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USMLE Step 1 First Aid - Pathology notes

Apoptosis (definition)

Programmed cell death; ATP required. Mediated by caspases.

Apoptosis is characterized by...?

Cell shrinkage, nuclear shrinkage and basophilia (pyknosis), membrane blebbing, pyknotic nuclear fragmentation (karyorrhexis), nuclear fading (karyolysis), and formation of apoptotic bodies, which are then phagocytosed. No significant inflammation.

When does apoptosis occur?

Occurs during embryogenesis, hormone induction (menstruation), immune cell-mediated death, injurious stimuli (e.g., radiation, hypoxia), atrophy (e.g., endometrial lining during menopause)

Necrosis (definition)

Enzymatic degradation of a cell resulting from exogenous injury.

Necrosis is characterized by...?

Enzymatic digestion and protein denaturation, with release of intracellular components. Inflammatory.

Necrosis morphologies

Coagulative (heart, liver, kidney) Liquefactive (brain) Caseous (tuberculosis) Fat (pancreas) Fibrinoid (blood vessels) Gangrenous (limbs, GI tract)

Characteristics of reversible cell injury

Cellular swelling Nuclear chromatin clumping Decr ATP synthesis Ribosomal detachment Glycogen depletion Fatty change

Characteristics of irreversible cell injury

Plasma membrane damage Lysosomal rupture Ca2+ influx --< oxidative phosphorylation Nuclear pyknosis, karyolysis, karyorrhexis Mitochondrial permeability

5 Characteristic signs of inflammation

Rubor (redness) Dolor (pain) Calor (heat) Tumor (swelling) Functio laesa (loss of fxn)

Fluid exudation in inflammation

Incr vascular permeability, vasodilation, endothelial injury.

Leukocyte activation in inflammation

Emigration (rolling, tight binding, diapedesis); chemotaxis (bacterial products, complement, cytokines); phagocytosis and killing.

Substances that are chemotactic for neutrophils

IL-8 C5a Leukotriene B4 Kallikrein

Fibrosis in inflammation

Fibroblast emigration and proliferation; deposition of ECM.

Acute inflammation

Neutrophil, eosinophil, and Ab-mediated. Rapid onset (seconds-minutes), lasts minutes-days.

Chronic inflammation

Mononuclear cell mediated: Characterized by persistent destruction and repair. Associated w/ blood vessel proliferation, fibrosis. Granuloma -- nodular collections of epithelioid macrophages and giant cells.

Granulomatous dz's

TB (caseating) Syphilis Listeria monocytogenes Wegener's granulomatosis Leprosy Bartonella Some fungal pneumonias Sarcoidosis Crohn's dz *Granuloma formation is IL-2, interferon-gamma mediated.

Resolution of inflammation

Restoration of normal structure. Granulation tissue -- highly vascularized, fibrotic. Abscess -- fibrosis surrounding pus. Fistula -- abnormal communication. Scarring -- collagen deposition resulting in altered structure and fxn.

Characteristics of trans udate

Hypocellular Protein-poor Specific gravity > 1.012 Due to: Incr hydrostatic pressure Decr oncotic pressure Na+ retention

Characteristics of ex udate

Cellular Protein-rich Specific gravity < 1.020 Due to: Lymphatic obstruction Inflammation

Leukocyte extravasation

Neutrophils exit from blood vessels at sites of injury and inflammation in 4 steps: 1.) Rolling 2.) Tight binding 3.) Diapedesis 4.) Migration <img src="218a.JPG" />

Rolling (step 1 in leukocyte extravasation)

Mediated by E-selectin and P-selectin on vascular endothelium binding to sialyl Lewis^x on the leukocyte. <img src="218a.JPG" />

Tight binding (step 2 of leukocyte extravasation)

Mediated by ICAM -1 on vascular endothelium binding to LFA-1 (integrin) on the leukocyte ("Hold on tight to your CAM era") <img src="218a.JPG" />

Diapedesis (step 3 in leukocyte extravasation)

Leukocyte travels btw endothelial cells and exits blood vessel; PECAM-1 is involved. <img src="218a.JPG" />

Migration (step 4 in leukocyte extravasation)

Leukocyte travels thru the interstitium to the site of injury or infxn guided by chemotactic signals (e.g., cytokines) <img src="218a.JPG" />

Things that initiate Free radical injury

Radiation exposure Metabolism of drugs (phase I) Redox rxtn Nitric oxide Transition metals Leukocyte oxidative burst *Reperfusion after anoxia induces free radical production (e.g., superoxide) and is a major cause of injury after thrombolytic therapy

Free radical injury induces cell injury thru...?

