Professional Documents
Culture Documents
Cell Adaptation
Causes
Pathology Review Flash Cards Increased/decreased demand or workload
trophic stimulation (ex: hormones, growth
General Pathology factors)
decreased nutrients/ischemia/denervation
chronic irritation/inflammation
Spring 2009 Types
hyperplasia
hypertrophy
atrophy
metaplasia
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Calcification Lipofuscin
Metastatic Insoluble, wear and tear pigment
Deposition of calcium phosphate in normal Does not harm cell or cellular functions
tissue
End product of membrane lipid peroxidation
hypercalcemia
Increased parathyroid hormone secretion Commonly accumulates in the elderly
vit. D toxicosis Most often in hepatocytes and myocardium
tumors associated with increased bone Combination of lipofuscin accumulation and
catabolism atrophy of organs is brown atrophy
multiple myeloma
Renal osteodystrophy secondary
hyperparathyroidism
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Inflammation Overview:
Inflammation Overview: Phagocytosis
Delivery of cells
Vasoactive: vasoconstriction followed by dilation Ingest material by phagocytes-neutros/monos/macros
opsonized particle internalized in phagosome that fuses
leads to increased blood flow---redness warmth
w/lysosome to form phagolysosome--WBC degranulates
Incr. Cap. perm: His, 5HT; leak protein & fluid - edema
Opsonization: coating particle by opsonins to
from endothelial contraction (gaps) in postcap. venules immobilize
Adhesion: to draw inflammatory
f cells to injury site IgG & C3b are examples of opsonins
Integrin: LFA-1 etc on WBCs bind endothelial ICAMs etc IgG binds fragments, WBCs bind Fc portion of IgG
Immunoglobulin-family adhesions: on endothelium C3b binds fragments, WBCs bind C3b also
bind integrins on WBCs, ICAM-1, ICAM-1, VCAM Microbial Killing: O2 dependent or independent
Selectins: induced by IL-1 & TNF; L on neutro bind O2 dependent: most important, uses NADPH oxidase in
endo phagosome to produce ROS-destroy proteins/microbe wall
E & P on endo, bind sialyl-Lewis X on WBCs
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Inflammation overview:
WBC emigration Adhesion molecules
Emigration: process of WBC migration from post capillary
venule, between endothelial cells, and into tissue
Weak P-selectin, E-selectin -
Margination: blood slowing, movement of WBCs to vessel selectin | sugars adhesion Neutrophil rolling
periphery
Adhesion: mediated by sequential expression of specific ICAM-1(endothelial cell):LFA-
surface molecules integrin | Ig Firm
Fi 1 iintegrin
t i (PMN)
Weak adhesion: between endothelial selectins and WBC surface family adhesion VCAM (endothelial cell):VLA4
carbohydrates, results in rolling integrin (monocyte)
Firm Adhesion: between endothelial ICAM/VCAM and WBC
integrins
Sequential expression of different CAMs determines what type of
WBC migrates at different phases of inflammation (PMN, mono,
etc)
Transmigration: WBC pseudopod formation, diapedesis
by crawling along ECM
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AL (Amyloid Light Chain) -derived from the Reactive (inflammatory) AA from SAA
immunoglobulin light chains; associated with Hemodialysis-related Beta-2 microglobulin
multiple myeloma
Hereditary Pre-albumin variants;
AA (amyloid associated) -derived from SAA and
transthyretin
found in secondary (reactive systemic) amyloidosis
A (Beta
(B t AAmyloid)
l id) -found
f d in
i bbrain
i llesions
i off M d ll
Medullary carcinoma
i off th
the P
Pro-calcitonin
l it i
Alzheimers disease patients thyroid
ATTR (Transthyretin) -present in senile amyloidosis Islet cell tumors, Type II Pro-insulin
ABeta2m (Beta-2 microglobulin) is a normal Diabetes
component of blood that builds up in patients on
long term dialysis. Senile cardiac amyloidosis Transthyretin
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DIC Acid-Base
Activation of DIC Henderson-Hasselbach
pH = 6.1 + log(HCO3)/pCO2* 0.03
Pathogenesis
General consideratoins
Clinical associations
pH rises with HCO3 or pCO2
Sepsis, Neisseria meningitidis pH falls with dec HCO3 or inc p
p pCO2
Clinical measures D-dimer; fibrinolytic dec pH w/inc CO2 = respiratory acidosis (HCO3 >30)**
peptides dec pH w/dec HCO3 = metabolic acidosis (HC03 <22)
inc pH w/dec CO2 = respiratory alkalosis (HCO3 <18)**
Pathologic findings
inc pH w/inc HCO3 = metabolic alkalosis (HCO3 > 28)
** if compensated metabolically
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Acid-Base Acid-Base
Clinical considerations Total CO2
Total CO2(mEq/L) = HCO3 + pCO2*0.03
CO2 changes reflect respiratory function
Serum potassium is often increased with acidosis and
HCO3 changes reflect renal/metabolic function
decreased in alkalosis
Compensatory mechanisms: renal function altered
Anion Gap may increase with metabolic acidosis
to compensate for
f respiratory
i disease
di while
hil
AG= Na-(Cl + HCO3) THINK MULEPAK
respiratory function is altered to compensate for
metabolic or renal disease Acidosis can be treated with bicarb to neutralize acid
or hyperventilation to breathe off excess CO2
The resulting attempt to compensate is never
complete (pH never gets back to 7.4). Alkalosis can be treated by hypoventilation, retention
of H+, or excretion of HCO3-
CDK inhibitors Prevent the movement from one cell Cell cycle has 2 check- points
cycle point to the next by inhibiting CDK. Between G1/S and G2/M
Cip/Kip and INK4/ARF are examples If DNA damage present- DNA duplication is arrested
Serve as tumor suppressors and frequently altered in tumors If DNA damage is reparable- repaired, if not undergoes
apoptosis
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Carcinogenesis Carcinogenesis
Initiation:
Basics
nonlethal DNA damage that affects oncogenes and
Carcinogenesis involves both genetic tumor-suppressor genes; occurs before promotion
damage and induction of proliferation examples: UV light, HPV type 16,18 integration
Oncogene: activated by mutation, promotes Promotion:
growth only one mutation required
growth, may be reversible, promotes proliferation of the
Tumor-suppressor gene: knocked-out by damaged cell
mutation, growth inhibitors (or DNA repair), examples: hormones, inflammation
both alleles must be mutated Complete carcinogen does both (cigarette
Angiogenesis or migration must occur for smoke)
the tumor to grow to a significant size inhaled chemicals mutate the DNA
smoke causes irritation inflammation
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Carcinogenesis Carcinogenesis
Tumor suppressor gene examples
RB: inhibits EF2 transcription (prevents G1 entry) DNA damage:
Phosphorylated/inactivated by CDK Pyrimidine dimers (radiation, UV)
Associated w/ retinoblastoma, osteosarcoma Chromosomal breaks (radiation)
p53: G1/S checkpoint, activates a CDK inhibitor to prevent Translocations (radiation)
RB pphosphorylation:
osp o y a o g growth
o p
prevention
e e o a and
d apop
apoptosis
os s o
of
damaged cells Gene amplification (n-myc, ERB B2)
Absent in Li-Fraumeni Syndrome Viral gene insertion
NF-1: Ras suppressor (Neurofibromatosis Type I) HPV: E6 inactivates p53, E7 inactivates Rb
BRCA-1(Breast&ovarian) & 2(breast) HBV: expression of HBx increases protein kinase C
Involved in DNA double strand break repair Also EBV, HHV-8, HTLV-1
2-hit hypothesis: Mutations in tumor-suppressor genes
Epigenetics: alteration of regulators/promoters
show dominant inheritance. By inheriting a mutated allele,
only one mutation is needed to cause cancer.
membranes
b C hi
Cushing S ll C
Small Cellll C
Carcinoma
i off the
th Lung
L ACTH or ACTH
ACTH-like
lik
Syndrome substances
Binding and growth at distant site adhesion to SIADH Small Cell Carcinoma of the Lung ADH or Atrial Natriuretic
epithelium with laminin and fibronectin (CXCR4 and Intracranial Neoplasms Hormones
CCR7 receptors on tumor emboli) egress through Hypercalcemia Squamous Cell Carcinoma of the Parathyroid hormone-
Lung related protein (PTHRP),
basement membrane Breast Carcinoma TGF-, TNF, IL-1
Mature cartilage and elastic tissue in arteries are Renal Carcinoma
Hyperthyroidism Hydatidform moles, TSH or TSH-like
resistant to invasion by malignant cells Choriocarcinoma, Some Lung substances
Neoplasms
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Staphylococci Staphylococci
Normal flora common cause of skin abscesses, wound infections
Types of Infection
Major cause of infection in burns, surgical wounds, nosocomial
Overgrowth of normal flora, access to sterile areas, ingestion,
infections
infection in immunosuppressed patients
Virulence factors for S. aureus, S. epidermidis, S. saprophyticus
Direct Organ Invasion:
All Catalase Pos; Only S. aureus is coagulase pos.
