Pathology exam 1

Patterns of cellular adaptation to disease

change in size- atrophy, hypertrophy

change in number- hyperplasia, involution/hypoplasia

change in differentiation- metaplasia

types of adaptations to environment change

metabolic- biochem like fasting

structural- change in morphology

cells response to injury

turns down gene coding for nl structural proteins

highly express genes for protective proteins to survive (like heat shock proteins, ubiquitin-proteosome)

heart nl vs pathology

nl- 250-300g

R ventricle 0.5cm, L ventricle 1.5cm

hypertrophy- larger heart, calcific stenosis of aortic valve (elderly)

larger cardiac muscle cells, large box car nuclei

L ventricle is larger and R is smaller

• - calcific stenosis of aortic valve leaflets- elderly pt, can lead to HTN

• - bicuspid aortic valve- heart murmur, congenital, can cause calcification and HTN

Dilated- congestive heart failure- both ventricles not pumping as should

what cells can go through hyperplasia?

liver

spleen

prostate glands- nodular hyperplasia in periurethral

marrow- at 50yo, 50% is cells, 50% is fat (50-50-50 is nl), cell hyperplasia

endometrium

lipofuscin, where you see it, other examples

intracellular age related pigment

brown in lysosomes, see brown atrophy in myocardium. looks brown and granular perinuclear, not pathological

atrophy also in endometrium w age

examples of involution/hypoplasia

hypoplasia of L ventricle- small L ventricle compared to R. most common cause of HF in 1st week of life

Thymus gland - involution w age, # of lymphocytes decrease and replaced by adipose (look for hasselbach corpuscles)

examples of metaplasia

bronchus- ciliated columnar epithelium becomes squamous with cigarette smoke

bladder- transitional to squamous with trauma

esophagus- squamous to glandular with gastric acid (Barrett esophagus)

examples of apoptosis

At microscopic level, getting rid of aged cells

main targets of damage in cells? Main molecular mechanisms?

membranes, cytoskeleton, mitochondria, DNA

Inadequate ATP production (membrane pumps don’t work)

cellular free ionized Ca damages membranes and mitochrondria (proteases)

oxygen metabolites (damages membranes, DNA, mitochrondria)

On a larger scale, cell injury can occur via…

Hypoxia

• ischemia- blocks blood flow

• inadequate oxygenation- like resp infect

• anemia- lose oxygen carrying capacity of blood

physical (like heat or cold)

chemical (EtOH hepatitis)

infectious (viral hepatitis)

process of hypoxic injury

loss of oxidative phosphorylation

decrease protein synthesis

decreased ATP generation by mitochrondria

glycogen depletion (glycolysis)

lactic acid produced

what does the failure of ATPase membrane transport do to the fluid balance?

influx of Na, Ca, H2O

efflux of potassium

microscopy of reversible hypoxia

electron micro

• membrane bound organelles swell

• rER- ribosomes start to come off

• mitochrondria- preservation of cristae, though swollen

light micro

• organelle swelling causing cell swelling

  • pale and cloudy cytoplasm,

  • intracytoplasmic vacuoles- water droplets (nucleus in center), lipid droplets (nucleus to side)

pathology of irreversible hypoxia

severe ATP depletion

intracellular release of lysosomal enzymes

extracellular cell membrane injury (released enzymes)

cell and tissue death

microscopy of irreversible damage

electron

• severe mitochrrondrial sweeling, cristae destroyed

• extensive plasma damage

• lysosome swelling (leaking enzymes, cell and nuclear digestion)

Light

• Necrosis

processes of necrosis

denaturation of proteins

enzymatic digestion of organelles

What happens to the nucleus when a cell dies

pyknosis- small, dense nucleus, condensed chromatin

karyorrhexis- fragmentation of cell nucleus

karyolysis- basophilia of chromatin fades, nucleus dissolves

what happens to the cytoplasm when a cell dies?

cytoplasmic proteins denature, becomes more eosinophillic (pink) due to loss of RNA and coag proteins

proteins liberates and can be detected in blood (troponin for heart)

Patterns of necrosis

coagulative- occlusion of blood supply (heart, kidney, liver spleen, etc but not brain) Intracellular acidosis, more protein denature than enzyme digestion

• heart- ghosted cell outline but no nucleus, very pink. Grossly, looks pale.

