Exam 1 Flashcards
Increase in Cell size and organ size is also known as
Hypertrophy
*inc. cell proteins
Examples:
1. Left ventricular (inc. systemic vascular resistance; hypertension)
- aortic stenosis (congenital bicuspid aortic valve or atherosclerosis)
Increase in Cell number
Hyperplasia
Examples:
- benign prostatic hyperplasia
- endometrial hyperplasia (estrogen)
- -thickened endometrial stripe - Secondary hyperparathyroidism due to low calcium and Vitamin D
Decrease in size or cell number as a result of catabolism of organelles and reduced cytosol volume
*autophagy
Atrophy
Examples:
- disuse atrophy in an injured limb
- atrophic brain in a patient w/ carotid stenosis and decreased brain perfusion; loss of innervation
Change from one cell type to another
Metaplasia
Examples:
1. Barrett esophagus
(change in distal 1/3 from squamous to intestinal; chronic gastric reflux)
- sqaumous metaplasia of proximal bronchi in smoker (ciliated, pseudostratified to squamous)
- -may be precursor to squamous cell carcinoma
_______ is an ultimate determinant of cell injury and death as is consistent with fundamental osteopathic prinicpals
Hypoxia
hypoperfusion — hypoxia – ATP depletion — no energy for essential cell. functions
Causes of reversible cell injury
reduced ox phos and decreased ATP
*see cellular swelling and influx of water on histology
Causes of irreversible cell injury
increased cytosolic Calcium
- activates enzymes
(phospholipase, protease, endonuclease, caspases (apoptosis))
- increases mitochondrial permeability
Calcium enters the cytosol and acts as a cofactor, activating enzymes.
Cytochrome C enters the cytosol activating what enzymes?
Caspases
*apoptosis
What are the features of Coagulation necrosis?
- -preserved architecture
- -eosinophilic (histological stains)
ex: solid organ infarct (heart, organ, kidney, lung can appear hemorrhagic)
What are the 4 types of cellular adaptation?
Hypertrophy, Hyperplasia, Atrophy, Metaplasia
Reversible adaptations
Change in:
- size (hypertrophy)
- number (hyperplasia)
- phenotype (metaplasia)
- metabolic activity (metaplasia, hypertrophy)
- Function (all; lack of fxn)
Examples of Physiologic Hypertrophy (normal)
- inc. functional demand
- -weight training
- -inc. muscle mass - hormones
- -pregnant/gravid uterus - growth factors
- -normal growth
Examples of Physiologic Hyperplasia
- Hormones of GF’s
- Compensatory inc. after damage
- chronic irritation
ex: lactating breast
- endometrium-menstrual phase
Hyperplasia can be induced by chronic irritation. What are examples of this?
- Itchy skin
- -thickened kertain layer (squamous)
* *lichen simplex chronicus (pruigo nodularis) - bronchial mucous gland
- -smoking, asthma, COPD
Hyperplasia may also be induced by inappropriate or excessive actions of
a. hormones
b. growth factors
c. viruses
d. all of the above
answer: all of the above
* Abs and chemical imbalance
This hyperplastic disease is a result of increased androgen stimulation that leads to increased sensitivity to DHT
Benign prostatic hyperplasia
HPV (DNA virus)
This hyperplastic disease is caused by HPV and results in “lesions” on the skin
Verruca wart
*closely associated w/ dysplasia
This is hyperplasia that results from over-stimulated antibodies against thyroid hormone receptors
Graves disease (hyperthyroidism)
What are examples of hyperplasia that are due to physiologic chemical imbalance?
- Iodine deficiency
–goiter
(hyperplasia and hypertrophy) - Compensatory parathyroid gland hyperplasia and Secondary hyperparathyroidism (from renal failure)
- –Hypocalcemia, hyperphosphatemia
- -due to lack of Vit. D
Physiologic atrophy includes
a. involution of a structure
b. formation of a ligament from embryonic/fetal structure
c. postpartum uterus
d. carotid stenosis
Answer: A-C
- involution
- pregnant uterus returning to normal size
- lactating breast no longer producing milk
Atrophy becomes pathologic when which of the following occurs?
a. Loss of innervation
b. Diminished blood supply
c. Inadequate nutrition
d. Loss of endocrine stimulation
e. Occlusion of secretory ducts
f. Pressure
Answer: All of the above
A. Loss of innervation
—Amyotrophic lateral sclerosis (SK muscle; motor neuron loss)
E. Occlusion
—cystic fibrosis
F. Pressure
–ischemia
*no energy or energy producing substrates (aa’s, TG, CHO or electron acceptors)
A form of atrophy due to calorie malnutrition.
Marasmus
- dec. somatic protein
- extreme muscle wasting
A form of atrophy due to protein malnutrition
Kwashiorkor
–loss of albumin = loss of oncotic pressure
Symptoms: puffy, bloated, pot-bellied
True/False: Cerebral Atrophy can be a result of decreased blood flow from advanced age or from atherosclerotic disease in carotid arteries
True
- also a cause of stroke
- brain (slide 27 cell tissue)
Which of the following are cellular mechanisms that can lead to atrophy?
a. cell shrinkage from catabolism of organelles and reduced cytosol volume
b. undigested lipids stored as residual bodies
c. decreased protein synthesis
d. increased protein degradation
Answer: all
A. autophagy
B. Brown atrophy (lipofuscin)
–insufficient peroxidation – residual bodies
C. muscle wasting in cancer or TNF cytokines
D. ubuiquitin-proteosome pathway
_______ is a reversible change from one cell type to another. It occurs in differentiated cell types (epithelial, mesenchymal) and can be induced by altered differentiation pathways of proximal stem cells
Metaplasia
–adaptive response to changes in cellular env.
