Pathology

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jknell
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Pathology
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2013-04-03 17:50:11
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  1. Apoptosis
    -pathways
    -characteristics
    • Programmed cell death
    • -ATP dependent
    • -single cells, or small groups
    • -no inflammation

    • Pathways:
    • 1. Intrinsic
    • 2. Extrinsic



    • Common pathway:
    • -activation of cytosolic caspases
    • -caspases activate endonucleases and proteases

    • Characteristics:
    • -cell shrinkage
    • -nuclear shrinkage (pyknosis)
    • -nuclear fragmentation (karyorrhexis)
    • -nuclear dissolution (karyolysis)
    • -basophilia
    • -membrane blebbing
    • -formation of apoptotic bodies (which are then phagocytosed by macrophages)
  2. Apoptosis: Intrinsic Pathway
    Involved in tissue remodeling in embryogenesis

    • Occurs when growth factor is withdrawn from a proliferating cell population
    • -decreased IL2 after resolved immune reaction
    • -loss of hormonal stimulation leads to endometrial shedding

    • Occurs after exposure to injurious stimuli
    • -radiation
    • -toxins
    • -hypoxia

    • Mechanism:
    • Changes in proportions of anti- and pro-apoptotic factors (decreased Bcl-2, increased Bax)
    • -increased mitochondria permeability and release of cytochrome C
    • -cytochrome C activates caspases in cytoplasm
  3. Apoptosis: Extrinsic Pathway
    • Ligand Receptor Interactions:
    • -FasL binding Fas (CD95) (eg: negative selection)
    • -TNF binds TNF Receptor

    • Immune cell:
    • -cytotoxic T cell release of perforin (creates pores) and granzyme B (activates caspases)
  4. Necrosis
    -background
    -types
    • Death of large groups of cells followed by acute inflammation
    • -enzymatic degradation and protein denaturation of a cell resulting from exogenous injury

    • Types:
    • -Coagulative
    • -Liquefactive
    • -Caseous
    • -Fatty
    • -Fibrinoid
    • -Gangrenous
  5. Coagulative Necrosis
    • Pathology:
    • -tissue remains firm
    • -cell shape and organ structure are preserved
    • -nuclei disappear

    • Characteristic of:
    • -ischemic infarction
    • -any organ except brain

    • Location:
    • -heart
    • -liver
    • -kidney
  6. Liquefactive Necrosis
    • Pathology:
    • -liquefied (enzymatic lysis of cells and protein)

    • Characteristic of:
    • -brain infarction (microglial cells produce enzymes)
    • -abscess (NPs produce enzymes)
    • -pancreatitis (enzymes from pancreas)
    • -pleural effusion
  7. Caseous Necrosis
    • Pathology:
    • -soft friable necrotic tissue
    • -"cottage cheese"

    • Characteristic of:
    • -TB
    • -systemic fungi
  8. Fatty Necrosis
    • Pathology:
    • -necrotic adipose tissue with chalky-white appearance (due to deposition of calcium)
    • -saponification (dystrophic calcification)

    • Characteristic of:
    • -peripancreatic fat
    • -trauma to breast
  9. Fibrinoid Necrosis
    • Pathology:
    • -leakage of proteins into vessel wall results in bright pink staining of wall

    • Characteristic of:
    • -malignant hypertension
    • -vasculitis
  10. Gangrenous Necrosis
    • Pathology:
    • -Dry Gangrene: ischemic coagulative necrosis that resembles mummified tissue
    • -Wet gangrene: bacterial infection superimposed

    • Characteristic of:
    • -limbs
    • -GI tract
  11. Reversible Cell Injury
    • Hypoxia impairs oxidative phosphorylation → decreased ATP synthesis
    • 1. Impaired Na+/K+ ATPase: sodium and water buildup in cell
    • 2. Impaired Ca2+ pump: Ca2+ buildup in cytosol
    • 3. Aerobic glycolysis: lactic acid production/low pH

    • Features:
    • -Hallmark = cellular swelling
    • -ER swelling → dissociation of ribosomes and decreased protein synthesis
    • -nuclear chromatin clumping
    • -decreased glycogen
    • -fatty change
  12. Irreversible Cell Injury
    Hallmark = membrane damage

    • Plasma Membrane Damage:
    • -cytosolic enzymes leak into serum (eg: cardiac troponin)
    • -additional Ca2+ enter cells → caspase activation

    • Mitochondrial Membrane Damage:
    • -loss of ETC
    • -Cytochrome c leaks into cytosol

