenosis type II (Pompe disease)
          glycogenosis type I and type II produce
           profound hypoglycemia
          glycogenosis type V (muscle phosphorylase
           deficiency, McCardle syndrome)
                muscle cramps and myoglobinuria following exercise
    C. Autosomal Recessive
   Phenylketonuria and other disorders of
    phenylalanine-tyrosine metabolism
       phenylketonuria
          can get false negative test for phenylalanine if
           measured too early in newborns
          children are blond and blue-eyed because of
           associated fault in melanin production
    C. Autosomal Recessive
   Phenylketonuria and other disorders of
    phenylalanine-tyrosine metabolism
       phenylketonuria
          neurologic signs may include seizures early in
           life in addition to severe retardation
          musty odor
     C. Autosomal Recessive
   Phenylketonuria and other disorders of
    phenylalanine-tyrosine metabolism (cont.)
       other errors of phenylalanine-tyrosine
          alkaptonuria
          albinism
     C. Autosomal Recessive
   Cystic fibrosis
       increased chloride ions in sweat, principal
        lesions in lungs and pancreas
       meconium ileus
       recurrent bouts of pneumonia, often with
       pancreatic involvement leads to steatorrhea
        with loss of fat soluble vitamins A, D, E, and K
       obstruction of pancreatic ducts results in
        acinar atrophy
     C. Autosomal Recessive
   Cystinuria
       a cause of familial renal stones
    D. Sexual Differentiation

   Sexual differentiation
       true hermaphroditism: ovarian and testicular
        tissue, X and Y chromosomes
                    E. Other

   Causes of congenital malformations
       rubella
       drugs
       Radiation
                   E. Other

   Anencephaly and other neural tube
       increased amniotic fluid alpha-fetoprotein
        important diagnostic indicator
                     E. Other

   Genetic disorders with clinical onset
    delayed until adulthood
       Huntington disease
       adult polycystic kidney (infantile form is
        autosomal recessive)
                     E. Other

   Autosomal recessive inheritance
       heterozygotes clinically normal
       both parents heterozygotes
       1 in 4 children are homozygotes or normals
       2 in 4 children are heterozygotes
       examples are phenylketonuria, cystic fibrosis,
        galactosemia, Tay-Sachs disease
                    E. Other

   Maple syrup urine disease
       deficiency of branched-chain keto acid
                   E. Other

   X-linked inheritance
       transmitted in maternal line
       half of progeny (male and female) carry
        affected X chromosome
       examples are classic hemophilia, Duchenne
        muscular dystrophy, X-linked
        agammaglobulinemia of Bruton, Fabry disease
                     E. Other

   Mitochondrial (cytoplasmic) inheritance
       entirely maternal in its mode of transmission
       men cannot pass on cytoplasmic DNA
   Multifactorial mode of inheritance
       diabetes mellitus is classic example and is
        thought to be mediated by a combination of
        genetic susceptibility, an environmental insult,
        and T-cell-mediated autoimmunity
                       E. Other

   Familial diseases that predispose to
       multiple polyposis (adenocarcinoma of colon)
       xeroderma pigmentosum
          skin cancer due to ineffective repair of sunlight-
           induced thymidine dimers
          autosomal recessive inheritance

       Down syndrome (leukemia)
                   E. Other

   Centimorgan
       measure of genetic distance
       one centimorgan means one meiotic
        crossover in 100 recombinations
             A. HLA Antigens

   Transplantation
       serologic testing for HLA-A and HLA-B used to
        predict graft survival
   Association with specific haplotypes
    suggests autoimmune etiology
       strongest association is HLA-B27 and
        ankylosing spondylitis
B. Mechanisms of Immune
B. Mechanisms of Immune
   Type I anaphylactic hypersensitivity
       immediate response such as local edema
        at site of a bee sting or generalized
       hay fever and extrinsic asthma are
B. Mechanisms of Immune
   Type I anaphylactic hypersensitivity
       characterized by degranulation of mast
        cells and basophils
          edema of tissues due to increased capillary
           permeability caused by histamine release
          eosinophilia in peripheral blood