• kidney- no nuclei in the tubules of kidney. Grossly, very pale area

liquefactive- occlusion of arterial blood to brain or bacterial infection. Digestion of tissue by lysosomal ezymes more than protein denature, semi-liquid tissue

• brain- lack of organization or structure, grossly- looks dark and shiny

• lung- neutrophils makes too much enzymes and causes abcess. grossly, pus-filled abcess.

caseous- tuberculosis. dead tissue is cream-cheese-like (soft and white), forms proteinaceous mass, no hist structure

• lung- not well organized. grossly, lumpy white tissue in cavitary lesion

fat- inflammation of pancreas and trauma to breast. tiny foci of hard, yellow dead adipose cells

• pancreas- can be called saponification, soapy look. grossly, white spots can be seen on surface

fibrinoid- vasculitis and hypertension (malignant) causing damaged vessel. fibrin deposited into vessel wall

• vasculitis- fibrinoid necrosis. inner wall looks like fibrin and is dead.

  • kidney- small arteries has a pink amorphous look. grossly, like tiny hemorrhages on surface of kidney “flea bitten”

hemodynamics disorders are secondary to… occurs by…

changes in nl fluid homeostasis

occurs via failure to maintain vessel wall integrity, but intravasc bp and osmolarity nl

OR can be changes in vasc volume, pressure, protein, or endothelial fx

Types of Hemodynamic disorders

 Interstitial water accumulation (edema)
 Augmented inflow (hyperemia)
 Impaired outflow (congestion)
 Local bleeding (hemorrhage)
 Excessive bleeding (shock)
 Migration of clots (embolism)
 Obstruction of blood flow resulting in cell
and tissue death (infarction)

edema in ___ is called ____

• Pericardium – Hydropericardium
• Thorax – Hydrothorax
• Peritoneum – Hydroperitoneum (ascites)
• Subcutaneous tissues
 Generalized – Anasarca
 Regional – Swelling of lower extremities
• Viscera
 Lungs – Pulmonary edema

difference between fluids in non-inflamm and inflamm edema

non-inflamm- “transudate” ultrafiltrate, low protein, low specific gravity. thin watery fluid. ex. pulm edema

inflamm- “exudate”, purulent fluid w/ fluid and cells (WBS/neutrophils), high protein, high specific gravity. ex. bacterial pneumonia

pathogenesis of edema (occurs bc)…

increased hydrostatic pressure- venous return is impaired, so transudate leaks from capillaries. ex. congestive HF (pulm venous return to LV or systemic venous return to RV)

decreased osmotic pressure- low albumin in blood

• albumin loss- leaky glom cap basment membrane (nephrotic syndrome)

• low albumin production- diffuse liver pathology/cirrhosis

lymphatic obstruction- impaired drainage via inflamm, postsurg, post irradiation, neoplastic. ex. arm lymphedema after mastectomy d/t lymph obstruction

electrolyte changes (Na ret)

inflamm

sx and micro of nephrotic syndrome

presents with high albumin in urine, low albumin in blood.

nl light microscopy

electron micro shows diffuse effacement of foot processes of podocytes

pathology of cirrhosis of liver

effacement of hepatic architecture leading to liver failure and ascites

1. hepatocytes destroyed (hepatitis, toxins, or genetic)

2. regen of residual hepatocytes as nodules (looks like light colored bubbles in histology)

3 fibrosis- scarring of liver, capillaries begin to leak

spleen grows bc blood backs up

pathology of non-inflamm edema

gross- thin clear fluid

micro- cell swelling, tissue matric separation

common sites- subcutaneous (anasarca), lungs, renal cortex, cerebral cortex

hyperemia and congestion pathology

both increased volume of blood in an area

hyperemia- active process, increased blood flow in, arterial dilatation. red tissue, engorged by oxygenated blood. ex. frost bite

congestion- passive process, decreased blood flow out, venous obstruction/low venous return, purple/maroon tissue, less oxygenated blood

• Acute- distended capillaries, interstitial edema

• Chronic- hemosiderin (rust colored) laden macrophages (in lungs related to CHF), cell atrophy and fibrosis (liver related to CHF)

in CHF, blood is backed up in which zone of hepatic lobule?