    • Lysosomal Membrane Damage:
    • -hydrolytic enzymes leak into cytosol
    • -activated by high levels of Ca2+

    • Nuclear Damage:
    • -pyknosis
    • -karyloysis
    • -karyorrhexis
  13. Ischemia Susceptible Areas
    • Brain:
    • -ACA/MCA/PCA boundary areas (watershed areas)
    • -Hypoxic Ischemic Encephalopathy: pyramidal cells of hippocampus and Purkinje cells

    • Heart:
    • -Subendocardium (LV)

    • Kidney:
    • -straight segment of proximal tubule (medulla)
    • -thick ascending limb (medulla)

    • Liver:
    • -area around central vein (zone III)

    • Colon:
    • -splenic flexure
    • -rectum
  14. Red Infarct vs Pale Infarct
    • Pale Infarct:
    • -occur in solid tissues with a single blood supply
    • -heart
    • -kidney
    • -spleen

    • Red Infarct:
    • -hemorrhagic, following reperfusion
    • -reperfusion injury due to damage by free radicals
    • -loose tissues with collaterals
    • -liver
    • -lungs
    • -intestines

  15. Hypovolemic/Cardiogenic Shock
    • Low-output failure
    • -↑ TPR
    • -Low cardiac output
    • -Cold, clammy patient (vasoconstriction)
  16. Septic Shock
    • High-output failure:
    • -↓ TPR
    • -Dilated arterioles, high venous return
    • -hot patient (vasodilation)
  17. Atrophy
    • Reduction in the size or number of cells

    • Causes:
    • -↓ hormones (uterus/vagina)
    • -↓ innervation (motor neuron damage)
    • -↓ blood flow
    • -↓ nutrients
    • -↑ pressure (nephrolithiasis)
    • -occlusion of secretory ducts (CF)

    • Mechanism:
    • -Decrease in cell number: apoptosis
    • -Decrease in cell size: ubiquitin-proteosome degradation of cytoskeleton, autophagy of cellular components
  18. Inflammation
    -characteristics
    -vascular components
    -cellular components
    • Characteristics:
    • -Rubor (redness)
    • -Dolor (pain)
    • -Calor (heat)
    • -tumor (swelling)
    • -functio laesa (loss of function)

    • Vascular Components:
    • -increased vascular permeability
    • -vasodilation
    • -endothelial injury

    • Cellular Components:
    • -Neutrophils (extravasate from circulation to injured tissue)
  19. Acute Inflammation
    -basic principles
    -time course
    -mediators
    -outcomes
    • Characterized by:
    • -edema
    • -neutrophils

    Arises in response to infection or tissue necrosis

    • Rapid onset (sec - min)
    • Lasts minutes to days

    • Mediators:
    • 1. TLRs (TLR4: LPS)

    • 2. Arachadonic Acid metabolites
    • -PGI2, PGD2, PGE2: vasodilation, increased vascular permeability
    • -PGE2: pain and fever
    • -LTB4: attracts and activates NPs
    • -LTC4, LTD4, LTE4: vasoconstriction, bronchospasm, increased vascular permeability

    • 3. Mast cells:
    • -activated by trauma, C3a/C5a, IgE cross linking
    • -immediate response: preformed histamine
    • -delayed response: production of leukotrienes

    • 4. Complement:
    • -C3a/C5a: mast cell degranulation
    • -C5a: chemotatic for NPs
    • -C3b: opsonin for phagocytosis
    • -MAC (C5a, C6-9): microbe lysis

    • 5. Hageman Factor:
    • -factor XII
    • -activates: coagulation and fibrinolytic system, C', Kinin system (Bradykinin)

    • 6. Neutrophils:
    • -phagocytosis
    • -degranulation
    • -inflammatory mediator release

    • Outcomes:
    • -Complete resolution
    • -abscess formation
    • -progression to chronic inflammation
  20. Chronic Inflammation
    -basic principles
    -stimuli
    -mediators
    -granuloma
    -outcomes
    • Characterized by:
    • -lymphocytes and plasma cells
    • -persistent destruction or repair
    • -blood vessel proliferation, fibrosis

    Delayed response but more specific

    • Stimuli:
    • -persistent infection
    • -infection with viruses, mycobacteria, parasites, fungi
    • -autoimmune disease
    • -foreign material
    • -some cancer