Skin: impetigo (honey-colored crust), cellulitis, abscesses,
Protein Abinds Fc receptor; protects from opsonization wounds (leave open to heal by 2nd intention if infected)
Coagulasefibrin clot protects from phagocytosis Pneumonia: 2 to viral infection or obstructive illnesses; abrupt
Penicillinaseinactivates penicillin onset of fever with lobar consolidation of lung and rapid
Hyaluronidasespreading factor; destroys connective tissue destruction of parenchyma with pleura effusions and empyema.
Exfoliatinscalded skin syndrome Osteomyelitis: usually boys < 12yo; hematogenous spread
Enterotoxinsheat stable,food poisoning (milk, meat, mayo) Acute Endocarditis: Massive, rapid destruction of heart valves
Toxic Shock Syndrome Toxin (TSST-1)superantigen; binds Septic Arthritis: Most common cause in kids and adults >50
MHC II and T-cell receptorpolyclonal activation S. saprophyticus: normal flora; urinary tract infections in women
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Mycoplasma Mycobacteria
Cell membrane contains sterols; no cell wall Acid fast, mycolic acid in cell walls, intracellular
Pneumonia (walking/atypical) M. pneumoniae Glycolipids prevent phagolysosomal membrane fusion
Xray looks worse than patient presents, high IgM titer. M. tuberculosis - *caseating granulomas*
Histiocytes (epithelioid cells), Langhans giant cells, peripheral collar of
MC pneumonia in school children/young adults, military. fibroblasts and lymphocytes
may have hemorrhagic bullous myringitis Granuloma formation macrophages unable to kill
cold agglutininimmune hemolytic anemia bacteriapersistent infectionrecruits TH1 cellssecrete
IFN activate epithelioid macrophages
diffuse, patchy inflammation in interstitial areas of PPD/Tuberculin test test for infection; Type 4 hypersensitivity
alveolar walls, intraalveolar hyaline membrane reaction
Urethritis NGU; Ureaplasma urealyticum, M.
hominis
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Herpes Varicella-Zoster
HSV1: gingivostomatitis (cold sores); HSV2: Transmitted by aerosols then viremia leads to
genital lesions; characteristic multinucleated rash beginning on face and spreading to rest of
giant cells with intranuclear inclusions body, including mucous membranes
TZANK prep. Vesicles resemble dew drop on rose petal,
Virus enters skin; infects and becomes latent in and occur in crops; itch when healing.
nerves.
nerves Latent in neurons of the DRG.
Can also cause keratitis, encephalitis, and Shingles occurs from reactivation of VZV and
disseminated disease (immunocompromised); is distributed along a sensory dermatome;
keratitis can lead to corneal blindness. painful, vesicular rash; rare interstitial
One of the TORCH diseases pneumonia, encephalitis, or necrotizing
lymphadenopathy, splenomegaly, necrosis, lesions.
corneal lesions, CNS damage.
Cytomegalovirus EBV
Cytoplasmic owls eye inclusions; spread by Mononucleosis self limited; pharyngitis, fever,
resp. drop. chills, sweats, headaches, swollen lymph nodes,
Most people get an asymptomatic infection. and hepatosplenomegaly with risk of splenic rupture
Other possible infections CMV Spread thru saliva; causes polyclonal activation of
mononucleosis; reactivation in AIDS (CMV B-cells (attaches to CD21)
retinitis); reactivation in bone marrow Atypical
At i l lymphocytes
l h t are T cells;
ll absolute
b l t
lymphocytosis
transplant (CMV pneumonitis); in AIDS patients
accompanied by PCP. Heterophile antibodies useful MONOSPOT TEST
(detect Ig against Horse RBCs)
Congenital infection (TORCH) hemolytic
Associated with Burkitts Lymphoma and
anemia, jaundice, thrombocytopenia purpura, nasopharyngeal carcinoma.
hepatosplenomegaly, deafness, chorioretinitis,
brain damage, encephalitis.
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Rotavirus Norwalk
encapsulated, dsRNA virus ssRNA virus
COMMON cause of gastroenteritis in children aged 6- causes gastroenteritis with watery diarrhea, nausea,
24 months; causes vomiting and watery diarrhea vomiting, abdominal pain
selective infection & destruction of mature enterocytes transferred via food, water, person-person; extremely
in small intestine, sparing crypt cell sturdy virus, difficult to kill
absorption of nutrients osmotic diarrhea and occur in epidemics, common on cruise ships
dehydration
1-2 day incubation, symptoms lasting 12-60 hours
outbreaks in day-care centers, hospitals
highly infectious: minimum infectious dose just 10
particles
immunity transferred through antibodies in maternal
milk, so infection common at weening
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Aspergillus Candida
Septate hyphae with narrow angle branching: Morphology
Fruiting Bodies pseudohyphae and budding yeasts
Pathology: Same as mucormycosis. Also has Path
aflatoxin (carcinogen/Liver cancer) Phenotypic switching
Allergic: Alveolitis (III, IV), asthma (I) Adhesion protiens (yeast bind manose, hypahe bind Fc)
Colonizing: Fungus Balls in pre-existing
pre existing Enzymes and adenosine (blocks oxegyn radical
cavities (minimal invasion) formation)
Associated w/ recurrent hemoptysis Stimulates TH1 response
Invasive: necrotizing pneumonia, sepsis (esp. Presents
heart valves, brain, kidney) Thrush, esophagitis, vaginaitis, coetaneous, invasive,
endocarditis,
Immunosupressed and debilated hosts
Normal flora
Superficial infx in healthy, disseminated in imunocomp.
Newborns, AIDS, Diabetics
Blastomycosis Coccidioidomycosis
Thermally dimorphic soil inhabitant in central/southeast US Thermally dimorphic soil inhabitant of southwest US
Infective conidia transform into round, thick-walled yeast Arthroconidia infect almost everyone; clinical illness in 10%
exhibiting broad-based budding
High infectivity requires careful handling by lab workers
Macrophages have limited ability to phagocytose
Inhibition of fusion of phagosome and lysosome; T-cell
Persistence of yeast leads to continued neutrophil
recruitment
stimulation results in granulomatous inflammation
Thick-walled, non-budding spherules within macrophages
Abrupt illness with tuberculosis-like symptoms
and giant cells
Nodular or miliary infiltrates with lobar consolidation on CXR
Rupture releases non-infectious endospores, stimulating a
Suppurative granulomas, most frequently in upper lobes superimposed pyogenic inflammation
Can disseminate to skin, causing raised, ulcerating San Joaquin Valley Fever: fever, cough, pleuritic pain,
verrucous lesions with epithelial hyperplasia; can be erythema nodosum or erythema multiforme
confused with squamous cell carcinoma
Rare dissemination to meninges or skin; pyogenic
Widespread dissemination in immunosuppressed inflammation may dominate, especially in
immunosuppressed
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Protozoa Protozoa
Babesiosis
Similar to malaria, but found in the US African Sleeping Sickness (Trypanosomiasis)
Protozoan transmitted by deer ticks (also carry Lyme Vector: Tsetse fly; Clinical: intermittent fevers,
disease)
lymphadenopathy, splenomegaly, leptomeningitis,
Sx: Fever, hemolytic anemia, worse in debilitated and
splenectomized cachexia, death
Trichomoniasis
Ti h i i Organism
O i growthth actually
t ll stimulated
ti l t d bby IFN
IFN-
Trophozoitesturnip-shaped motile organisms gamma; tissue destruction from antigen/antibody
Colonize vagina and male urethra vaginitis, complex deposition
cervicits, urethritis
Red, rubbery chancre at site of infection; ulcer &
No tissue invasion with little inflammatory rxn, green
frothy discharge mononuclear infiltrate
Strawberry mucosa, mixed cell infiltrate
Protozoa GI Protozoa
Chagas Disease (T.Cruzi) Amebiasis (Entamoeba histolytica)
vector: kissing bug; most common cause of heart Infections cysts lyse colonic epithelium of cecum and
ascending bowel flask-shaped ulcers
failure in Brazil
Trophozoites invade the crypts of colonic glands, 40%
chagoma at site of infection; infects penetrate portal vessels liver abscess
p g ;p
macrophages; penetrates smooth,, skeletal,, and Clinical: dysentery ( in only 10%)
cardiac muscle
Giardia (Giardia lamblia)
Acute: intracellular pseudocysts, fever, dilated Transmission via cysts in contaminated water and fecal-oral;
cardiomyopathy,arrhythmias Not killed by chlorine trophozoites resemble cartoon ghost
Chronic: cardiac damage due to Antibody-T cell Clinical: diarrhea, steatorrhea, constipation, IgA Deficiency
cross reaction and the immunosupressed are more susceptible (but not
worse clinical disease)
Clubbing of villi, but no invasion of intestinal wall;
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Cestodes Nematodes
Taenia solium Ingestion of undercooked pork Pinworms (Enterobius vermicularis)
ingestion of eggs, extruded from anus. Anal pruritis, scotch tape test.