3 (zone 3 to zone 3 congestion from RV failure

hemorrhage pathology

blood extravasacation following vessel rupture

• Petechiae: 1-2mm
 Skin, mucous membranes, serosal surfaces
 Capillary source of bleeding and usually associated with thrombocytopenia
• Purpura: >3mm
 Increased vascular fragility associated with vasculitis of small vessels
• Ecchymoses: >1-2cm
 Bruises
 Trauma

Larger accumulations in body cavities
• Hemothorax
• Hemoperitoneum
• Hemopericardium
• Intracranial
 Epidural – middle meningeal artery
 Subdural – bridging veins (midline)
 Subarachnoid – cerebral artery aneurysm (circle of Willis) “worst HA of life”
 Basal ganglia (putamen)- hypertension causes tiny aneurysms in putamen referred to as Charcot-Bouchard aneurysms

Shock pathology

secondary to reduction of cardiac output (cardiogenic), loss of traumatic or natural blood volume (hypovolemic), or sepsis

leads to systemic hypoperfusion, causes hypotension, impaired organ perfusion, and cell hypoxia

Brain (encephalopathy)- cortical edema

Heart (arrhythmia)- necrosis of myocardium

Kidneys (oliguria)- necrosis of tubules

Lungs (ARDS)- damage to alveolar capillaries

Intestines (GI blood loss)- hemorrhagic necrosis

Liver (liver failure)- fatty change/necrosis

Embolus pathology

detached intravascular mass carried to a distant site

99% from a thrombus (RBC, fibrin, platelets)

• venous thrombus (pulmonary thromboembolus)- deep leg veins—> IVC—> RV—> lungs

• arterial thrombus (systemic thromboembolus)- heart thrombus (mural thrombus) from myocardial infarct (80%) or in aorta from atherosclerosis—> aorta—> brain (10%), spleen, kidneys, lower extremities (75%)

fat embolus- comes from bone fractures—>pulm veins— lung capillaries.10% fatal

air embolus- 100ml of air, IV, transfusions, or lap surgeries

Amniotic fluid- uncommon, squamous cells from amnion—> placental bed—>mom circulation—> microvasc thrombi

Talc embolus- IV drug abuse (polarization can show them as very light)

most common preventable cause of death

pulmonary thromboembolism

gross and micro of pulmonary thromboembolus

granular surface, twisted, coiled. Can be cord-like.

Saddle thromboembolus- occupies main pulmonary trunk and main R and L pulm arteries

micro- fibrin platelets and RBCs in kind of a marbled look

Infarction pathology

recognizable area of necrosis in the organ due to local ischemia

caused by inadequate blood supply (usually occlusion) and ischemic necrosis, leads to scar tissue in all tissues but brain

Grossly can be

• pale (anemic)- end arterial occlusion (heart, kidney, spleen). Often coag necrosis (heart dilates from this)

• Red (hemorrhagic)- dual circulation (lungs, intestine, liver), or venous occlusion (gonadal torsion, intestine volvulus, turns BLACK)

  • commonly wedge shaped

Brain- ischemic liquefactive necrosis followed by repair leading to cystic change, usually caused by atherosclerosis of R and L internal carotid artery

• thromboembolus of R internal carotid a at bifurcation of R middle cerebral a common

epidemiology of fetal loss “truisms”

major part of fetal loss occurs in 1st half

Early gestation deaths more associated with death from gross chromosomal and genetic defects (25%)

later gestation deaths more associated with problems arisen during pregnancy (placenta or mom) (10%)

Management of fetal development- can it be controlled?

more intrauterine shunts and surgery for certain anomalies, but has risks

ex. intrauterine surgery placing a shunt can cause umbilical cord entrapment

Malformation vs disruption vs deformation

malformation- morphologic defect of organ/area from an /intrinsically/ abnl development, within developmental field

• ex. anencephaly- most common neural tube defect (1/500), folate deficiency. “froglike” face w no cranium and less brain. Increased alpha fetoprotein and acetylcholinesterase

• ex. omphalocele- saccular malformation of umbilical cord w portions of intestinal tract w umbilical ring widely open. covered by membrane, umbilical cord inserts into this defect laterally. Can be fixed but messes up the diaphragm.

• ex. gastroschisis- hole in R abdominal wall, viscera exposed and eviscerated from abdomen. umbilical cord inserts lateral to defect.

• ex. conjoined twins- single ovum, secondary to incomplete fission, majority in sternal region. Difficult when it involves fused heart.

disruption- morphologic defect of organ or area from /extrinsic/ breakdown of a nl developmental process. Sporadic occurrence.

