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Apoptosisaka
Programmed cell death.
Apoptosis
characteristics
cell shrinkage, chromatincondensation, membrane blebbing,
andformation of apoptotic bodies, whichare then phagocytosed.
Apoptosiswhen
- embryogenesis, hormone -induction(menstruation), -immune cell–
mediated death,- injurious stimuli (e.g., radiation,
hypoxia),
-atrophy.
Enzymatic degradation of a cellresulting from exogenous injury.
Necrosis
Characterized by enzymatic digestionand protein denaturation, with release
ofintracellular components.
Necrosis
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Necrosisdifferent types and there locations
Morphologically occurs as-coagulative (heart, liver, kidney),
-liquefactive (brain),
-caseous (tuberculosis),-fat (pancreas),
-fibrinoid, or gangrenous (limbs, GItract).
Cell injuryreversible or irreversible
Cellular swelling?Reversible
Cell injuryreversible or irreversible
Nuclear chromatin clumping?Reversible
Cell injuryreversible or irreversible
Decreased ATP synthesis?Reversible
Cell injuryreversible or irreversibleRibosomal detachment?
Reversible
Cell injuryreversible or irreversible
Glycogen depletion?Reversible
Cell injuryreversible or irreversible
Plasma membrane damage?Irreversible
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Cell injuryreversible or irreversible
Lysosomal rupture?Irreversible
Cell injuryreversible or irreversibleCa2+ influx → oxidative
phosphorylation?
Irreversible
Cell injuryreversible or irreversible
Nuclear pyknosis, karyolysis,karyorrhexis?
Irreversible
Cell injuryreversible or irreversible
Mitochondrial permeability?irreversible
Inflammation5 features
Characterized by-rubor (redness),
-dolor (pain),-calor (heat),
-tumor (swelling)-functio lassa (loss of function).
cells in acute InflammationNeutrophil, eosinophil, and antibody
mediated
cells in chronic Inflammation Mononuclear cell mediated:
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Phases of Inflammation
Fluid exudationLeukocyte activation
Fibrosis AcuteChronic
Resolution
What happens in different phases ofInflammation?Fluid exudation
Increased vascular permeability,vasodilation, endothelial injury
What happens in different phases of
Inflammation?Leukocyte activation
Emigration (rolling, tight binding,diapedesis)
Chemotaxis (bacterial products,complement, chemokines)Phagocytosis and killing
What happens in different phases ofInflammation?
Fibrosis
Fibroblast emigration and proliferationDeposition of ECM
What happens in different phases ofInflammation?
Acute
Neutrophil, eosinophil, and antibodymediated
What happens in different phases ofInflammation?
Chronic
Mononuclear cell mediated:
Characterized by persistentdestruction and repair
Granuloma—nodular collections ofmacrophages and giant cells
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What happens in different phases ofInflammation?
Resolution 5 different outcomes
-Restoration of normal structure
-Granulation tissue—highlyvascularized, fibrotic
-Abscess—fibrosis surrounding pus
-Fistula—abnormal communication
-Scarring—collagen depositionresulting in altered structure and
function
Leukocyteextravasation
what mediatesRolling?
E-selectin on vascular endothelium
binding to Sialyl-LewisXon the leukocyte.
Leukocyteextravasationwhat mediatesTight binding?
ICAM-1 on vascular endotheliumbinding to LFA-1 on
the leukocyte.
Stages of Leukocyteextravasation
1. Rolling2. Tight binding3. Diapedesis4. Migration
Leukocyteextravasationwhat mediates
migration?
chemotactic signals (e.g., cytokines).
What is Diapedisis ––leukocyte travels between
endothelial cells and exits blood
vessel.
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Free radical injurywhat initiates it
Initiated viaradiation exposure,
metabolism of drugs (phase I), redoxreaction,
nitric oxide,transition metals,
leukocyte oxidative burst.
Free radical injurywhen is it a big problem
reperfusion after thrombolytic therapy.
Free radical injurywhat are the antioxidants
(vitamins E and A).
• Abnormal proliferation of cells withloss of size, shape, and
orientation ––dysplasia
• Normal cells with basal → apicaldifferentiation
Normal cells
• Cells have increased in number– hyperplasia
• Neoplastic cells have not invadedbasement membrane
• High nuclear/cytoplasmic ratio andclumped chromatin• Neoplastic cells encompass entire
thickness
• In situ carcinoma
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• Cells have invaded basementmembrane using collagenases and
hydrolases• Can metastasize if they reach a
blood or lymphatic vessel
Invasive carcinoma
-plasia definitionsHyperplasia
–– ↑ in number of cells (reversible).
