1
Q
apoptosis
A
- programmed cell death; ATP required
- intrinsic or extrinsic pathway; both pathways–>activation of cytosolic caspases that mediate cellular breakdown
- no significant inflammation
- characterized by cell shrinkage, nuclear skrinkage (pyknosis) and basophilia, membrane blebbling nuclear fragmentation (karyorrhexis), and formation of apoptotic bodies, which are then phagocytosed
2
Q
intrinsic pathway
A
- involved in tissue remodeling in embryogenesis
- occurs when a growth factor is withdrawn from a proliferating cell population (eg. dec IL-2 after a completed immune rxn–>apoptosis of proliferating effector cells)
- also occurs after exposure to injurious stimuli (eg. radiation, toxins, hypoxia)
- changes in proportion of anti- and pro-apoptotic factors lead to increased mitochondria permeability and cytochrome c release
3
Q
extrinsic pathway
A
- 2 pathways:
- ligand receptor interactions (Fas ligand binding to Fas (CD95)
- immune cell (cytotoxic T cell release of perforin and granzyme B)
4
Q
necrosis
A
- enzymatic degradtion and protein denaturation of cell resulting from exogenous injury.
- intracellular components extrasate
- inflammatory process (unlike apoptosis)
- types of necrosis:
- -coagulative–heart, liver, kidney
- -liquefactive–brain, bact abscess, pleural effusion
- -caseous–TB, systemic fungi
- -fatty–peripancreatic fat (saponification via lipase)
- -fibrinoid–blood vessels
- -gangrenous–dry (ischemic coagulative) or wet (with bacteria); common in limbs and in GI tract
5
Q
cell injury:
- reversible with O2
- irreversible
A
- reversible with O2
- dec ATP synthesis
- Cellular swelling (no ATPimpaired Na+/K+ pump)
- nuclear chromatin clumping
- dec glycogen
- fatty change
- ribosomal detachment (dec protein synthesis) - irreversible
- nuclear pyknosis, karyolysis, karyorrhexis
- Ca2+ influxcaspase activation
- plasma membrane damage
- lysosomal rupture
- mitochondrial permeability
6
Q
Ischemia: susceptible areas:Organ & location
- Brain
- heart
- kidney
- liver
- colon
A
- areas susceptible to hypoxia and ischemia/infarction
1. ACA/MCA/PCA boundary areas. Watershed areas receive dual blood supply from most distal branches of 2 arteries, which protects these areas from single-vessel focal blockage. However, these areas re susceptible to ischemia from systemic hypoperfusion. Hypoxic ischemic encephalopathy (HIE) affects pyramidal cells of hippocampus and Purkinjie cells
2. Subendocardium (LV)
3.Straight segment of proximal tubule (medulla)
Thick ascending limb (medulla)
- Area around central vein (zone III)
- Splenic flexure, rectum. Watershed areas receive dual blood supply from most distal branches of 2 arteries, which protects these areas from single-vessel focal blockage. However, these areas re susceptible to ischemia from systemic hypoperfusion. Hypoxic ischemic encephalopathy (HIE) affects pyramidal cells of hippocampus and Purkinjie cells.