–LOF, inc. propensity for malignant transformation
Barret esophagus is a pathologic example of
Metaplasia (glandular)
*change in distal 1/3 of esophagus from squamous to intestinal type (columnar w/ goblet)
–inc risk for dysplasia
*chronic gastric reflux (heartburn)
What happens in squamous metaplasia of the proximal bronchi in a smoker?
The normal columnar respiratory mucosa changes to squamous epithelium
- smoking, chronic bronchitis, squamous carcinoma
- slide 30
______ is disorganized with abnormal maturation
Dysplasia
True/False: Cell injury can be due to ______:
- Oxygen deprivation
- –hypoxia - Physical agents
- Chemical agents
- –Free radical injury (reactive oxygen species) - Infectious agents
- Immunologic reactions
- Reactions to self and foreign (viral) antigens
- Genetic derangements
- Nutritional imbalances
True
What tissue are most susceptible to hypoxia?
- Brain
- -watershed areas of cerebral vasculature - Heart
- -subendocardium - Kidney
- -PST, TAL - Liver
- -zone 3/central vein - Colon
- -splenic flexure
Reversible injury is characterized by reduced ox phos and decreased ATP.
It includes the following features:
- Cellular swelling
- Fatty changes
What are examples of each?
Cellular swelling:
- hydropic change
- vacuolar degeneration
- dec. Na/K+ pump
- dec. protein synthesis
Fatty changes
Irreversible cell injury occurs due to loss of the Ca2+ - ATPase pump as a result of lack of ATP. You also see increased cytosolic Calcium which activates the enzymes phospholipase, protease, endocnuclease and caspase.
What are the functions of these enzymes?
Phosphoipase: membrane damage
Protease: cytoskeleton damage
Endonucleases: damages nuclear chromatin
note: increased mitochondrial permeability and Cyt C release (activates caspases)
- nuclear pyknosis
- inner mit. membrane gradient lost
Cellular response to injry depens on the nature of the injury, and clinical consequences depend on the type and adaptability of the injured cell.
T/F: Reduction in ATP levels is fundamental to the process of cell injury and can lead to cell death
True
- ischemia: ATP depletion
- Hypoxia: dec. ATP production
Which of the following is an effect of ATP depletion?
a. Cellular swelling due to decreased activity of plasma membrane Na/K+ ATPase
b. Efflux of Ca2+
c. Increased protein synthesis
Answer: A
- Influx of Ca2+ = enzyme activation
- altered cell. metabolism (anaerobic glycolysis – lactic acid buildup)
- reduced proteins synthesis
Which of the following is an effect of mitochondrial damage?
a. formation of mitochondrial permeability transition pore
b. loss of membrane potential in inner mito. membrane
c. formation of ROS
d. release of intramembranous proteins
e. None of the above
Answer: All
B. dec. ox phos and dec. ATP
D. intramembranous proteins: Cyt c
–sequestered bewteen membranes, activates apopstosis via caspase
What are the effects of Increased cytosolic Calcium in cells?
inc. mitochondrial permeability and activates enzymes which can harm the cell
Which of the following are examples of free radical damage due to ROS?
a. chemical and radiation injury
b. ischemia-reperfusion injury
c. inc. mitochondria
Answer: A and B
A. cancer treatment; acetaminophen
B. myocardial infarction
Also: normal cellular aging and normal phagocytic killing of microbes (inc. NADPH oxidase in phagolysosomes – neutrophils and monocytes)
Free radicals may be generated by:
a. normal metabolic processes
b. activated leukocytes in inflammation
c. metabolism of chemicals and drugs
What are examples?
Answer: all of the above
C. CCL4 converted to free radical in the liver (necrosis/fatty change)
How does ionizing radiation produce free radicals?
splits H2O into OH and H+
How do transition metals produce free radicals?
Iron overload — hemochromatosis
- Hereditary form = genetic abnormality in Fe absorption
- –too much Fe absorbed in diet - HFE C282 Y most common
* too much Fe can produce OH
* liver cirrhosis and pancreatic dysfunction
(diabetes, liver failure, cardiomyopathy, bronze skin, joint pain)
Describe how acetaminophen can generate free radicals and induce cell injury
- Cyt P450 – free radical intermediate (NAPQ1)
- Glutathione dec. NAPA1
- –antioxidant - Toxic drug levels overwhelm the liver
- -reduce glutathione
- -inc. toxic intermediate
**worsened by EtOH (upregulated P450 and inc. NAPQ1)
How does ethanol produce a fatty liver?
Increases NADPH
DHAP – glycerol #-P – fatty liver
The following are mechanisms by which free radicals are removed from the body:
- antioxidants
- spontaneously
- cellular enzymes
Give examples of antioxidants
-Vit. A, C, E
-protein binding of free Fe and Copper
minimized ability to generate ROS
The following are mechanisms by which free radicals are removed from the body:
- antioxidants
- spontaneously
- cellular enzymes
Spontaneous methods can be unstable and wane. What are examples of cellular enzymes?
Catalase, Superoxide dismutase, glutathione peroxidase
Which of the following is a pathologic effect of free radicals?
a. lipid peroxidation of membranes
b. oxidative modification of proteins
c. DNA damage
All of the above
DNA damage: if severe, cannot be corrected
–apoptosis
There are 2 forms of cell death: Necrosis and Apoptosis
Necrosis has characteristic and noteworthy patterns in different tissues depending on the type of injury. It involves cellular changes which can be seen grossly and histologically. What are these changes?
