Pathology

ATP-dependent programmed cell death- Intrinsic and extrinsic pathways; both pathways activate caspases (cytosolic proteases) → cellular breakdown including cell shrinkage, chromatin condensation, membrane blebbing, and formation of apoptotic boides, which are then phagocytosed.- Characterized by deeply eosinophilic cytoplasm and basophilic nucleus, pyknosis (nuclear shrinkage), and karyorrhexis (fragmentation caused by endonuclease-mediated cleavage).- Cell membrane typically remains intact without significant inflammation.- DNA laddering (fragments in multiples of 180 bp) is a sensitive indicator of apoptosis.

Enzymatic degradation and protein denaturation of cell due to exogenous injury → intracellular components leak. Inflammatory process.

Red infarct: Red (hemorrhagic) infarcts occur in venous occlusion and tissues with multiple blood supplies such as liver, lung, intestine, testes; reperfusion. Reperfusion injury is due to damage by free radiacals. Pale infarct: Pale (anemic) infarcts occur in solid organs with a single (end-arterial) blood supply, such as heart, kidney, and spleen.

Response to eliminate initial cause of cell injury, to remove necrotic cells resulting from the original insult, and to initiate tissue repair. The inflammatory response itself can be harmful to the host if the reaction is excessive (eg, septic shock), prolonged (eg, persistent infections such as TB), or inappropriate (eg, autoimmune diseases such as SLE). Rubor (redness), calor (warmth): Vasodilation → ↑ blood flow- Histamine, prostaglandins bradykinin Dolor (pain): Sensitization of sensory nerve endings- Bradykinin, PGE2 Tumor (swelling): Endothelial contraction/disruption (eg, from tissue damage) → ↑ vascular permeability → leakage of protein rich fluid from postcapillary venules into interstitial space → ↑ oncotic pressure- Endothelial contraction: leukotriens (C4, D4, E4), histamine, serotonin Functio laesa (loss of function)

Dystrophic calcification- Ca2+ deposition: In abnormal tissues- Extent: Tends to be localized (eg, calcific aortic stenosis)- Associated conditions: TB (lung and pericardium) and other granulomatous infections, liquefactive necrosis of chronic abcesses, fat necrosis, infarcts, thrombi, schistosomiasis, congenital CMV, toxoplasmosis, rubella, psamomma bodies, CREST syndrome, atherosclerotic plaques- Etiology: 2° to injury or necrosis- Serum Ca2+ levels: Patients are usually normocalcemic Metastatic calcification- Ca2+ deposition: In normal tissues- Extent: Widespread (ie, diffuse, metastatic)- Associated conditions: Predominantly in interstitial tissues of kidney, lung, and gastric mucosa (these tissues lose acid quickly; ↑ pH favors Ca2+ deposition)- Nephrocalcinosis of collecting ducts may lead to nephrogenic diabetic insipidus and renal failure.- Etiology: 2° to hypercalcemia (eg, 1° hyperparathyroidism, sarcoidosis, hypervitaminosis D) or high calcium-phosphate product levels (2° hyperparathyroidism, long-term dialysis, calciphylaxis, multiple myeloma)- Serum Ca2+ levels: Patients usually have abnormal serum Ca2+ levels

Extravasation predominantly occurs at postcapillary venules. WBCs exit from blood vessels at site of tissue injury and inflammation in 4 steps: 1. Margination and rolling (vasculature/stroma – leukocyte)- E-selectin (upregulated by TNF and IL-1) – Sialyl-Lewis- P-selectin (released from Weibel-Palade bodies) – Sialyl-Lewis- GlyCAM-1, CD34 – L-selectin- Defective in leukocyte adhesion deficiency type 2 (↓ Sialyl-Lewis) 2. Tight binding (adhesion) (vasculature/stroma – leukocyte)- ICAM (CD54) – CD11/18 integrins (LFA-1)- VCAM-1 (CD106) – VLA-4 integrin- Defective in leukocyte adhesion deficiency type 1 (↓ CD18 integrin subunit) 3. Diapedesis (transmigration): WBC travels between endothelial cells and exits blood vessels- PECAM-1 (CD31) – PECAM-1 (CD31) 4. Migration: WBC travels through interstitium to site of injury or infection guided by chemotactic signals- Chemotactic products released in response to bacteria: C5a, IL-8, LTB4, kallikrein, platelet-activating factor