Membrane lipid peroxidation Protein modification DNA Breakage

Free radical degradation

Produced thru enzymes (catalase, superoxide dismutase, glutathioe peroxidase), spontaneous decay, antioxidants (Vitamins A, C, E).

Amyloid structure

Beta-pleated sheet demonstrable by apple-green birefringence of Congo red stain under polarized light; affected tissue has waxy appearance.

Type of amyloid protein: Primary Protein? Derived from...?

AL protein Derived from Ig L ight chains (multiple myeloma) (AL = L ight chains)

Type of amyloid protein: Secondary Protein? Derived from...?

AA protein Derived from serum amyloid-associated (SAA) protein (chronic inflammatory dz) (AA = A cute-phase reactant)

Type of amyloid protein: Senile cardiac Protein? Derived from...?

Protein = transthyretin Derived from AF (AF = old F ogies)

Type of amyloid protein: DM2 Protein? Derived from...?

Amylin protein Derived from AE (AE = E ndocrine)

Type of amyloid protein: Medullary carcinoma of thyroid Protein? Derived from...?

A-CAL protein Derived from calcitonin (A-CAL = CAL citonin)

Type of amyloid protein: Alzheimer's dz Protein? Derived from...?

Beta-amyloid Derived from amyloid precursor protein (APP)

Type of amyloid protein: Dialysis-associated Protein? Derived from...?

Beta-2 microglobulin Derived from MHC class I proteins.

Hypovolemic/cardiogenic shock

Low-output failure. Findings: cold, clammy pt; low cardiac output; Incr TPR.

Septic shock

High-output failure; high mixed venous pressure. Findings: hot pt, dilated arterioles, decr TPR.

Neoplastic progression: normal state, before anything goes wrong

Normal cells w/ basal --< apical differentiation <img src="220a.JPG" />

Neoplastic progression: step 1 Hyperplasia/dysplasia

Cells have increased in # (hyperplasia ) Abnormal proliferation of cells w/ loss of size, shape, and orientation (dysplasia ) <img src="220b.JPG" />

Neoplastic progression: step 2 In situ carcinoma

Neoplastic cells hae not invaded basement membrane. High nuclear/cytoplasmic ratio and clumped chromatin Neoplastic cells encompass entire thickness Tumor cells are monoclonal <img src="220c.JPG" />

Neoplastic progression: step 3 Invasive carcinoma

Cells have invaded basement membrane using collagenases and hydrolases Can metastasize if they reach a blood or lymphatic vessel <img src="220d.JPG" />

Neoplastic progression: step 4 Metastasis

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... Angiogenesis allows for tumor survival Decr cadherin, incr laminin, integrin receptors <img src="220e.JPG" />

Hyperplasia

Incr in # of cells. Reversible.

Metaplasia

1 adult cell type is replaced by another. Often 2' to irritation and/or environmental exposure (e.g., squamous metaplasia in trachea and bronchi of smokers) Reversible.

Dysplasia

Abnormal growth w/ loss of cellular orientation, shape, and size in comparizon to normal tissue maturation; commonly preneoplastic. Reversible.

Anaplasia

Abnormal cells lacking differentiation; like primitive cells of the same tissue, often equated w/ undifferentiated malignant neoplasms. Little or no resemblance to tissue of origin. Irreversible.

Neoplasia

A clonal proliferation of cells that is uncontrolled and excessive. Irreversible.

Desmoplasia

Fibrous tissue formation in response to a neoplasm. Irreversible.

Tumor grade

Degree of cellular differentiation based on histologic appearance of tumor. Usually graded I-IV based on degree of differentiation and number of mitoses per high-power field; character of tumor itself.