• ex. ADAM Complex- amnionic deformties, adhesions, mutilations due to amnionic bands getting disrupted. Torpin’s theory- mesodermic fibrous strips get tangled when amnion and chorion surface peeling away and sticking

deformation- abnl form, shape, or position of part of body caused by extrinsic or intrinsic /mechanical/ forces

• ex. flexion deformatities, severe contractions due to placenta being very restricted (circumvallate placenta) causing reduction in amniotic cavity

types of pediatric pathology

congenital anomalies

inherited disorders

prematurity

neoplasia

Patterns of morphologic defects

sequence- from one anomaly leading to uniform pathogenesis of pattern of defects. etiology is variable but phenotype is uniform

syndrome- A recognized pattern of multiple anomalies known or thought to be
pathogenetically related and not known to represent a sequence

association- A nonrandom occurrence in two or more individuals of multiple
anomalies not known to be a sequence or syndrome

• ex. VATER Association-

  • Vertebral defects

  • Anal atresia

  • Tracheo-esophageal fistula

  • Esophageal atresia

  • Renal/radial anomalies

Patterns of Oligohydramnios/cystic kidneys

1. Potter phenotype- non-inherited- pathogenesis is from oligohydramnios sequence (lack of fluid, compression) causes “old man facies” w inner canthal folds, flat nose, low ears, recessed chin, round feet, renal multicystic dysplasia (cartilage bubbles!)

2. polycystic kidneys- inherited cystic kidney disease) with ribbon like tubules, dilated.

3. obstructive dysplasia of the kidneys- posterior urethral valve has anomaly blocking urinary flow causes dilated and thick bladder and ureters

4. Renal agenesis- absence of kidneys. adrenal glands flatten and can be mistaken for kidneys

Examples of syndromes

21 trisomy- Down Syndrome

• Flattened facial features, Oblique palpebral fissures

• Depressed nasal bridge, small rounded ears

• Flat occiput, Brachycephaly, nuchal skin fold

• Transverse crease in hand

• Plantar groove between 1st and 2nd toes

• 40% have ventricular septal defect

• 10% GI anomaly like Duodenal atresia

• 33% mortality of 1st yr, 50% of 3-4 yrs

18 Trisomy- Edward Syndrome

• Low-set, elf-like ears

• Broad cranium, micrognathia, prominent occiput

• overlapped fingers, clinodactyly

• narrow pelvis

• prominent calcaneus (Rocker bottom)

• 30% mortality 1st mo, 90% 1st yr, 99% 10 yr

13 Trisomy- Patau Syndrome

• Cleft lip/palate, proboscis

• microphthalmia (small eyes)

• microcephaly and holoprosencephaly (fused hemis)

• Symmetrical polydactyly in hands and feet

22 trisomy- resp distress, bradycardia, brachycephalic, hypertelorism, prominent cleft lip palate, skin tags, absent right ear

Examples of association

VATER Association-

• Vertebral defects

• Anal atresia

• Tracheo-esophageal fistula

• Esophageal atresia

• Renal/radial anomalies

examples of autosomal recessive, dominant, and X Linked disorders

Autosomal Recessive
• Cystic Fibrosis- most common lethal genetic disorder affecting caucasians

• Chromosome 7 (CFTR gene- cystic fib transmemb conductance regulator) affects anion transport and exocrine glands (lung, pancreas, liver) and meconium ileus in newborns (sxs- SOB, not gaining weight, sweat Cl- of 116meg/l, pneumonia, hepatosplenomegaly)

• micro- pancreas has dilated ducts, acina replaced by fat. Liver- fatty bubbles, biliary cirrhosis. lung has dilated bronchi and scar tissue (fibrosis)

• gross- liver has nodules (cirrhosis) lung has bronchiectasis, marked dilatation of bronchi

• Gaucher Disease- a lysosomal storage disease, huge liver and spleen

• micro- spleen has reticuloendothellial cells that store substrate-glucocerebroside (cells with uniform light pink cytoplasm). Liver has Kupffer cells store substrate-glucocerebroside (lighter pink). Lymph node has Gaucher cells w pink cytoplasm w wrinkled tissue paper appearance

• Pompe Disease- a glycogen storage disease that targets the heart.

• gross- infant with cardiomegaly

• micro- very light looks like open spaces in the smooth muscle. A PAS stain shows intense glycogen deposition

Autosomal Dominant
• Marfan Syndrome

X-Linked
• Muscular Dystrophy

lysosomal storage diseases

Tay-Sachs- deficiency of hexosaminidase A

Niemann-Pick- def of Sphingomyelinase

Gaucher- def of Glucocerebrosidase

Glycogen storage diseases

Type I- Von Gierke- targets liver and kidney

Type II- Pompe- targets heart, etc.

