Unit 2b Flashcards
(202 cards)
1
Q
Transudates are caused by…
A
increased hydrostatic pressure OR reduced oncotic (osmotic) pressure
vascular wall still intact
EX) heart failure, fluid overload, liver disease, venous obstruction
2
Q
Exudates are caused by…
A
increased vascular permeability (endothelial contraction or direct damage) and inflammation
EX) Inflammation, toxins, burns
3
Q
Transudate typically is made up of…
A
- low proteins, low specific gravity
- NO WBCs
- high fluid/serum glucose ratio
4
Q
Exudate typically is made up of…
A
- high protein content, high specific gravity
- low fluid/serum glucose ratio (eaten by inflammatory cells)
- lots of WBCs!
5
Q
Edema
A
fluid accumulation in interstitial TISSUE
6
Q
Effusion
A
fluid accumulation on body cavity (SPACE)
7
Q
Congestion (characteristics)
A
- impaired blood flow to tissue/organ
- impaired venous outflow (blood backs up into organ)
- pathologic, passive
- deoxygenated blood (pale or red/blue)
8
Q
Hyperemia
A
- increased blood flow to a tissue or organ
- caused by arteriolar dilation
- physiologic, active (exercise, etc. can cause this - need more nutrient rich blood to an area)
- Oxygenated blood (red)
9
Q
Left heart failure –> ?
A
Left heart failure →
fluid not moving out of LV
→ build up fluid in lungs (pulmonary edema, pleural effusions), low BP, low tissue perfusion
→ decreased renal blood flow → tries to fix that by holding onto fluid - retention of Na+ and H2O
→ increase blood volume → peripheral edema
→ fluid eventually builds up in right heart
10
Q
Right heart failure –> ?
A
Right heart failure →
fluid builds up in venous system
→ liver congestion
→ backup fluid into spleen (splenic congestion), gut (GI tract varices), and ascites (fluid collection in abdomen)
11
Q
Hemorrhage (def), and what causes it (3)
A
def: Blood outside of the vasculature due to vessel damage.
1) Impaired integrity of vessel walls (trauma, etc.)
2) Low level / function of platelets
3) Low level / function of coagulation factors
12
Q
Petechia
Purpura
Ecchymoses
Hematoma
A
Types of hemorrhage
Petechia = 1-2 mm (small, pinpoint hemorrhage)
Often due to problem with clotting/platelets
Purpura = > 3 mm Ecchymoses = 1-2 cm Hematoma = large blood collection within tissue
13
Q
Key elements of Virchow’s Triad that leads to thrombosis
A
1) Endothelial injury (hypercholesterolemia, inflammation)
2) Hypercoagulability (Inherited or acquired - cancer)
3) Abnormal Blood Flow (Stasis - bed rest, afib or Turbulence - atherosclerotic vessel narrowing)
14
Q
Thromboemboli - venous
source
organs affected
clinical outcome
A
source = *deep leg veins, arm veins
organs affected = lungs (pulmonary embolus)
clinical outcome - respiratory insufficiency, chest pain
15
Q
Deep vein thrombosis
A
largely due to stasis
Causes/Risks: immobility, recent surgery, estrogen, pregnancy or post-partum, previous/current cancer, coagulation abnormalities, limb trauma and/or ortho procedures, obesity
Block venous outflow
16
Q
Atheroemboli
source
organs affected
clinical outcome
A
source: *athersclerotic plaque of aorta, iliac, carotid arteries
organs affected: legs, brain, GI tract, kidney
clinical outcome: stroke, tissue necrosis in the leg, GI pain, GI bleeding, acute kidney injury
17
Q
Fat/Bone Marrow emboli
source
organs affected
clinical outcome
A
source: *longbone fractures –> vein damage
organs affected: lungs
clinical outcome: respiratory insufficiency 1-3 days post trauma, Altered mental status
18
Q
Amniotic fluid emboli
source
organs affected
clinical outcome
A
source: torn placental membranes, uterine vein rupture
organs affected: lungs, brain vasculature
clinical outcome: during labor or immediately postpartum onset of respiratory insufficiency, shock, seizures, DIC
**10% of maternal deaths
19
Q
Tumor emboli
source
organs affected
clinical outcome
A
source: Mucin-secreting adenocarcinomas, liver, kidney
organs affected: lungs
clinical outcome: espiratory insufficiency, chest pain
20