Occurs when repair cannot be accomplished by cell regeneration alone. Nonregenerated cells (2° to severe acute or chronic injury) are replaced by connective tissue. 70-80% of tensile strength regained at 3 months; little thereafter. Hypertrophid:- Collagen synthesis: ↑ (type III collagen)- Collagen organization: Parallel- Extent of scar: Confined to borders of original wound- Recurrence: Infrequent Keloid- Collagen synthesis: ↑↑↑ (disoranized types I and III collagen)- Collagen organization: Disorganized- Extent of scar: Extends beyond borders of original wound with "claw-like" projections typically on earlobes, face, upper extremities- Recurrence: Frequent- ↑ incidence in ethnic groups with darker skin

Tissue mediators:- PDGF: Secreted by activated platelets and macrophages. Induces vascular remodeling and smooth muscle cell migration.- FGF: Stimulates angiogenesis- EGF: Stimualtes cell growth via tyrosine kinases- TGF-β: Angiogenesis, fibrosis- Metalloproteinases: Tissue remodeling- VEGF: Stimulates angiogenesis Phases of wound healing:Inflammatory (up to 3 days after wound)- Platelets, neutrophils, macrophages- Clot formation, ↑ vessel permeability and neutrophil migration; macrophages clear debris 2 days laterProliferative (day 3-weeks after wound)- Fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages- Deposition of granulation tissue and type III collagen, angiogenesis, endothelial cell proliferation, dissolution of clot, wound contraction- Delayed wound healing in vitamin C deficiency and copper deficiencyRemodeling (1 week-6+ months after wound)- Fibroblasts- Type III collagen replaced by type I collagen, ↑ tensile strength of tissue- Collagenases (require zinc to function) break down type III collagen- Zinc deficiency → delayed wound healing

Bacterial:- Mycobacteria (tuberculosis, leprosy)- Bartonella henselae (cat scratch disease)- Listeria monocytogenes (granulomatosis infantisepcica)- Treponema pallidum (3° syphilis) Fungal: endemic mycoses (eg, histoplasmosis) Parasitic: schistosomiasis Chronic granulomatous diseaseAutoinflammatory:- Sarcoidosis- Crohn disease- Primary biliary cirrhosis- Subacute (de Quervain/granulomatous) thyroiditis- Granulomatosis with polyangiitis (Wegener)- Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)- Giant cell (temporal) arteritis- Takayasu arteritis Foreign material: berylliosis, talcosis, hypersensitivity pneumonitis

Transudate:- Hypocellular (clear)- ↓ protein (<2.5 g/dL)- Due to: ↑ hydrostatic pressure (eg, HF, Na+ retention), ↓ oncotic pressure (eg, cirrhosis, nephrotic syndrome) Exudate:- Cellular (cloudy)- ↑ protein (>2.9 g/dL)- Due to: Lymphatic obstruction (chylous), inflammation/infection, malignancy Light criteriaPleural effusion is exudative if ≥1 of the following criteria is met:- Pleural effusion protein/serum protein ratio >0.5- Pleural effusion LDH/serum LDH ratio >0.6- Pleural effusion LDH >2/3 of the upper limit of normal for serum LDH

Products of inflammation (eg, fibrinogen) coat RBCs and cause aggregation. The denser RBC aggregates fall at a faster rate within a pipette tube → ↑ ESR. Often co-tested with CRP levels. ↑ ESR- Most anemias- Infections- Inflammation (eg, giant cell arteritis, polymyalgia rheumatica)- Cancer (eg, metastases, multiple myeloma)- Renal disease- Pregnancy ↓ ESR- Sickle cell anemia (altered shape)- Polycythemia (↑ RBCs "dilute" aggregation factors)- HF- Microcytosis- Hypofibrinogenemia

