Signs of apoptosis
cell shrinkage nuclear shinkage (pyknosis) basophilia membrane blebbing nuclear fragmentation (karyorrhexis)
When is intrinsic pathway most active
embryogenesis with tissue remodeling
Injury repair
Describe the intrinsic pathway
Increased Bax
Decreased Bcl-2
mitochondrial permeability
cytochrome C release
Describe the extrinsic pathway
Fas ligand binds Fas-R (CD95)
- Cytosolic caspases activated
- Cellular breakdown
OR
Killer T cell releases granzyme and perforin
Which organs have liquefactive necrosis
Brain, pleural effusion
When do you see fibrinoid necrosis
Blood vessels (HTN or vasculitis)
When do you see gangrenous necrosis
dry (ischemic)
wet (with bacteria)
Occurs in LIMBS and GI TRACT
Which parts of kidney are most susceptible to damage?
medulla
-thick ascending limb and proximal tubule
Which parts of colon are susceptible to hypoxia?
splenic flexure and rectum
–dual blood supply to distal areas protects from single vessel blockage, but not systemic ischemia (aka watershed)
Which cells of brain are killed first in global ischemia of brain
pyramidal cells of hippocampus
purkinje cells
Red infarct
dual supply organs from reperfusion and free radical damage
–lung, liver, intestine
pancreatic cancer risk
tobacco
obesity
gastric cancer risk
nitrates
tobacco
alcohol
liver cancer risk
Hep
cirrhosis
hemachromatosis
aflatoxin
CRC cancer risk
IBD
Obesity
charred food
renal cancer
smoking
obesity
HTN
bladder cancer
tobacco
rubber, aniline dyes
textile
Breast cancer
early menarch
late menopause
nulliparity
BRCA
Prostate
African american
age
neutrophil rolling
vessel: E/P-selectin
WBC: sialyl lewis
neutrophil binding
vascular: ICAM-1
WBC: LFA-1 (integrin)
WBC diapedesis
Vessel and WBC: PECAM-1
Migration
C5a
IL-8
LTB4
Kallikrein
mechanisms by which free radicals damage cells
membrane peroxidation
protein modification
DNA breaks
Examples of free radical injury
retinopathy of prematurity
bronchopulmonary dysplasia (neonates given PPV and O2)
carbon tetrachloride=liver necrosis
Acetaminophen overdose (fulminant hepatitis)
Iron overload
Reperfusion after anoxia and thrombolytic therapy
Three phases of wound healing
inflammatory (neutrophils)
Proliferative (2-3 days, macrophages, keratinocytes, myofibroblasts)
Remodeling (1 week, fibroblasts)
Proliferative wound healing
Deposition of granulation tissue(macro) and collagen (fibroblasts)
epithelial cell proliferation (keratinocyte)
contraction of wound (myofibroblast)
angiogenesis (endothelial cells)
Dissolution of clot
Remodeling wound healing
Type III collagen replaced by type I
Th1 cells
secrete gamma IFN, activating macrophages
Macrophages secrete TNF-alpha
Maintenance of granuloma
Be wary of giving TNF-alpha inhibitors to
TB pts
Causes of exudate
lymphatic obstruction or inflammation
Decreased ESR:
Problems with RBCs usually…
sickle cell
polycythemia
CHF (known)
Increased ESR
cancer, pregnancy, SLE
How does iron cause cell death
peroxidation of membrane lipids
Acute iron poisoning sx:
gastric bleed
Chronic iron poisoning sx:
metabolic acidosis and GI obstruction
Amyloid light chain dz
plasma cell disorder or multiplemyeloma
Amyloid A dz seen in:
RA, IBD, spondyloarthropathy, chronic infection. Multisystem disorder
Dialysis related amyloidosis
Fibrils of B2 microglobulin in ESRD pts causing deposition.
–Carpal tunnel and joint problems
Heritable amyloid disease
Transthyretin gene mutation
Age related amyloidosis
Deposition of normal tranthyretin causes slowly progressive amyloidosis
Organ specific amyloidosis
Alzheimer’s disease
How do cancer cells become metastatic?
Release of hydrolases and collagenases to break through basement membrane
Anaplasia vs neoplasia
anaplasia: no differentiation, primitive looking with no resemblance to original tissue
Neoplasia: clonal proliferation that is excessive
Desmoplasia
Fibrous tissue formation in response to neoplasm
Which is more prognostic, grade or stage?
Stage usually
Carinoma vs sarcoma
sarcoma means mesenchymal origin
which cytokines are responsible for cachexia?