-degeneration of intracellular proteins
-enzymatic digestion of the cell
(lysosomes, WBC’s – autolysis)
- **eosinophilia (H&E)
- nuclear changes
What are the classic morphologic patterns of necrosis?
- coagulative
- liquifactive
- caseous
- fat
- fibrinoid
Coagulative necrosis is necrosis that involves denaturation of enzymes and proteins as a result of
a. increased lactic acid
b. heavy metals
c. ionizing radiation
d. none of the above
NOTE: wedge shaped if involves dichotomous branching vessel
answer: all
–diminishes autolysis of cellular material
- better architectural preservation
- anucleate cells
- hypereosinophilic
Examples: Pulmonary infarct, Renal infarct and Myocardial infarction (thrombosis in stenotic artery; LAD)
_________ necrosis is characterized by:
- dead cells digested
- leukocytes involved
- pus-like appearance
- bacterial and fungal infections
- hypoxia of CNS
Liquefactive necrosis
- cerebral infarct - hypoxia of CNS
- brain is unique
________ necrosis is characterized by
- variant of coagulation necrosis
- “cheese-like,” friable white material
- granulamotous inflammation
Caseous necrosis
Ex: mycobacterium TB
*also form of inflammation
______ necrosis (a.k.a. enzymatic ____ necrosis) is characterized by:
- focal areas of fat destruction
- released fatty acids that combine w/ Ca2+
- commonly seen in setting of pancreatitis
- can also be seen in dystrophic calcification
Fat necrosis
*also due to trauma
(Ca2+ in breast; abdomen in blunt trauma)
*pancreatitis: lipase and phospholipase; dystrophic calcification
________ necrosis often involves blood vessels. It is typically caused by an immune reaction.
Examples include: immune vasculitis, Rheumatic fever, malignant hypertension, pre-eclampsia and graft rejection
Fibrinoid necrosis
*small muscular arteries, arterioles, venules, glomerular capillaries
Apoptosis involves the activation of intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.
It is also known as prorammed cell death.
WHat are common triggers for apoptosis?
- growth factor deprivation
- DNA damage
- protein misfolding
Which of the following are examples of normal apoptosis under physiologic conditions:
a. destruction of cells during embryogenesis
b. involution of hormone-dependent tissues upon withdrawal
c. cell loss in proliferating tissues
d. elimination of potentially harmful self-reactive lymphocytes
Answer: ALL
*also: short-lived cells of the immune response (neutrophils)
Apoptosis can be recognized histologically at the cellular level, but is characterized by a minimal host reaction (WON’T see inflammation).
What are the histologic features?
-cell shrinkage
-deeply eosinophilic cytoplasm
-chromatin condensation
(pyknotic nucleas, basophilia, karyorrhectic/fragmenting)
- cytoplasmic blebs or formation of apoptotic bodies
- results in phagocytosis
What are examples of apoptosis in pathology?
Infections: HBV, HCV
(acute hepatitis, cancers, autoimmune)
other bacterial and neurodegenerative diseases
Homeostasis depends on a balance b/t pro-apoptotic and anti-apoptotic proteins.
There are 2 pathways involved in apoptosis. Both converge with the release of what key enzymes? What are these 2 pathways?
***caspases
- mitochondrial pathway (intrinsic)
–Cyt C
(triggered by loss of survival signals, DNA damage, accumulation of misfolded proteins) - Extrinsic
- -FADD activates caspase
- -death receptors (Fas, TNF)
What are examples of intracellular accumulations/inclusions?
- lipids (cholesterol)
- proteins (Igs, ubiquinated, amyloid)
- glycogen
- exogenous/endogenous pigments (melanin)
Intracellular lipid accumulation is assciated with what diseases?
- liver steatosis (lipid accumulation)
- diseases of abnormal metabolism
- -diabetes - ethanol
- cholesterolosis of gallbladder
- Xanthelasma
_______ is unmistakable with Prussian blue staining, but on H&E can be misinterpreted as lipofuscin. Both occur commonly in the liver and are brown
Iron
Diseases:
- *hemochromatosis
- macrophage accumulation (bruising; heart failure)
________ is polymers of lipids and phospholipids in a protein complex. It occurs by peroxidation of membrane lipids. It can arise from normal cellular turnover or from free radical damage
Lipofuscin
- “wear and tear” pigment
- heart and liver
- no effect on cell. function
______ is derived from Hb and serves as the major storage form of iron (Fe2+). It is Iron stored w/ apoferritin protein to form ferritin micelles
Hemosiderin
- aggregates of ferritin
- synthesized and stored in macrophages, **bone marrow, liver hepatoctyes
NOTE: serum ferritin: reflects iron storage
*heart failure, hemochromatosis
_________ calcification occurs in abnormal tissue in the setting of a normal range plasma Ca2+ level. It can occur in areas of necrosis, atherosclerosis, damaged heart valves, or sites of granulomatous inflammation
Dystrophic calcification
*plasma Ca2+ = NORMAL
_________ calcification occurs in normal tissues in the setting of HYPERcalcemia.
Metastatic calcification
ex: hyperparathyroidism
(parathyroid tumor; PTH protein)
ex: bone resorption
ex: Vit-D disorders
ex: Renal failure
(retain phosphate; secondary hyperparathyroidism)
________ is defined as “new growth” or a disorder of cell growth triggered by a series of acquired mutations affecting a single cell and its clonal progeny
Neoplasis
-tumor
The following are characteristics of what kind of tumor?