Ingest cysticercus (larvae) adult tapeworm in intestine
Ingest eggs cysticerci in brain neurocysticercosis Whipworm (Trichuris trichiura)
hydrocephalus, focal neuro deficits ingestion of eggs migration to colon abdominal pain, diarrhea
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RA Pathogenesis RA Pathogenesis
Characteristic lesions: Rheumatoid Factor (RF) can form immune complexes,
Pannus- proliferative response in synovial lining activate complement, and augment synovial
Joint space loss - tissue destruction, chronic cell-mediated
inflammation as well as cause extra-articular disease
response, fibrosis, ankylosis High RF titers may show vasculitis -> purpura, cutaneous
ulcers
Juxta-articular bone erosions from cytokine-mediated
Also,, see serosal disease
stimulation
ti l ti off osteoclast
t l t activity
ti it
MCP, PIP, ankles, feet, knees, upper spine commonly
TNF & IL-1 induce resorption of cartilage and bone, involved
enhance accumulation of leukocytes, stimulate Lumbosacral spine, hips spared
fibroblast proliferation Rheumatoid nodules - subcutaneous reaction with
80% have IgM antibodies to IgG (Rheumatoid Factor) prominent histiocytes, lymphocytes, and plasma cells,
- may be from plasma cells in synovium similar to granuloma; not adjacent to involved joints;
seen in 25% of patients
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Radial deviation of wrists; ulnar deviation of fingers Lymphocyte and cell-mediated damage to
synovium
Constitutional symptoms - fever, weight loss,
Cytokine mediated joint destruction, and proliferative responses
fatigue, lymphadenopathy Juxta-articular bone erosion osteoclastic activity
Rheumatoid nodules (25%)- firm, nontender Pannus formation hyperplastic synovium with
nodules in subcutaneous tissue analogous to
lymphocytes, histiocytes and plasma cells
granulomas
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Gout Gout
Middle aged men Acute arthritis- neutrophils, synovium edematous,
Episodic intense local pain- foot ankle, big toe(cooler mononuclear infiltrate
areas) Chronic tophaceous arthritis- repeated acute arthritis
Exacerbated by alcohol urates encrust articular surface, synovium hyperplastic,
Tophus-
p pathognomonic
p g lesion fibrotic and thickened by inflammatory cells, granulomatous
mass of urate crystals surrounded by inflammation reaction with multinucleated giant cells
(macrophages, lymphocytes, foreign body giant cells), Gouty nephropathy- urate crystal deposits in
usually on the ear, olecranon, patellar bursae, periarticular medullary interstitium
ligaments, connective tissue forms tophi in tubules, leads to uric acid stones
Joint aspiration- needle shape crystals (negative
birefringence) and neutrophils
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Churg-Strauss Atherosclerosis
Churg-Strauss
Small vessels : skin, lung, heart inflammatory/healing reaction of the
Eosinophil-rich granulomatous reaction endothelium of large & medium sized arteries
Affects atopic people resulting in focal intimal lesions
Associated with allergic rhinitis, asthma and blood NO primary lesions in media/adventitia
eosinophilia
P-ANCA in 70% 2 Main Features:
Coronary arteritis and myocarditis Accumulation of cholesterol due to uptake of
Most common cause of morbidity and mortality oxidized LDL by macrophages and smooth muscle
Pulmonary necrotizing vasculitis cells forming foam cells
Henoch Schonlein Purpura: affects children
Healing phase with fibroblast proliferation
segmental fibrinoid necrosis with IgA deposition
formation of fibrous cap & deposition of ECM
sequela to upper respiratory infection (maybe post-strep) components
palpable purpura, arthralgia, abdominal pain w/ intestinal
hemorrhage, renal damage, fever Lesions = fibrofatty plaques
Atherosclerosis Atherosclerosis
Pathogenesis
Fatty streaks (earliest lesions) contain foam cells
Local cell injury accumulation and oxidation of lipid with variable amounts of proteoglycans, extracellular
(LDLs) endothelial cell activation & increased lipid and T cells can be seen in toddlers
vascular permeability adhesion/influx of platelets & Lesions progress with age become raised
monocytes into intima secretion of cytokines coalesce into plaques
further influx of inflammatory Over time,
time fibrotic plaque becomes unstable
cellsmigration/activation of smooth muscle cells & fracture exposure of collagen promotes platelet
fibroblasts secretion of collagen & ECM adhesion and local thrombus formation
components Fissuring or rupture of a plaque can produce emboli
Oxidized lipid appears to play a central role they are and acute infarctions at distant sites (e.g MI)
chemotactic for monocytes, inflammatory cytokines, Lipid/cholesterol emboli a particular problem in the
macrophage motility and are toxic to endothelial kidney
cells/smooth muscle
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Atherosclerosis Varicosities
Distribution = abdominal aorta > coronary arteries >
Varicose veins are abnormally distended, lengthened
popliteal arteries > descending thoracic aorta > internal
and tortuous veins
carotids > circle of willis occurs at branching points,
ostia of vessels Most commonly located at the superficial saphenous
Major Risk Factors = hypertension, smoking, vein, they can also be found in the distal esophagus
yp p
hyperlipidemia/ hypercholesterolemia(**),
yp ( ), diabetes (portal HTN), anorectal region (hemorrhoids), or
Key components scrotum (varicocele)
fibrous cap Caused by incompetence of the venous valves which
core of cellular debris, foam cells, cholesterol crystals can be exacerbated by pregnancy, prolonged
standing, obesity, oral contraceptives, and age
shoulders with activated cells, foam cells,
migrating/proliferating smooth muscle cells There is a familial association
**NOTE : hypothyroidism assoc with They can develop secondary to DVTs which cause
hypercholesterolemia** dilation of the veins
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Myocardial Infarction
Congenital Heart Disease
Complications
dysfunctional heart muscle Separation of right heart from left heart
Arrhythmias VSD most common congenital heart disease
ASD
within minutes; most common cause of death
Separation of atria from ventricles
extensions of the infarct Tricuspid
aneurysm/dilatation
/dil t ti Mitral
ventricular rupture (septal or free wall) Division of pulmonary and arterial outflow
Only after 4-5 days Pulmonic
Aortic
mural thrombus Truncus arteriosus
pericardial effusion/pericarditis Transpositions of the Great Arteries
papillary muscle infarction
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thickened organizes
diastolic dysfunction and insufficient forward flow Fibrinous or Serous fluid mixed with MOST FREQUENT TYPES OF PERICARDITIS
Serofibrinous fibrinous exudate Acute myocardial infarction, Dresslers syndrome (post
myofiber disarray; the myocytes are hypertrophied, in Organization of exudate may myocardial immune-mediated disease), UREMIA,
a haphazard array, surrounded by interstitial and result, but may resolve chest radiation, lupus, rheumatic fever, trauma
Suppurative infections in adjacent tissues
replacement fibrosis DEVELOPMENT OF A LOUD FRICTION RUB is the
Hypertrophy of the interventricular septum, results in hallmark
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Infectious Myocarditis
Toxic Myocardial Diseases
Condition Morphology Notes
Viral myocarditis: Interstitial mononuclear Most common cause of myocarditis; assoc. with Condition Morphology Notes
Coxsackie A, B (lymphocytic) infiltration infants, immunosuppressed, pregnant women
Alcohol Dilated myocardial Direct toxic effect by alcohol and its
HIV Focal necrosis of Usually follows primary viral infection elsewhere
myocytes
disease metabolites (acetaldehyde)
ECHO, Polio, Post-infectious fibrosis May have an immune component; first humoral Nutritional Dilated myocardial Thiamine deficiency, of ten assoc. with
Influenza anti-viral response followed by T-cell mediated (Beriberi) disease chronic alcoholism
damage Adriamycin Myofiber swelling and Anthracyclin chemotherapeutic agents
Parasitic Parasitism of myocytes Protozoal South American myocarditis; may (Doxorubicin
(Doxorubicin, vacuolization fatty
vacuolization, Dose dependent
Dose-dependent
diseases: with scattered affect 50% daunorubicin) change, myocytolysis Lipid peroxidation of myofiber membranes
Chagas Disease inflammatory infiltrate Most develop progressive cardiac insufficiency
(Trypanosoma due to chronic immune-mediated damage; die 20 Catecholamines Foci of myocardial Seen with pheochromocytomas; large
cruzi) yrs. later necrosis with contraction doses of vasopressor agents such as
Trichinella Encysted Trichinella with Most common helminthic disease with cardiac bands; monocytic dopamine; cocaine
inflammatory infiltrate, involvement infiltrate Direct toxicity due to calcium overload and
eosinophils Similar to reperfusion vasomotor constriction of myocardial
Bacterial diseases Patchy myocyte necrosis Mediated by diptheria exotoxin injury circulation
Corynebacterium with sparse lymphocyte Peripartum Globally dilated heart Associated with hypertension, volume
diptheriae infiltrate
state overload, nutritional deficiency; Reversible
Lyme disease Spirochete infection of Occurs in 2/3
Borrelia brugdorferi myocytes
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Asbestosis Silicosis
Most common lesion = benign fibrous pleural plaque (caused
by cytokine damage to diaphragm, asbestos fibers NOT
sandblaster or foundry worker (rock & quartz)
present in plaques) slow progression of nodular, fibrotic masses;
DIFFUSE INTERSTITIAL (vs. Silicosis [nodular]) filled w/ hard silica crystals; eggshell LN
Most common Cancer = bronchogenic Ca (smoking synergism) calcification
2nd most common CA = mesothelioma ((v. malignant)g ) Upper lung zones
ship yard pipe fitter/ roofer; spear-like asbestos bodies
Increased risk of TB!