Type V McArdle- targets skeletal muscle

diseases of prematurity

hyaline membrane disease- most common cause of distress in newborn, most common cause of death in premature infants

 Insufficient Surfactant—> Poor expansion of lung, Atelectasis (collapse)
 Hypoxia
 Damage to pulmonary capillaries—> very red lungs, micro- pink fibrin like material on the surface of alveoli—> can cause pneumomediastinum
 Leakage of plasma
 Hyaline Membranes—>Intraalveolar fibrin deposition

necrotizing entereocolitis

 Prematurity
 Distended abdomen
 Intestinal ischemia
 Necrosis and dilatation of intestines- greenish and thicker than pencil, under micro may see air trapped in layers of intestine
 Fulminant inflammation of small and large intestines

intraventicular hemorrhage

 Hypoxia- Premature infants with HMD
 Vascular damage within periventricular germinal plate matrix leading to
hemorrhage which breaks into the adjacent lateral ventricle

• hemorrhage is red, breaks through ventricular spaces, to the subarrachnoid space surrounding brainstem and cerebellum

 Ventricular and subarachnoid involvement associated with high mortality

Neoplasia (-oma)

mass or tumor, growth continues after stimulus

benign- slow growth, encapsulated, lipoma (mesenchymal) or adenoma (glands/epithelial). Rubbery

malignant- fast growth, invasive, can metastasize, sarcoma (mesenchymal), carcinoma (epithelial)

pediatric neoplasia’s

benign- menangioma

malignant-

• leukemia (hematopoietic)

• medulloblastoma (nervous system)

  • infratentorial, cerebellum tumor of small cells (PNET or primitive neuroectodermal tumor)—> spreads via CSF

  • micro- small round blue cells

• neuroblastoma (nervous system)

  • Neural crest origin, 75% in abd (50% adrenal gland), small cells (PNET)

• sarcoma (soft tissue) more common in young

  • Osteosarcoma- Most common tumor in bone, usually proximal tibia and distal femur

    • Presenting age <25yo, bone pain that doesn’t go away
      micro- malignant osteoblasts (very dark) plus osteoid (unmineralized bone)

    • gross- lifts off periosteum off bone (Codman’s triangle)

  • Ewings Sarcoma- diaphysis (shaft) of long bones and ribs, pelvis, scapula

    • presenting age <15yo

    • micro- small and dark blue nuclei, glycogen in cytoplasm does NOT look like bone

• nephroblastoma- Wilm’s tumor. most common renal malignancy in peds

  • Presenting in 2-4yo, palpable abd mass

  • micro- triphasic

  • - tightly packed blue cells of blastema

  • - immature epithelial tubules

  • - spindle cell stroma

incidence of ped vs adult brain tumors

peds- 70% is below tentorium

adults- 70% is above tentorium

inflammation purposes and harmful if…

chronic or acute response to cause of cell injury, removes necrotic cells

initiates tissue repair

excessive, prolonged, or inappropriate (autoimmunity)

sxs of inflammation (5)

rubor (red), calor (heat). tumor (swelling), dolor (pain), functio laesa (loss of fx)

acute inflammation

mins-hrs after stimulus, lasts hours to days, neutrophils in tissue, innate immunity. Mostly neutrophils (multinuclear) and macrophages (oval nucleus, big cytoplasm)

• 1. increased blood flow- vasodilation, vascular congestion (redness and heat) from nitric oxide

• 2. leakage of fluid and proteins- histamine! swelling, loss of fxn, pain

• 3. neutrophils leave capillaries, accumulate at site, ingest/destroy agent

  • A) margination- stasis and slow blood flow cause neutrophils to be pushed up against endothelium

  • B) rolling- E-selectin (induced by TNF and IL-1) and P-selectin (Weibel-Palade bodies, induced by histamine) attach to neutrophils (Sialyl-Lewis X) just enough to help them roll on the surface of endothelial cells. Low affinity

    • Leukocyte adhesion deficiency type 2 (LAD-2)- no leukocytes at site

  • C) stopping and adhering- CD11/18 integrins on neutrophils attach of ICAM-1 integrin ligands on endothelial cells. high affinity

    • leukocyte adhesion deficiency 1 (LAD-1)- autosom rec in CD18 subunit of integrins, more neutrophils in blood, bact infect w/o pus

  • D) diapedesis/transmigration- neutrophils go through endothelium via piercing through PECAM-1 bound endothelial cells and basement membranes (coll IV) by secreting collagenases

• 4. neutrophils accumulate at site, ingest/destroy agents

  • chemotaxis- neutrophils migrate to bacterial products, cell-derived mediators

    • chemokines (IL-8) and leukotrienes (B4) from mast cells, macrophages, other dendritic cells

    • Plasma proteins like components of complement system (C5a)

  • Lysosomes contain enzymes, reactive oxygen species (superoxide anion, hydrogen peroxide, bleach), and reactive nitrogen species. Destroy engulfed bacteria in phagolysosome