- indolent
- amenable to surgical resection w/ unlikely recurrence
- “oma” (typically)
Benign tumor
–mesenchymal consistent w/ phenotype or cell origin
–epithelial: vary in nomenclature
- A benign tumor w/ fingerlike projections coming from an epithelial surface
- a benign tumor w/ a visible projection above a mucosal surface
- a benign tumor w/ various clinical implications based on context. However, it most often refers to a tumor of gland forming cells
- A benign tumor of adipose tissue (mesenchynal tissue)
- Papilloma
- Polyp
- -some malignant tumors - Adenoma
- Lipoma
______ are cancerous. They can invade and destroy adjacent structures, spread to distant sites (metastasis), and cause death
Malignant tumors
Malignant tumors:
- Tumors of mesenchymal origin are called ________
- Tumors of epithelial origin are called ______
- Leukemias
- Lymphomas
- Sarcoma
- -osteosarcoma, leiomyosarcoma - Carcinoma
- -tissue type, organ involved, cell pattern
*not all malignant tumors have a benign counterpart
These tumors form from divergent differentiation of a single clone or as a germ cell teratoma (all 3 germ layers)
Mixed tumors
Single clone: benign mixed tumor (pleomorphic adenoma of salivary gland; parotid)
Teratoma: (cystic teratoma)
______ describes disorganized benign masses of cells that are in the appropriate anatomic location
Hamartoma
______ describes heterotopic rests of cells that are NOT in the appropriate anatomical location
e.g. pancreas tissue in other areas of the GI tract
Choristoma
Benign tumors can be differentiated from malignant tumors via histologic and microscopic assessment. What are common features of benign tumors?
- well differentiated
- resemble normal cell type morphology and function
e.g. lipoma (looks/feels like fat)
Benign tumors can be differentiated from malignant tumors via histologic and microscopic assessment. What are common features of malignant tumors?
- graded based on differentation
- associated w/ necrosis
- anaplasia (undifferentiated form)
NOTE: can be well differentiated (have to look to other features to define malignancy (needle biopsy))
What are the features of anaplasia (a characteristic of malignant tumors)?
- pleomorphism (assume diff. forms)
- abnormal nuclear morphology
- abnormal mitoses
- loss of polarity
ex: rhabdomyosarcoma
________ is disordered growth (typically epithelium in adults; organs in peds). It is most commonly seen in surface epithelium of skin and mucosa
Dysplasia
What are the features of dysplasia (disordered growth)?
- nuclear pleomorphism
- hyperchromasia (darkly stained nuclei)
- loss of polarity
- High N-C ratio
- abundant/inappropriately located mitotic figures
ex: carcinoma in situ (severe dysplasia)
ex2: hematopoietic cells can show dysplastic features (e.g. myelodysplasia)
How is dysplasia graded?
mild, moderate, severe
Severe: carcinoma in situ
Colonic adenocarcinoma is an example of what kind of tumor?
Malignant tumor
- glands (abnormal)
- irregular size/shape
- hyperchromatic nuclei
True/False: Dysplasia may be a precusor to malignancy, however, does not invariably progress to cancer
True
- standardized grading for some tissues
- once tumor cells breach basement membrane — invasice malignancy
_______ tumors tend to be localized, grow in a cohesive pattern, and lack the ability to infiltrate, invade and metastasize. They can expand, however, and compromise function. On the other hand, ______ tumors can infiltrate, invade and destroy tissue and have the capacity to metastasize.
- Benign tumors
- -capsule – slow progressive growth - Malignant tumors
Malignancy is determines based on the presence of what?
- metastasis
- invasion
Metastasis is defined as spread to sites that are physically discontinuous with the primary tumor.
It is the major determinate of cancer staging and prognosis (TNM system).
What determines the sites to which a cancer may metastasize?
- anatomic and tumor specific features
- vascular and lymph distribution
- tissue specific homing
What are the pathways of metastatic spread?
- hematogenous
- direct seeding of body cavities or surfaces
- lymphatic
Metastasis via lymphatic spread is commonly seen with carcinomas (e.g. breast) and some sarcomas.
It is the major component of cancer staging. Describe spread via lymph.
-Sentinel node: first node in region to receive lymph flow from tumor
(breast – axilla)
-tumor cells in subcapsular sinus part of lymph node
Metastasis via hematogenous (bloodstream) spread can occur in both sarcomas and carcinomas. Metastasis by this route is dependent on the anatomic vasculature.
Where does it spread?
–Bones
- paravertebral plexus (batson plexus)
- -prostate - axial skeleton
- -ribs and vertebrae
- -breast, prostate, lung
ex: colon – venous drainage to liver
Most common cancer deaths in men and women
women:
- lung
- breast
- colon and rectum
Males:
- lung
- breast
- colon and rectum
Most common cancer deaths in men and women
women:
- lung
- breast
- colon and rectum
*reduced hormone replacement therapy
Males:
- lung
- prostate
- colon and rectum
*use Prostate
antigen blood testing
*liver, thyroid, and melanoma on the rise
What are the most dominant risk fasctors for cancer?