    • Mediators:
    • 1. CD4 T cells
    • -Signal 1: MHC II and TCR
    • -Signal 2: B7 on APC, CD28 on T cells
    • -Th1: IL2 and IFNg (CD8s, MPs)
    • -Th2: IL4 and IL5 (class switching, eosinophils)

    • 2. CD8 T cells
    • -Signal 1: MCH I and TCR
    • -Signal 2: cytokines (IL2 from CD4)
    • -killing via perforin/granzyme or Fas

    • 3. B cells
    • -Antigen binding to IgM and IgD
    • -CD4 T cells: MCH II and TCR, CD40
    • -class switching, hypermutation, plasma cells

    • Granuloma:
    • -defining feature = epitheloid histocytes
    • -giant cells
    • -MP present Ag to CD4 cells
    • -MP secrete IL12 → Th1 differentiation
    • -Th1 secrete IFNg
    • -caseating or non-caseating

    • Outcomes:
    • -scarring
    • -amyloidosis
  21. Leukocyte extravasation
    • Step 1 (Rolling):
    • -Stroma: E-selectin (induced by TNF and IL1), P-selectin (Weibel-Palade bodies)
    • -Leukocyte: Sialyl-LewisX
    • -"selectin speed bump"

    • Step 2 (Tight Binding):
    • -Stroma: ICAM-1 (TNF and IL1)
    • -Leukocytes: LFA1 Integrin (C5a, LTB4)

    • Step 3 (Diapedesis):
    • -leukocyte travels between endothelial cells and exits blood vessels
    • -Stroma: PECAM-1
    • -Leukocyte: PECAM-1

    • Step 4 (Migration):
    • -leukocyte travels through interstitium to site of injury or infection guided by chemotactic signals
    • -Bacterial Products: C5a, IL8, LTB4, Kallikrein (CILK)

  22. Free Radical Injury: Damages to cells
    • Damage cells via:
    • -membrane lipid peroxidation
    • -protein modification
    • -DNA breakage
  23. Free Radical Injury: Pathologic Generation


    • Ionizing radiation
    • -water to hydroxyl radical

    • Inflammation
    • -leukocyte oxidative burst (NADPH oxidase)

    • Metals
    • -Fe2+: Fenton reaction
    • -Cu

    • Metabolism of Drugs
    • -eg: acetaminophen
    • -P450 system of liver

    Nitric Oxide
  24. Free Radical Injury: Mechanisms of Elimination
    • Enzymes
    • -Catalase: in peroxisomes, eliminates H2O2
    • -Superoxide Dismutase: in mitochondria, converts superoxide to H2O2
    • -Glutathione Peroxidase: in mitochondria

    • Antioxidants
    • -glutathione
    • -Vitamins A, C, E

    • Metal Carrier proteins
    • -transferrin
    • -ceruloplasmin

    Spontaneous decay
  25. Free Radical Injury: Pathologies
    Retinopathy of prematurity

    Bronchopulmonary dysplasia

    • Carbon Tetrachloride:
    • -organic solvent in drycleaning industry
    • -converted to CCl3 free radical by P450 system
    • -cellular swelling/swelling of RER → ribosomes detach (impair protein synthesis)
    • -Decreased apolipoproteins leads to fatty change in liver

    • Acetaminophen Overdose:
    • -fulminant hepatitis

    • Iron Overload
    • -Hemochromatosis

    • Reperfusion after anoxia
    • -return of blood to ischemic tissues produces superoxide
    • -especially after thrombolytic therapy
    • -can see continued rise in cardiac enzymes after reperfusion of infarcted myocardial tissue
  26. Wound Healing
    -phases
    -types of tissues
    • Phases:
    • 1. Inflammatory (immediate)
    • 2. Proliferative (2-3 days after wound)
    • 3. Remodeling (1 week after wound)

    • Labile Tissue:
    • -stem cells that continuously cycle
    • -small and large bowel
    • -skin
    • -bone marrow
    • -REGENERATE

    • Stabile Tissue:
    • -cells that are quiescent (G0) but can reenter cell cycle
    • -liver
    • -REGENERATE

    • Permanent Tissue:
    • -myocardium
    • -skeletal muscle
    • -neurons
    • -can't regenerate, heal by REPAIR
  27. Wound Healing: Inflammatory Phase
    -mediators
    -characteristics
    • Mediators:
    • -Platelets
    • -Neutrophils
    • -Macrophages

    • Characteristics:
    • -clot formation
    • -increased vessel permeability and NP migration to tissue
    • -MPs clear debris two days later
  28. Wound Healing: Proliferative Phase
    2-3 days after wound