• 5. macrophages show up (2-3 days), can decide what to do next (ex. IL-8 recruits more neutrophils and makes abcess, can activate helper T cells causing chronic inflammation, IL-10 and TGF-B can start healing)

stimuli for acute inflammation

infection- streptococcus pyogenes (pus in throat), staphylococcus aureus, corynebacterium diptheriae (diptheria pharyngitis- pseudomembrane in the throat, unvaccinated)

necrosis- hypoxia, ischemia, trauma, chemicals/toxins

foreign bodies (splinter, etc.)

immune rxns (bee sting, etc)

collateral damage of acute inflammation

neutrophils and macrophages kill normal cells causing liquefactive necrosis, walls it off, forming abcess. Deep in organ, tissue, or confined space

micro- central region of pink necrotic neutrophils and tissue cells, surrounded by live neutrophils (dark purple), surrounded by viable tissue (light purple)

chronic inflammation

might be from acute inflamm or insidious, lasting weeks-years

mononuclear cells predominate (lymphocytes, macrophage, plasma): Adaptive

• 1. macrophages start tissue repair, secrete mediators (TNF, IL-1, chemokines), and display antigens to CD4 T helper cells. T cells secrete cytokines—>inflammation), B cells become plasma cells (make antibodies)

  • plasma cells- nucleus shoved on one side, paler perinuclear pot on other side, chromatin is a clock pattern

• May cause granuloma-(ex. TB, fungi such as histoplasma capsulotum, foreign bodies, sarcoidosis, Crohn disease) central necrosis (gooey pink necrotic debris), surrounded by macrophages (epithelial histiocytes, big cytoplasm) and giant cells (fused macrophages)

chronic inflammation caused by

persistent infections, viral infections (adenovirus, rhinovirus looks like red small spots on soft palate)

hypersensitive/autoimmune (allergic dermatitis, IBS, rheumatoid arthritis)

prolonged toxins (cigarette smoke, silica)

Systemic effects of inflammation

acute phase reaction

fever- response to pyrogens (exogenous- bacterial products, endogenous- IL-1, TNF)—> produces prostaglandins in hypothalamus, esp PGE2 (resets temp point)

acute phage proteins- Plasma proteins, many synthesized in the liver (Hepatocytes are stimulated by cytokines: IL-6, IL-1, TNF)

• C-reactive protein (CRP)- Sensitive laboratory measure of inflammation
  Fibrinogen- Binds to red blood cells, forming stacks of RBCs (rouleaux)

  • ◦ RBC sediment more rapidly—> faster erythrocyte sedimentation rate (ESR), Laboratory test for inflammatory response

• Hepcidin- Reduces iron availability and absorption

  • ◦ Responsible for anemia of chronic disease

leukocytosis- Leukocyte count rises to 15,000 to 100,000 cells/mL (bc of TNF and IL-1)

Bacterial infections (Acute) “left shift”
◦ Increase in neutrophil count = neutrophilia
◦ Accelerated release of cells from the bone marrow- More immature neutrophils in the blood – bands, metamyelocytes, myelocytes, promyelocytes (>10% bands)

Viral infections (Chronic) and transient stress such as seizure
◦ Increase in lymphocyte count = lymphocytosis

Allergies, skin rash, and parasitic infections
◦ Increase in eosinophils = eosinophilia

Increase in basophils is not common and should prompt consideration of neoplasm

Regeneration vs repair

regen- replacement w native tissue

• labile tissue- stem cells continuously recycle (bowel mucosa, marrow, skin)

• Stabile tissue- quiescent cells can reenter cell cycle when needed (liver

repair- replacement w fibrous scar

• permanent tissue- can’t repair (myocardium, neurons)

• regenerative stem cells lost (deep skin cut which went past basal stem cell layer)

repair process of deep skin cut

secondary intention (no stitches)

1. 1. Inflammatory- 24-48 hr- thrombus, dehydration (scab), neutrophils (enzymes clear debris)

2. 2. Proliferative- Day 3-7- neutrophils replaced by macrophages, granulation (rich prolif of blood vessels with inflammatory cells)

   1. endothelial cells—> angiogenesis via vascular endothelial growth factor (VEGF) and proliferates

   2. fibroblasts—> loose conn tissue (collagen III, transforming growth factor (TGFB) and fibroblast GF (FGF))

   3. myofibroblasts—> wound contraction

3. 3. remodeling- 1 wk-6 mo

   1. fibroblasts—> increased tensile strength (type III coll replaced by type I)