Tumor stage

Degree of localization/spread based on site and size of 1' lesion, spread to regional LNs, presence of metastases; spread of tumor in a specific pt. S tage = S pread

TNM staging system

T = size of T umor N = N ode involvement M = M etastases

Which usually has more prognostic value, tumor stage or grade?

Usually stage < grade

Tumor nomenclature: Epithelium What do you call a benign tumor of this tissue? .. a malignant one?

Benign: Adenoma, papilloma Malignant: Adenocarcinoma, papillary carcinoma

Tumor nomenclature: Blood cells What do you call a benign tumor of this tissue? .. a malignant one?

Benign: -- Malignant: Leukemia, lymphoma

Tumor nomenclature: Blood vessels What do you call a benign tumor of this tissue? .. a malignant one?

Benign: hemangioma Malignant: Angiosarcoma

Tumor nomenclature: Smooth muscle What do you call a benign tumor of this tissue? .. a malignant one?

Benign: Leiomyoma Malignant: Leiomyosarcoma

Tumor nomenclature: Skeletal muscle What do you call a benign tumor of this tissue? .. a malignant one?

Benign: Rhabdomyoma Malignant: Rhabdomyosarcoma

Tumor nomenclature: Bone What do you call a benign tumor of this tissue? .. a malignant one?

Benign: Osteoma Malignant: osteosarcoma

Tumor nomenclature: Fat What do you call a benign tumor of this tissue? .. a malignant one?

Benign: lipoma Malignant: liposarcoma

Tumor nomenclature: < 1 cell type What do you call a benign tumor of this tissue? .. a malignant one?

Benign: mature teratoma (women) Malignant: immature teratoma and mature teratoma (men)

Carcinoma vs. sarcoma

Carcinoma = epithelial origin Sarcoma = mesenchymal origin (blood vessels, muscle, bone, fat, etc.) Both imply malignancy

Benign

Usually well-differentiated, slow growing, well-demarcated, no metastasis.

Malignant

May be poorlly differentiated, erratic growth, locally invasive/diffuse, may metastasize.

Dz: Down syndrome What is the associated neoplasm?

ALL (we ALL fall Down ) AML

Neoplasm: ALL (we ALL fall Down ) AML With what dz is this associated?

Down syndrome

Dz: Xeroderma pigmentosum, albinism What is the associated neoplasm?

Melanoma, basal cell carcinoma, and esp. squamous cell carcinomas of the skin

Neoplasm: Melanoma, basal cell carcinoma, and esp. squamous cell carcinomas of the skin With what dz is this associated?

Xeroderma pigmentosum, albinism

Dz: Chronic atrophic gastritis, pernicious anemia, postsurgical gastric remnants What is the associated neoplasm?

Gastric adenocarcinoma

Neoplasm: Gastric adenocarcinoma With what dz is this associated?

Chronic atrophic gastritis, pernicious anemia, postsurgical gastric remnants

Dz: Tuberous sclerosis (facial angiofibroma, seizures, mental retardation) What is the associated neoplasm?

Astrocytoma, angiomyolipoma, and cardiac rhabdomyoma

Neoplasm: Astrocytoma, angiomyolipoma, and cardiac rhabdomyoma With what dz is this associated?

Tuberous sclerosis (facial angiofibroma, seizures, mental retardation)

Dz: Actinic keratosis What is the associated neoplasm?

Squamous cell carcinoma of the skin

Neoplasm: Squamous cell carcinoma of the skin With what dz is this associated?

Actinic keratosis

Dz: Barrett's esophagus (chronic GI reflux) What is the associated neoplasm?

Esophageal adenocarcinoma

Neoplasm: Esophageal adenocarcinoma With what dz is this associated?

Barrett's esophagus (chronic GI reflux)

Dz: Plummer-Vinson syndrome (atrophic gastritis, esophageal webs, anemia; all due to iron deficiency) What is the associated neoplasm?

Squamous cell carcinoma of esophagus

Neoplasm: Squamous cell carcinoma of esophagus With what dz is this associated?

Plummer-Vinson syndrome (atrophic gastritis, esophageal webs, anemia; all due to iron deficiency)

Dz: Cirrhosis (alcoholic, hepatitis B or C) What is the associated neoplasm?