7
Q
Infarcts: red vs. pale
A
- Red (hemorrhagic) infarcts occur in loose tissues with collaterals, such as liver, lungs, or intestine, or following reperfusion
- pale infarcts occur in solid tissues with a single blood supply, such as heart, kidney, and spleen
- Red=perfusion
- Reperfusion injury is due to damage by free radicals
8
Q
Shock:
- Hypovolemic/cardiogenic
- Septic
A
- Hypovolemic/cardiogenic
- Low-output failure
- Inc TPR
- Low cardiac output
- Cold, clammy patient (vasoconstriction) - Septic
- High-output failure
- Dec TPR
- Dilated arterioles, high venous return
- Hot patient (vasodilation)
9
Q
Atrophy
A
- Reduction in the size or number of cells. Causes include:
- Dec hormones (uterus/vagina)
- Dec innervation (motor neuron damage)
- Dec blood flow
- Dec nutrients
- Inc pressure (nephrolithiasis)
- Occlusion of secretory ducts (cystic fibrosis)
10
Q
Inflammation:
- vascular component
- cellular component
A
Characterized by rubor (redness), dolor (pain), calor (heat), tumor (swelling), and function lasesa (loss of function)
- vascular component–inc vascular permeability, vasodilation, endothelial injury
- cellular component–neutrophil extravasation from circulation to injured tissue to participate in inflammation through phagocytosis, degranulation, and inflammatory mediator release
11
Q
Inflammation:
- Acute
- Chronic
A
- Acute- neutrophil,eosinophil, antibody mediated. Acute inflammation is rapid onset (second to minutes), lasts minutes to days. Outcomes include complete resolution, abscess formation, and progression to chronic inflammation
- Chronic–mononuclear cell mediated: characterized by persistent destruction and repair. Associated with blood vessel proliferation, fibrosis. Granuloma: nodular collections of epithelioid macrophages and giant cells. Outcomes include scarring and amyloidosis
12
Q
Leukocyte extravasation in 4 steps
A
Neutrophils exit from blood vessels at sites of tissue injury and inflammation in 4 steps:
Step, vasculature/stroma, leukocyte
1.rollingE selectin, P-selectinSialyl-Lewis X
2.tight bindingICAM-1LFA-1 (integrin)
3.diapedesis-leukocyte travels btw endothelial cells and exit blood vesselPECAM-1-PECAM-1
4.Migration—leukocyte travels through interstitium to site of injury or infection guided by chemotactic signals-bacterial products: C5a, IL-8, LTB4, and Kallikrein (CILK)various
13
Q
Free radical injury
A
-free radical damage cells via membrane lipid peroxidation, protein modification, and DNA breakage
-initiated via radiation exposure, metabolism of drugs (phase1), redox rxn, nitric oxide, transition metals, leukocyte oxidative burst
-free radicals can be eliminated by enzymes (catalase, superoxide dismutase, glutathione peroxidase), spontaneous decay, antioxidants (vits A, C, E)
Pathologies include:
1.Retinopathy of prematurity
2.Bronchopulmonary dysplasia
3.Carbon etrachloride, leading to liver necrosis (fatty change)
4.Acetaminophen overdose (fulminant hepatitis)
5.Iron overload (hemochromatosis)
6.Reperfusion after anoxia (eg superoxide), especially after thrombolytic therapy
14
Q
Wound healing:
- Phase (3)
- mediators
- characteristics
A
- Inflammatory (immediate)–> platelets, neutrophils, macrophages–>clot formation, inc vessel permeability and neutrophil migration into tissue; macrophages clear debris 2 days later
- Proliferative (2-3 days after wound)–> fibroblasts, myofibroblasts , endothelial cells, keratinocytes, macrophages–> deposition of granulation tissue and collagen, angiogenesis, epithelial cell proliferation, dissolution of clot, and wound contraction (mediated by myofibroblasts)
- Remodeling (1wk after wound)–> fibroblasts–>type II collagen replaced by type I collagen inc tensile strength of tissue
15
Q
Granulomatous disease
A
- Mycobacterium tuberculosis
- Fungal infections (eg histoplasmosis, coccidiodomycosis)
- Treponema pallidum (syphilis)
- M. leprae (leprosy)
- Bartonella henselae (cat scratch disease)
- Sarcoidosis
- Crohn’s dz
- Granulomatosis with polyangiitis (Wegener’s)
- Churg-Straus syndrome
- Berylliosis, silicosis
- Th1 cells secrete gamma interferon, activating macrophages.
- TNF alpha from macrophages induce and maintain granuloma formation.