-plasia definitions
Metaplasia
––1 adult cell type is replaced by
another (reversible). Often 2°
-plasia definitionsDysplasia–
–abnormal growth with loss of cellularorientation, shape, and size incomparison to normal tissue
maturation; commonly preneoplastic(reversible).
-plasia definitions Anaplasia
––abnormal cells lackingdifferentiation; like primitive cells of
same tissue, oftenequated with undifferentiated
malignant neoplasms.
-plasia definitionsNeoplasia
––a clonal proliferation of cells that isuncontrolled and excessive.
Tumor grade vs. stagedescribe
Grade = histo apperance, often basedon the mitoses per high pwer field
number
Stage = ammount of spread based onsite and size
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Tumor grade vs. stagewhich is usually more prognostic
Stage
TNM staging system:T = size of Tumor
N = Node involvementM = Metastases
The term ?????? implies epithelialorigin, whereas sarcoma denotes
???????origin. Both terms imply?????.
carcinoma
sarcoma
malignancy
The term carcinoma implies ???????origin, whereas sarcoma denotes??????origin. Both terms imply
?????.
epithelial
mesenchymal
malignancy
Tumor nomenclatureBenign tumor of
Mesenchyme
Blood cells = There isn't one
Blood vessels = Hemangioma
Smooth muscle = Leiomyoma
Skeletal muscle = Rhabdomyoma
Bone = Osteoma
Fat = Lipoma
Tumor nomenclatureBenign vs malignant tumor of
Epithelium
Adenoma, papilloma
Adenocarcinoma, papillary carcinoma
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Tumor nomenclatureBenign vs malignant tumor of
> 1 cell type
benign = mature teratoma
malignint = Immature teratoma
Tumor nomenclaturemalignant tumor of
Mesenchyme
Blood cells = Leukemia, lymphoma
Blood vessels = Angiosarcoma
Smooth muscle =Leiomyosarcoma
Skeletal muscle =Rhabdomyosarcoma
Bone = Osteosarcoma
Fat = Liposarcoma
What is the Neoplasm/s associatedwith Down syndrome?
ALL (we ALL fall Down), AML
What is the Neoplasm/s associatedwith Xeroderma pigmentosum,
albinism?
Melanoma and basal,squamous cell carcinomas
of skin
What is the Neoplasm/s associatedwith Chronic atrophic gastritis,
pernicious anemia,postsurgical gastric remnants?
Gastric adenocarcinoma
What is the Neoplasm/s associated
with Tuberous sclerosis?
Astrocytoma and cardiac
rhabdomyoma
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What is the Neoplasm/s associatedwith Actinic keratosis?
Squamous cell carcinomaof skin
What is the Neoplasm/s associatedwith Barrett’s esophagus?
Esophagealadenocarcinoma
What is the Neoplasm/s associated
with Plummer-Vinson syndrome?
Squamous cell carcinoma
of esophagus
What is the Neoplasm/s associatedwith Cirrhosis (alcoholic, hepatitis B or
C)?Hepatocellular carcinoma
What is the Neoplasm/s associatedwith Ulcerative colitis?
Colonic adenocarcinoma
What is the Neoplasm/s associatedwith Paget’s disease of bone?
2° osteosarcoma andfibrosarcoma
What is the Neoplasm/s associatedwith Immunodeficiency states?
Malignant lymphomas
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What is the Neoplasm/s associatedwith AIDS?
Aggressive malignantlymphomas (non-Hodgkin’s)
and Kaposi’s sarcoma
What is the Neoplasm/s associatedwith Autoimmune diseases?
Benign and malignantthymomas
What is the Neoplasm/s associated
with Acanthosis nigricans?
Visceral malignancy
(stomach, lung, breast,uterus)
What is the Neoplasm/s associatedwith Dysplastic nevus?