Hepatocellular carcinoma

Neoplasm: Hepatocellular carcinoma With what dz is this associated?

Cirrhosis (alcoholic, hepatitis B or C)

Dz: Ulcerative colitis What is the associated neoplasm?

Colonic adenocarcinoma

Neoplasm: Colonic adenocarcinoma With what dz is this associated?

Ulcerative colitis

Dz: Paget's dz of bone What is the associated neoplasm?

Secondary osteosarcoma and fibrosarcoma

Neoplasm: Secondary osteosarcoma and fibrosarcoma With what dz is this associated?

Paget's dz of bone

Dz: Immunodeficiency states What is the associated neoplasm?

Malignant lymphomas

Neoplasm: Malignant lymphomas With what dz is this associated?

Immunodeficiency states

Dz: AIDS What is the associated neoplasm?

Aggressive malignant lymphomas (non-Hodgkin's) and Kaposi's sarcoma

Neoplasm: Aggressive malignant lymphomas (non-Hodgkin's) and Kaposi's sarcoma With what dz is this associated?

AIDS

Dz: Autoimmune dz's (e.g., Hashimoto's thyroiditis, myasthenia gravis) What is the associated neoplasm?

Benign and malignant lymphomas

Neoplasm: Benign and malignant lymphomas With what dz is this associated?

Autoimmune dz's (e.g., Hashimoto's thyroiditis, myasthenia gravis)

Dz: Acanthosis nigricans (hyperpigmentation and epidermal thickening) What is the associated neoplasm?

Visceral malignancy (stomach, lung, breast, uterus)

Neoplasm: Visceral malignancy (stomach, lung, breast, uterus) With what dz is this associated?

Acanthosis nigricans (hyperpigmentation and epidermal thickening)

Dz: Dysplastic nevus What is the associated neoplasm?

Malignant melanoma

Neoplasm: Malignant melanoma With what dz is this associated?

Dysplastic nevus

Dz: Radiation exposure What is the associated neoplasm?

Sarcoma

Neoplasm: Sarcoma With what dz is this associated?

Radiation exposure

Oncogenes

Gain of fxn --< cancer. Need damage to only 1 allele.

Oncogene: abl Associated tumor?

CML

tumor: CML What is the associated oncogene?

abl

Oncogene: c-myc Associated tumor?

Burkitt's lymphoma

tumor: Burkitt's lymphoma What is the associated oncogene?

c-myc

Oncogene: bcl-2 Associated tumor?

Follicular and undifferentiated lymphomas (inhibits apoptosis)

tumor: Follicular and undifferentiated lymphomas (inhibits apoptosis) What is the associated oncogene?

bcl-2

Oncogene: erb-B2 Associated tumor?

Breast, ovarian, and gastric carcinomas

tumor: Breast, ovarian, and gastric carcinomas What is the associated oncogene?

erb-B2

Oncogene: ras Associated tumor?

Colon carcinoma

tumor: Colon carcinoma What is the associated oncogene?

ras

Oncogene: L -myc Associated tumor?

L ung tumor

tumor: L ung tumor What is the associated oncogene?

L -myc

Oncogene: N -myc Associated tumor?

N euroblastoma

tumor: N euroblastoma What is the associated oncogene?

N -myc

Oncogene: ret Associated tumor?

Multiple endocrine neoplasia (MEN) types II and III

tumor: Multiple endocrine neoplasia (MEN) types II and III What is the associated oncogene?

ret

Oncogene: c-kit Associated tumor?

Gastrointestinal stromal tumor (GIST)

tumor: Gastrointestinal stromal tumor (GIST) What is the associated oncogene?

c-kit

Tumor suppressor genes

Loss of fxn --< cancer; both allels must be lost for expression of dz.

Tumor suppressor gene: Rb chromosome? Associated tumor?

Chr. 13q Assoc.: Retinoblastoma, osteosarcoma

Chr. 13q Assoc.: Retinoblastoma, osteosarcoma What is the tumor suppressor gene?

Rb

Tumor suppressor gene: BRCA1 chromosome? Associated tumor?