- Anti-TNF drugs can, as a side effect, cause sequestering granulomas to breakdown, leading to disseminated disease
16
Q
Transudate vs. exudate
A
Transudate
- Hypocellular
- Protein poor
- Specific gravity 1.02
- Due to: lymphatic obstruction, inflammation
17
Q
Erythrocyte sedimentation rate:
Increase/decrease ESR
A
-Products of inflammation (eg fibrinogen) coat RBCs and cause aggregation. When aggregated, RBCs fall at a faster rate within the test tube
Increase ESR
- Infections
- inflammation (eg temporal arteritis),
- CA
- pregnancy
- SLE
Decrease ESR
- Sickle cell (altered shape)
- polycythemia (too many)
- CHF (unknown)
18
Q
Iron poisoning:
- mechanism
- symptoms
A
-One of the leading cause sof fatality from toxicological agents in children
mechanism-Cell death due to peroxidation of membrane lipids
- Acute—gastric bleeding
- Chronic—metabolic acidosis, scarring leading to GI obstruction
19
Q
Amyloidosis
A
Abnormal aggregation of proteins or their fragments into beta-pleated sheet structures, leading to cell damage and apoptosis. Affected tissue has waxy appearance
20
Q
Amyloidosis common types: six
A
- AL (primary)
- due to deposition of proteins from Ig Light chain. -Can occur as a plasma cell disorder or associated with multiple myeloma.
- Often multiple organ system impact, including renal (nephrotic syndrome), cardiac (heart failure, arrhthemia), hematologic (easy bruising), hepatomegaly, and neuropathy - AA (secondary)
- seen with chronic dz like RA, IBD, spondyloarthropathy, chronic infections.
- Fibrils composed of serum Amyloid A.
- Often multisystem like AL amyloidosis - Dialysis-related
- fibrils composed of Beta2-microglobulin in patients with ESRD and long term dialysis.
- Often presents as carpal tunnel syndrome and other joint issues - Heritable
- heterogenous group of disorders.
- Example is ATTR neurologic/cardiac amyloidosis due to transthyretin (TTR or prealbumin) gene mutation - Age-related (senile)
- systemic due to deposition of normal (wild-type) TTR in myocardium and other sites.
- Slower progression of cardiac dysfunction vs. AL amyloidosis - Organ-specific
- amyloid deposition localized to a single organ. -Most important form is amyloidosis in Alzheimer’s dz due to deposition of amyloid-beta protein cleaved from amyloid precursor protein (APP)
21
Q
nonplastic progression
A
- Hallmarks of cancer–evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, tissue invasion, and metastasis
1. Normal cells with basal–>apical differentiation
2. cells have increased in number–>hyperplasia - abnormal proliferation of cells with loss of size, shape, and orientation–>dysplasia
3. Carcinoma in situ - neoplastic cells have not invaded basement membrane
- high nuclear/cytoplasmic ratio and clumped chromatin
- neoplastic cells encompass entire thickness
4. Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases) - can metastasize if they reach a blood or lymphatic vessel
5. Metastasis–>spread to distant organ - must survive immune attack
- seed and soil theory of metastasis
- seed=tumor embolus
- soil=target organ–liver, lungs, bone, brain, etc
22
Q
–plasia definitions (reversible)
3 types
A
- Hyperplasia increase in number of cells
- Metaplasia one adult cell type is replaced by another. Often 2’ to irritation and/or environmental exposure (eg. Squamous metaplasia in trachea and bronchi of smokers)
- Dysplasia abnormal growth with loss of cellular orientation, shape, size in comparison to normal tissue maturation; commonly preneoplastic
23
Q
–plasia definitions (irreversible)
3 types
A
- Anaplasia abnormal cells lacking differentiation; resemble primitive cells of same tissue, often equated with undifferentiated malignant neoplasms. Little or no resemblance to tissue of origin
- Neoplasia a clonal proliferation of cells that is uncontrolled and excessive. Neoplasia may be benign or malignant
- Desmoplasia fibrous tissue formation in response to neoplasm
24
Q
Tumor grade vs stage
A
Grade
- Degree of cellular differentiation based on histologic appearance of individual tumor.