    • Mediators:
    • -Fibroblasts (type III collagen)
    • -Myofibroblasts
    • -Endothelial cells
    • -Keratinocytes
    • -Macrophages

    • Characteristics:
    • -deposition of granulation tissue and collagen
    • -angiogenesis
    • -epithelial cell proliferation
    • -dissolution of clot
    • -wound contraction (myofibroblasts)
  29. Wound Healing: Remodeling
    1 week after wound

    • Mediators:
    • -fibroblasts

    • Characteristics:
    • -Remove Type III collagen by collagenase (zinc as cofactor)
    • -Type III collagen replaced by type I collagen (less flexible, more tensile strength)
  30. Abberant Wound Healing
    • Infection
    • -S. aureus

    • Vitamin C deficiency:
    • -hydroxylation of proline and lysine on procollagen residues
    • -necessary for collagen cross linking

    • Copper deficiency:
    • -cofactor for lysyl oxidase
    • -cross links lysine and hydroxylysine to form stable collagen

    • Zinc deficiency:
    • -cofactor for collagenase
    • -replaces type III collagen with type I collagen
  31. Granulomatous Diseases
    -granuloma formation
    -diseases
    • Granuloma Formation:
    • -Th1 cells secrete IFNg, activating MPs
    • -TNFa from MPs induce and maintain granuloma formation
    • **anti-TNFa drugs can cause granuloma breakdown leading to disseminated disease

    • Diseases:
    • -Mycobacterium tuberculosis
    • -Fungal Infections (histo, cocci)
    • -Treponema pallidum (syphilis)
    • -M. leprae (leprosy)
    • -Bartonella henselae (stellate shaped cells)
    • -Sarcoidosis
    • -Crohn's Disease
    • -Wegener's
    • -Churg-Strauss
    • -Berylliosis, Silicosis
  32. Transudate vs Exudate


    • Transudate:
    • -increased hydrostatic pressure
    • -decreased oncotic pressure
    • -Na+ retention

    • Exudate:
    • -lymphatic obstruction
    • -inflammation
  33. Erythrocyte Sedimentation Rate
    -Elevated
    -Decreased
    • -Products of inflammation (eg: fibrinogen) coat RBCs and cause aggregation
    • -When aggregated, RBCs fall at a faster rate within the test tube

    • Elevated ESR:
    • -infections
    • -inflammation (temporal arteritis)
    • -cancer
    • -pregnancy
    • -SLE

    • Decreased ESR:
    • -Sickle cell (altered shape)
    • -Polycythemia (too many)
    • -CHF (unknown)
  34. Iron Poisoning
    -mechanism
    -symptoms
    -one of the leading causes of fatality from toxicologic agents in children

    • Mechanism:
    • -cell death due to peroxidation of membrane lipids

    • Symptoms:
    • -Acute: gastric bleeding
    • -Chronic: metabolic acidosis, scarring leading to GI obstruction
  35. Amyloidosis
    -basic principles
    -types
    • Basic Principles:
    • -abnormal aggregation of proteins or their fragments into β-pleated sheets (deposited in extracellular space)
    • -can't be degraded
    • -leads to cell damage and apoptosis
    • -congo red staining and apple-green birefringence
    • -can be systemic or localized

    • Types:
    • -AL (primary)
    • -AA (secondary)
    • -Dialysis-related
    • -Heritable
    • -Senile systemic
    • -Organ specific
  36. AL (primary) Amyloidosis
    -pathophysiology
    -presentation
    • Pathophysiology:
    • -deposition of proteins from Ig Light chain
    • -associated with plasma cell dyscrasias (ie: multiple myeloma)

    • Often multiple organ system impact:
    • -Renal (nephrotic syndrome)
    • -Cardiac (heart failure, arrhythmia)
    • -Hematologic (easy bruising)
    • -Hepatomegaly
    • -Neuropathy
  37. AA (secondary) Amyloidosis
    -pathophysiology
    -presentation
    • Pathophysiology:
    • -systemic deposition of AA amyloid
    • -derived from SAA (acute phase reactant)
    • -seen with chronic diseases: RA, IBD, Spondyloarthropathy, chronic infections, Familial Mediterranean Fever (dysfunction of neutrophils)

    • Presentation:
    • -often multisystem like AL amyloidosis
  38. Dialysis Related Amyloidosis
    • Pathophysiology:
    • -fibrils composed of β2-microglobulin (MHC I)
    • -not filtered well from blood during dialysis
    • -patients with ESRD and long-term dialysis