Chr. 17q Assoc.: Breast and ovarian cancer

Chr. 17q Assoc.: Breast and ovarian cancer What is the tumor suppressor gene?

BRCA1

Tumor suppressor gene: BRCA2 chromosome? Associated tumor?

Chr. 13q Assoc: breast cancer

Chr. 13q Assoc: breast cancer What is the tumor suppressor gene?

BRCA2

Tumor suppressor gene: p 53 chromosome? Associated tumor?

Chr. 17p Assoc: most human cancers (crap!), Li-Fraumeni syndrome

Chr. 17p Assoc: most human cancers (crap!), Li-Fraumeni syndrome What is the tumor suppressor gene?

p 53

Tumor suppressor gene: p 16 chromosome? Associated tumor?

Chr. 9p Assoc: Melanoma ("MelaN oma is N ine")

Chr. 9p Assoc: Melanoma ("MelaN oma is N ine") What is the tumor suppressor gene?

p 16

Tumor suppressor gene: APC chromosome? Associated tumor?

Chr. 5q Assoc: Colorectal cancer (assoc w/ FAP)

Chr. 5q Assoc: Colorectal cancer (assoc w/ FAP) What is the tumor suppressor gene?

APC

Tumor suppressor gene: WT1 chromosome? Associated tumor?

Chr. 11p Assoc: Wilms' tumor

Chr. 11p Assoc: Wilms' tumor What is the tumor suppressor gene?

WT1

Tumor suppressor gene: NF1 chromosome? Associated tumor?

Chr. 17q Assoc: Neurofibromatosis type 1

Chr. 17q Assoc: Neurofibromatosis type 1 What is the tumor suppressor gene?

NF1

Tumor suppressor gene: NF2 chromosome? Associated tumor?

Chr. 22q Assoc: Neurofibromatosis 2 ("Type 2 = 22")

Chr. 22q Assoc: Neurofibromatosis 2 ("Type 2 = 22") What is the tumor suppressor gene?

NF2

Tumor suppressor gene: DPC chromosome? Associated tumor?

Chr. 18q Assoc: Pancreatic cancer [DPC = D eleted in P ancreatic C ancer"]

Chr. 18q Assoc: Pancreatic cancer

[DPC = D eleted in P ancreatic C ancer"] What is the tumor suppressor gene? DPC

Tumor suppressor gene: DCC chromosome? Associated tumor?

Chr. 18q Assoc: Colon cancer [DCC = D eleted in C olon C ancer]

Chr. 18q Assoc: Colon cancer

[DCC = D eleted in C olon C ancer] What is the tumor suppressor gene? DCC

How should tumor markers be used clinically?

Tumor markers should not be used as the primary tool for cancer Dx. They may be used to confirm Dx, to monitor for tumor recurrence, and to monitor response to therapy.

Tumor markers: PSA

Prostate-Specific Ag. Used to screen for prostate carcinoma. Can also be elevated in BPH and prostatitis.

Tumor markers: Prostatic acid phospatase

Prostate carcinoma.

Tumor markers: CEA

Carcinoembryonic Ag. Very nonspecific, but produced by ~70% of colorectal and pancreatic cancers; also produced by gastric and breast carcinomas.

Tumor markers: alpha-fetoprotein

Normally made by fetus. Hepatocellular carcinomas. Nonseminomatous germ cell tumors of the testis (e.g., yolk sac tumor)

Tumor markers: Beta-hCG

"HCG" H ydatidiform moles C horiocarcinomas G estational trophoblastic tumors

Tumor markers: CA-125

Ovarian, malignant epithelial tumors

Tumor markers: S-100

Melanoma, neural tumors, astrocytomas.

Tumor markers: Alkaline phosphatase

Metastases to bone, obstructive biliary dz, Paget's dz of bone.

Tumor markers: Bombesin

Neuorblastoma, lung, and gastric cancer.

Tumor markers: TRAP

Tartrate-resistant acid phosphatase. Hairy cell leukemia -- a B-cell neoplasm. "TRAP the hairy animal."

Tumor markers: CA-19-9

Pancreatic adenocarcinoma

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