- Usually graded 1-4; 1=low grade, well differentiated to 4=high grade, poorly differentiated, anaplastic
- Stage usually has more prognostic value than grade
Stage
-Degree of localization/spread based on site and size of 1’ lesion, spread to regional lymph nodes, presence of metastases; spread of tumor in a specific patient.
-Based on clinical or pathology findings: ex: cT3N1M0
-TNM staging system )stage=spread
T=tumor size
N=node involvement
M=metastases (important prognostic factor)
25
Tumor nonmenclature: cell type, benign, malignant
1. Epithelium
2. Mesenchyme
2a. blood cells
2b. blood vessels
2c. smooth muscles
2d. striated muscle
2e. connective tissue
2f. bone
2g. fat
1.Epithelium-->adenoma, papilloma-->adenocarcinoma, papillary carcinoma
2. Mesenchyme
- blood cells-->none-->leukemia, lymphoma
- blood vessels--> hemangioma-->angiosarcoma
- smooth muscle--> leiomyoma-->leiomyosarcoma
- striated muscle--> rhabdomyoma--> rhabdomyosarcoma
- connective tissue--> fibroma--> fibrosarcoma
- bone--> osteoma--> osteosarcoma
- fat--> lipoma--> liposarcoma
The term carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin, Both terms imply malignancy.
26
Tumor differences:beinign, malignant
- Benign usually well differentiated, slow growing, well demarcated, no metastasis
- Malignant may be poorly differentiated, erratic growth, locally invasive/diffuse, may metastasize
27
Cachexia
Cachexia- weight loss, muscle atrophy, and fatigue that occur in chronic dz (eg CA, AIDS, heart failure, tuberculosis). Mediated by TNF-alpha (nicknamed cachecin), IFN-gamma, IL-6
28
Disease conditions associated with neoplasma
Condition--->neoplasma
1.down syndrome
2.Xeroderma pigmentosum, albinism
3.chronic atrophic gastritis, pernicious anemia, postsurgical gastric remnants
4.tuberous sclerosis (facial angiofibroma, seizures, mental retardation)
5.actinic keratosis
6.Barrett’s esophagus (chronic GI reflux)
7.Plummer-vinson syndrome (dec iron)
8.Cirrhosis (alcoholic, hepatitis B or C)
9.Ulcerative colitis
10.Paget’s disease of bone
11.Immunodeficiency states
12.AIDS
13.Autoimmune diseases (eg. Hashimoto’s thyroiditis, myasthenia gravis)
14.Acanthosis nigricans (hyperpigmentation and epidermal thickening)
15.Dysplastic nevus
16.Radiation exposure
1. ALL (we all fall down), AML
2. melanoma, basal cell carcinoma and especially squamous cell carcinoma of skin
3. gastric adenocarcinoma
4. giant cell astrocytoma, renal angiomyolipoma, cardiac rhabdomyoma
5. squamous cell carcinoma of skin
6. esophageal adenocarcinoma
7. squamous cell carcinoma of skin
8. hepatocellular carcinoma
9. colonic adenocarcinoma
10. ’ osteosarcoma and fibrosarcoma
11. malignant lymphomas
12. aggressive malignant lymphomas (non-Hodgkin’s) and Kaposi’s sarcoma