    • Presentation:
    • -carpal tunnel syndrome
    • -other joint issues
  39. Heritable Amyloidosis
    -pathophysiology
    -presentation
    • -heterogenous group of disorders
    • -eg: "Familial Amyloid Cardiomyopathy"

    • Pathophysiology:
    • -mutated serum transthyretin (TTR)
    • -deposits in heart → restrictive cardiomyopathy
  40. Age-Related (Senile) Systemic Amyloidosis
    • Pathophysiology:
    • -deposition of wild-type transthyretin (TTR)
    • -in myocardium and other sites

    • Presentation:
    • -slower progression of cardiac dysfunction vs AL amyloidosis
    • -usually asymptomatic
  41. Organ-Specific Amyloidosis
    • Alzheimer's
    • -deposition of amyloid-β protein cleaved from amyloid precursor protein (c 21)
  42. Hallmarks of Cancer
    • -evasion of apoptosis
    • -self-sufficiency in growth signals
    • -insensitivity to anti-growth signals
    • -sustained angiogenesis
    • -limitless replicative potential
    • -tissue invasion
    • -metastasis
  43. Neoplasm Progression
    • 1. Normal
    • 2. Hyperplasia/Dysplasia
    • 3. Carcinoma in situ/preinvasive
    • 4. Invasive Carcinoma
    • 5. Metastasis

  44. Hyperplasia
    • -increase in number of cells (production of new cells from stem cells)
    • -abnormal proliferation of cells
    • -reversible!

    **BPH: does not increase risk of prostate cancer
  45. Dysplasia
    • -loss of size, shape and orientation
    • -often arises from long-standing hyperplasia or metaplasia
    • -reversible!
  46. Carcinoma in situ
    • -neoplastic cells have not invaded basement membrane
    • -high nuclear/cytoplasmic ratio and clumped chromatin
    • -neoplastic cells encompass entire thickness
  47. Invasive Carcinoma
    • -cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases)
    • -can metastasize if they reach a blood or lymphatic vessel
  48. Metastasis
    • -spread to distant organ
    • -must survive immune attack

    • "Seed and Soil" theory of metastasis:
    • -seed = tumor embolus
    • -soil = target organ
  49. Reversible -plasias
    • Hyperplasia
    • -increase in number of cells

    • Metaplasia
    • -change in stress leads to a change in cell type
    • -often secondary to irritation and/or environmental exposure
    • -squamous metaplasia in trachea and bronchi of smokers
    • -Barrett's esophagus

    • Dysplasia:
    • -abnormal growth with loss of cellular orientation, shape, and size
    • -commonly preneoplastic
  50. Irreversible -plasias
    • Anaplasia:
    • -abnormal cells lacking differentiation
    • -resemble primitive cells of same tissue
    • -often equated with undifferentiated malignant neoplasms
    • -little or no resemblance to tissue of origin

    • Neoplasia:
    • -clonal proliferation of cells that is uncontrolled and excessive
    • -may be benign or malignant

    • Desmoplasia:
    • -fibrous tissue formation in response to neoplasm
  51. Tumor Grade
    • Microscopic assessment of differentiation
    • -how much a cancer resembles the tissue in which it grows
    • -graded 1-4

    • 1: low grade, well differentiated
    • 2: high grade, poorly differentiated, anaplastic

    *less prognostic value than stage
  52. Tumor Stage
    • Degree of localization/spread
    • -based on clinical (c) or pathology (p) findings

    • TNM
    • T: Tumor size
    • N: Node involvement
    • M: Metastases (most important prognostic factor)
  53. Tumor Nomenclature
  54. Benign Tumor
    -characteristics
    • -well differentiated
    • -slow growing
    • -well demarcated
    • -mobile
    • -no potential for metastasis
  55. Malignant Tumor
    -characteristics
    • -may be poorly differentiated (does not have to be)
    • -erratic growth/fast growing
    • -locally invasive/diffuse
    • -may metastasize
  56. Cachexia
    -presentation
    -caused by
    -mediators
    • Presentation:
    • -weight loss
    • -muscle atrophy
    • -fatigue