Q
Thromboemboli - arterial
source
organs affected
clinical outcome
A
source: Heart (vegetations or mural thrombi), aorta, carotid artery
organs affected: Legs (75%) and Brain (10%)
clinical outcome: Stroke, tissue necrosis in the leg
21
Q
Gas bubble emboli
source
organs affected
clinical outcome
A
source: Diving (nitrogen), IV, IA, or chest trauma (air)
organs affected: muscle, joints, lungs, heart
clinical outcome: Bends (skeletal and joint pain), chokes (lung edema and hemorrhage), respiratory insufficiency, myocardial ischemia
22
Q
Disseminated Intravascular Coagulation (DIC)
A
Thrombosis and hemorrhage occur simultaneously
Generalized activation of clotting (procoagulant release - tissue factor)
→ widespread THROMBOSIS (fibrin deposition)
→ consumption of platelets and clotting factors
→ deficiency in platelets and clotting factors → BLEEDING
23
Q
Signs/Symptoms of DIC
A
Respiratory insufficiency, MSC, Convulsions, Acute renal failure, Petechiae Purpura, GI or oral hemorrhage
Shock
Hemolytic anemia, thrombocytopenia, low fibrinogen, and elevated D-dimer and other fibrin degradation products
24
Q
Infarction
A
- tissue death (necrosis) caused by vessel occlusion
- Typically coagulative necrosis (liquefactive necrosis in the brain)
25
White infarction (4 characteristics)
Arterial insufficiency
Single blood supply
NO reperfusion
Dense tissue type (EX - heart, kidney, spleen)
26
Red infarction (4 characteristics)
Venous insufficiency
Dual blood supply
YES reperfusion
Loose tissue type (EX - lung, liver, intestine)
27
Shock
hypoperfusion of cells and tissue
Circulating blood volume or blood pressure is not adequate to perfuse body tissues → multiorgan dysfunction/damage
28
Cardiogenic Shock
myocardial pump failure
Myocardial damage, extrinsic compression, outflow obstruction
29
Hypovolemic shock
low blood volume
Severe dehydration (vomiting, diarrhea), hemorrhage, burns
30
BOTH cardiogenic shock and hypovolemic shock lead to...
Low cardiac output, low BP → vasoconstriction, increased HR, renal conservation of fluid
NOT sufficient → coolness and pallor of skin, tachycardia, low urine output
31
Septic Shock
microbial infection (bacteria, fungi) = Systemic Inflammatory Response Syndrome (SIRS)
Process: Immensely elevated inflammatory mediators → fever, DIC, ARDS widespread
1) Arterial vasodilation → hypotension, warm, flushed skin
2) Vascular leakage → hypotension, edema
3) Venous blood pooling → reduced cardiac output, increased HR
Often NOT responsive to IV fluids
32
Three types of tissues in the body and their homeostatic states
1. Continuously dividing: skin, gut epithelium, hematopoietic system, constant turnover, commonly gives rise to cancer because of high frequency of division—more likely to have an error.
2. Quiescent tissues/cells: normally little turn over, capacity for proliferation if needed
EX) hepatocytes in liver can “regrow” a liver with damage.
3.Non-dividing tissue/cells: Little to no capacity for proliferation
EX) CNS neurons are terminally differentiated
33
Hypertrophy
increase in cell size (no increase in cell #)
Physiologic or pathologic, may be reversible.
34
Physiologic example of hypertrophy
change in uterus during pregnancy--reversible
35
Pathologic example of hypertrophy
change in heart secondary to HTN—difficult to reverse, goal is to prevent it from worsening
36
Hyperplasia
increase in cell number
Physiologic or pathologic
37
Hyperplasia is associated with increased risk of ____
neoplasia
38
Physiologic example of hyperplasia
change in breast tissue during puberty and pregnancy
39
Pathologic example of hyperplasia
change in endometrium
40
Metaplasia
change from one benign, differentiated cell type to another, usually in response to injury
ALWAYS PATHOLOGIC
41
Metaplasia is associated with increased risk of _____
neoplasia
42
2 examples of metaplasia
Lining of bronchus is usually columnar epithelium with ciliated border, but changes to squamous metaplasia with smoking.