- Primary amyloidosis: AL from Ig Light chains. Seen in plasma cell disorders and multiple myeloma. - Secondary amyloidosis (Serum Amyloid A, AA): Seen in chronic inflammatory conditions, eg, rheumatoid arthritis, IBD, familial Mediterranean fever, protracted infection.  - Dialysis-related amyloidosis (β2-microglobulin): Seen in patients with ESRD and/or on long-term dialysis.  Manifestations:- Cardiac (eg, restrictive cardiomyopathy, arrhythmia)- GI (eg, macroglossia, hepatomegaly)- Renal (eg, nephrotic syndrome)- Hematologic (eg, easy bruising, splenomegaly)- Neurologic (neuropathy)- Musculoskeletal (carpal tunnel syndrome)

A yellow-brown "wear and tear" pigment associated with normal aging.Insoluble pigment composed of lipid polymers and protein-complexed phospholipids. Formed by oxidation and polymerization of autophagocytosed organellar membranes. Is a product of free radical injury and lipid peroxidization. Autopsy of elderly person will reveal deposits in heart, colon, liver, kidney, eye, and other organs.

Differentiation – degree to which a tumor resembles its tissue of origin.Anaplasia – complete lack of differentiation of cells in a malignant neoplasm. Grade: Degree of cellular differentiation and mitotic activity on histology. Range from low-grade (well differentiated) to high grade (poorly differentiated, undifferentiated or anaplastic). Stage: Degree of localization/spread based on site and size of 1° lesion, spread to regional lymph nodes, presence of metastases. Based on clinical (c) or pathology (p) findings.- Stage generally has more prognostic value than grade.- Each TNM factor has independent prognostic value; N and M are often most important.

Cancer incidence:Men:1. Prostate2. Lung3. Colon/rectumWomen:1. Breat2. Lung3. Colon/rectumChildren:1. Leukemia2. Brain and CNS3. Neuroblastoma

Anti-NMDA receptor encephalitis: Psychiatric disturbance, memory deficits, seizures, dyskinesias, autonomic instability, language dysfunction- Ovarian teratoma Opsoclonus-myoclonus ataxia syndrome: "Dancing eyes, dancing feet"- Neuroblatoma (children), small cell lung cancer (adults) Paraneoplastic cerebellar degeneration: Antibodies against antigens in Purkinje cells- Small cell lung cancer (anti-Hu), gynecologic and breast cancers (anti-Yo), and Hodgkin lymphoma (anti-Tr) Paraneoplastic encephalomyelitis:  Antibodies against Hu antigens in neurons- Small cell lung cancer Lambert-Eaton myasthenic syndrome: Antibodies against presynaptic (P/Q-type) Ca2+ channels at NMJ- Small cell lung cancer Myasthenia gravis: Antibodies against polysynaptic ACh receptors at NMJ- Thymoma

Polycythemia: ↑ Erythropoietin- Pheochromocytoma, renal cell carcinoma, hepatocellular carcinoma, hemangioblastoma, leiomyoma Pure red cell aplasia: Anemia with low reticulocytes- Thymoma Good syndrome: Hypogammaglobulinemia- Thymoma Trousseau syndrome: Migratory superficial thrombophlebitis- Adenocarcinomas, especially pancreatic Nonbacterial thrombotic (marantic) endocarditis: Deposition of sterile platelet thrombi on heart valves- Adenocarcinomas, especially pancreatic

Hypercalcemia: PTHrP- Squamous cell carcinomas of lung, head, and neck; renal, bladder, breast, and ovarian carcinomas↑ 1,25-(OH)2 vitamin D3 (calcitriol)- Lymphoma Cushing syndrome: ↑ ACTH- Small cell lung cancer Hyponatremia (SIADH): ↑ ADH- Small cell lung cancer