    • Occurs in chronic disease
    • -cancer
    • -AIDS-heart failure
    • -TB

    • Mediated by:
    • -TNFa (cachectin)
    • -IFNg
    • -IL6
  57. Down Syndrome
    • ALL ("we ALL fall Down")
    • AML
  58. Xeroderma Pigmentosum
    • Melanoma
    • Basal cell carcinoma
    • Squamous cell carcinoma (especially)
  59. Albinism
    • Melanoma
    • Basal cell carcinoma
    • Squamous cell carcinoma (especially)
  60. Chronic atrophic gastritis
    Gastric adenocarcinoma
  61. Pernicious Anemia
    Gastric adenocarcinoma
  62. Postsurgical gastric remnants
    Gastric adenocarcinoma
  63. Tuberous Sclerosis
    • Giant cell astrocytoma
    • Renal angiomyolipoma
    • Cardiac rhabdomyoma
  64. Actinic Keratosis
    Squamous cell carcinoma of skin
  65. Barret's esophagus
    Esophageal adenocarcinoma
  66. Plummer-Vinson Syndrome (decreased iron)
    Squamous cell carcinoma of esophagus
  67. Cirrhosis
    -alcoholic
    -hep B or C
    Hepatocellular carcinoma
  68. Ulcerative Colitis
    Colonic adenocarcinoma
  69. Paget's Disease of Bone
    • Secondary Osteosarcoma
    • Secondary Fibrosarcoma
  70. Immunodeficiency States
    Malignant Lymphoma
  71. AIDS
    • Aggressive malignant lymphomas (Non-Hodgkins)
    • Kaposi's Sarcoma
  72. Autoimmune Diseases
    Lymphoma
  73. Acanthosis Nigricans
    • Visceral malignancy (stomach, lung, uterus)
    • -associated with gastric carcinoma
  74. Dysplastic nevus
    Malignant melanoma
  75. Radiation Exposure
    • Leukemia
    • Sarcoma
    • Papillary thyroid cancer
    • Breast cancer
  76. Oncogenes
    -description
    -examples
    • -proto-oncogenes are essential for cell growth and proliferation
    • -oncogenes lead to unregulated cellular growth

    • -Gain of function leads to increased cancer risk
    • -Need damage only one allele

    • Examples:
    • -abl
    • -cmyc
    • -bcl2
    • -HER2/neu
    • -ras
    • -L-myc
    • -N-myc
    • -ret
    • -c-kit
  77. abl
    • Associated tumor:
    • -CML

    • Gene Product:
    • -tyrosine kinase
  78. c-myc
    • Associated Tumor:
    • -Burkitt's lymphoma

    • Gene Product:
    • -transcription factor
  79. bcl-2
    • Associated Tumor:
    • -Follicular and undifferentiated lymphoma

    • Gene Product:
    • -anti-apoptotic molecule
  80. HER2/neu
    • Associated Tumor:
    • -breast carcinoma
    • -ovarian carcinoma
    • -gastric carcinoma

    • Gene Product:
    • -tyrosine kinase
    • -epidermal growth factor receptor
  81. ras
    • Associated tumor:
    • -colon cancer
    • -mutated in 70-80% of human tumors

    • Gene Product:
    • -GTPase (signal transduction of growth signal)
  82. L-myc
    • Associated tumor:
    • -Lung tumor

    • Gene Product:
    • -transcription factor
  83. N-myc
    • Associated tumor:
    • -neuroblastoma

    • Gene Product:
    • -transcription factor
  84. ret
    • Associated Tumor:
    • -MEN2A, MEN2B

    • Gene Product:
    • -tyrosine kinase
  85. c-kit
    • Associated tumor:
    • -gastrointestinal stromal tumor (GIST)

    • Gene Product:
    • -cytokine receptor
  86. Tumor Suppressor Genes
    -description
    -examples
    -regulate cell growth

    • -Loss of function increases cancer risk
    • -both alleles must be lost for disease

    • Examples:
    • -Rb
    • -p53
    • -BRCA1
    • -BRCA2
    • -p16
    • -BRAF
    • -APC
    • -WT1
    • -NF1
    • -NF2
    • -DPC4
    • -DCC
  87. Rb
    • Associated tumor:
    • -Retinoblastoma
    • -Osteosarcoma
    • **non-familial: unilateral retinoblastoma

    • Gene Product:
    • -inhibits E2F
    • -blocks G1 to S phase transition
  88. p53
    • Associated Tumor:
    • -most human cancers
    • -Li Fraumeni syndrome

    • Gene Product:
    • -transcription factor for p21
    • -blocks G1 to S phase transition
  89. BRCA1/2
    • Associated tumor:
    • -breast cancer
    • -ovarian cancer