13. lymphoma
14. visceral malignancy (stomach, lung, uterus)
15. malignant melanoma
16. leukemia, sarcoma, papillary thyroid cancer, breast cancer
29
Oncogenes: 1.gene 2.associated tumor 3.gene product
1. abl
2. c-myc
3. bcl-2
4. HER2/neu (c-erbB2)
5. ras
6. L-myc
7. N-myc
8. ret
9. c-kit
-gain of function-->inc cancer risk. Need damage to only 1 allele
1. CMLtyrosine kinase
2. Burkitt’s lymphomatranscription factor
3. Follicular and undifferentiated lymphomas (inhibits apoptosis)anti-apoptotic molecule
4. Breast, ovarian, and gastric carcinomastyrosine kinase
5. Colon carcinomaGTPase
6. Lung tumortranscription factor
7. Neuroblastomatranscription factor
8. Multiple endocrine neoplasia (MEN) types 2A & 2Btyrosine kinase
9. Gastrointestinal stromal tumor (GIST)cytokine receptor
30
Tumor suppressor: 1.gene 2.associated tumor 3.gene product
1. Rb
2. p53
3. BRCA1
4. BRCA2
5. p16
6. BRAF
7. APC
8. WT1
9. NF1
10. NF2
11. DPC4
12. DCC
- loss of function-cancer risk-both alleles must be lost for expression of disease
1. Retinoblastoma, osteosarcoma-->Inhibits E2F; blocks G1- S phase
2. most human cancers, Li-Fraumeni syndrome-->transcription factor for p21, blocks G1, S phase
3. Breast and ovarian cancer-->DNA repair protein
4. Breast and ovarian cancer--> DNA repair protein
5. Melanoma-->none
6. Melanoma--> B-raf
7. Colorectal cancer (associated with FAP)-->none
8. Wilm’s Tumor (nephroblastoma)-->none
9. NeuroFibromatosis type 1-->RAS GTPase activating protein (RAS-GAP)
10. NeuroFibromatosis type 2--> Merlin (schwannomin) protein
11. pancreatic cancer-->DPC-deleted in Pancreatic Cancer
12. colon cancer-->DCC-Deleted in Colon Cancer
31
Tumor markers:
1. PSA
2. Prostatic acid phosphatase
3. CEA
4. alpha-fetoprotein
5. beta-hCG
6. CA-125
7. S-100
8. Alkaline phosphate
9. Bombesin
10. TRAP
11. CA-19-9
12. Calcitonin
1. PSA- Prostate-specific antigen. Used to follow prostate carcinoma. Can also be elevated in BPH and prostatitis. Questionable risk/benefit for screening.
- Tumor markers shouldn’t be used as the 1 tool for cancer diagnosis. They may be used to confirm diagnosis, to monitor response to therapy
2. Prostatic acid phosphatase- Prostae carcinoma.
3. CarcinoEmbryonic Antigen. Very nonspecific but produced by~ 70% of colorectal and pancreatic cancers; also produced be gastric, breast, and medullary thyroid carcinomas
4. alpha-fetoprotein- Normally made by fetus. Hepatocellular carcinomas. Nonseminomatous germ cell tumors ( e.g, testis, ovary.)
5. beta-hCG- Hydatidiform moles and Choriocarcinomas( Gestational trophoblastic disease)
- hCG is commonly associated with pregnancy.
6. CA-125- Ovarian cancer.
7. s-100- Melanoma, neural tumors, schwannomas.