Environment
*genetic susceptibilitiy is related to env. influence
Examples of Geographic variation
- China
- Japan
- Southeast Asia
- Sub-saharan Africa
- China
- -nasopharyngeal carcinoma
- -EBV
- -esphageal squamous carcinoma - Japan
- gastric adenocarcinoma
- -smoked food (nitrosamines) - Southeast Asia
- -hepatocell. carcinoma (HBV) - Africa
- -Burkitt lymphoma (EBV)
- -Kaposi (HHV-8 w/ HIV)
Environmental factors that influence cancer development
- infectious agents
- smoking
- -up to 90% lung cancer deaths - alcohol
- -oropharynx, esophagus, larynx, liver
- -synergism w/ cigarettes - diet
- obesity
- higher death rates
- inc. breast and endometrial
- inc. peripheral aromatase conversion of androgens to estrogens - reproductive history
- environmental carcinogens
- -UV radiation, occupational hazards
**asbestos: lung, mesothelioma
True/False: Most cancers occur late in life. Longevity allows for the accumulation of somatic mutations
True
Acquired pre-disposing conditions to cancer
- chronic inflammation
- -inc. stem cells
- -genotoxiv reactive O2 species
- -metaplastic changes
- clonal lymphocyte population (in response to insult) - Precursor lesions
- Immunodeficiency states
- -defecient T cell immunity
- -viral induced neoplasia (HIV)
Precursor lesions may arise in the background of chronic inlammation (e.g. Barret’s esophagus). However, cancer progression is not inevitable. If precursor lesions are amenable to treatment, cancer risk can be reduced.
What are recognizable and treatable precursor lesions?
- Barrett esophagus (esophageal carcinoma)
- Endometrial hyperplasia
(endometrial adenocarcinoma) - Leukoplakia
(mucosal surfaces; squamous carcinoma) - High grade cervical dysplasia
- -cervical cancer
- -seen on Pap - Adenomatous GI polyps
- -benign neoplasm to adenocarcinoma
List the possible ways to prevent development of cancer
- lifestyle changes
- immunizations
- antioxidants
(N-acetyl cystein; Vit. C, E) - Cervical Pap smears, HPV testing
- Colonoscopy
- -remove dysplastic polyps - Screening
- -low dose CT scanning (lung)
- -mammography - Digital rectal exam
- Treat pre-existing conditions
Which of the following statements about cancer is true?
a. cancer is the result of non-lethal genetic damage
b. tumors are clonal
c. regulatory genes are involved in cancer mutations
d. cancer can occur secondary to LOF mutations in genes that normally maintain genomic stability or regulate the cell cycle
Answer: all of the above
*also carcinogenesis occurs in step-wise fashion
Hallmarks of cancer
- avoid immune destruction
- evading growth suppression
- enabling replicative immortality
- tumor-promoting inflammation
- invasion and metastasis
- genomic instability
- induce angiogenesis
- resist cell death
- dregulate cellular energetics
- sustain proliferative signals
Cancer cells acquire the capacity for autonomous growth. Proto-oncogenes play a role in this acquisition:
proto-oncogene – (mutation) oncogene – oncoprotein
What do oncogenes encode?
growth factor receptors
(receptor tyrosine kinases)
- mutated form allow persistent tyrosine kinase activity
- pro-growth oncoproteins allow self-sufficient growth
EGFR is encoded by ERBB1.
Point mutations in ERBB1 are found in many cancers. These mutations result in constitutive ______ activity.
-constitutive tyrosine kinase activity
What are drugs that can be used to block persistent tyrosine kinase activity caused by ERBB1 mutations?
- Colon adenocarcinoma
- Cetuximab and Panitumumab - Lung adenocarcinoma
- -EGFR inhibitors in NSCLC w/ EGFR mutations
a. Erlotinib (Tarceva)
b. Afatinib (Gilotrif)
c. Gefitinib (Iressa)
True/False: HER2/neu is encoded by ERBB2. The gene is amplified leading to overexpression of HER2 receptor. Overexpression leads to constitutive tyrosine kinase activity.
True
- testing = standard of care
- Trastuzumab (Herceptin)
RAS is a G-protein (GTP binding protein). Point mutations in the RAS family is the most common abnormality in proto-oncogenes.
Mutations cause what effects?
–reduce GTPase activity of RAS leaving it in an active state
–involved in 15-20% of human tumors
- -90% pancreatic adenocarcinoma
- -40-50% colon
–testing for KRAS and NRAS mutations in colon cancer (BRAF)
(EGFR inhibitors will not be effective)
BCR-ABL is an oncogene created by a translocation. It results in chronic myelogenous leukemia.
How is it activated?
- ABL = non-receptor tyrosine kinase
- translocation of ABL = constiutive activation of kinase activity
- Philadelphia chromosome
(9: 22 BCR-ABL) - exposed concept of oncogene addiction
- one of first diseases diagnosed and classified on a molecular basis
Tx: tyrosine kinase inhibitor (imatinib)
Symptoms of chronic myelogenous leukemia (BCR-ABL)
older patient
- high WBC count
- left shifted peripheral blood population
- neurtrophils and basophils
Alterations in transcription factors such as MYC, a master transcriptional regulator can result in the activation of what?
–activation of cell growth genes (cell cycle, protein synthesis, reprogramming and upregulation)
- NMYC - neuroblastoma (pediatric malignancy of the adrenal gland)
- MYC - Brukitt lymphoma
Tumor suppressor genes protect against unregulated cell growth.
Which of the following is correct about tumor suppressors?
a. inhibiting mitogenic signalling pathways
b. inhibiting cell cycle progression
c. inhibiting invasion and metastasis
d. inhibiting pro-growth metabolism and angiogenesis
e. DNA repair
f. genomic instability
Answer: all of the above
Tumor suppressor genes protect against unregulated cell growth.