          IgE-mediated, complement not involved
                requires bridging (cross-linking) of adjacent IgE
                 molecules on mast cell surface
    B. Mechanisms of Immune
   Type I anaphylactic hypersensitivity
       hereditary angioedema due to deficiency of
        C1 esterase inhibitor; serum C4 is low and
        other complement components such as C3 are
B. Mechanisms of Immune
   Type II hypersensitivity (cytotoxic
       reaction of antibody and complement with
        antigen that is intrinsic component of
        target cell surface
       examples are erythroblastosis fetalis,
        hemolytic transfusion reactions,
        Goodpasture syndrome (antiglomerular
        basement membrane antibody disease)
       serum complement decreased
B. Mechanisms of Immune
   Type III immune complex diseases
       involve antigen, antibody, and complement
       antigen not intrinsic component of cell
       Arthus reaction is localized form
       examples of organ-specific forms are
        membranous glomerulonephritis and
        poststreptococcal glomerulonephritis
B. Mechanisms of Immune
   Type III immune complex diseases
       SLE and serum sickness are examples of
        multisystem immune complex disease
       serum complement decreased
       membranous glomerulonephritis can be
        mimicked in experimental animals by
        repeated antigenic exposure
    B. Mechanisms of Immune
   Type IV T-cell-mediated hypersensitivity
    (exemplified by tuberculosis)
       delayed hypersensitivity mediated by CD4+ T
        cells and macrophages
       contact dermatitis is an example of delayed
            C. Congenital
   X-linked hypogammaglobulinemia of
       prone to bacterial but not viral or fungal
       recurrent infections with Staphylococcus and
        Haemophilus beginning after 6 months of
       protection by maternal antibodies accounts
        for freedom from infection for first several
        months of life
            C. Congenital
   X-linked hypogammaglobulinemia of
       absent germinal centers in lymph nodes
       no plasma cells
              C. Congenital
   DiGeorge syndrome
       prone to viral but not bacterial infections
       failure of development of 3rd and 4th
        pharyngeal pouches
       hypoplasia of thymus and parathyroids  T-
        cell deficiency and hypocalcemia
       congenital heart defects
              C. Congenital
   IgA deficiency
       most common hereditary immunoglobulin
   Wiskott-Aldrich syndrome
       recurrent infection
       thrombocytopenia
       eczema
       X-linked inheritance
             C. Congenital
   Severe combined immunodeficiency
    disease (SCID)
       no B- or T-cell function
       most common form is X-linked
       another form is due to adenosine deaminase
       can develop graft-versus-host disease from
        blood transfusions
      D. AIDS and T-Cell
 HIV virus found in blood, semen,
    vaginal secretions, breast milk, saliva
   Transmitted by blood transfusion before
    screening was worked out
      D. AIDS and T-Cell
             Deficiencyfollow up
 ELISA test is presumptive;
    with Western blot
   Paradoxical increase in serum IgG
   Marked reduction in CD4 (helper) T
         D. AIDS and T-Cell
   CD4/CD8 (helper/suppressor) ratio
    decreased to <1.0
   Decreased total number of lymphocytes
   Kaposi sarcoma
         D. AIDS and T-Cell
   Opportunistic infections such as
    Pneumocystis carinii, CMV, Candida,
    herpes, Mycobacterium avium-
    intracellulare, cryptococcal meningitis,
    Cryptosporidium, etc., all due to reduced
    T-cell function
   Non-Hodgkin lymphomas
          D. AIDS and T-Cell
   T-cell functions
       delayed hypersensitivity, as in tuberculin
       macrophage activation
       helper and suppressor regulation of
        antibody production
       allograft rejection, as in acute rejection of
        renal transplants
       memory T cells
   E. Connective Tissue
Diseases and Autoimmunity
   Systemic lupus erythematosus (SLE)
       young women
       characteristic facial (malar) rash
       joint pain
       Raynaud phenomenon
       multisystem immune complex disease
       diffuse interstitial pulmonary fibrosis
       diffuse fibrosing alveolitis
       inflammation of serosal membranes such as
   E. Connective Tissue
Diseases and Autoimmunity
   Systemic lupus erythematosus (SLE)
       membranous glomerulonephritis
       onion-ring appearance of splenic arterioles
       nonbacterial verrucae on underside of cardiac
        valves (Libman-Sacks)
       antinuclear antibodies, especially rim pattern
        of nuclear fluorescence; also anti-Sm and
        anti-double-stranded DNA
   E. Connective Tissue
Diseases and Autoimmunity
   Rheumatoid arthritis
       rheumatoid factor is an IgM
        immunoglobulin directed against the Fc
        combining site of IgG
       Felty syndrome is rheumatoid arthritis with
        splenomegaly and leukopenia
   E. Connective Tissue
Diseases and Autoimmunity
   Sjögren syndrome
       keratoconjunctivitis sicca (dry eyes)
       xerostomia (dry mouth)
       lymphocytic infiltrates with destruction of
        acini in lacrimal and salivary glands
       can have tubulointerstitial nephritis
   E. Connective Tissue
Diseases and Autoimmunity
   Systemic sclerosis (scleroderma)
       atrophy of skin and appendages and increase
        in fibrous tissue
       diffuse fibrosis and vascular changes in skin,
        joints, internal organs, especially esophagus
        (dysphagia), gastrointestinal tract
        (heartburn), lung (dyspnea), heart, and
       renal arteriolar and glomerular damage
   E. Connective Tissue
Diseases and Autoimmunity
   Polymyositis
     lymphocytic infiltrate and necrotic
      muscle cells
   Polyarteritis nodosa
       type III hypersensitivity (immune complex)
   E. Connective Tissue
Diseases and Autoimmunity
   Associations of autoimmune diseases
       autoantibodies
            incidence increases with age
       other autoimmune diseases
       morphologic changes such as lymphoid follicle
        formation, as in Hashimoto thyroiditis
       association with specific HLA haplotypes
               F. Amyloidosis