    • Gene Product:
    • -DNA repair protein
  90. p16
    • Associated tumor:
    • -Melanoma
  91. BRAF
    • Associated Tumor:
    • -Melanoma

    • Gene Product:
    • -Braf
  92. APC
    • Associated Tumor:
    • -Colorectal cancer
    • -associated with FAP
  93. WT1
    • Associated Tumor:
    • -Wilm's Tumor (nephroblastoma)
  94. NF1
    • Associated Tumor:
    • -NF type 1

    • Gene Product:
    • -RAS GTPase activating protein (RAS-GAP)
  95. DPC4
    • Associated tumor:
    • -Pancreatic cancer

    • Gene Product:
    • -DPC: Deleted in Pancreatic Cancer
  96. DCC
    • Associated tumor:
    • -colon cancer

    • Gene Product:
    • -DCC: Deleted in Colon Cancer
  97. Tumor Markers
    -use
    -examples
    • Use:
    • -screening
    • -monitor for recurrence
    • -monitor response to therapy
    • -should not be used as primary tool for cancer diagnosis

    • Examples:
    • -PSA
    • -Prostatic acid phosphatase
    • -CEA
    • -α-fetoprotein
    • -β-hCG
    • -CA-125
    • -S-100
    • -Alkaline Phosphatase
    • -Bombesin
    • -TRAP
    • -CA-19-9
    • -Calcitonin
  98. PSA
    • -used to follow prostate carcinoma
    • -can also be elevated in BPH and prostatis
    • -questionable risk/benefit for screening
  99. Prostatic acid phosphatase
    -prostate carcinoma
  100. CEA
    CarcinoEmbryonic Antigen

    • -very non-specific
    • -produced by 70% of colorectal and pancreatic cancers
    • -also produced by gastric, breast and medullary thyroid carcinomas
  101. α-fetoprotein
    -normally made by fetus

    • -Hepatocellular carcinoma
    • -non-seminomatous germ cell tumors (testis, ovary)
  102. β-hCG
    • Hydatidiform moles
    • Choriocarcinoma
    • (Gestational trophoblastic disease)

    *commonly associated with pregnancy
  103. CA-125
    Ovarian cancer
  104. S-100
    • Melanoma
    • Neural tumors
    • Schwannomas
  105. Alkaline Phosphatase
    • -metastases to bone
    • -Paget's disease of bone
  106. Bombesin
    • Neuroblastoma
    • Lung cancer
    • Gastric cancer
  107. TRAP
    Tartrate-Resistant Acid Phosphatase (TRAP)

    -Hairy cell leukemia (B cell neoplasm)

    "TRAP the Hairy animal!"
  108. CA-19-9
    Pancreatic adenocarcinom
  109. Calcitonin
    Medullary Thyroid Carcinoma
  110. Oncogenic Microbes
    • HTLV1
    • HBV, HCV
    • EBV
    • HPV
    • HHV-8
    • H pylori
    • Schistosoma haematobium
    • Liver fluke (clonorchis sinesis)
  111. HTLV1
    Adult T cell leukemia/lymphoma
  112. HBV, HCV
    Hepatocellular carcinoma
  113. EBV
    • Burkitt's lymphoma
    • Hodgkin's lympohoma
    • Nasopharyngeal carcinoma (asian men)
    • CNS lymphoma (in immunocompromised)
  114. HPV
    • Cervical Carcinoma
    • Penile/Anal Carcinoma
    • Upper respiratory SCC
  115. HHV8
    • Kaposi's sarcoma
    • Body cavity fluid B cell lymphoma
  116. H pylori
    Gastric adenocarcinoma and lymphoma
  117. Schistosoma haematobium
    Bladder cancer (squamous cell)
  118. Liver fluke (Clonorchis sinensis)
    Cholangiocarcinoma
  119. Chemical Carcinogens
    • Aflatoxin
    • Vinyl chloride
    • Carbon tetrachloride
    • Nitrosamines
    • Cigarette smoke
    • Asbestos
    • Arsenic
    • Napthalene (aniline) dyes
    • Alkylating agents
  120. Aflatoxin
    -from aspergillus (can get into improperly stored grains)

    • Associated Tumor:
    • -hepatocellular carcinoma
  121. Vinyl Chloride
    • Associated Tumor:
    • -hepatic angiosarcoma
  122. Carbon Tetrachloride
    • Centrilobular necrosis
    • Fatty change