Which of the following is correct about tumor suppressors?
a. inhibiting mitogenic signalling pathways
b. inhibiting cell cycle progression
c. inhibiting invasion and metastasis
d. inhibiting pro-growth metabolism and angiogenesis
e. DNA repair
f. genomic instability
Answer: all of the above
**RB, p53
- RB - regulates G1 to S checkpoint
- -hyperphosphorylated: active
- -hypophosphorylated: inactive
Which of the following are protein products of tumor suppressor genes?
a. tf’s
b. cell cycle inhibitors
c. signal transduction molecules
d. WNT
Answer: A-C
*also, cell surface receptors and regulators of cell. responses to DNA damage
RB is a tumor suppressor that is inactive when hypophosphorylated, and active when hyperphosphorylated.
The anti-proliferative effect of RB is removed by:
a. LOF function mutation
b. gene amplification of CDK 4 and cyclin D genes
c. loss of cyclin dependent kinase inhibitors (P16/INK4a)
d. viral oncoproteins that bind and inhibit RB (E7 protein of HPV)
Answer: All of the above
This tumor suppressor gene is the most frequently mutated gene in cancer.
Most cancers have bi-allelic loss of function mutation in the TP53 gene.
p53
- Li Fraumeni
- -loss of p53
- -cancers of brain, sarcomas, leukemia, breast (under 50) - p53 protein monitors for DNA damage, mutations
- -cell cycle arrest
- -DNA repair
*irreparable damage = apoptosis
______ cells: Stem cells: bone marrow, skin, intestinal crypts
______ cells: G0 phase: liver, SM, endometrium
______ cells: cannot replicate, skeletal/cardiac muscle, neurons
- Labile cells
- Stable cells
- Permanent cells
Adenomatous polyposis (familial polyposis syndrome) is a clinical example of a mutation in the APC tumor suppressor gene.
What are the features?
- part of WNT
- prevents nuclear transcription (via degradation of B-catenin)
Symptoms:
- numerous colon polyps @ young age
- high risk of colon, stomach cancer (100% penetrance)
- sporadic colon cancer
- somatic mutations
Cancer cells prefer to undergo aerobic glycolysis because it provides dividing cells with metabolic intermediates for the synthesis of new cellular components. This is known as
Warburg effect
Normal cells: gf’s stimulate uptake of glucose and glutamine
Mutation: de-regulate this process
PET: exploits glucose hunger
*cancer staging
Evasion of apoptosis is necessary for cancer cell development and survival. What mutations (in regulatory genes) allow this?
mutated BCL 2 (anti-apoptotic)
- prevents Cyt C egress from mitochondria
- survival and drug resistance
ex: follicular B cell lymphoma
There are 2 main mechanisms that cancer cells use to evade apoptosis: Intrinsic mechanism and Extrinsic mechanisms
Describe the intrinsic system
- loss of p53
- upregulate anti-apoptotic factors (BCL-2)
- loss of APAF 1
- upregulate apoptosis inhibitors
There are 2 main mechanisms that cancer cells use to evade apoptosis: Intrinsic mechanism and Extrinsic mechanisms
Describe the extrinsic system
- reduced CD 95 expression
- inactivation of death induced signalling complex
Follicular B cell lymphoma is a cancer caused by overexpression of the BCL-2 protein.
What are its features?
t14: 18
- prevents apoptosis of B lymphocytes
- Cyt C doesn’t enter cytosol
Tumors require O2 and nutrition to grow and to maintain viability of the primary tumor (and metastatic foci).
One of the ways by which they do this is via angiogenesis. How does this occur?
- capillary sprouts from pre-existing capillaries
- endothelial precursor cells
Influenced by:
- Hypoxia
- VEGF - Tumor suppressor and oncogenes
- -p53 – loss of antiangiogenic factors (thrombospondin-1
Drug that inhibits VEGF
Bevacizumab
Tx:
- non-small cell lung (adeno)
- metastatic colon
- renal cell
- Her 2 (-)
What are factors that can stimulate angiogenesis
- TNF (from macrophages)
- chemotactic factors (tumor cells and macrophages)
- enzymes (proteases
List the steps involved in invasion of the ECM by cancer cells
- Loosening of cell-cell contacts
- -inactivates E-cadherin - Degradation of ECM
- -proteolytic enzymes (by tumor cells and stromal cells; matrix metalloproteinases, cathepsins) - liberate growth, angiogenic and chemotactic factors
- Attachment to novel ECM components
- -fibronectin - Migration of tumor cells
- –cytokines that stimulate locomotion
True/False: Cancer cell migration involves intravasation (entry into the bloodstream) and extravasation (exit into tissue). During this process, they either evade or are destroyted by immune cells. Survivors form tumor emboli
True
The following are potential determinants of where cancer may metastasize?
- anatomic factors
- cellular, subcellular factors
Explain
- Anatomic factors
–1st capillary bed encountered
–venous/lymph drainage
(portal vein – liver; vena cava –lungs) - Cell/Subcell
- -ligands (target organs for specific adhesion molecule)
- -chemokine receptors
- -cell environment (unfavorable – spleen, SK muscle)
Tumor antigens are important as they alow the body’s immune system to recognize a problem and to induce elimination.