Esophagus is usually squamous, but with acid reflux changes to columnar metaplasia (Barrett esophagus)
43
Neoplasia
“new formation”, progressive unchecked increase in cell number, CLONAL process
Generally pathologic and irreversible
44
Benign neoplasia
non-invasive, non-metastatic
Cause injury largely by compression/interference in function of adjacent structures (like in the brain)
45
Pathology of benign neoplasia
necrosis uncommon, circumscribed/encapsulated
Microscopic: well differentiated, low rate cell turnover, cytologic uniformity (cells similar to each other), boundary maintained between tumor/adjacent tissue
46
Epithelial benign neoplasia (2)
adenoma
| papilloma
47
mesenchymal benign neoplasia (3)
osteoma
chondroma
fibroma
48
Benign neoplasia clinical correlates
Treated by excision/surgical resection alone
- May recur (especially if incompletely excised)
- Generally do NOT progress to malignancy
* ** Important exception: benign, BUT premalignant neoplasms
49
Malignant neoplasms
invasive, metastatic = “CANCER”
1. Tumor progression, acquisition of more and more genetic mutations allowing angiogenesis and metastasis
2. Cause injury by local tissue destruction and distant dissemination tissue destruction
50
Pathology of malignant neoplasms
necrosis common, invasive into adjacent tissue
Microscopic: variable differentiation, high rate cell turnover, cytologic pleomorphism, loss of boundary between tumor/adjacent tissue
51
Epithelial malignant neoplasms
Carcinoma (most common cancer)
i. Premalignant lesion, in-situ phase, invasive and metastatic, grade and stave predictive of behavior
Adenocarcinoma (carcinoma with formation of glandular structures)
52
Mesenchymal malignant neoplasms
Sarcoma
No pre-malignant lesion, in in-situ phase
- Invasive and metastatic
- Grade and stage predictive of behavior
53
Hematopoietic malignant neoplasms
Lymphoma (lymph node origin), leukemia (bone marrow origin)
- Some premalignant lesion (myelodysplasia), but usually no known site of origin
- No in-situ phase
- N/A - invasion, metastasis
- Grade is predictive of behavior (stage is N/A)
54
CNS malignant neoplasms
- No premalignant lesion or in-situ phase
- Invasive, BUT rarely metastatic outside of CNS
- Grade predictive of behavior (stage is N/A)
55
Pediatric neoplasms
very different from adults
- Arise in context of developing tissues/organs
- Origin in developmental precursors
- Tend to recapitulate developmental program of tissue of origin
- Short latency, and early metastasis
- Few mutations - lots of epigenetic dysregulation
- Relative chemosensitivity (at a cost)
56
Epidemiology of cancer
1 in 2 americans will get cancer and 1 in 5 will die
57
Non genetic etiology of cancer (6)
1. Age (accumulate more mutations as you get older)
2. Lifestyle/environment (tobacco and EtOH use)
3. Occupational hazards and chemical carcinogens (radium, asbestos)
4. Radiation (UV light)
5. Infection (viruses like HPV
6. Inflammation (inflammatory bowel disease, ulcerative colitis)
58
Genetic AD diseases that lead to cancer (4)
retinoblastoma-RB, Li-Fraumeni syndrome- p53, Familial adenomatous polyposis- APC, breast/ovarian tumor-BRCA1/2
59
Genetic AR diseases that lead to cancer (2)
XP, ataxia telangiectasia
60
Familial cancers (3)
breast, pancreatic, ovarian
61
Hallmarks of cancer (3)
1. Disruption of normal homeostatic mechanisms
2. Limitless replicative potential and angiogenesis
3. Ability to invade surrounding tissue and spread to distant sites
62
Altered cell-autonomous mechanisms
(activation of oncogenes, inactivation of tumor suppressors)
Ongoing genetic alterations + selection → clonal evolution
63
Altered cell-nonautonomous mechanisms
Altered microenvironment (surrounding tissue, stroma blood vessels, immune cells) and macroenvironment (circulating cells, factors)
64
Cancer cells express ___ and ___ to achieve limitless replicative potential and angiogenesis
Express telomerase - avoid normal replicative senescence
Express VEGF - promote angiogenesis
65
Dysplasia
“Disordered Growth”
1.Hallmark of early premalignant neoplasia in epithelia
66
Histologic features of dysplasia(3)
1. Loss of cytologic uniformity
2. Loss of normal histologic maturation
3. Loss of architectural orientation
*** Assigned histologic grade
67
Low grade dysplasia
more differentiation, greater resemblance to normal
68
High grade dysplasia
less differentiation, less resemblance to normal
69
Tumor grade predictability
Can be predictive of biologic behavior (tumor dependent), but overall less reliable than disease stage
70
TNM classification
T= tumor: range is from Tis (in situ dysplasia or intramucosal carcinoma) to T4 (tumor invades adjacent organs or visceral peritoneum).