TNF-alpha
IFN-y
IL-6
Down’s associated with
ALL, AML
xeroderma pigmentosum, albinosum associated w
squamous cell carcinoma
also melanoma and basal cell
gastric adenocarinoma assoc’d w
atrophic gastritis
pernicious anemia
tuberous sclerosis associated with
giant cell astrocytoma
renal angiomyolipoma
cardiac rhabdomyoma
Plummer vinson syndrome assoc’d with
squamous cell carcinoma of esophagus
barrett’s esophagus
esophageal adenocarcinoma
ulcerative colitis
colonic adenocarc
paget’s disease of bone
secondary osteosarcoma and fibrosarcoma
Immunodeficiency states
malignant lymphomas
AIDS+other autoimmune disorders
lymphomas
Acanthosis nigracans
visceral malignancy
radiation exposure
leukemia, sarcoma, papillary thyroid cancer and breast cancer
abl gene
Tyrosine kinase–>CML
oncogene
c-myc
burkitt’s–>transcription factor
oncogene
bcl-2
follicular and other lymphomas
oncogene
HER2/neu
breast, ovarian, gastric carcinomas–>tyrosine kinase
oncogene
Ras
colon carcinoma–>GTPase
oncogene
L-myc
Lung tumor–>transcription factor
oncogene
N-myc
neuroblastoma–>transcription factor
oncogene
ret
MEN2A and MEN2B–>tyrosine kinase
oncogene
c-kit
gastrointestinal stromal tumor–>cytokine receptor
oncogene
Rb
retinoblastoma osteosarcoma
inhibits E2F; G1-S
tumor suppressor
p53
Li-Fraumeni etc.
transcribes p21; G1-S
tumor suppressor
BRCA1/2
Breast and ovarian
DNA repair protein
tumor suppressor
p16
melanoma
tumor suppressor
BRAF
melanoma–>B-raf protein
tumor suppressor
WT1
Wilm’s tumor
tumor suppressor
NF1
Neurofibromatosis
RAS GTPase activating protein
tumor suppressor
NF2
Neurofibromatosis Merlin protein (schwannomin)
tumor suppressor
DPC4
Pancreatic cancer
tumor suppressor
DCC
Colon cancer
tumor suppressor
Li Fraumeni
Inherited AUTOsomal dominant loss of p53
- -inherit only one allele, 2nd hit hypothesis
- -malignancies under age 45
PSA elevated in
BPH and prostatitis
Prostatic acid phosphatase
Dx for prostate cancer
CEA
pancreatic and CRC cancer
Also, gastric, breast, and medullary thyroid
alpha fetoprotein
HCC
nonseminomatous germ cell tumors
beta hCG
hydatidiform moles and choriocarcinomas
CA-125
ovarian cancer
S-100
melanoma, schwannomas
alkaline phosphatases
Bone metastases
Liver cancer
Paget’s disease of bone
Bombesin
Neuroblastoma
lung/gastric
TRAP
hairy cell leukemia
CA-19-9
pancreatic adenocarcinoma
Chlonorchis sinensis
Cholangiocarcinoma (liver fluke)
HHV-8
kaposi’s sarcoma
HPV
upper respiratory SCC
HTLV-1
Adult T cell leukemia
EBV
burkitt’s
hodgkin’s
nasopharyngeal carcinoma
CNS lymphoma
CCl4 causes
centrilobular necrosis and fatty liver
arsenic
squamous cell carcinoma
angiosarcoma
naphthalene
transitional cell carcinoma of bladdder
alkylating agents
leukemia
Vinyl chloride
angiosarcoma of liver
Nitrosoamines (smoked food)
gastric cancer
cigarette smoke
squamous cell (larynx) squamous/small cell (lung) renal cell carcinoma transitional cell carcinoma pancreatic adenocarcinoma
ACTH peptide
Small cell lung cancer
ADH
small cell carcinoma (intracranial)
PTHrP
squamous cell cancer
RCC
Vitamin D
Hodgkins lympoma
other lymphomas
Erythropoietin
Renal cell
Hemangioblastoma
HCC
Pheo
“Ride Hard Pedal Hard (w/ lance)”
Lambert Eaton
Small cell lung cancer
Psamomma bodies
Papillary thyroid
Serous (ovary)
Meningioma
mesothelioma
Highest incidence cancers in men
Prostate
Lung
Colon/rectum
Highest incidence cancers in women
Breast
Lung
Colon/rectum
Highest mortality cancer men
lung
prostate
Highest mortality cancer women
lung
breast
Which cancers metastasize to brain?
Lung>breast>GU>osteosarcoma>melanoma>GI
–>usually at gray/white matter junction
which cancers metastasize to liver?
COLON
stomach, pancreas
Which cancers metastasize to bone?
Prostate, breast>lung>thyroid/testes
Lung=lytic bone lesions
prostate=blastic bone lesions
breast-lytic and blastic bone lesions
What is lipofuscin?
intracellular, yellow brown pigment resulting from free radical injury and lipid peroxidation.
Seen in the heart/liver of aging/cachectic patients. Caused by “wear and tear”
What does hemosiderin look like?
yellow brown pigment
Superficial venous thromboses (thrombophelbitis) is an indication of
Visceral cancer
–Cancers can produce a thromboplastin like substance
N-myc
oncogene seen in neuroblastoma
Cyclin D overexpression
breast, lung, esophageal cancers and lymphomas
WT-1
tumor suppressor=Wilm’s tumor
Kras
proto oncogene