2 forms:
1. serpentine chrysotiles (curly/flexible, cause fibrosis but
SLIGHTLY increased risk of bronchogenic
NOT mesothelioma bc cilia can remove) carcinoma
2. Amphibole (straight/stiff; impale epithelium, reside in
interstitium; form golden brown colored dumbbells)
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Nose/Sinuses Nose/Sinuses
Rhinitis
infectious (usually viral [adeno-, echo-, rhino-]) Neoplasms:
atopic (IgE-mediated, recurrent BENIGN
POLYPS=hypertrophic swellings, edematous juvenile angiofibroma (non-metastasizing,
stroma) hemorrhagic)
inverted papilloma
Sinusitis:
MALIGNANT:
acute
t inflammation
i fl ti obstruction
b t ti infection
i f ti nasopharyngeal carcinoma (EBV-assoc, children
by S. pneumoniae, H. flu, M. cat, S. aureus in Africa/China, poor prognosis)
mucor; assoc w/diabetes; may extend into lethal midline granuloma (T-cell lymphoma;
bone/other sinuses necrotizing/ulcer)
Kartageners: bronchiectasis, situs inversus, plasmacytoma (normal lymph structure)
sinus infect. Bc defective cilia olfactory neuroblastoma (radiation-sensitive)
Wegeners granulomatosus: acute necrotizing
granulomas; involve lung; c-ANCA
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Folate Deficiency No
B12 Deficiency
neurological signs!
The major cause of folate deficiency is decreased intake in B12 Deficiency defective DNA synthesis
diet, especially in Alcoholics only a few months worth of asynchronism between cell division and
folate is stored in the body (unlike B12 which has enough
stored for years) hemoglobin synthesis Megaloblastic anemia
major dietary source = green leafy veggies Urine methymalonic acid increased and serum
Phenytoin inhibits the absorption of folate in the jejunum homocysteine levels are elevated, serum B12
b bl
by blocking
ki iintestinal
t ti l conjugase
j andd can also
l cause ffolate
l t may be decreased
deficiency
Methotrexate inhibits Dihydrofolate Reductase leading to Macrocytosis, leukopenia with
folate def. (cant reduce dihydrofolate to tetrahydrofolate) hypersegmented granulocytes, mild to
Diagnostic Test for folate def. : give patient Histidine an moderate thrombocytopenia
increase in FIGlu will appear in the urine of a folate def.
patient Increased hemolysis may lead to iron overload
*Hypersegmented Neutrophils in blood are characteristic
of both B12 and Folate def.
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5/3/2009
B12 DeficiencyNeurologic
B12 Deficiency Causes
Complications
Decreased intake: Strictly vegetarian diet,
B12 Deficiency but not Folate Deficiency may include Malabsorption, achlorhydria, gastrectomy, diffuse
neurological complicationsB12 more likely due to intestinal disease or resection (Crohns), decreased
malabsorption and folate due to dietary insufficiency intrinsic factor (pernicious anemia), exocrine pancreas
Increased levels of methylmalonate may lead to dysfunction
abnormal fatty acids that may be incorporated into Increased requirement: Pregnancy, hyperthyroid,
neuronal lipids and produce neurological Cancer, Fish tapeworm (Diphyllobothrium latum)
complications Intrinsic
I i i ffactor secreted dbby parietal
i l cells
ll peptic
i
Subacute Combined Degeneration - Degeneration digesting and binding to cobalophilins B12 release
of lateral and posterior columns of spinal cord from cobalophilins in duodenum IF-B12 complex
(decreased vibration, light touch, joint proprioception) absorbed in ileum by binding to IF-specific receptors
AND upper motor neuron signs due to lateral column Pernicious Anemia-Antibodies to gastric mucosa,
demyelination; Bilateral symptoms; Dementia 2 to Antibodies that block IF-B12 complex formation, or
CNS demyelination Antibodies that block IF-B12 binding and absorption
Microscopic: diffuse spongy degeneration of the white Pancreatic enzymes needed to release B12 from
matter, myelin and axonal degeneration, macrophage rapid binders (cobalophilins)
response and gliosis
20
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Hemoglobin H Disease (-
Alpha Thalassemias
The most common form of Thalassemias in Southeast
Thalassemia)
Asia cuased by DELETIONS of one or more of the Results from a deletion of three of the three alpha-
four Alpha-globulin genes located on chromosome 16 microglobulin chain genes on chromosome 16.
resulting in defective heme synthesis Results in the pathologic formation of Beta-
Symptoms Depend on the number of gene deletions: microglobulin tetratmers called HbH (4).
-a/aa: Asymptomatic/Silent HbH has an increased affinity for oxygen and thus
--/aa: More Common in Africa-microcytic anemia is not useful for oxygen exchange due to its
-a/-a: More Common in Asia-microcytic anemia inability to release oxygen to the peripheral
--/-a: Hemoglobin H disease-severe anemia tissues.
Heinz bodies and target cells on smear In addition, cells are unable to withstand oxidative
--/--: Hb Barts-hydrops fetaelis/death in utero stresses creating a shortened half-life.