N=regional lymph nodes: range is from NO (no regional lymph node metastasis) to N2 (metastasis in 4+ regional lymph nodes)
M= distant metastasis: MO (no distant mets) to M1 (distant mets or seeding of abdominal organs)
71
Invasion
infiltration of adjacent tissue by malignant cells
72
Metastasis
transfer of malignant cells from the primary site to a non-connected (secondary) site
73
Malignant tumors =
invasion + metastasis
74
3 mechanisms of metastasis
1. lymphatogenous
2. hematogenous
3. cavitary
75
Why is it favorable for tumor cells to undergo metastasis
Conditions get crowded and harsh at primary tumor site
- selective pressure to gain ability to “move out” or metastasize
76
4 steps of tumor progression (metastatic cascade)
1. Invasion
2. Intravasation
3. Extravasation
4. Colonization
77
4 major theories of metastasis
1. Clonal Evolution Model:
- Mutations accumulate in genetically unstable cancer cells
- Tumor becomes heterogenous → set of subclones develop ability to complete metastasis
- Rare cell acquires all necessary genetic alterations to complete steps
2. Metastasis is the result of multiple abnormalities that occur in many cells of a primary tumor - early in development of tumor = metastasis signature
3. Background genetic variation and resulting variation in gene expression in the human population contributes to generation of metastases
- Everything strongly impacted by background genetics
4. Tumor microenvironment and influences like chronic inflammation effect metastasis
78
4 stages of invasion
1. dissociation of cells from one another (alteration in adhesion molecules)
2. local degradation of basement membrane and interstitial connective tissue
3. changes in attachment of tumor cells to ECM proteins
4. locomotion, propel tumor cells through degraded basement membranes and zones of matrix proteolysis
79
Glycoprotein that holds together epithelial cell
E cadherin
80
___ connects E-cadherins to actin cytoskeleton
B-catenin
81
Adenocarcinomas → E-cadherins ___->
Adenocarcinomas → E-cadherins down-regulated → facilitate detachment from primary tumor
82
Epithelial to mesenchymal transition
normal developmental process used inappropriately by cancer cells → loss of E-cadherin expression
83
MMPs regulate tumor invasion by: (2)
1. Remodeling soluble components of basement membrane
2. Releasing ECM-sequestered growth factors
- Cleavage products of collagen and proteoglycans have chemotactic, angiogenic, and growth-promoting effects
84
Ameboid migration
cell squeezes through spaces in cell matrix instead of cutting through it (with proteases)
- Quicker, collagen fibers used as “high-speed railways”
85
Tumor cells can switch between ___ and ___ migration
ameboid
| MMP
86
Describe the changes in attachment of tumor cells to ECM proteins
Receptors (integrins) for basement membrane lamin/collagens on basal surface allow epithelial cells to maintain resting differentiated state
Loss of adhesion → apoptosis (normal cells)
Tumor cells resistant to apoptosis and matrix is modified to promote invasion and metastasis
Modifications to bm
87
Tumor cell modifications to basement membrane
cleavage of bm proteins (collagen IV and lamin) by MMP2 or MMP9 → novel sites that bind to receptors on tumor cells and stimulate migration
88
Final stage of invasion process
Attach matrix at leading edge, detach matrix at trailing edge, and contract actin cytoskeleton to ratchet forward
89
Cells and signaling factors involved in the final stage of invasion
a. Movement potentiated/directed by tumor cell-derived cytokines (autocrine motilite factors)
b. Collagen, lamin, and growth factors also have chemotactic activity for tumor cells - liberated by proteolytic cleavage of matrix
c. Stromal cells → produce paracrine effectors of cell motility (hepatocyte GF-scatter factor)
d. Tumor-associated Fibroblasts → can encode ECM molecules, proteases, protease inhibitors and GFs
90
Intravasation
getting into the vasculature
91
In circulation, tumor cells are vulnerable to destruction by: (3)
1. Mechanical shear stress
2. Apoptosis stimulated by loss of adhesion (anoikis)
3. Immune defense
92