   Causes
       chronic inflammation, especially rheumatoid
       plasma cell disorders, especially multiple
       inherited forms of amyloidosis
                     G. Other

   Complement activation
       classic pathway triggered by immune
       alternative pathway triggered by microbial
        surfaces and endotoxin
       can also be activated by plasmin activation of
                    G. Other

   Graft-versus-host disease (GVHD)
       CD8+ T cells from graft directly damage host
       cytokines from graft CD4+ T cells recruit
        macrophages which damage host cells
       can be caused by whole blood transfusion to
        patients with severe combined
        immunodeficiency (SCID)
                     G. Other

   Graft-versus-host disease (GVHD) (cont.)
       clinical features include fever, rash,
       target organs are liver, skin, and
        gastrointestinal mucosa
                     G. Other

   Anti-idiotypic antibodies
       specificity for antibody-combining sites
                    G. Other
   Transplantation rejection
       hyperacute
         primarily mediated by preformed antibodies
         occurs within minutes

       acute
         primarily T-cell-mediated
         occurs within days to months

         morphologic counterpart is interstitial
          lymphocytic infiltrate
                    G. Other
   Transplantation rejection
       chronic
          primarily antibody-mediated
          occurs within months to years
                 G. Other
   Major cytokines secreted by Th1 cells are
    tumor necrosis factor-beta and interferon-
   Following successful bone marrow
    transplantation, new blood cells will have
    markers (such as blood group antigens or
    chromosome complement) characteristic
    of the donor; disappearance of such
    elements is an indicator of rejection
    A. Criteria for Malignancy

   Most important criterion is correlation of
    behavior in patients
   Anaplasia: atypical mitoses, distorted
    polarity, hyperchromatism, pleomorphism,
    presence of nucleoli
    B. Epidemiologic Factors
     and Other Associations
   Environmental factors
       mesothelioma: asbestosis
       bladder cancer: aniline dyes (beta-
       angiosarcoma of liver
          vinyl chloride
          Thorotrast

       hepatocellular carcinoma
            hepatitis B virus, cirrhosis regardless of etiology,
             aflatoxin B1
    B. Epidemiologic Factors
     and Other Associations
   Environmental factors (cont.)
       skin cancers
          sunlight (ultraviolet light): ultraviolet light 
           pyrimidine (thymine) dimers  cutaneous
          arsenic (squamous cell carcinoma)

       carcinoma of esophagus
          tobacco and alcohol
          presenting sign usually dysphagia

       carcinoma of stomach
          nitrosamines
          possibly Helicobacter pylori
    B. Epidemiologic Factors
     and Other Associations
   Environmental factors (cont.)
       bronchogenic carcinoma
          cigarette smoking
          chromium

          nickel

       clear cell adenocarcinoma of vagina
            intrauterine exposure to diethylstilbestrol (DES)
       carcinoma of larynx: cigarette smoking
    B. Epidemiologic Factors
     and Other Associations
   Viral associations
       Epstein-Barr virus: Burkitt lymphoma (EBV
        also associated with infectious
        mononucleosis and nasopharyngeal
        carcinoma [in Asia])
       hepatitis B virus: hepatocellular carcinoma
    B. Epidemiologic Factors
     and Other Associations
   Viral associations
       human papillomavirus: carcinoma of
        uterine cervix, laryngeal papillomas,
        condyloma acuminatum (condyloma
        acuminatum in children suggests sexual
       human T-lymphotropic virus I (HTLV-I): T-
        cell leukemia-lymphoma
    B. Epidemiologic Factors
     and Other Associations
   Other associations
       carcinoma of breast
          strong familial association
          first degree female relatives