Gain of function mutation converts proto-oncogene (normal gene) to oncogene → ↑ cancer risk. Need damage to only one allele. ALK: Receptor tyrosine kinase- Lung adenocarcinoma BCR-ABL: Tyrosine kinase- CML, ALL BCL-2: Antiapoptotic molecule (inhibits apoptosis)- Follicular and diffuse large B cell lymphomas BRAF: Serine/threonine kinase- Melanoma, non-Hodgkin lymphoma, papillary thyroid carcinoma c-KIT: Cytokine receptor- Gastrointestinal stromal tumor (GIST) c-MYC: Transcription factor- Burkitt lymphoma HER2/c-erbB2: Receptor tyrosine kinase- Breast and gastric carcinomas JAK2: Tyrosine kinase- Chronic myeloproliferative disorders KRAS: GTPase- Colon cancer, lung cancer, pancreatic cancer MYCL1: Transcription factor- Lung tumor N-myc: Transcription factor- Neuroblastoma RET: Receptor tyrosine kinase- MEN 2A and 2B, papillary thyroid cancer

Loss of function → ↑ cancer risk; both alleles must be lost for expression of disease. APC: Negative regulator of β-catenin/WNT pathway- Colorectal cancer (associated with FAP) BRCA1/BRCA2: DNA repair protein- Breat, ovarian, and pancreatic cancer CDKN2A: p16, blocks G1 → S phase- Melanoma, pancreatic cancer DCC: Deleted in Colon Cancer SMAD4 (DPC4): Deleted in Pancreatic Cancer MEN1: Menin NF1: Neurofibromin (Ras GTPase activating protein) NF2: Merlin (schwannomin) protein PTEN: Negatively regulates PI3k/AKT pathway- Breast cancer, prostate cancer, endometrial cancer Rb: Inhibits E2F; blocks G1 → S phase- Retinoblastoma, osteosarcoma TP53: p53, activates p21, blocks G1 → S phase- Most human cancers, Li-Fraumeni syndrome (multiple malignancies at early age, aka, SBLA cancer syndrome: Sarcoma, Breast, Leukemia, Adrenal gland) TSC1: Hamartin protein; TSC2: Tuberin protein- Tuberous sclerosis VHL: Inhibits hypoxia inducible factor 1a WT1: Transcription factor that regulates urogenital development- Wilms tumor (nephroblastoma)

EBV: Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, 1° CNS lymphoma (in immunocompromised patients) HBV, HCV: Hepatocellular carcinoma HHV-8: Karposi sarcoma HPV: Cervical and penile/anal carcinoma, head and nek cancer H pylori: Gastric adenoma and MALT lymphoma HTLV-1: Adult T-cell leukemia/lymphoma Liver fluke (Clonorchis sinensis): Cholangiocarcinoma Schistosoma haematobium: Bladder cancer (squamous cell)

Laminated, concentric spherules with dystrophic calcification. Seen in:- Papillary carcinoma of thyroid- Serous papillary cystadenocarcinoma of ovary- Meningioma- Mesothelioma

Alkaline phosphatase: - Metastases to bone or liver, Paget disease of bone, seminoma (placental ALP) α-fetoprotein:- Hepatocellular carcinoma, hepatoblastoma, yolk sac tumor, mixed germ cell tumor, ataxia-telangectasia- High levels associated with neural tube and abdominal wall defects- Low levels associated with Down syndrome β-hCG:- Hydatidiforme moles and choriocarcinomas, testicular cancer, mixed germ cell tumor CA15-3/CA27-29: Breast cancer Ca19-9: Pancreatic adenocarcinoma Ca125: Ovarian cancer Calcitonin: Medullary thyroid carcinoma (alone and in MEN2A, MEN2B) CEA: Carcinoembryonic antigen. Very nonspecific.- Major associations: Colorectal and pancreatic cancers- Minor associations: Gastric, breast, and medullary thyroid carcinomas Chromogranin: Neuroendocrine tumors LDH: Testicular germ cell tumors, ovarian dysgerminoma, other cancers- Can be used as an indicator of tumor burden. PSA: Prostate cancer- Can also be elevated in BPH and prostatitis