How do tumor cells enhance survival in circulation? (2)
aggregating in clumps and with blood cells (esp platelets), activating coagulation factors (forms emboli)
93
Extravasation
Getting out of vasculature at distant site
94
Process of extravasation
Adhesion to endothelium → egress through basement membrane (uses adhesion molecules - integrins, lamin receptors, proteolytic enzymes)
95
CD44
adhesion molecule, expressed on normal T-lymph
1. Used by cancer cells to migrate to selective sites in lymphoid tissue
2. Overexpression of CD44 favors metastatic spread
96
Site of exit for circulating tumor cells
Site of exit for circulating tumor cells may be due to anatomic location of primary tumor
**** Natural pathways of drainage do not wholly explain distribution of metastases
97
Two theories of tumor colonization
1. Seed and soil theory
| 2. Ewing's mechanical arrest theory
98
Seed and soil theory
Organ-specific patterns explained by needs of cancer cell (seed) for a specific environment (soil) to initiate and maintain growth
a. Extravasation requires adhesion to endothelium: tumor cells express adhesion molecules and endothelial cells of target organ and vascular beds express ligands for adhesion molecules
b. Chemokines: chemokine receptors on cancer cell and tissues that cancer cells commonly metastasize to express that chemokine
c. Some tissues are nonpermissive environment (unfavorable soil)
i. e.g. skeletal muscle
99
Ewing's mechanical arrest theory
cells mechanically arrest in the first capillary bed encountered
100
Seed and Soil vs. Ewing's
Two theories NOT mutually exclusive - cells arrest due to mechanical obstruction and chemical signals and then require suitable microenvironment for maintenance of secondary tumor growth (colonization)
101
Tumor cells efficacy colonizing new regions
Tumor cells actually not that good at colonizing new regions
a. Dormancy = prolonged survival of micrometastases without progression
b. Tumor cells secrete cytokines, GFs, and ECM molecules that act on stromal cells → in turn make metastatic site habitable for cancer cell
102
Ultimate effects of metastasis
Direct effect of metastases: invasive masses interfere with normal function
Indirect effect of metastases: paraneoplastic syndrome (paracrine/endocrine effects) - in 7-15% of patients with cancer
103
Ultimate causes of mortality due to cancer (5)
i. Infection (41.6%)
ii. Organ Failure (19.2%)
iii. Hemorrhage (8.8%)
iv. Thromboembolism (12.2%)
v. Emaciation (7.7%)
104
__% of malignant neoplasms are caused by environmental factors. How do we know this?
80%
i. Regional differences in cancer rates
ii. Worldwide differences in rates of specific types of cancers
1.Not due to genetics alone - migrants’ descendants adopt cancer risk of country to which they move and lose risk from where they’ve come
105
Top 3 leading causes of death from cancer in males
lung cancer (34% of cancer deaths), then prostate (12% of deaths) and colon/rectum (11%)
106
Top 3 cancers with highest incidence in men
prostate, lung, then colorectal
107
Top 3 leading causes of death from cancer in females
lung (21% of deaths), breast (18%), colon/rectum (13%)
108
Top 3 cancers with highest incidences in women
breast, lung/bronchus, and then colon/rectum
109
___% of all cancer deaths due to tobacco
30%
110
Top 4 environmental carcinogen classes
1. polycyclic aromatic hydrocarbons
2. Aromatic amines
3. Nitrosamines and nitrosamides
4. Aflatoxin
*** often "activated chemicals
111
Polycyclic aromatic hydrocarbons
EX:(benzo(a)pyrene)
from incomplete combustion of fossil fuels
1.Ultimate carcinogen is the diol, epoxide
112
Aromatic amines
- Industrial and consumer products
| - N-hydroxylation and sulfation are required
113
Nitrosamines
- formed when 2-amines in food react with nitrous acid in stomach
- Microsomal hydroxylation leads to carbonium intermediate
114
Aflatoxin
common in moldy grains and ground nuts (especially in tropics/developing nations)
1. In US most exposure comes from moldy corn and wheat
2. Produced by Aspergillus flavus
3. Microsomal epoxidation is required
115
chemical carcinogen differ in structure but are similar how?