Which of the following correctly describes tumor antigens?
a. products of mutated genes
b. overexpressed or abnormally expressed cell proteins
c. produced by oncogenic viruses
d. altered cell surface glycolipids/glycoproteins
All of the above
b. overexpressed
- -tyorsinase; MART (melanoma)
c. HPV, EBV
Also:
-Cell type specific differentiation antigens (CD 20 in B cell lymphoma)
-Oncofetal antigens (tumor markers - CEA, AFP)
Anti-tumor activity is mediated predominantly by
Cell-mediated T cells
- MHC I
- CD 8 Cyt T cells
How do Tumors evade the immune system? \
a. induce apoptosis
b. immunoediting
c. reduced MHC molecules
d. activate immunoregulatory pathways
Answer: B, C, D
b. Immunoediting
- -select Ag-negative variants
c. dec. MHC
d. Immunoregulatory pathways
- -PD-1 (inhibit T cells)
- -downregulate immune
- -secrete immunosuppressive factors (TGF-B)
PD-1 inhibitors (checkpoint therapy) include
- Pembrolizumab (Keytruda)
–metastatic
(melonama, NSCLC)
–companion diagnostic test
- Nivolumab
- Optivo
- -metastatic (melanoma, NSCLC, Renal cell carcinoma)
An inherently unstable genome pre-disposes to mutations and subsequent neoplasia. Genetic alterations leading to increased mutation are commonly seen in cancers.
What are examples?
- Genetic alterations
- -BRCA mutations (genomic instability)
An inherently unstable genome pre-disposes to mutations and subsequent neoplasia.
Defects in DNA repair can increase the risk of neoplasia. What is an example?
Hereditary non-polyposis coli (Lynch syndrome)
–defect in DNA mismatch repair (MMR genes)
–autosomal dominant
–colon and endometrial cancer
Xeroderma pigmentosa is caused by genomic instability. What is its mechanism?
inability to repair pyrimidine dimers
- -UVB radiaiton
- -autosomal recessive
Epigenetic changes can affect gene expression by:
a. hypermethylation of tumor suppressor genes
b. histone modification
c. differentiation
d. self-renewal
e. drug sensitiviy/resistance
Answer: all of the above
*hypermethylation and histone modification - major
Cigarettes are one of the most important carcinogens known and are involves in some of the most frequently sen cancers in health care.
What is the most common carcinogen implicated in smoking illnesses and what are common illnesses?
Polycyclic hydrocarbons
- head and neck squamous carcinoma
- lung and pleura
Carcinogens can be direct acting or indirect acting.
- In ______-acting, conversion is not required. An example is alkylating agents.
- In _____-acting, conversion/metabolism is required. It is associated with p450 polymorphisms in patients. Examples include polycyclic hydrocarbons (benzo-a-pyrene, aromatic amines and azo dyes.
- Direct acting
- Indirect-acting
NOTE: indirect acting carcinogens are also considered initiators of carcinogenesis because they create a mutation
What are the steps in cancer formation?
- Initiation:
- irreversible mutation - Promotion:
- stimulates cells to enter cell cycle
- -tumors continue to replicate
–ex: promoters of hyperplasia (estrogen)
*promoters cannot induce cancer on their own
- Progression
- development of tumor heterogeneity
- –continued replication inc. chances of selecting for favorable growth attributes
There are different types of radiation carcinogenesis including:
- Ionizing radiation
- UV radiation
Describe ionizing radiation
*Initiator of carcinogenesis
- produces hydroxyl free radical
- DNA injury
- chromosome breakage
-occupational hazards (radiology, nuclear materials)
Example: leukemias, papillary thyroid carcinoma, lung, breast, liver
What are examples of initatiors of carcinogenesis?
- UVB radiation
- Nitrosamines
- asbestos
- polycyclic hydrocarbons
- HPV
There are different types of radiation carcinogenesis including:
- Ionizing radiation
- UV radiation
Describe UV radiation
- UVB forms pyrimidine dimers
- actinic damage leads to sun-related skin cancers
Examples: melanoma, squamous cell and basal cell carcinomas
Microbial carcinogens include:
- bacteria
- parasites
- viruses
What are common examples of bacterial carcinogens?
H. pylori
gastric adenocarcinoma and lymphoma
Microbial carcinogens include:
- bacteria
- parasites
- viruses
What are common examples of parasitic carcinogens?
- Schistosoma hematobium
- -squamous carcinoma of bladder - Clonorchis sinensis and Opisthorchis viverrini
- -bile duct carcinoma
Microbial carcinogens include:
- bacteria
- parasites
- viruses
What are common examples of viral carcinogens?
- DNA
- -EBV (Burkitt – translocation of MYC)
- -HPV
- -HBV - RNA
- -HTL-V-1
- -HCV
NOTE: HCV and HBV have multi-factorial pathogenesis – chronic inflammation, inc. cell death, inc. cell turnover)
Human papillomavirus (HPV) is involved in
- benign squamous papillomas (warts)
- Genital warts (condylomas)
- Cancers of the cervix, anogenital region, head and neck
Which strains are involved with each disease?
- HPV 1, 2, 4, 7
- HPV 6, 11
- HPV 16, 18
Vaccines:
- recombinant with 4, 9
- Most important: 16, 18, 31, 33
*L1 capsid in vaccine results in production of viral-like particles to which the body produces immune response
HPV is able to randomly integrate into the genome of the host without consistent association with a proto-oncogene.
These viral-integrated cells show genomic instability, leading to overexpression of ____ and ____ oncoproteins.