Most sarcomas spread hematogenously; most carcinomas spread via lymphatics. 4 carcinomas that route hematogenously: - Follicular thyroid carcinoma- choriocarcinoma- Renal cell carcinoma- Hepatocellular carcinoma Brain: Lung > breast > melanoma, colon, kidney- 50% of brain tumors are from metastases- Commonly seen as multiple well-circumscribed tumors at gray/white matter junction. Liver: Colon >> stomach > pancreas Bone: Prostate (blastic), breast (mixed) > lung (lytic), thyroid (lytic), kidney (lytic)

Reversible:- Cellular/mitochondrial swelling (↓ ATP → ↓ activity of Na+/K+ and Ca2+ pumps)- Ribosomal/polysomal detachment (↓ protein synthesis)- Membrane blebbing- Nuclear chromatin clumping Irreversible:- Rupture of lysosomes and autolysis- Plasma membrane damage (degradation of membrane phospholipid) → leakage of cytosolic enzymes into serum, influx of Ca2+ activating lysosomal enzymes- Nucleus: pyknosis (condensation), karyorrhexis (fragmentation) or karyolysis (fading)- ↑ Mitochondrial permeability

- Involved in tissue remodeling in embryogenesis. Occurs when a regulating factor is withdrawn from a proliferating cell population (eg, ↓ IL-2 after a completed immunologic reaction → apoptosis of proliferating effector cell). Also occurs after exposure to injurious stimuli (eg, radiation, toxins, hypoxia). - Regulated by Bcl-2 family of proteins. BAX and BAK are proapoptotic, while Bcl-2 and Bcl-xL are antiapoptotic. - BAX and BAK form pores in the mitochondrial membrane → release of cytochrome C from inner mitochondrial membrane into the cytoplasm → activation of caspases. - Bcl-2 keeps the mitochondrial outer membrane impermeable, thereby preventing cytochrome C release from the inner mitochondrial matrix. Bcl-2 overexpression (eg, follicular lyphoma t[14;18]) → ↓ caspase activation → tumorigenesis.

2 pathways:- Ligand receptor interactions (FasL binding to Fas or TNF-α binding to its receptor)- Immune cell (cytotoxic T-cell release of perforin and granzyme B) - Fas-FasL interaction is necessary in thymic medullary negative selection. Mutations in Fas ↑ numbers of circulating self-reacting lymphocytes due to failure of clonal deletion. - Defective Fas-FasL interactions cause autoimmune lymphoproliferative syndrome.

Ischemia/infarcts in most tissues (except brain), eg, heart, liver, kidney. - Ischemia or infarction; injury denatures proteins denatures enzymes → proteolysis blocked Histology:- Preserved cellular architecture (cell outlines seen) but nuclei disappear- ↑ cytoplasmatic binding of eosin stain (→ ↑ eosinophilia; red/pink color)

Bacterial abscesses, brain infarcts - Neutrophils release lysosomal enzymes that digest the tissue Histology:- Early: cellular debris and macrophages- Late: cystic spaces and cavitation (brain)- Neutrophils and cell debris seen with bacterial infection

TB, systemic fungi (eg, Histoplasma capsulatum), Nocardia - Macrophages wall off the infecting microorganism → granular debris Histology:- Fragmented cells and debris surrounded by lymphocytes and macrophages (granuloma)

Enzymatic: acute pancreatitis (saponification of peripancreatic fat)Nonenzymatic: traumatic (eg, injury to breat tissue) - Damaged cells release lipase, which breaks down triglycerides; liberated fatty acids bind calcium → saponification Histology:- Outlines of dead fat cells without peripheral nuclei- Saponifcation of fat (combined with Ca2+) appears dark blue on H&E stain