    (decrease protein synthesis of apolipoproteins)
  123. Nitrosamines
    -from smoked foods

    • Associated Tumor:
    • -gastric cancer
  124. Cigarette Smoke
    • Carcinogens:
    • -arsenic
    • -polycyclic hydrocarbons
    • -naphthylamine

    • Associated tumors:
    • -Squamous cell carcinoma of lung
    • -Small cell carcinoma of lung
    • -Renal cell carcinoma
    • -Transitional cell carcinoma (bladder etc)
    • -Pancreatic adenocarcinoma
  125. Asbestos
    • Associated Tumors:
    • Bronchogenic carcinoma > Mesothelioma
  126. Arsenic
    • Associated Tumors:
    • -Squamous cell carcinoma (keep skin fair)
    • -Liver angiosarcoma
  127. Naphthalene (aniline) dyes
    -found in cigarette smoke

    • Associated Tumors:
    • -Transitional cell carcinoma
  128. Alkylating dyes
    -chemotherapeutics

    • Associated tumors:
    • -leukemia
  129. Paraneoplastic Syndromes
    • Ectopic Hormones:
    • -ACTH
    • -ADH
    • -PTHrP
    • -Calcitriol
    • -Epo
    • -Lambert-Eaton Syndrome
  130. Paraneoplastic Syndromes: ACTH
    • Effect:
    • -Cushing's syndrome

    • Neoplasms:
    • -Small cell lung carcinoma
  131. Paraneoplastic Syndromes: ADH
    • Effect:
    • -SIADH

    • Neoplasms:
    • -Small cell lung carcinoma
    • -intracranial neoplasms
  132. Paraneoplastic Syndromes: PTHrP
    • Effect:
    • -hypercalcemia

    • Neoplasms:
    • -Squamous cell lung carcinoma
    • -renal cell carcinoma
    • -breast cancer
  133. Paraneoplastic Syndromes: Calcitriol
    1,25 (OH)2 Vitamin D

    • Effect:
    • -Hypercalcemia

    • Neoplasm:
    • -Hodgkin's lymphoma
    • -some non-Hodgkin's lymphomas
  134. Paraneoplastic Syndromes: Epo
    • Effect:
    • -Polycythemia

    • Neoplasms:
    • -Renal cell carcinoma
    • -Hemangioblastoma
    • -Heptatocellular carcinoma
    • -pheochromocytoma
  135. Paraneoplastic Syndromes: Lambert Eaton Syndrome
    Antibodies against presynaptic Ca channels at NMJ

    • Neoplasms:
    • -Small cell lung carcinoma
  136. Psammoma bodies
    • Description:
    • -laminated, concentric, calcific spherules

    • Seen in:
    • -Papillary adenocarcinoma of thyroid
    • -Serous papillary cystadenocarcinoma of ovary
    • -Meningioma
    • -Malignant Mesothelioma

    PSaMMoma
  137. Cancer Incidence
    • Male:
    • 1. Prostate (32%)
    • 2. Lung (16%)
    • 3. Colon/rectum (12%)

    • Female:
    • 1. Breast (32%)
    • 2. Lung (13%)
    • 3. Colon/rectum (12%)

    ** lung cancer incidence has dropped in men but has not changed significantly in women
  138. Cancer Mortality
    • Male:
    • 1. Lung (33%)
    • 2. Prostate (13%)

    • Female
    • 1. Lung (23%)
    • 2. Breast (18%)

    **Cancer is the second leading cause of death in the US
  139. Common Sites of Metastasis
    • Brain
    • Liver
    • Bone

    Carcinomas tend to metastasize via lymphatics

    Sarcomas tend to spread hematogenously

    • Carcinomas that spread hematogenously:
    • -Renal cell carcinoma
    • -hepatocellular carcinoma
    • -follicular carcinoma of thyroid
    • -choriocarcinoma
  140. Brain Metastases
    Lung > Breast > GU > Osteosarcoma > Melanoma > GI

    • 50% of brain tumors are from mets
    • Typically multiple well-circumscribed tumors at gray/white matter junction
  141. Liver Metastases
    Colon >> stomach > pancreas

    Liver and lung are the most common sites of metastasis after regional LNs
  142. Bone Metastases
    Prostate/breast > Lung > Thyroid, Testes

    Bone mets > primary tumors

    whole-body bone scan shows predilection for axial skeleton

    • Lung = lytic
    • Prostate = blastic
    • Breast = lytic and blastic

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