- overexpresion of E6 and E7 oncoproteins
- inactivate tumor suppressors (RB, p53)
- activate cyclins
- inhibit apoptosis
- reduce senescence
Epstein Barr virus (EBV) is a DNA herpes virus that infects B lymphocytes and some epithelial cells.
It causes what cancer?
- Burkitt lymphoma (endemic)
- translocation 8; 14 inc. MYC
- B cell lympoma in immunocompromised
- some Hodgkin, nasopharyngeal carcinoma
Although not common, physical injury or trauma may be associated with neoplasia.
The causes are most likely multi-factorial. What are examples of cancers developed from physical injury or trauma?
-squamous carcinoma
Causes:
- 3rd degree burn
- chronic inflammation:
- inc. stem cells
- genotoxic ROS
- bacterial products (osteomyelitis, draining sinuses)
The following include clinical effects of cancer:
- cachexia
- hemostasis abnormalities
- paraneoplastic syndromes
_______ is a generalized catabolic process that is characterized by anorexia, muscle wasting, loss of subcu adipose tissue, and fatigue.
Cachexia
Cancer cells release mediators:
- TNF-alpha
- PIF (ubiquitin proteasome pathway)
- LIF (inc. TNF-a)
The following include clinical effects of cancer:
- cachexia
- hemostasis abnormalities
- paraneoplastic syndromes
________ of chronic disease involves hepcidin. It can also be related to iron deficiency (bleeding, GI loss).
Anemia
- macrocytic
- -folate loss (for RBC synthesis) - hemolytic
- -cold agglutinins
The following include clinical effects of cancer:
- cachexia
- hemostasis abnormalities
- paraneoplastic syndromes
_______ occurs when cancer creates a thrombophilic state and becomes hypercoagulable. This increases the risk for DVT, blood clots, and disseminated intravascular coagulation (DIC).
hemostasis abnormalities
- deep vein thrombosis
- blood clots
- DIC
The following include clinical effects of cancer:
- cachexia
- hemostasis abnormalities
- paraneoplastic syndromes
________ are clinical signs that are distant from or otherwise not attributable to anatomic or functional location of the primary (metastatic tumor). It involves 10% of cancer patients and is a significant cause of morbidity.
Paraneoplastic syndromes
–mimics metastatic disease
(hypercalcemia)
–earliest manifestation of occult cancer
–ectopic hormone and hormonal effects are most common (endocrinopathies)
Paraneoplastic syndromes include SiADH and Cushing syndrome.
What are their features?
- SiADH
- -hyponatremia
- -small cell carcinoma of lung - Cushing
- -small cell carcinoma
- -increase corticotropin and POMC
- –too much cortisol
Hypercalcemia is a paraneoplastic syndrome associated w/ what cancers?
a. squamous carcinoma of the lung
b. breast carcinoma
c. renal carcinoma
d. small cell carcinoma
Answer: A, B, C
- Parathyroid hormone related protein
- other cytokine effects - IL-1, TNF, TGF-a
(endocrinopathy)
________ is a paraneoplastic syndrome characterized by patches of dark, thickened, hyperkeratotic skin. It is related to insulin-like growth factor (IGF-1) and is not specific to cancer.
Acanthosis nigricans
- gastric, lung, uterine carcinoma
- immunologic
- IGF-1
_______ is a paraneoplastic syndrome seen in lung carcinoma. It involves a periosteal reaction of the distal phalanx. Clubbing may also be seen.
Hypertrophic osteoarthropathy
- fingers
- not specific to cancers
Tumor markers, or biomarkers can contribute to detection of cancer, though are not used for definitive diagnosis.
When are they used?
- detection
- -PSA as screening test - determine effectiveness of therapy
- monitor recurrence
- estimate tumor burden (LDH in lymphoma)
- clinical stagning (LDH and hcG in testicular tumors)
* not specific to one disease process, but have limited diagnostic differential
Examples of tumor markers (biomarkers)
- AFP
- hepatocell. carcinoma
- yolk sac tumors of ovary and testes - CEA
- colorectal and pancreatic cancers
- -monitor for recurrence
- -lung and stomach too - PSA
- prostate cancer and hyperplasia
- -quantity is important
What are the criteria for cancer grade?
a. degree of differentiation
b. invasiveness
c. nuclear features
d. all of the above
All of the above
- differentiation
- -how well do cells resemble normal cells - invasiveness
- -does the tumor breach the BM or invade into vessels? - Nuclear
- -enlargement (high N to C)
- -chromatin clump
- -abnormal mitotic figures
- -hyperchromasia (dark nucleus)
Cancer staging uses the TNM system. Staging is the most important prognostic indicator.
What are the criteria for staging?
T: tumor (size)
N: nodal involvement
M: Metastasis
M > N > T
*PET scanning after initial diagnosis (can detect metastatic disease)
Laboratory diagnosis of cancer involves many techniques. What is the gold standard?
Tissue biopsy (needle)
- needle, open, surgical excision, fine needle aspiration
- all H&E stain
Ancillary techniques used to interrogate tissue samples include
a. special stains
b. immunohistochemistry to exploit varying specificitis of antigen expression
c. In situ hybridization and gene amplification (ex: HER2)
all of the above
Molecular diagnostics of cancer include
- diagnosis and prognosis
- detection of minimal residual disease
- hereditary predispositon to cancer
- RNA expression profiling
- DNA sequencing
- DNA copy number
Give examples of each (if applicable)
- FISH for t(14;18) in follicular B cell lymphoma
- BCR-ABL transcripts in CML
- BRCA 1/2
- Next Gen sequencing