Immune reactions in vessels (eg, polyarteriitis nodosa), preeclampsia, hypertensive emergency - Immune complexes combine with fibrin → vessel wall damage (type III hypersensitivity) Histology:- Vessel walls are thick and pink

Distal extremity and GI tract, after chronic ischemia Dry: ischemia- Histology: coagulative Wet: superinfection- Histology: liquefactive superimposed on coagulative

Inadequate blood spply to meet demand. Mechanisms include ↓ arterial perfusion (eg, atherosclerosis), ↓ venous drainage (eg, testicular torsion, Budd-Chiari syndrome), and shock. Brain – ACA/MCA/PCA boundary areasHeart – Subendocardium (LV)Kidney – Straight segment of proximal tubule (medulla), thick ascending limb (medulla)Liver – Area around central vein (zone III)Colon – Splenic flexure, rectum - Watershed areas (border zones) receive blood supply from most distal branches of 2 arteries with limited collateral vascularity. These areas are susceptible to ischemia from hypoperfusion.- Neurons most vulnerable to hypoxic-ischemic insults include Purjinke cells of the cerebellum and pyramidal cells of the hippocampus and neocortex (zones 3, 5, 6).

Red infarct: Red (hemorrhagic) infarcts occur in venous occlusion and tissues with multiple blood supplies.- Liver- Lungs- Intestine- Testicles- Reperfusion (eg, after angioplasty). Reperfusion injury is due to damage by free radicals.Red = reperfusion Pale infarct: Pale (anemic) infarcts occur in solid organs with a single (end-arterial) blood supply.- Heart- Kidney- Spleen

Fever: Pyrogens (eg, LPS) induce macrophages to release IL-1 and TNF → ↑ COX activity in perivascular cells and hypothalamus → ↑ PGE2 → ↑ temperature set point Leukocytosis: Elevation of WBC count. Type of cell that is predominantly elevated depends on the inciting agent or injury (eg, bacteria → ↑ neutrophils) - Leukemoid reaction – severe elevation in WBC (>40,000 cells/mm3) caused by some stressors or infections (eg, Clostridium difficile). ↑ plasma acute-phase proteins: Factors whose serum concentrations change significantly in response to inflammation. Produced in the liver in both acute and chronic inflammatory states.- Notably induced by IL-6

Positive (upregulated)- Ferritin: Binds and sequesters iron to inhibit microbial iron scavenging.- C-reactive protein: Opsonin; fixes complement and facilitates phagocytosis. - Fibrinogen: Coagulation factor; promotes endothelial repair; correlates with ESR.- Serum amyloid A: Prolonged elevation can lead to amyloidosis.- Hepcidin: ↓ iron absorption (by degrading ferroportin) and ↓ iron release (from macrophages) → anemia of chronic disease Negative (downregulated)- Albumin: Reduction conserves amino acids for positive reactants.- Transferrin: Internalized by macrophages to sequester iron.

Transient and early response to injury or infection. Characterized by neutrophils in tissue, often with associated edema. Rapid onset (seconds to minutes) and short duration (minutes to days). Represents a reaction of the innate immune system (ie, less specific response than chronic inflammation). Stimuli: Infections, trauma, necrosis, foreign bodies. Mediators: Toll-like receptors, arachidonic acid metabolites, neutrophils, eosinophils, antibodies (pre-existing), mast cells, basophils, complement, Hageman factor (factor XII).- Inflammasome – cytoplasmic protein complex that recognizes products of dead cells, microbial products, and crystals (eg, uric acid crystals) → activation of IL-1 and inflammatory response. Components:- Vasodilation and ↑ endothelial permeability to bring cells and rptoeins to site of injury or infection.- Extravasation of leukocytes (mainly neutrophils) from postcapillary venules. 4 steps: margination and rolling, adhesion, transmigration, and migration (chemoattraction). Outcomes:- Resolution and healing (IL-10, TGF-β)- Persistent acute inflammation (IL-8)- Abscess (acute inflammation walled off by fibrosis)- Chronic inflammation (antigen presentation by macrophages and other APCs → activation of CD4+ Th cells)- Scarring- Macrophages predominate in the late stages of acute inflammation (peak 2-3 days after onset) and influence the outcome of acute inflammation by secreting cytokines.