Must be “Activated: Chemical carcinogen metabolized by microsomal enzymes (CYP450) → chemically active form
116
Active metabolite of carcinogens
strong electrophile, can chemically modify protein, RNA and DNA → bases modified or “bulky” adducts → no excision/repair then mutations occur (mispairing or frameshift)
117
Direct acting carcinogens
Not all carcinogenic compounds require activation - some are direct acting
1. Alkylating agents
2. Acylating agents
118
Ames Test
Measures ability of given chemical to “mutagenize” a set of specific strains of the bacterium Salmonella (in presence of CYP450)
Process: Load onto plate without histidine, plus 10^8 His (-) bacteria, and liver enzymes (CYP450)- mutagenized bacteria able to grow without histidine
1. → 90% of carcinogens tested are mutagens in Ames test →proves they produce mutations in our DNA
2. Potency of mutagens parallels their carcinogenicity
- Fast, inexpensive, sensitive
119
Principles of carcinogenesis (8)
i. The effect of a chemical is dose-dependent in causing cancer
ii. Specific carcinogen often causes one specific type of cancer
iii. Carcinogenesis requires time (lag from exposure → cancer)
iv. Carcinogenesis requires cell proliferation
v. Cellular changes that trigger carcinogenesis are stably transmitted to daughter cells
vi. The cell at risk for becoming malignant is the stem (or reserve cell)
vii. Malignant cells are stem cells that fail to differentiate normally
viii. Cancers develop through two distinct stages
120
Tissues at greatest risk of carcinogenesis
ones that are continually proliferating
121
Two distinct stages of cancer development
Stage 1: Initiation - direct effect of carcinogen, mutation (irreversible)
Stage 2: Promotion - effect of a non carcinogen (reversible), requires repeated application following initiation
122
Tumor promoter
Not mutagen or carcinogen
Often irritants, but not all irritants are promoters
Often cause inflammation (produces ROS → mutagenic, promotes cell proliferation → decreases chance mutation is fixed)
EX) Ulcerative colitis, cholecystitis, atrophic gastritis, chosteomyelitas, schistosomiasis, chronic hepatitis
123
EX of tumor promoter
Phorbol ester - competitively inhibits binding of diacylglycerol to protein kinase C → sustained activation of kinase → promotes cell proliferation
124
Why are cancers common in elderly?
Takes time to accumulate mutations - some theories that it is associated with decline in immune system function
125
Pathology of benign tumor (3)
i. NOT malignant, never invades nor metastasizes
ii. Grow slowly, encapsulated by thin rim of CT
iii. Dangerous in a confined space, and can overproduce harmful proteins
126
Histology of benign tumor (3)
uniform appearance, less differentiated than normal epithelial cells (still resemble normal epithelial cells), low mitotic activity
127
Pathology of malignant tumor
i. Invasion: tumor cells break through basement membrane that separates epithelium from underlying submucosal and CT stroma → invades CT stroma
ii. Metastasis: emigrating tumor cells access lymphatic and venous tributaries through sub mucosa
1. Can also directly shed and seed body cavities without breaking through the basement membrane
128
Histological feature associate with "invasion"
Breaking of basement membrane
129
Tumor grade
state of differentiation of tumor cells seen in histological sections
1. Low grade = cells well differentiated, feature of normal cells
2. High grade = cells do not resemble “normal” epithelial cells
a. Pleomorphic, anaplastic (lack differentiation), high N:C ratio, unusual mitotic figures, high mitotic rate
130
Tumor stage
extent of tumor spread at time of diagnosis
- Strongest predictor of prognosis
- Advanced stage = large tumor primary, positive nodes, and distant metastasis
- Determined with TNM classification
131
Risk factors for lung cancer (5)
Smoking (duration and level), age, occupational history, exposure to air pollutants, family history
132
Four major types of lung carcinoma
1. squamous
2. adenocarcinoma
3. large cell
4. small cell
133
Clinical presentation of lung carcinoma
cough (or change in cough), dyspnea, secondary pneumonia, CP, persistent hoarseness, facial swelling, weight loss, signs of distant mets
134
4 characteristics of lung carcinoma
1. Survival strongly correlated with stage