       acanthosis nigricans: visceral malignancies
       pheochromocytoma: neural crest origin
       small cell bronchogenic carcinoma:
        inappropriate ADH secretion
    B. Epidemiologic Factors
     and Other Associations
   Other associations (cont.)
       squamous cell bronchogenic carcinoma:
        hypercalcemia and increased
        parathormone-like activity
       renal cell carcinoma: flank pain, mass,
       adenocarcinoma of esophagus: precursor
        lesion is Barrett esophagus (precursor of
        Barrett esophagus is acid gastric reflux)
       carcinoma of larynx
          hoarseness
          smoking
          squamous cell carcinoma
    B. Epidemiologic Factors
     and Other Associations
   Other associations (cont.)
       xeroderma pigmentosum: failure of DNA
        repair enzymes  variety of neoplasms,
        especially in the skin
       germ cell tumors of testis and ovary:
        increased human chorionic gonadotropin
        (hCG) (hCG also increased with
        choriocarcinoma, hydatidiform mole, normal
        and ectopic pregnancy)
    B. Epidemiologic Factors
     and Other Associations
   Other associations (cont.)
       neuroblastoma
         gene amplification
         can differentiate and become more mature
       C. Cancer Diagnosis

   Positive staining for keratin indicates an
    epithelial (carcinomatous) origin of
    otherwise unidentifiable tumor cells
      C. Other markers for
       specific neoplasms
   leukocyte common antigen (leukemias
    and lymphomas)
   vimentin (most sarcomas)
   desmin (muscle cell origin)
      C. Other markers for
       specific neoplasms
   CA-125 (ovarian cancer)
   carcinoembryonic antigen (CEA) (colon,
    pancreas, lung, stomach, and breast, but
    especially colon)
   alpha-fetoprotein (AFP) (hepatocellular
    carcinoma and non- seminomatous germ
    cell tumors, especially yolk sac tumor
    S100 (melanoma)
           D. Monoclonality

   Plasma cell proliferation, with some cells
    showing lambda specificity and others
    showing kappa specificity, is polyclonal
    and reactive rather than monoclonal and
   Monoclonality can also be determined by
    G6PD studies
       E. Radiation-Induced
   Myeloid (not lymphocytic) leukemia,
    thyroid, osteosarcoma, squamous cell
    carcinoma of skin
    F. Oncogenes and Tumor
       Suppressor Genes
   Burkitt lymphoma: t(8;14); c-myc
    (chromosome 8) translocated to site
    adjacent to immunoglobulin heavy chain
    gene (chromosome 14)
   Ras protein (p21) is analogous to a G
    protein and is activated by GTP binding;
    mutant ras proteins have faulty GTPase
    (hydrolase) inactivation
F. Oncogenes and Tumor
   Suppressor Genes
   Sis oncogene has partial homology for
    platelet-derived growth factor
F. Oncogenes and Tumor
   Suppressor Genes
   Retinoblastoma is prototype of cancer
    suppressor gene-mediated
       Rb (on 13p14) is a cancer suppressor
        gene: retinoblastoma and osteosarcoma
        due to homozygous inactivation of Rb
       mechanism is germ cell mutation followed
        by somatic cell mutation (“reduction to
       two-hit hypothesis of Knudson
       familial form likely to be bilateral
    F. Oncogenes and Tumor
       Suppressor Genes
   p53 is another important cancer
    suppressor gene related to many other
        G. Grading and Staging