Abnl tissue repair

infection, DM, malnutrition, mechanical factors, injury type/extent/location

wound dehiscence- rupture due to increased pressure

ulceration- local defect via sloughing or inflamed necrotic tissue (ex. atherosclerosis or neuropathic ulcers of diabetic neuropathy)

keloid- excessive collagen, raised scar growing beyond original wound (ex. burns, surgical, acne)

• micro- broad, disorganized bands of dermal coll fibers

Contractures- exageration of wound contraction, can compromise joint movement (ex. severe burns)

levels of how pathogenic microorganisms are

severity of disease

microorganisms can be commensal, minimally virulent, or very virulent

Major routes of entry

skin- mechanical injury

• ex. pseudomonas aeruginosa- blue-green pus in burn wound infection

GI tract- food, drink contaminated by feces

• ex. Helicobacter pylori uses urease to combat stomach acid

• ex. vibrio cholera adheres to mucous coat of small intestine—> diarhea

• ex. norovirus- resistance to acid, bile, and pancreatic enzymes (cruises)

• ex. salmonella, shigella, campylobacter, entamoaeba histolytica invades intestinal mucosa and cause ulceration—>dysentery (bloody diarrhea)

• ex. C difficile- attacks normal gut flora, usually spreads to immunocompromised ppl

respiratory tract- inhalation

• ex. H influenza, M pneumonia and bordetella pertussis- toxins gets past the mucociliary clearance, smoking also kills cilia

• ex. TB resistant to phagocytosis destruction in macrophages

Urogenital tract- direct spread or sex

• ex. E coli- adheres to urothelium. risk factors include prostatic hyperplasia, abnl anatomy

• ex. yeast infection can grow due to antibiotics that kill lactobacilli- ferment glucose to lactic acid, supressing pathogen growth

• ex. HPV- immature proliferating epithelial cells are exposed and infected via minor trauma

placental

spread of microorganisms

Staphylococcus aureus (MRSA)- degrades extracellular matrix between cells

varicella zoster (chicken pox)- peripheral nerves within axons (shingles)

bartonella henselae (cat scratch disease)- lymphatics to lymph nodes

Blood-spread depends on virulence, magnitude, pattern of seeding, and host (immune system, etc)

• low virulence- brushing teeth

• high virulence-

  • ex. pseudomonas infection in burn victim—> septic shock.

    • ex. military TB—> spreads through blood, forming new foci “seeding”

Immune responses to microorganisms

suppurative (purulent)

• ex. staph pneumonia- adheres to cells, secretes enzymes and toxins, damaged cells become substrate for bacteria growth, inflammation—> increased vasc permeability, neutrophils infiltrate—> pus—> alveolar walls destroyed, abcess, scar formation

chronic inflammation- granulomatous inflammation

• ex. TB- replicates in macrophages—> lymphocytes, plasma cells, and macrophages infiltrate—> granuloma—> fibrosis and calcification

cytopathic-cytoproliferative rxn

• ex. HPV- viral oncogenes stimulate cell growth and survival, can cause genetic aberrations—> chronic inflammation w T cells and plasma cells—> infected cells become cancer cells if immune system fails

tissue necrosis

• ex. Clostridium perfringens- secretes toxins causing gangrenous necrosis—> lack of inflammatory response (no oxygen)—> rapidly progressive, death within 1 week

chronic inflammation/scarring

• ex. chronic hep C- infects hepatocytes—> evades immune system—> chronic inflammatory cells (esp T cells)—> repetitive injury—> fibrosis and loss of nl tissue architecture—> cirrhosis (bumpy liver)

neoplasm definition

abnl mass of tissue that grows too fast and keep growing after cessation of stimuli

Part of a tumor

proliferating tumor cells

stroma (extracellular matrix and vessels- determines consistency (scant/soft or desmoplasia/sclerosis)

Types of neoplasia

Benign

mesoderm/mesenchymal- osteoma (bone), chondroma (cartilage, lipoma (fat)

epithelial/ectoderm or endoderm-

• polyp- tumor going into lumen of mucosa lined organ

• adenoma- gland forming histologically or arise from a gland

• papilloma- papillary architecture, lined by different epithelium, varied location

Malignant

epithelial- carcinoma

• adenocarcinoma- gland forming

• squamous cell carcinoma

mesenchymal- sarcoma (less common)

• osteosarcoma, chrondosarcoma, etc.

hematopoietic- lymphoma/leukemia

• diffuse large B cell lymphoma, etc.