Anisocytosis and poikilocytosis w/immature RBC on smear Produces a mild to moderate anemia
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22
5/3/2009
Paroxysmal nocturnal
Spherocytosis
hemoglobinuria (PNH)
Path Path
Mutation causing loss in Decay accelerating factor
Autosomal dominant (DAF)
RBC membrane protein defect results in decreased No DAF means complement destroys RBCs
membrane and spherocytes Presents
Anykrin mutation leads to decrease in spectrin Intravascular hemolysis
Presents Episodic hemoglobinuria
Extravascular hemolysis: splenomegaly, jaundice Increased thrombosis risk
Increased permeability of spherocytes to Na Labs
(diagnostic) (osmostic fragility test) Normocytic anemia, pancytopenia
Urine Hb
Sucrose hemolysis test is positive
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WHO/REAL Classification
Neoplastic cell Morphology % Small Cell Lymphocytic/CLL
(associated w/ chronic leukemia spectrum of same
CLL/Small cell Small, mature Diffuse effacement of lymph 4
lymphoma looking node disease distinction is site of origin, but histo is the same)
lymphocytes Proliferation centers Bone marrow involved EARLY CLL
Leukemia/smudge cells
Generalized lymphadenopathy around age 60 or older,
Follicular lymphoma Small cells with Nodular or nodular and diffuse 45 males
cleaved nuclei growth
Prominent white pulp follicles in Least necrosis and least effacement of node of all the NHL
spleen Fairly normal looking follicular cells
Diffuse large B-cell Large cell size Diffuse growth 20 well-differentiated, more hyperplastic than anaplastic
lymphoma**
low grade = indolent = not responsive to chemo
Acute lymphoblastic Lymphoblasts Bone marrow mostly leukemic 85 Increased infections secondary to
leukemia/lymphoma presentation hypogammaglobulinemia (normal immune system is
(B-cell) High mitotic rate
compromised)
Acute lymphoblastic Lymphoblasts Thymic involvement 15
(T-cell) High mitotis rate B cells: CD 19 and 20, CD5
26
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27
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diagnosis
4
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Nutritional Aspects of
Nutritional Aspects of Malabsorbtion
Malabsorbtion
Almost all syndromes will cause weight loss, anorexia, B12 and folate deficiencies lead to megaloblastic
abdominal distension, borborygmi, muscle wasting anemia; also neuropathy (subacute combined
General endocrine: amenorrhea, impotence, infertility degeneration) with B12
Fat malabsorbtion causes deficiencies of related vitamins B12 deficiency is common in disease of the terminal ilium
Vitamin A: dermatitis, hyperkeratosis, peripheral neuropathy Also isolated deficiency with lack of intrinsic factor, as in
Vitamin D: hypocalcemia with osteopenia and tetany atrophic
hi gastritis
ii
Vitamin K: abnormal bleeding Iron deficiency leads to microcytic, hypochromic
Lipid membrane defects from essential fatty acid deficiency, anemia
leading to characteristic burr cells on peripheral blood smear Must rule out colon cancer before diagnosing any other
as in abetalipoproteinemia malabsorbtive condition
Protein deficiency with retained carbohydrate absorbtion Electrolyte abnormalities and dehydration from
leads to low albumin with edema, as in pancreatic
protracted diarrhea
insufficiency
5
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6
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Dysentery Dysentery
Shigella (g-, FA, non-motile, non-coliform, S. flexneri) fecal- Salmonella (g-, flagellate, non-coliform, produce H2S)
oral, virulent contaminated meats NO TOXIN
Path: invades epitheliaescapes phagolysosomelysis cell Typhoid fever Signs: rose spots - chest/abdomen,
Shigatoxin causes mucosal necrosis: fibrinosuppurative hepatosplenomegaly, dysentery Labs: neutropenia
exudate + hemorrhagic colitis and hemolytic uremic Enteric fever: fever, bacteremia associated with sickle cell
syndrome and schistosomiasis
Sequelae: reactive arthritis: Reiters syndrome Food poisoing: vomiting + diarrhea, self-limited except for
(nongonococcal urethritis+reactive arthritis+conjunctivitis) immunocomp
80% HLA-B27, one month following genitourinary blunted villi, vascular congestion, mononuclear infiltrate in ileum
(Chlamydia) or GI (Shigella, Salmonella, Yersinia, and colonpeyer patch ulceration with S. typhi get massive
Campylobacter) low back, ankles, knees, feet asymetrically reticuloendothelial proliferationsplenomegalytyphoid
Morph: hyperemia, edema, enlargement of mucosal nodules in liver
lymphoid nodules in distal coloninflammation and erosion
with thick purulent exudate
Dysentery Dysentery
Campylobacter (g-, comma, flagellate, oxidase and catalase Clostridium difficil (g+, anaerobe, normal gut flora, sporulator)
positive) most common cause: diarrhea, gastritis, and antibiotic-induced colitis
dysentery can develop to sepsis bad for Path: long course broad spec antibioticsovergrowth C.
immunocompramised difficileproduction apoptotic toxins: enterotoxin A and
C. jejuni Path: flagella binds epiinvades mucosacausing cytotoxin B inflammatory cells over lesion form
diarrhea dysentery
diarrhea, dysentery, or enteric fever (when disseminates to p
pseudomembrane
mesenteric nodes with toxin/invasive lesion, crypt abscess) Clinical: acute or chronic diarrhea after surgery or antibiotics
Sequelae: reactive arthritis (with Shigella, Salmonella, Morph: formation of fibropurulent membrane
Yersinia) and Guillan Barre Syndrome UNIQUE denuded epithelium with neutrophil infiltrate,
C. festus = undercooked beef, grows 25, capsule S fibrin thrombi in lamina propria, and mushrooming
protein inhibits C3b binding mucopurulent exudate from crypts
C. jejuni = chicken, grows 42
8
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Hepatitis B Hepatitis B
Chronic infection -risk of hepatocellular carcinoma
Double-stranded DNA hepdhnavirus, "Dane particle"
Acute Dx: HBsAg(hepatisis B surface Ag) and IgM
Transmission through all body fluids excluding stool,
anti-HBc (HepB core)
vertical transmission leads to infant carrier state
Carrier Dx: HBsAg without anti-HBs AB
Can develop acute (most cases) or chronic infection-
T ll mediated
T-cell di t d iimmunity
it responsible
ibl ffor disease
di Dx active viral replication: HBeAg
manifestations "window period" is time between disappearance of
Long incubation (3 months) with carrier state HBs antigen and subsequent appearance of anti-HBs
antibody; during this time period, anti-HBc and anti-
Necessary for Hepatitis D infection
HBe are the only markers
10
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Wilsons Disease
Hemochromatosis - Pathology (hepatolenticular
Deposition of ferritin and hemosiderin in organs Autosomal recessive deficiencydegeneration)
in hepatic canalicular
copper transport protein
Free radicals form in Fenton reaction Liver cannot excrete copper in bile or load onto
Lipid peroxidation, stimulation of collagen formation, and ceruloplasmin
DNA damage First accumulates in liver, then spills into blood by age 5 and
deposits in organs
Hepatic hemosiderosis with micronodular cirrhosis Levels typically symptomatic in young adulthood (rarely
Pancreatic iron deposition with fibrosis younger than 5 or older than 30)
Deposits in liver with fatty change and chronic hepatitis
Myocardial iron deposition with Mallory bodies
arrhythmia, restrictive cardiomyopathy mixed cirrhosis and hepatic encephalopathy
Iron deposition in many other organs deposits stain with rhodamine
excess melanin production, arthralgia, hypogonadism,
Copper deposits in brain, especially basal ganglia
impotence Parkinsonism, inappropriate behavior, and dementia
Kidney disease leading to osteoporosis, renal calculi
Kayser-Fleischer rings: copper deposits outside iris
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Pancreatic Cancer
Almost always adenocarcinoma. >99% ductal.
Associated w/ smoking, diet, industrial toxins, not
alcohol
clinical
Often arises in pancreatic head jaundice
Involvement of pancreatic tail 2 diabetes
abdominal pain radiating to back, anorexia, migratory
thrombophlebitis (Trousseau sign), distended gall bladder
Histology
ranges from well-differentiated glandular adenocarcinomas
to anaplastic cuboidal epithelium
Deeply infiltrative growth
Strong desmoplastic response
Silent and widespread dissemination (massive hepatic
metastasis). <1 yr survival.
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1
5/3/2009
2
5/3/2009
3
5/3/2009
Membranoproliferative
IgA Nephropathy (Bergers Disease)
Glomerulonephritis
Characterized by hypercellular glomeruli caused by mesangial and frequent cause of recurrent gross or microscopic
endothelial cell proliferation and leukocyte infiltration hematuria
tram track appearance of the capillary wall caused by
mild proteinuria is seen and nephrotic syndrome may
reduplication of glomerular basement membrane
Two Types develop
Type I Characterized by IgA deposition within the mesangium
granular deposits of complement with or without
immunoglobulin Often seen after respiratory, gastrointestinal, or urinary
Subendothelial electron-dense deposits tract infection in children and young Adults
Type II lesions vary considerably
C3 Nephritic factor; IgG usually absent (alternative pathway)
Prominent electron-dense deposits along the lamina densa focal proliferative glomerulonephritis
within the basement membrane (splitting of basement focal segmental sclerosis
membrane)
Features of nephritis and protein loss; hypocomplementemia crescentic glomerulonephritis
Chronic immune complex disease, SLE
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Diabetic Nephropathy
Diabetic Nephropathy: Pathology
Characterized by glomerulosclerosis and a range of
Capillary basement membrane thickening
nephropathies
diffuse glomerulosclerosis
non-nephrotic proteinuria, nephrotic syndrome, & chronic renal
failure
diffuse increase in mesangial matrix with PAS postivive
deposit
Also causes continuous with hyaline thickening of arterioles
arteriolar sclerosis nodular glomerulosclerosis (Kimmelstiel-Wilson disease)
increased susceptibility to infection (papillary necrosis/Acute ovoid or spherical hyaline masses situated in the
pyelonephritis) periphery of the glomerulus that lie within mesangial core
tubular lesions uninvolved lobules and glomeruli all show striking diffuse
glomerulosclerosis
Pathogenesis
arteriolosclerosis both afferent and efferent (in
thickened basement membrane and increased mesangial matrix
hypertension, only afferent)
Increased amount and synthesis of collagen type IV and
fibronectin
ischemic tubular atrophy, interstitial fibrosis, and
contraction in size of kidneys
nonenzymatic glycosylation of proteins
5
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6
5/3/2009
Urinalysis Urinalysis
Protein: Glucose: the threshold of blood glucose is 250 mg percent.