Malignant melanoma
Oncogene or Tumor suppressorand what is the associated tumor
abl
Oncogenes
CML
Oncogene or Tumor suppressorand what is the associated tumor
c-myc
Oncogenes
Burkitt’s lymphoma
Oncogene or Tumor suppressorand what is the associated tumor
bcl-2
Oncogenes
Follicular and undifferentiatedlymphomas (inhibits apoptosis)
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Oncogene or Tumor suppressorand what is the associated tumor
erb-B2
Oncogenes
Breast, ovarian, and gastriccarcinomas
Oncogene or Tumor suppressorand what is the associated tumor
ras
Oncogenes
Colon carcinoma
Oncogene or Tumor suppressorand what is the associated tumor
L-myc
Oncogenes
Lung tumor
Oncogene or Tumor suppressorand what is the associated tumor
N-myc
Oncogenes
Neuroblastoma
Oncogene or Tumor suppressorand what is the associated tumor
ret
Oncogenes
Multiple endocrine neoplasia (MEN)types II and III
Oncogene or Tumor suppressorand what is the associated tumor
Rb
Tumor suppressor
Retinoblastoma, osteosarcoma
Oncogene or Tumor suppressorand what is the associated tumor
BRCA1 and 2
Tumor suppressor
Breast and ovarian cancer
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Oncogene or Tumor suppressorand what is the associated tumor
p53
Tumor suppressor
Most human cancers, Li-Fraumenisyndrome
Oncogene or Tumor suppressorand what is the associated tumor
p16
Tumor suppressor
Melanoma
Oncogene or Tumor suppressorand what is the associated tumor
APC
Tumor suppressor
Colorectal cancer
Oncogene or Tumor suppressorand what is the associated tumor
WT1
Tumor suppressor
Wilms’ tumor
Oncogene or Tumor suppressorand what is the associated tumor
NF1
Tumor suppressor
Neurofibromatosis type 1
Oncogene or Tumor suppressorand what is the associated tumor
NF2
Tumor suppressor
Neurofibromatosis type 2
Oncogene or Tumor suppressorand what is the associated tumor
DPC
Tumor suppressor
Pancreatic cancer
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Oncogene or Tumor suppressorand what is the associated tumor
DCC
Tumor suppressor
Colon cancer
Tumor markers
PSA
Prostate-specific antigen. Prostaticcarcinoma.
Tumor markers
CEA
Very nonspecific but
colorectal and pancreaticcancers; also others
Tumor markers
α-fetoprotein
Hepatocellular carcinomas.
yolk sac tumor
Tumor markers
β-hCG
Hydatidiform moles,Choriocarcinomas,
Gestational trophoblastic tumors.
Tumor markers
CA-125Ovarian, malignant epithelial tumors.
Tumor markers
S-100
Melanoma, neural tumors,astrocytomas.
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Tumor markers
Alkaline phosphatase
-Metastases to bone,-obstructive biliary disease, -Paget’s
disease of bone.
Tumor markers
Bombesin
Neuroblastoma, lung and gastriccancer.
Tumor markers
TRAP
Hairy cell
leukemia––a B-cell neoplasm.
Tumor markers
CA-19-9Pancreatic adenocarcinoma.
what is TRAPTartrate-resistant acid phosphatase.
Hairy cellleukemia––a B-cell neoplasm.
Oncogenic virusesname the tumor associated with
HTLV-1
Adult T-cell leukemia
Oncogenic virusesname the tumor associated with
HBV, HCV
Hepatocellular carcinoma
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Oncogenic virusesname the tumor associated with
EBV
Burkitt’s lymphoma, nasopharyngealcarcinoma
Oncogenic virusesname the tumor associated with
HPV
Cervical carcinoma (16, 18),penile/analcarcinoma
Oncogenic virusesname the tumor associated with
HHV-8
Kaposi’s sarcoma, body cavity fluid B-
celllymphoma
Types of HPV that cause CIN 16, 18
Cancer caused by
AflatoxinsLiver (hepatocellular carcinoma)
Cancer caused by
Vinyl chlorideLiver (angiosarcoma)
Cancer caused by
CCl4
Liver (centrilobular necrosis, fattychange)
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Cancer caused by
NitrosaminesEsophagus, stomach
Cancer caused by
Cigarette smokeLarynx, lung, ...
Cancer caused by
Asbestos
Lung (mesothelioma and
bronchogenic carcinoma)
Cancer caused by
ArsenicSkin (squamous cell carcinoma)
Cancer caused by
Naphthalene (aniline) dyesBladder (transitional cell carcinoma)
Cancer caused by
Alkylating agentsBlood (leukemia)
Paraneoplastic effects of tumorsneoplasm and Mech
Cushing’s syndrome
Small cell lung carcinoma
ACTH or ACTH-like peptide
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Paraneoplastic effects of tumorsneoplasm and Mech
SIADH
Small cell lung carcinoma andintracranial neoplasms
ADH
Paraneoplastic effects of tumorsneoplasm and Mech
Hypercalcemia
Squamous cell lung carcinoma,renal cell carcinoma, breast
carcinoma, multiplemyeloma, and bone
metastasis (lysed bone)
PTH-related peptide, TGF-β, TNF-α,IL-1
Paraneoplastic effects of tumorsneoplasm and Mech
Polycythemia
Renal cell carcinoma,hemangioblastoma
Erythropoietin
Paraneoplastic effects of tumorsneoplasm and Mech
Lambert-Eaton syndrome
Thymoma, small cell lungcarcinoma
Antibodies against presynaptic Ca2+channels at neuromuscular junction
Paraneoplastic effects of tumorsneoplasm and Mech
Gout, urate nephropathy
Leukemias and lymphomas
Hyperuricemia due to excess nucleicacid
turnover (i.e., cytotoxic therapy)
1° tumors that metastasize to brain
Lots of Bad Stuff Kills Glia.