2. Cure requires complete surgical excision of cancer
3. Peak incidence at age 70
4. Risk: smoking (pack:years) - 10% of heavy smokers develop lung cancer
135
Squamous carcinoma is linked to
cigarette smoking
136
Changes that occur in squamous carcinoma
Pseudostratified ciliated columnar epithelial cells replaced by squamous epithelium (metaplasia)
1.Arise from areas of squamous metaplasia and dysplasia (centrally, usually in major bronchi)
137
Histology of squamous carcinoma
Large, necrotic, moderately differentiated, stain + for keratin
138
Common molecular signatures of squamous carcinoma
P53 mutation, loss of RB/p16 are common molecular signatures
139
Squamous carcinomas spread via
lymphatics or blood
140
Treatment of squamous carcinoma
aurgery and radiation
141
Adenocarcinoma is the most common type of lung cancer in __ and ___
women and nonsmokers
-"least bad" of the lung cancers
142
Location of lung adenocarcinomas
central or periphery
| - "scar carcinoma" in areas of previous scarring
143
Adenocarcinomas form
primitive gland like structures
144
Adenocarcinomas stain positive for
mucin
145
Common mutation in adenocarcinomas
k- ras
146
Treatment of lung adenocarcinomas
Surgery and radiation
147
Bronchioalveolar carcinoma
subclass of adenocarcinoma, not linked to smoking, best prognosis
-LEAST linked to smoking
From alveolar septae along airspace structures, little stroma
148
Large Cell carcinoma
(10-15% of cases)
1. Undifferentiated, high grade, lung cancer, very aggressive
2. Arise from anywhere in the lung
3. ANAPLASTIC appearing cancer cells, very pleomorphic in appearance
a. No keratin or mucin
149
Small cell carcinoma link
Strong link to cigarette smoking
150
Small cell carcinoma
arise from anywhere in lung
151
small cell carcinoma treatment
not treated with surgery, only chemo
152
Histology small cell carcinoma
small, dark staining, form cluster
153
Small cell carcinomas stain + for
neuroendocrine markers
154
Prognosis of small cell carcinoma
terrible
155
Clinical presentation pancreatic carcinoma
back pain, unexplained jaundice (cancer growth blocks common bile duct), cachexia, migratory thrombophlebitis
1.Terrible 5 year survival (
156
Risk factors of pancreatic cancer
largely unknown
age, smoking, chronic pancreatitis from alcoholism, DM, family hx
157
Pathology of pancreatic carcinomas
1. Arise in major ducts, not acini (focal areas of non-invasive epithelial cell proliferations)
2. Well differentiated adenocarcinomas
3. Desmoplasia
158
Desmoplasia
synthesis of prominent CT stroma → rock hard feeling
159
Prognosis of pancreatic carcinoma
terrible prognosis (worse than lung cancer)
1. Silent cancer growth without symptoms or signs - wide metastases at time of diagnosis (mets to liver, abdominal nodes, celiac nerve plexus)
2. Best case = small tumor found at head of pancreas
160
Treatment of pancreatic cancer
1. Non-resectable usually → radiation + chemo treatment
| 2. Surgery = Whipple
161
98% of colorectal carcinomas are ___
adenocarcinomas
162
Pathology of colorectal carcinomas
1. Moderately well differentiated adenocarcinomas - arise in innermost mucosal layer of bowel wall
a. Mucosa → then can invade submucosa and muscularis layers
2. Sporadic - arise in preexisting adenomatous polyps
3. often metastasize to the liver
163
Two types of neoplastic colonic polyps
1. tubular adenoma
| 2. villious adenoma
164
Spread of colorectal cancer
lymphatics or blood
165
Symptoms of colorectal cancer
Symptoms depend on if cancer is in left or right (descending) colon
Left → constipation, change in stool caliber, colon obstructed
Right → very big before producing symptoms, abdominal pain, mucus or blood in stool, anemia (due to subclinical colonic bleeding)
166
Germline mutations of colorectal cancer (4)
1. Rare Familial Adenomatous Polyposis (APC)
2. HNPCC - loss of mismatch DNA repair
3. Loss of mutY base excision DNA repair enzyme
4. Somatic mutations = sporadic mutations in APC, K-ras, p53, DCC, MCC
167
Gleason grading of prostate cancer
looks at morphologic resemblance to normal prostate and degree of invasiveness
168
Grade 1 of gleason
very well differentiated, neoplastic glands uniform
169
Grade 5 of Gleason
no gland formation, tumor cells infiltrate as sheets and cords
a.Highest grade
170
How do you get the final Gleason score?