Minimal proteinuria- (< 0.5 grams per day)- associated with When glucose exceeds this number, the glucose transporters or
glomerulo-nephritis, polycystic disease of the kidneys, renal the PCT saturate and sugar overflows into the urine. Glucose
tubular disorders, the healing phase of acute glomerular should not be found in the urine normally (except in pregnancy
nephritis, and latent or inactive stages of glomerulonephritis. which will decreases the saturation capacity of glucose in the
Moderate proteinuria, ( 0.5 grams to 3.5 grams per day) PCT))
may be found in the vast majority of renal diseases, such as Bilirubin: the presence may suggest hepatocellular disease
mild diabetic nephropathy, and chronic glomerulo-nephritis. versus the presence of hepatobiliary obstruction or viral
Severe proteinuria, ( > 3.5 grams per day) is significant for hepatitis
nephrotic syndrome. It can also bee seen in nephrosclerosis, Urobilinogen: small amounts are normal in the urine. An
amyloidal disease, systemic lupus erythematosus, renal vein increase may be indicative of liver disease, congestive heart
thrombosis and congestive heart failure. failure, or hemolytic anemia. An absence of urobilinogen
indicates hepatobilliary obstruction
7
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Urinalysis Urinalysis
Nitrites: usually sensitive for nitrogen releasing bacteria
(E.Coli). Bacteria reduce nitrates to nitrite via a reductase Color: affected by concentration of urine. Darker urine
enzyme. indicates either highly concentrated urine or the
Leukocyte esterase: released from neutrophils in response to presence of billirubin. Red urine indicates blood or
bacterial infections of the GU tract, sign of infection. (Urnalysis myoglobin. Bright yellow urine may be secondary to
with positive Leukocyte esterase but negative bacterial
cutlures--> chlamydia). vitamin intake.
Casts: indication of tubular damage. Turbidity: normal urine is clear
clear. Amorphous
RBC casts =glomerular inflammation (nephritic syndromes) phosphates or amorphous urates may cause urine to
WBC casts =tubulointerstitial nephritis, acute pyelonephritis, appear more cloudy or hazy.
glomerular disorders.
Granular (muddy brown) casts = acute tubular necrosis. Red blood cells: normal should be 0-2. > 2 red blood
Waxy cast =often very broad, are a sign of chronic renal cells may indicate trauma (stone), menstruation,
failure. infection, cancer, or neprhitic syndrome.
Hyaline casts =nonspecific and often naturally occuring. White blood cells: > 5-10 white blood cells may be
Fatty casts = nephrotic syndrome an indication of inflammation or infection.
8
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Prostate BPH
(Benign Nodular Hyperplasia) Prostate Adenocarcinoma
Common in men > age 50, rubbery nodular enlargement on Also in men > age 50 (most common cancer of older men)
digital rectal exam increases w/ age, hard irregular nodule on digital rectal exam
Not pre-malignant, but can coexist with prostate cancer Increased Total PSA w/ decreased Free PSA and increased
Symptoms: urgency, hesitancy, frequency, nocturia, dysuria complexed PSA suggests malignancy
complications of urinary retention include UTI, cystitis, & in BPH, Free PSA is increased in proportion to Total PSA
h d
hydronephrosis
h i Spread
S dbby di
directt llocall iinvasion
i and
d th
through
h bl
blood
d & llymph
h
Hyperplasia of both glandular epithelium and fibromuscular Local extension to seminal vesicles & bladder
stroma compresses urethral lumen into vertical slit Metastasis to obturator nodes and pelvic nodes via lymph
Found in periurethral and transitional zones of prostate Metastasis to bone via blood
(inner zones) Osteoblastic metastasis to lumbar spine (most common sites
Increased Free fraction of prostate specific antigen (PSA) are axial skeleton, proximal femur & pelvis)
Dihydrotestosterone (DHT) level is the major trophic factor Alkaline phosphatase is elevated w/ bone metastasis from
Finasteride therapy inhibits 5a-reductase, lowers DHT & prostate
shrinks prostate
10
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11
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12
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Adrenal Pathology
Hypercalcemia/Hypocalcemia
ACTH levels cause adrenal cortex:
Hypercalcemia Hyperplasia: pituitary or paraneoplastic ACTH-
Sx: fatigue, N/V, metastatic calcifacation, renal stones,
secreting tumors, 21-hydroxylase deficiency
short QT, wide T wave Atrophy: exogenous steroids, adrenal cortical
adenoma (rest of gland shrinks), 2o
Causes: HyperPTH (Squamous cell Ca of Lung
Lung, adrenocortical
d ti l iinsufficiency
ffi i ((which
hi h iis d
defined
fi d as
parathyroidoma), HCT use (high reabsorption), low ACTH)
hyperVitaminD (high GI absorption), bone lysis (multiple
Note that adrenal can be small also from
myeloma, Pagets disease)
autoimmune destruction (Addisons) or large
Hypocalcemia from metastatic tumors
Sx: Tetany (Trousseau&Chvostek), spacticity, long QT Adrenal medulla: only pathology is
Causes: low PTH/VitD, defective VitD activation pheochromocytoma
(liver/renal failure), HypoMg
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Adrenogenital Syndromes
Hyperaldosteronism continued Congenital adrenal hyperplasia
Most commonly due to 21-hydroxylase deficiency
Secondary aldosteronism aldosterone, cortisol, androgens, ACTH
Activation of renin-angiotensin system by: Salt-wasting syndrome w/ complete lack of enzyme
Hyponatremia, hyperkalemia, hypotension, cardiovascular collapse
Decreased renal perfusion
Male=precocious puberty in boys, oligospermia in older males
Nephrosclerosis, renal artery stenosis
Female=ambiguous
Female ambiguous genitalia in infants, virilization in girls/women
Arterial hypovolemia and edema Simple virilizing adrenogenital syndrome w/ partial lack of enzyme
CHF, cirrhosis, nephrotic syndrome Morphology: bilaterally hyperplastic adrenals; brown cortex due to
depletion of lipid
Pregnancy
Adrenocortical neoplasms
estrogen induced renin increase Androgen secreting adrenal carcinoma
Increased levels of plasma renin
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Non-enzymatic glycosylation in
Type 2 Diabetes Mellitus Diabetes
Often manifests later (>40); accounts for 80-90% of cases Glucose binds to proteins on cell surfaces via ketoamine
Hyperglycemia due to responsiveness of peripheral tissues to linkages
insulin followed by worsening -cell dysfunction
Genetic factors more important than type 1 but no HLA Amount of glycosylation directly related to degree of
associations hyperglycemia
Environmental factors: obesity, sedentary lifestyle, dietary Glycosylated RBCs (A1c) can be measured to dx DM
habits
Plasma insulin concentration is normal or often increased until late Rearrange to form Advanced Glycosylated Endproducts
in the disease due to -cell burnout (AGEs) that crosslink and bind to cell surface receptors of
Ketoacidosis is much less common endothelium, monocytes, macrophages, lymphocytes, and
Pancreas morphology: subtle reduction in islet cell mass; amyloid mesangial cells
replacement of islets; fibrosis in later stages
Cause chemotaxis, cytokine release, vascular leakage,
thrombosis, increased synthesis of ECM, entrapment of
LDL in vessel walls
Complications: Atherosclerosis, CAD, stroke, microvascular
injury (neuropathy, nephropathy, retinopathy)
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1
5/3/2009
Subacute Sclerosing
Spongiform Encephalopathy
Panencephalitis
Creutzfeldt-Jakob Disease
rare disease of children and adolescents 40 and 80 years of age
associated with a defective measles virus sporadic; transmission has occurred by corneal
(myxovirus) transplant or administration of contaminated growth
hormone
personality changes, intellectual decline
progressing to dementia. The course is dementia and myoclonus
progressive deterioration, with a duration of 1 deterioration, with death occurring usually in 3-12
months
month to several years.
routine CSF findings are usually normal
Changes involve both white matter and gray spongiform encephalopathy in gray matter throughout
matter with cortical atrophy and demyelination. brain and spinal cord
Oligodendrocytes and neurons contain inclusion Kuru - cannibalism
bodies "Mad Cow" Disease new variant CJD
2
5/3/2009
Toxicities Toxicities
Alcholol Korsakoffs psychosis anterograde amnesia and
Associated with petechial hemorrhages and gliosis milder retrograde amnesia; impairment in visuo-
of the mamillary bodies, discoloration of structures spatial, abstract, and conceptual reasoning;
(hemosiderosis) surrounding the third ventricle, confabulation; reponds variably to thiamine
aqueduct, and fourth ventricle replacement
toxic vs.