melanocytic- melanoma

All 3 germ cell layers- teratoma/dermoid cyst, found in ovary, testes

Nl tissue in wrong place- choristoma

Mass of disorganized cells of native tissue- hamartoma

monoclonality vs polyclonal

monoclonal- more common- one precursor cell

polyclonal- multiple precursor cells

natural history of malignant neoplasm

transformation- malignant change in target cell

growth of transformed cell

local invasion

metastasis

characteristics of tumors

differentiation- well differentiated still look like original, poorly-differentiated looks different

• anaplasia- lack of differentiation

• pleomorphism highly variated in size (poor differentiation)

• hyperchromasia is darkly staining nuclei (big nuclei is a sign of malignancy)

dysplasia- disordered growth in epithelial lined structures, but not past basement membrane

growth rate- fast growing is malignant. micro- bigger nuclei compared to cytoplasm, variation in size and shape, mitoses

local invasion- infiltrative appearance is more malignant, jagged edges, less defined edges, basement membrane is breached (in situ is still safe)

metastasis- spread into multiple tumors

• direct seeding of cavities and surfaces (like in abd and pelvis)

• lymphatic spread (lymph nodes)

• hematogenous spread (everywhere, esp lungs)

clinical presentation of tumors

screening- to catch a tumor that is worth catching early, low risk screen

• tests- Lab work, radiology (lungs), or pathology (pap smear)

• clinician exam- manual breast exam, prostate, skin check

• procedure- colonoscopy

Symptoms- “B symptoms” (fever, night sweats, lymphadenopathy, infections), obstructive sxs (infections, jaundice), bleeding, weight loss

Incidental- find by accident

Cancer staging and grading

AJCC defines staging for most cancers

clinical vs pathologic stage

TNM staging (tumor, node, metastasis)

• Tumor- pT1 (low) - pT4 (high) size and spread

• Node- lymph nodes, size in lymph nodes, or extranodal extension into fat

• metastasis- Mx (no), M1 (yes)

Grading- micro appearance, no good definitions for most

• endometrial- FIGO grade

• breast- Nottingham grade

  • Kidney- Furman grade

development of cancer

mutation that makes it unable to repair or do apoptosis

• oncogene- the mutated form of a cell growth gene (proto-oncogene—> oncogene) ex. Her2/NEU, MYC, ABL, RAF

• tumor suppressor gene- holds cell in check. 2 hit model (one copy in 2 chromosomes, both must be knocked out, one mutation can just predispose to cancer) ex. BRCA1, P53, CDKN2A (P16), APC

• apoptosis genes- pro-apoptosis (knock out), vs anti-apoptosis (if adjacent to a gene always active, it becomes invincible)

  • DNA repair genes- nucleotide excision repair (repairs DNA from UV radiation, mutation causes xeroderma pigmentosum), base excision repair (BER), mismatch repair (MMR)

carcinogens

radiation

• UV radiation

  • UVA- free radicals

  • UVB- sunscreen! direct cause, dimerize adjacent thymine

  • UBC- blocked by ozone layer, except welders

• ionizing radiation- electromagnetic (Xrays) or particulate (a, B, protons, neutrons, etc.) causes DNA damage

infections- most are viruses (HPV, HBC/HCV, Epstein-Barr, HTLV1, Merkel cell polyomavirus, HHV8)

• HPV inhibits tumor suppressor genes of squamous epithelium (P53, RB)

• also H pylori (MALT lymphoma on marginal zone), aspergillus flavus (fungus that makes aflatoxin B1, causes hepatocellular carcinoma)

Toxins/chemicals

• direct alkylating agents- treats cancer but can also cause other cancer

• polycyclic hydrocarbons- cigarettes, smoked meats causing lung and bladder cancer

• asbestos—> mesothelioma

• vinyl chloride—> angiosarcome of liver

• arsenic—> skin cancer

cancer epidemiology

2nd leading cause of death in US (2019)

Men most common- prostate, lung/bronchus, colon/rectum

Men most deadly- lung/bronchus, prostate, colon/rectum

Women most common- breast, lung/bronchus, colon/rectum

Women most deadly- lung/bronchus, breast, colon/rectum

Most common cancers (2021)- breast (female), prostate, lung/bronchus, colorectal, skin (more common, less deadly)

Peds cancer is most common cause of death past infancy

• ~15,590 new cases in 2021, 1780 will die of cancer

• most common- leukemia (B cell acute lymphoblastic or B-ALL), brain/CNS tumors, lymphoma, neuroblastoma, kidney, done

• inherited neoplasms present younger, excellent prognosis