Lung,Breast,
Skin (melanoma),Kidney (renal cell carcinoma),
GI.
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approximately ??%of brain tumors are from metastases.
50
??????the most common sites ofmetastasis after the regional lymph
nodes.
liverand
Lungs
tumors that metastasize to the liver
mne: Cancer Sometimes PenetratesBenign Liver.
Colon > Stomach > Pancreas > Breast> Lung.
most common Liver cancer Metastasis
These 1° tumors metastasize to bone
P. TT. Barnum Loves Kids.
PROSTATE, Thyroid, Testes,BREAST, Lung, Kidney.
Features of 1° tumors thatmetastasize to bone
Lung = Lytic.Prostate = blastic.
Breast = Both lytic and blastic.
Most common Bone Tumors Mets from (esp Prostate or Breast)
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Cancer epidemiology
Most common cancers inMen
..deaths in men
Prostate (32%)Lung (16%)
Colon and rectum (12%)..
Lung (33%)Prostate (13%)
Cancer epidemiology
Most common cancers inwomen
..deaths in women
Breast (32%)Lung (13%)
Colon and rectum (13%)...
Lung (23%)Breast (18%)
1st and 2nd leading killers in the U.S.
heart disease
cancer
Changes in lung cancer deathsDeaths from lung cancer have
plateaued in males butcontinue to ↑ in females.
Retinoblastoma, osteosarcoma
GeneChromosome
andOncogene or Tumor suppressor
Rb
13q
Tumor suppressor
Breast and ovarian cancer (BRCA)
GeneChromosome
andOncogene or Tumor suppressor
BRCA1 and 2
17q, 13q
Tumor suppressor
Most human cancers, Li-Fraumenisyndrome
GeneChromosome
andOncogene or Tumor suppressor
p53
17p
Tumor suppressor
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Melanoma
GeneChromosome
andOncogene or Tumor suppressor
p16
9p
Tumor suppressor
Colorectal cancer
GeneChromosome
andOncogene or Tumor suppressor
APC
5q
Tumor suppressor
Wilms’ tumor
GeneChromosome
andOncogene or Tumor suppressor
WT1
11q
Tumor suppressor
Neurofibromatosis type 1
GeneChromosome
andOncogene or Tumor suppressor
NF1
17q
Tumor suppressorNeurofibromatosis type 2
GeneChromosome
andOncogene or Tumor suppressor
NF2
22q
Tumor suppressor
Pancreatic cancer
GeneChromosome
andOncogene or Tumor suppressor
DPC
18q
Tumor suppressor
Colon cancer
Gene
Chromosomeand
Oncogene or Tumor suppressor
DCC 18q Tumor suppressor
and
ras Oncogenes
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CML
GeneChromosome
andOncogene or Tumor suppressor
abl
9:22
Oncogenes
Burkitt’s lymphoma
GeneChromosome
andOncogene or Tumor suppressor
c-myc
8:14
Oncogenes
Follicular and undifferentiatedlymphomas
GeneChromosome
andOncogene or Tumor suppressor
bcl-2
14:18
Oncogenes
Breast, ovarian, and gastriccarcinomas
GeneChromosome
andOncogene or Tumor suppressor
erb-B2
Oncogenes
Colon carcinoma
GeneChromosome
and
Oncogene or Tumor suppressor
ras
OncogenesLung tumor
GeneChromosome
andOncogene or Tumor suppressor
L-myc
Oncogenes
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Neuroblastoma
GeneChromosome
andOncogene or Tumor suppressor
N-myc
Oncogenes
Multiple endocrine neoplasia (MEN)types II and III
GeneChromosome
andOncogene or Tumor suppressor
ret
Oncogenes
Gastrointestinal stromal tumor (GIST)
GeneChromosome
andOncogene or Tumor suppressor
c-kit
Oncogenes