vs nutritional; DEFICIENCY OF THIAMINE Wernickes syndrome
y sixth nerves p
palsy
y and ataxia;;
nystagmus
peripheral neuropathy
clinical triad: ophthalmoplegia, ataxia, and global
bilateral limb numbness, tingling, and paresthesia
confusion
alcoholic cerebellar degeneration; ataxia, wide- disoriented, indifferent, and inattentive; ocular
based gait; cerebellar vermic atrophy nystagmus on lateral gaze; lateral rectus palsy (usually
cognitive problems and dementia bilateral); conjugate gaze palsies, and ptosis
psychiatric: anxiety, hallucinations, paranoid ataxia improves more slowly than the ocular motor
delusions abnormalities
Berry Aneurysm
Hemorrhages
Congenital weakness of intracerebral artery wall (1 in
Tearing of middle Epidural hematoma 100)
meningeal artery Saccular aneurysm near Circle of Willis
Tearing of bridging veins Subdural hematoma If ruptures, results in subarachnoid hemorrhage
((headache,
eadac e, b blood
ood in CS
CSF))
Tearing of branches of Duret hemorrhages Rupture when reach 4-7 mm
basilar artery Often asymptomatic until rupture
Associated with other malformations, familial
Rupture of berry Subarachnoid
syndromes
aneurysm hemorrhages
Autosomal dominant polycystic disease
Ehlers-Danlos syndrome
Does not result in herniation
3
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4
5/3/2009
Ischemic Stroke
Ischemic Stroke Involves cortex, aphasia
Involves thrombotic obstruction of arterial flow particularly speech areas
Most common: thrombosis of atherosclerotic plaque Broca motor
and downstream ischemia Wernicke - receptie
Less common: embolic disease Contralateral, differential between upper and
lower limbs (homunculus)
Most common: middle cerebral artery
Rapidly progressive, may reverse with return of
Primary pathophysiology: advanced blood flow
atherosclerosis, atherosclerosis of carotids,
Initial injury: edema which reverses
hypercholesterolemia
May be preceded by transient ischemic attacks
Necrosis leads to liquefactive necrosis, atrophy
Remote cyst formation
5
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Adults Adults
Glioblastoma multiforme Astrocytomas
25% of adult tumors (half of glial tumors) large nuclei, prominent fibers, and negligible
mitotic activity
Most common intracranial malignant tumor
Oligodendromas
Middle age
Intracerebral glial tumors
Rapidly progressive intracerebral gowth
Solitary, well-circumscribed masses
(weeks to months)
Homogeneous cells with dark nuclei, stain with
Invasive, not circumscribed GFAP
Necrosis, nuclear pseudopalisading, Oligodendromas vs. astrocytomas
hyperchromatic cells
Astrocytomas less well circumscribed
Perinecrotic palisading
Astrocytomas more common
Glomeruloid vascular proliferation
6
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7
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Arnold-Chiari Other
Type I (adult type) has variable herniation Central pontine myelinolysis
of cerebellar tonsils and is frequently Too rapid correction or normalization of
hyponatremia
accompanied by syringomelia Osmotic demyelination
Type II (infantile type), called the Arnold- Results from chronic adaptation to
Chiari malformation here,
here hyponatremia
yp with formation of intracellular
osmoles
polymicrogyria Most often a result of alcoholism
meningomyelocele Can also occur with rapid normalization of sodium
from SIADH
hydrocephalus Prognosis is poor
beak-shaped colliculi, displacement of the
medulla and fourth ventricle down into the
cervical segments
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Myasthenia gravis
decrease in number of muscle acetylcholine receptors
Eaton-Lambert syndrome
secondary to anti-receptor antibodies
paraneoplastic syndrome (most commonly small
can be passively transferred to animals cell carcinoma of the lung)
circulating anti-AChR causes decrease in receptor number
proximal muscle weakness with autonomic
(increased receptor internalization and destruction) and
damage to post-synaptic membrane secondary to
dysfunction
complement fixation does
d nott respond
d tto Tensilon
T il ttestt or show
h
often associated with thymic hyperplasia or increased weakness with repetitive stimulation
thymomas; patients respond to thymectomy ACh receptors OK, but fewer vesicles are
Morphology released on synaptic transmission
muscle biopsies unrevealing; may have diffuse changes with passive transfer of syndrome with IgG
Type 2 atrophy
immune complexes present in synaptic cleft
thymic hyperplasia with germinal centers
11
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Other
Beckers Muscular Dystrophy Facioscapulohumeral muscular dystrophy
AUTOSOMAL DOMINANT
X-LINKED RECESSIVE
disease of adolescents-young adults
similar to Duchennes, but less common and weakness of muscles of face, neck, and shoulder
less severe girdle
onset later in childhood and into adolescence dystrophic myopathy with inflammatory infiltrate
slower, variable rate of progression Limb-girdle dystrophy
involves changes to, not loss of dystrophin gene AUTOSOMAL RECESSIVE/SPORADIC CASES
locus onset as adolescent or young adults
normal life span with rare cardiac involvement weakness of proximal muscles of upper and lower
extremities
progression variable; variable dystrophic myopathy
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Nevi Nevi
Progression Junctional/Compound/and Dermal forms
begins as small tan dot; grows as uniformly colored tan- Cells migrate to dermis on maturation
brown area with well-defined, rounded borders
change from dendritic single cells to nests of round
after 1-2 decades gradually flattens and returns to normal
to oval cells
Maturation of Nevi increase in number of melanocytes in basal
migration of cells into dermis accompanied by process epidermal
p layer
y with hyperpigmentation
yp p g
termed maturation form nests at tips of rete ridges
less mature, more superficial cells are larger, produce migrate into dermis to form cellular lesion
more melanin pigment, grow in nests dermal components differentiate along lines of
more mature, deeper nevi cells are smaller, produce little Schwann cells
or no pigment, grow in cords core of 20 yr. old nevus composed of
the lack of maturation in melanomas is a key feature neuromesenchyme
distinguishing melanomas from nevi undergoes fibrosis, flattening, eventual
disappearance
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resembles squamous cell carcinoma but may heal Hydradenoma Apocrine Ducts line by apocrine type
spontaneously papilliferum gland cells
flesh-colored, dome-shaped nodules with central, Syringoma Eccrine Multiple, small, tan Eccrine ducts lined by
keratin-filled plug gland papules on lower membranous eosinophilic
p g eyelids
lid cubicles
bi l
Pathologic features Trichoepithelioma Hair follicle Multiple, Pale, pink glassy cells;
semitransparent, resembles uppermost
keratin-filled crater surrounded by lip of proliferating dome-shaped portion of hair follicle
epithelial cells papules on face,
scalp, and upper
atypical, eosinophilic. "glassy" cytoplasm; stromal trunk
response with inflammatory cells
Sebaceous Sebaceous Cytoplasmic lipid vacuoles;
host response may determine regression or progression adenoma gland
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Erythema multiforme
self-limited hypersensitivity to certain infections and drugs
Pemphigus vulgaris
multiform lesions: macules, papules, vesicles, or bullae
separation of stratum spinosum from basal
associated infections, drug hypersensitivities, tumors, collagen
vascular diseases. layer
penicillin, sulfonamides, barbiturates, salicylates, vesicle contains lymphocytes,
hydantoins, antimalarials
lupus,
lupus dermatomyositis,
dermatomyositis periarteritis nodosa macrophages,
p g , eosinophils,
p , neutrophils
p
bilateral involvement of extremities (especially shins) and rounded keratinocytes ("acantholytic
lymphocyte-mediated epidermal necrosis cells")
accumulation of lymphocytes at dermal-epidermal border
with dermal edema IgG autoantibodies to intercellular
epidermal necrosis, blister formation; sloughing with shallow
erosions substance of the epidermis (desmoglein)
variants may be associated with other autoimmune
febrile disease in children: Stevens-Johnson Syndrome
toxic epidermal necrolysis diseases such as myasthenia gravis, SLE
Psoriasis Psoriasis
common, familial (1-2% of population in US) Pathology (Entire skin is abnormal)
large, erythematous, scaly plaques with silvery Thickened epidermsis (hyperkeratosis and
scales parakeratosis) w/ a thinned/absent stratum
commonly observed on extensor-dorsal surfaces, Nail corneum. Dilated and Tortuous Capillaries
changes occur in 30% Elonagated papilla with Munros abscesses
severe disease may be associated with arthritis
arthritis, collections