Add Gleason grade of subordinate pattern and predominant pattern
a. Values of 8-10 = aggressive behavior
171
Clinical presentation of prostate cancer (3)
1. Enlarged prostate (not always though)
2. Difficulty with urinary voiding
3. Typically occurs in periphery of gland
172
Risk factors of prostate cancer
age (rare before 40, common by 80), race (most in African-Americans, least in Asians), geography, family hx (genetics)
173
Death in prostate cancer
Most men die with Pca but not of it
174
Screening methods of prostate cancer (3)
1. Digital rectal exam
2. Digital guided biopsies through the rectum
3. Prostate specific proteolytic enzyme in serum (PSA >4 ng/ml)
175
Treatment of prostate cancer
radical prostatectomy, with/without radiation, anti-androgen therapy-
176
Adjuvant chemotherapy
Local Therapies first (Surgery/radiation) then chemo
Can increase effectiveness of surgery/radiation and improve overall survival and increased relapse free survival
177
Neoadjuvant Chemotherapy
Chemo first, then local therapies (surgery/radiation)
Used before surgery/radiation to spare vital normal organs
May also kill micrometastatic disease
178
Primary induction chemotherapy
Drug treatment is primary treatment strategy (no surgery or radiation)
Often used for advanced tumor/metastatic disease patients for which no effective other treatment exists
179
Conventional Cytotoxics
- damage normal cells and tumor cells
| - small therapeutic window (try to kill tumor cells without killing normal cells)
180
Both conventional and targeted therapies attempt to...
Hit specific targets (e.g. topoisomerase/DNA) that interfere with fundamental aspects of cell biology
181
Targeted therapies differ in that they...
hit target that is different/faulty in tumor cells, but not normal cells
- MTD less relevant for targeted therapy (less toxic)
- widens therapeutic window
182
Key points for combining anti-tumor agents (5)
1) Combine agents that work at least some extent on their own
2) Avoid overlapping toxicities
3) Use drugs at optimal doses
4) Keep treatment-free schedules as short as possible
5) Avoid removal or dose reduction of drug (could result in outgrowth/resistant cell line)
183
Main mechanisms of chemo-resistance (5)
1) Enhance drug efflux out of cancer cell
2) Enhance inactivation of drug
3) Alter drug target
4) Generate adaptive responses
5) Make apoptosis dysfunctional
**can be specific to drug or more general resistance**
184
DNA modifying agents typically develop resistance by...(6)
1) Up-regulating DNA repair mechanisms
2) Inactivating drug
3) Resistance of apoptosis
4) increased drug efflux
5) mutation in drug target enzyme
6) increase amount of target enzyme present
185
Antimicrotubule drugs
Target cytoskeleton (stabilize or de-polymerize microtubules)
Specifically this class of drug can be neuro-toxic
186
Hormonal agents resistance mechanisms
Activate receptor by other mechanisms (without hormone)
Mutate receptor to alter response to drug
EX) Tamoxifen, anti-androgens
187
Antibody therapies can work by...
binding target molecule and inhibiting function of molecule
-Can also be used as immunoconjugates to deliver toxins / chemotherapeutic drugs to tumor cells specifically - inhibit function and kill cell!
188
Kinase inhibitors typically work by...
binding directly to active site of kinase enzyme where ATP binds
EX) Imatinib - treats CML/GIST
189
Typical toxicities
- GI toxicity
- Myelosuppression (suppress hematopoiesis)
- Neurotoxicity (antimicrotubule agents)
- Cause secondary malignancies
- Damage to fast growing cells
190
Fludrocortisone
high MC activity, very high salt retaining side effects (oral only)
191
Alkylating agents mechanism of action
cross link DNA, prevents DNA replication
192
Cyclophosphamide is a chemo drug that is an __________.
alkylating agent
193
Cisplatin is ________
an alkylating agent (chemo drug) (platinum compound)
194
Carboplatin and Oxaliplatin are ___________
alkylating agents (platinum compounds)
195
Methotrexates is ________.
Mechanism of action?
an anti-metabolite
reversible, competitive inhibitor of DHFR in synthesis of nucleotides
196
5-fluorouracil is ________
mechanism of action?
an anti-metabolite
pyrimidine analog - inhibits DNA synthesis
197
anti-Topoisomerase drugs act by...
causing DNA strand breaks
198
Doxorubicin and etoposide are _____________
anti-Topoisomerase drugs
199
Vinblastine and vincristine (aka vinca alkaloids) are ___________
anti-microtubule agents
200
Paclitaxol and Docetaxel (aka Taxanes) are _____________
anti-microtubule agents
201
anything ending in mab = _______
EX) Rituximab, trastuzumab/Herceptin, Bevacizumab/Avastin
antibody chemo agent
202
Imatinib/Gleevec are ____________
kinase inhibitors