   Grading
       based on morphologic characteristics such as
        cytologic differentiation of tumor cells, cell of
        origin, etc.
       lack of differentiation (e.g., failure of gland
        formation) is poor prognostic sign; e.g.,
        Gleason system of grading for prostate
    G. Grading and Staging
   Staging
       based on extent of disease (tumor size and
        degree of dissemination, as in Dukes
        staging for carcinoma of the colon (e.g.,
        Dukes Class IV indicates distal metastases)
        or as in the Ann Arbor classification for
        Hodgkin disease and non-Hodgkin
        lymphomas, in which staging is partially
        based on presence or absence of fever and
        other constitutional symptoms
    G. Grading and Staging
   Staging
       more important than grading in
        determining prognosis
       distal metastases are signs of advanced
       prognosis of early-stage malignant
        melanoma most closely related to depth
        (thickness) of the lesion
H. Invasion and Metastasis
   Most resistant site to cancer invasion is
   Metastasis is a multistep process:
    presence of cells within vessels is not a
    definitive indicator of metastasis
   Individual malignant cells may have
    differing metastatic potential
   Metastasis often facilitated by type IV
    collagenase, which cleaves type IV
    collagen of epithelial and vascular
    basement membranes
                    I. Other
   Hamartoma
       non-neoplastic tumor-like growth of cells
        regularly found in affected organ
   Chemotherapy and radiotherapy most
    effective with rapidly dividing cells, as in
    choriocarcinoma and seminoma
   Tumor progression
       exemplified by increasing number of
        (molecular or cytogenetic) abnormalities over
                        I. Other
   Multiple endocrine neoplasia (MEN)
       MEN I: parathyroid, pancreatic, and pituitary
       MEN IIa: medullary carcinoma of thyroid,
        pheochromocytoma, parathyroid hyperplasia
            association with ret oncogene
       MEN IIb (or MEN III): like MEN IIa except for
        mucosal neuromas and marfanoid features
      A. Ionizing Radiation
   Lymphocytes earliest blood cell affected
   Most sensitive cells: lymphoid,
    hematopoietic, germ, gastrointestinal
    mucosal, rapidly dividing tumor
   Can cause acute myeloblastic (not
    lymphoblastic) leukemia
   Cause of neoplasia in bone, skin,
    thyroid, lung, breast, and myeloid (but
    not lymphoid) leukemias
         B. Ultraviolet Light
   Actinic keratosis
   Melanoma, squamous cell, and basal cell
    carcinomas of skin
        C. Gunshot Wounds

   When from distance, entrance wound may
    be smaller than bullet
                  D. Burns
   Early fatalities most often due to fluid loss
   Later fatalities most often due to infection
   Infection is often due to Pseudomonas
   Electrical injury can cause dermal burns
    with blister formation
             E. Alcohol Abuse
   Dilated cardiomyopathy
   Alcoholic hepatitis and cirrhosis
   Acute and chronic pancreatitis
   Encephalopathy
       Wernicke syndrome (ataxia, confusion,
        ophthalmoplegia, and often nystagmus)
       Korsakoff syndrome (memory loss and
         E. Alcohol Abuse
   Myopathy
   (Along with tobacco): carcinoma of
    mouth, pharynx, larynx, esophagus,
         E. Alcohol Abuse
   Fetal alcohol syndrome (microcephaly,
    mental retardation, facial and cardiac
   Not a cause of optic nerve damage:
    methyl (not ethyl) alcohol toxicity can
    cause blindness due to optic nerve
               F. Tobacco

   Squamous cell carcinoma of larynx,
    squamous cell and small cell bronchogenic
    carcinoma, transitional cell carcinoma of
    urinary bladder
   Chronic obstructive pulmonary disease
   Atherosclerosis and other vascular
    occlusive disease, such as Buerger disease
        G. Carbon Monoxide
   Irreversible hypoxic damage, especially to
   Most significant findings in basal ganglia
    and lenticular nuclei
        H. Lead Poisoning
   Basophilic stippling of erythrocytes
   Anemia
   Increased RBC and plasma
    protoporphyrins (increased zinc
    protoporphyrin concentration),
    porphyrinuria, and delta-aminolevulinic
   Increased radiodensity in epiphyses of
    long bones, appearing as a dense line in
   Lead line in gums
                      I. Other

   Cocaine
       mini-infarcts in fetal brain
   Polychlorinated biphenyls (PCBs)
       chloracne, impaired vision, impotence
   Electrocution
       cutaneous burns at entrance and exit
       earliest skin change is edema with vesicle
                     I. Other

   Vinyl chloride
       hepatic angiosarcoma
   Beta-naphthylamine and aniline dyes
       transitional cell carcinoma of urinary bladder
   Nephrotoxic drugs
       cause necrosis of proximal convoluted tubules
                    I. Other

   Ethylene glycol (antifreeze)
       metabolically converted to oxalate
       calcium oxalate crystals in tubular lumina
        visualized with polarized light
       can cause acute tubular necrosis (involving
        proximal convoluted tubules)

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