ll ti off neutrophils
t hil att ttop off elongated
l t d papillae
ill
myopathy, enteropathy, etc. collections of acute inflammatory cells in
Pathogenesis (T-cell mediated): epidermal spinous layer & mononuclear
Deregulation of epidermal proliferation& an abnormality inflammatory cells in dermis
in the dermal microcirculation
Auspitz' sign multiple, minute bleeding points
increased TNF associated with lesions; TNF-antagonists
when a scale is removed
provide significant improvements
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Osteomyelitis Osteomyelitis
Pathogenesis
Clinical course 80-90% (penicillin-resistant) ***Staph. aureus***,
fever, systemic illness complication of sickle cell Salmonella
60% positive blood cultures, radionuclide scans may be drug addicts Pseudomonas
helpful if X-rays negative infants/neonates Group B streptococcus
Associations TB vetebrae (Pott
(Pottss disease and Psoas abscess)
Developed countries, dental/sinus infection bone Morphology
Compound fractures sub-periosteal chronic nidus of infection = Brodie's abscess
Toes and feet of diabetics with chronic ulcers; bone surgery smoldering infection osteoblastic activity Garre's
Intravenous drug use sclerosing osteomyelitis
Underdeveloped countries, hematogenous spread devitalized bone (sequestra) surrounded by reactive bone
formation (invulcrum)
Ends of long bones most common (esp. children); also
draining sinus tracts to surface
vertebrae in adults
Squamous cell carcinoma at orifice of sinus tract
Other Osteoporosis
Aneurysmal bone cyst Reduced bone mass with increased porosity &
Solitary, expansile, erosive lesion of bone thinning of trabeculae & cortex
Adolescent females (2:1) Involves entire skeleton, but some areas more
Metaphysis of lower extremity long bones affected than others
Secondary to localized hemorrhage due to trauma, Increased risk of fractures: femoral neck, vertebral
vascular disturbance, or increased venous pressure compression fractures, Colles fracture of wrist
Sometimes secondary to tumors or fibrous Not detected by x-ray until 30-40% loss; serum
dysplasia calcium, phosphorus, alkaline phosphatase normal
Tenderness and pain with limited range of motion Rx: estrogen replacement therapy,
Appears as cyst on x-ray bisphosphanates, PTH, adequate Vit D & calcium,
exercise
www.bonetumor.org
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Leiomyoma/Leiomysarcoma Rhadbomyosarcoma
Leiomyoma Rhadbomyosarcoma
Children; one of more common soft tissue tumors in
>95% of leiomyomas in female genital tract head/neck/urogenital areas; highly malignant
in addition to female genital tract, leiomyosarcomas rapidly enlarging masses located near surface of body
occur in the retroperitoneum, wall of the deep neoplasms grow to large masses; 20-40% have
gastrointestinal tract, and subcutaneous tissue metastases at diagnosis
benign - small, multiple, adolescence and early SARCOMA BOTRYOIDES - variant of embryonal form;
adulthood grapelike clusters, occurs in children under 10; nasopharynx,
bladder, vagina
Leiomyosarcoma Stain with vimentin
malignant uncommon Synovial Sarcoma
superficial - good prognosis; deep - poor prognosis Multipotential mesenchymal cells, not synovial cells
Histologically, leiomysarcoma is differentiated from develop in vicinity of large joints (knee); deep seated mass that
leiomyoma by the number of mitoses per high has been noted for several years;
power field morphologically resembles synovium
t(X;18) translocation
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Vagina Vagina
Gartner duct cyst Squamous cell carcinoma
Retention cyst arising from Gartners ducts occurring along
the remnants of Wolffian ducts rare; (0.6/100,000 yearly)
Usually asymptomatic and small 95% squamous cell, upper posterior
Vaginal Intraepithelial neoplasia (VAIN) CIN of vagina
the vagina
precancerous lesion; high risk papilloma viruses (types 16,
Usually due to extension of sq. cell CA
18) may
18), ma be multicentric
m lticentric of the cerivx or vulva
(analogous to high-grade CIN) #1 risk factor sq. cell CA in cervix or vulva
10-30% associated with squamous neoplasm in vulva Vagina usually not the primary site
or cervix
graded as mild, moderate, or severe
white or pigmented plaques on the vagina
risk of progression to invasive cancer with
age/immunosuppression
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Cervix
Vagina Endocervical polyps
Adenocarcinoma (clear cell variant) Soft, mucoid polyps w/loose, fibromyomatous
Clear cell variant found in daughters of stroma
mothers who took diethylstilbestrol (DES), an inflammatory proliferation of cervical mucosa
anti-abortificant (only 0.14% develop it) NOT TRUE NEOPLASMS
Presents age 15-20 found in 2-5% of adult women
Vaginal adenosis = precursor to clear cell Most in endocervical canal; may protrude thru os
adenocarcinoma Protrustion can lead to irregular spotting and post-
Embryonal rhabdomyosarcoma coital bleeding
<5 yo; tumor of malignant embryonal associated with dilated mucous-secreting
rhabdomyoblasts; bulky mass endocervical glands
may fill and project out of vagina (sarcoma inflammation, squamous metaplasia
botryoides)
Projection resembles a bunch of grapes Tx - simple curettage or surgical excision
Cervix Cervix
Cervical Intraepithelial Neoplasm (CIN) Squamous cell carcinoma 95% of cervical
HPV most important agent (95% of cervical ca), but cancer
NOT only factor in development of Peak occurrence in middle aged women
Viral gene product E6interrupts cell death cycle Usually from pre-existing CIN at squamocolumnar jxn
by binding p53
PAP decreases mortality via early detection of CIN and
E7bind RB and disrupts cell cycle CA
CIN stages Intraepithelial and invasive neoplasm
CIN I mild dysplasia involving lower 1/3 raised or flat
lesion, indistinguishable from condylomata accuminata 3 forms - fungating (exophytic), ulcerating, infiltrative
CIN II moderate dysplasia atypical cells in lower 2/3 extends by direct continuity
CIN III severe dysplasia/ carcinoma in situ (if its full metastasizes to lymph nodes; liver, lungs, bone marrow
thickness)
PAP decreases mortality via early detection of CIN and
**Koilocytes may be present at all stages**
CA
Takes 10 years to go CIN ICIN II
Histology - 95% large cells, keratinizing or non-
Takes another 10 to go CIN IICIN III keratinizing
Cervix Uterus
Cinical Course/Management Endometrial Hyperplasia
Symptoms - irregular vaginal bleeding, leukorrhea, Abnormal proliferation of endometrial glands, usually caused
bleeding or pain on coitus; dysuria by excess estrogen stimulation
PAP smear is insufficient for prevention/diagnosis Excess estrogen may be due to
All abnormalities visualized by colposcopy Anovulatory cycles, polycystic ovary dz, estrogen-
Acetic acid application will reveal CIN secreting ovarian tumors (ex. granulosa cell tumors), and
White
Whit patches
t h off cervix;
i ffollow
ll up with
ith punch
h estrogen replacement therapy
biopsy Manifest clinically with postmenopausal bleeding
CIN I - Pap smear follow-up Can be a precursor lesion of endometrial carcinoma
CIN II, III cryotherapy, laser, loop electrosurgical Risk of CA directly correlated with degree of cellular atypia
excision procedure (LEEP), or cone biopsy Simple hyperplasia (aka cystic or mild) rarely leads to
Invasive CA - hysterectomy and/or radiation carcinoma
(depends on stage) high grade (atypical or adenomatous + atypia) - cellular
Survival: 80-90% stage I; 75% stage II; 35% stage atypia, irregular epithelium; 25% lead to carcinoma
III; 10-15% stage IV
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Placenta
Spontaneous abortions Placental abnormalities
placenta acretia - partial or complete absence of the decidua
10-15% of recognized pregnancies; probably close to with adherence of placenta directly to myometrium; failure of
22% of all conceptions; chromosomal studies are placental separation may cause postpartum bleeding (life
recommended with habitual or recurrent abortion or with threatening); up to 60% association with placenta previa;
malformed fetus uterine rupture (placenta percreta)
fetal influences placenta previa - implantation in the lower uterine segment
defective implantation or ce
o cervix assoc
associated
ated with
t se
serous
ous a
antepartum
tepa tu bbleeding
eed g a and
d
genetic or acquired developmental abnormality premature labor
chromosomal abnormalities in >50% placenta abruptio separation of the placenta prior to
maternal influences delivery
inflammatory diseases (local and systemic),
uterine abnormalities
Twin placenta
infection monochorionic implies monozygotic twins; may have one or
two amnions
dizygotic twins usually have dichorionic, diamniotic placenta
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