Inflammation of prolonged duration characterized by infiltration of tissue by mononuclear cells (macrophages, lymphocytes, and plasma cells). Tissue structure and repair (including angiogenesis and fibrosis) occur simultaneously. May or may not be preceded by acute inflammaition. Stimuli: Persistent infections (eg, TB, T pallidum, certain fungi and viruses) → type IV hypersensitivity, autoimmune diseases, prolonged exposure to toxic agents (eg, silica) and foreign material. Mediators: Macrophages are the dominant cells. Chronic inflammation is the result of their interaction with T lymphocytes.- Th1 cells secrete IFN-γ → macrophage classical activation (proinflammatory)- Th2 cells secrete IL-4 and IL-13 → macrophage alternative activation (repair and antiinflammatory) Outcomes: Scarring, amyloidosis and neoplastic inflammation

Free radicals damage cells via membrane lipid peroxidation, protein modification, and DNA breakage.Initiated via radiation exposure (eg, cancer therapy), metabolism of drugs (phase I), redox reactions, nitric oxide (eg, inflammation), transition metals, WBC (eg, neutrophils, macrophages) oxidative burst.Free radicals can be eliminated by scavenging enzymes (eg, catalase, superoxide dismutase, glutathione peroxidase), spontaneous decay, antioxidants (eg, vitamins A, C, E), and certain metal carrier proteins (eg, transferrin, ceruloplasmin) Examples:- Oxygen toxicity: retinopathy of prematurity (abnormal vascularization), bronchopulmonary dysplasia, reperfusion injury after thrombolytic therapy- Drug/chemical toxicity: acetaminophen overdose (hepatotoxicity), carbon tetrachloride (converted by cytochrome P-450 into CCl3 free radical → fatty liver [cell injury → ↓ apolipoprotein synthesis → fatty change], centrilobular necrosis)- Metal storage diseases: hemochromatosis (iron) and Wilson disease (copper)

- Alzheimer disease: β-amyloid protein. Cleaved from amyloid precursor protein (APP) - Type 2 diabetes: Islet amyloid polypeptide (IAPP): Caused by deposition of amylin in pancreatic islets - Medullary thyroid cancer: Calcitonin (A Cal) - Isolated atrial amyloidosis (ANP): Common in normal aging, ↑ risk of atrial fibrillation - Systemic senile (age-related) amyloidosis: Normal (wild-type) transthyretin (TTR). Seen predominantly in cardiac ventricles. Cardiac dysfunction more insidious than in AL amyloidosis.

- Familial amyloid cardiomyopathy: Mutated transthyretin (ATTR) (vs normal TTR in age-related amyloidosis). Ventricular endomyocardium deposition → restrictive cardiomyopathy, arrhythmias. 5% of African Americans are carriers of mutant allele. - Familial amyloid polyneuropathies: Mutated transthyretin (ATTR). Due to transthyretin gene mutation.

- Evasion of apoptosis- Growth signal self-sufficiency- Anti-growth signal insufficiency- Warburg effect – shift of glucose metabolism away from mitochondria toward glycolysis)- Sustained angiogenesis- Limitless replicative potential- Tissue invasion- Metastasis

1. Normal cells with basal → apical polarity.  2. Dysplasia: Loss of uniformity of cell size and shape (pleomorphism); loss of tissue orientation; nuclear changes (eg, ↑ nuclear:cytoplasmic ratio) 3. Carcinoma in situ/preinvasive: Irreversible severe dysplasia that involves the entire thickness of epithelium but does not penetrate the intact basement membrane. 4. Invasive carcinoma: Cells have invaded basement membrane using collagenases and hydrolases (metalloproteinases). Cell-cell contacts lost by inactivation of E-cadherin. 5. Metastasis: Spread to distant organ(s) via lymphatics or blood. "Seed and soil" theory of metastasis. Seed = tumor embolus. Soil = target organ is often the first-encountered capillary bed.