8. Alkaline phosphatase- Metastases to bone, liver, Paget’s disease of bone.
9. Bomesin- Neuroblastoma, lung and gastric cancer.
10. TRAP- Tartrate-Resistant Acid Phosphatase (TRAP). TRAP the hairy animal.
11. CA-19-9- Pancreatic adenocarcinoma.
12. Calcitonin- Medullary thyroid carcinoma.
32
```
Oncogenic microbes:
Microbes & Associated CA
1.HTLV-1
2.HBV, HCV
3.EBV
4.HPV
5.HHV-8 (Kaposi's sarcoma-associated herpesvirus)
6.H. pylori
7.Schistosoma haematobium
8.Liver fluke (Clonorchis sinensis)
```
1. HTLV-1- Aldult T-cell leukemia/lymphoma
2. HBV, HCV- Hepatocellular carcinoma
3. EBV- Burkitt’s lymphoma, Hodgkin’s lymphoma,nasopharyngeal carcinoma, CNS lymphoma(in immunocompromised patients)
4. HPV- Cervical carcinoma(16, 18), penile/anal carcinoms, upper respiratory SCG
5. HHV-8 (Kaposi’s sarcoma-associated herpesvirus)- Kaposi’s sarcoma, body cavity fluid B-cell lymphoma
6. H. pylori- Gastric adenocarcinoma and lymphoma
7. Schistosoman haematobium- Bladder cancer(spuamous cell)
8. Liver fluke(clonorchis sinensis)- Cholangiocarcinoma
33
chemical carcinogens: toxin, organ, impact
1. Aflatoxins(Aspergillus)-
2. Vinyl chloride-Liver-
3. Carbon tetrachloride-
4. Nitrosamines(smoked foods)-
5. Cigarette smoke-
6. Asbesto
7. Arsentic
8. Naphthalene(aniline)dyes-
9. Alkylating agent-
1. Liver--> Hepatocellular carcinoma
2. Liver--> Angiosarcoma
3. Liver--> Centrilobular necrosis, fatty change
4. Stomach--> Gastric cancer
5. Larynx--> Squamous cell carcinoma
- Lung--> Squamous cell and small cell carcinoma
- Kidney- Renal cell carcinoma
- Bladder- Transitional cell carcinoma
- Pancreas- Pancreatic adenocarcinoma
6. Lung--> Bronchogenic carcinoma greater than> mesothelioma
7. Skin-->cell carcinoma
- Liver- Angiosarcoma
8. Bladder--> transitional cell carcinoma
9. Blood--> Leukemia
34
Paraneoplastic syndromes: hormones/agent, effect, neoplasm(s)
1. ACTH or ACTH-like peptide
2. ADH
3. PTHrP
4. 1,25-(OH)2D3 (calcitriol)
5. Erythropoietin
6. ANtibodies against presynaptic Ca2+ channels at NMJ
1. cushing’s syndrome--> Small cell lung carcinoma
2. SIADH--> Small cell lung carcinoma and intracranial neoplasms
3. Hypercalcemia--> Squamous cell lung carcinoma, renal cell carcinoma, breast cancer
4. Hypercalcemia--> Hodgkin’s lymphoma, some non-Hodgkin’s lymphomas
5. Polycythemia--> renal cell carcinoma, hemangioblastoma, hepatocellular carcinoma, pheochromocytoma
6. Lambert-Eaton syndrome (muscle weakness)--> small cell lung carcinoma
35
Psammoma bodies
```
Laminated, concentric, calcific spherules seen in:
-papillary adenocarcinoma of thyroid
-serous papillary cystadenocarcinma of ovary
-meningioma
-malignant mesothelioma
**PSaMMoma:
Papillary (throid)
Serous (ovary)
Meningioma
Mesothelioma
```
36
Cancer epidemiology: male, female, notes
1. incidence
2. mortality
1. incidence.male- prostate (32%), lung (16%), colon/rectum (12%)
1. mortality male- lung (33%), prostate (13%)
2. incidence female- breast (32%), lung (13%), colon/rectum (13%)
2. mortality female- lung (23%), breast (18%)
3. incidence notes- lung cancer incidence has dropped in men, but gas bot changed significantly in women
3. mortality notes- cancer is 2nd leading causes of death in the US (heart disease is 1st)
37
Common metastases:
1. Site of metases
2. 1’ tumor
3. notes
Brain
2. 1’ tumorlung>breast>genitourinary>osteosarcoma>melanoma>GI
3. notes50% o brain tumors are from metastases. Typically multiple well-circumscribed tumor at gray/white matter junction
Liver
2. 1’ tumorcolon>stomach>pancreas
3.notesliver and lung are the most common sites of metastasis after the regional lymph notes
Bone
2. 1’ tumorprostate, breast>lung>thyroid, testes
3.notesbone metastasis>> primary bone tumors. Whole body bone scan shows tumor predilection for axial skeleton. Lung=lytic, prostate=blastic, breast=lytic and blastic
USMLE First AID
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