Hamartoma: Disorganized overgrowth of tissues in their native location, eg, Peutz-Jeghers polyps. Choristoma: Normal tissue in a foreign location, eg, gastric tissue located in distal ileum in Meckel diverticulum.

Dermatomyositis: Progressive muscle weakness, Gottron papules, heliotrope rash- Adenocarcinomas, especially ovarian Acanthosis nigricans: Hyperpigmented velvety plaques in axilla and neck- Gastric adenocarcinoma and other visceral malignancies (but more commonly associated with obesity and insulin resistance) Sign of Leser-Trélat: Sudden onset of multiple seborrheic keratoses- GI adenocarcinomas and other visceral malignancies Hypertrophic osteoarthropathy: Abnormal proliferation of skin and bone at distal extremities → clubbing, arthralgia, joint effusions, periostosis of tubular bones- Adenocarcinoma of the lung

Aflatoxins (Aspergillus): Hepatocellular carcinoma- Stored grains and nuts Alkylating agents: Leukemia/lymphoma- Oncologic chemotherapy Aromatic amines (eg, benzidine, 2-naphthylamine): Transitional cell carcinoma of the bladder- Textile industry (dyes), cigarette smoke (2-naphthylamine) Arsenic: Angiosarcoma of the liver, lung cancer, squamous cell carcinoma of the skin - Herbicides (vineyard workers), metal smelting Asbestos: Bronchiogenic carcinoma > mesothelioma- Old roofing material, shipyard workers Cigarette smoke: Bladder, cervix, esophagus, kidney (renal cell carcinoma), larynx, lung (squamous cell and small cell carcinoma), pancreas Ethanol: Squamous cell carcinoma of the esophagus, hepatocellular carcinoma Ionizing radiation: Papillary thyroid carcinoma Nitrosamines: Gastric cancer- Smoked foods Radon: Lung cancer (2nd leading cause after cigarette smoke)- By-product of uranium decay, accumulates in basements Vinyl chloride: Angiosarcoma of the liver- Used to make PVC pipes (plumbers)

Determine primary site of origin for metastatic tumors and characterize tumors that are difficult to classify. Can have prognostic and predictive value. Vimentin: Mesenchymal tissue (eg, fibroblasts, endothelial cells, macrophages)- Mesenchymal tumors (eg, sarcoma), but also many others (eg, endometrial carcinoma, renal cell carcinoma, meningeoma) S-100: Neural crest cells- Melanoma, schwannoma, Langerhans cell histiocytosis Desmin: Muscle- Muscle tumors (eg, rhabdomyosarcoma) Cytokeratin: Epithelial cells- Epithelial tumors (eg, squamous cell carcinoma) GFAP: Neuroglia (eg, astrocytes, Schwann cells, oligodendrocytes)- Astrocytoma, glioblastoma Neurofilament: Neurons- Neuronal tumors (eg, neuroblastoma) PSA: Prostatic epithelium- Prostate cancer TRAP: Tartrate-resistant acid phosphatase- Hairy cell leukemia Chromogranin and synaptophysin: Neuroendocrine cells- Small cell carcinoma of the lung, carcinoid tumor

Also known as multidrug resistance protein 1 (MDR1).Transmembrane protein that functions as an ATP-dependent efflux pump.  Classically seen in adrenocortical carcinoma but also expressed by other cancer cells (eg, colon, liver). Used to pump out toxins, including chemotherapeutic agents (one mechanism of ↓ responsiveness to chemotherapy over time).

Weight loss, muscle atrophy, and fatigue that occur in chronic disease (eg, cancer, AIDS, heart failure, COPD). Mediated by TNF-α, IFN-γ, IL-1, and IL-6.