General Pathology

Etiology: Hypoxia/ischemia (most common), physical agents (trauma, temperature, radiation), chemical agents (drugs, toxins, pollution), infectious agents (viruses, bacteria, fungi, parasites), immunologic reactions (hypersensitivity, autoimmune), genetic defects (inborn errors, mutations), nutritional imbalances (deficiency/excess), aging. ATP depletion: hallmark of ischemic/hypoxic injury. Loss of Na+/K+ ATPase → cellular swelling. Failure of Ca2+ ATPase → Ca2+ influx → activation of enzymes (phospholipases, proteases, endonucleases, ATPases). Reactive oxygen species (ROS): superoxide (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH-). Sources: mitochondria (ETC leak), peroxisomes, inflammatory cells (NADPH oxidase), xenobiotic metabolism (P450), radiation. Defenses: superoxide dismutase (SOD), glutathione peroxidase, catalase, vitamin E/C. Calcium dysregulation: influx → mitochondrial damage, enzyme activation, cytoskeletal damage. Membrane damage: loss of selective permeability. DNA damage: p53 activation → cell cycle arrest/apoptosis.

Reversible: cellular swelling (hydropic change, vacuolation), fatty change (steatosis), blebbing, loss of microvilli, ribosome detachment, chromatin clumping. Irreversible: inability to reverse mitochondrial dysfunction (MPT pore opening, loss of cytochrome c), severe membrane damage. Morphology: mitochondrial vacuolation (flocculent densities), nuclear changes (pyknosis → karyorrhexis → karyolysis), myelin figures, enzyme leakage (CK, LDH, troponin).

Coagulative necrosis: most common. Denatured proteins preserve architecture. Heart, kidney, spleen, liver (except brain). Ischemic injury (MI, renal infarct). Cell outlines preserved. Macrophages clear debris. Liquefactive necrosis: enzymatic digestion → liquid viscous mass. Brain (hypoxia/infarct → cyst). Bacterial abscesses (neutrophils). Caseous necrosis: coagulative + liquefactive. Soft, friable, cheese-like. Granulomatous inflammation. Tuberculosis. Fat necrosis: pancreatic lipases → saponification (Ca2+ + FFA → white chalky). Acute pancreatitis. Traumatic fat necrosis (breast). Gangrenous necrosis: coagulative + liquefactive. Dry (ischemic, line of demarcation). Wet (superimposed infection, putrid, sepsis). Gas gangrene (Clostridium perfringens, crepitus, α-toxin). Fibrinoid necrosis: immune complex in vessel walls (PAN, malignant HTN). Eosinophilic, smudgy.

Programmed cell death (caspase-dependent). Single cells, no inflammation. Cell shrinkage, nuclear fragmentation (apoptotic bodies), membrane blebbing, rapid phagocytosis. Intrinsic (mitochondrial) pathway: stress → pro-apoptotic BCL-2 family (BAX, BAK) form pores → cytochrome c → apoptosome (Apaf-1 + procaspase-9) → caspase-9 → executioner caspases 3,6,7. Anti-apoptotic: BCL-2, BCL-XL. BH3-only sensors (BIM, BID, BAD, PUMA, NOXA). p53 ↑ BAX/PUMA. Extrinsic (death receptor): FasL/Fas (CD95), TNF/TNFR1 → DISC → caspase-8 → caspase-3. FLIP inhibits. Execution: caspases 3,6,7 cleave DNase inhibitor, lamin, cytoskeleton. Phagocytosis: phosphatidylserine flip → MFG-E8, Gas6. Dysregulation: too little → cancer/autoimmune; too much → neurodegeneration, HIV, ischemia.

Autophagy: lysosomal degradation via autophagosome. mTOR inhibits, AMPK activates, Beclin-1, ATG family. Recycled nutrients. Excessive → type II PCD. Danon disease (X-linked vacuolar myopathy). Necroptosis: programmed necrosis, caspase-independent. TNF/RIPK1/RIPK3/MLKL → membrane rupture. Ischemia-reperfusion, pancreatitis. Pyroptosis: caspase-1 (inflammasome) → IL-1β/IL-18, gasdermin D pores. Salmonella, Shigella, Listeria.

Atrophy: decreased cell size/number. Disuse, denervation, ischemia, starvation, aging. Ubiquitin-proteasome, autophagy. Hypertrophy: increased cell size. Physiologic (muscle, uterus). Pathologic (LVH in HTN/AS, RVH in pulmonary HTN). Mechanical stretch, IGF-1, TGF-β. Hyperplasia: increased cell number. Physiologic (hormonal, compensatory liver). Pathologic (endometrial, BPH, HPV warts). Metaplasia: reversible cell type change. Squamous (bronchus → smoking), Barrett (esophagus → acid), vitamin A deficiency. Dysplasia: disordered growth, pre-neoplastic. Nuclear atypia, CIN, carcinoma in situ (full-thickness).

Lipids: steatosis (fatty liver) alcohol, NAFLD, DM, obesity, drugs (methotrexate, amiodarone, CCl4), toxins, starvation. Macrovesicular vs microvesicular (worse Reye, AFLP, valproate). Foamy macrophages (atherosclerosis). Proteins: Russell bodies (plasma cells), Mallory bodies (alcoholic liver), reabsorption droplets (renal tubules), neurofibrillary tangles (tau), Lewy bodies (α-synuclein), prion aggregates. Glycogen: DM, GSD (von Gierke, Pompe). PAS+. Pigments: Exogenous (carbon/anthracosis, tattoo). Endogenous: lipofuscin (wear-and-tear, brown atrophy), hemosiderin (iron overload, Prussian blue+), bilirubin (jaundice), melanin (excess in melanoma/Addison).

Dystrophic: dead tissue, normal Ca2+. Basophilic, psammoma bodies (papillary thyroid, meningioma, serous ovarian). Atherosclerotic plaques, old TB, AS, fat necrosis. Metastatic: normal tissue, high Ca2+. Hyperparathyroidism, malignancy, vit D excess, sarcoidosis, milk-alkali, renal failure. Sites: kidney (nephrocalcinosis), lung, stomach, vessels. Aging hallmarks: genomic instability (telomere attrition), epigenetic alterations, proteostasis loss, mitochondrial dysfunction, cellular senescence (p16INK4a, SASP), stem cell exhaustion, altered communication (inflammaging). Telomerase in germ/stem/90% cancers. Caloric restriction extends lifespan (sirtuins, AMPK, mTOR).

Vascular changes: transient vasoconstriction → vasodilation → increased blood flow (rubor, calor). Increased vascular permeability (post-capillary venules). Mechanisms: endothelial contraction (histamine, bradykinin, leukotrienes immediate transient), endothelial retraction (IL-1, TNF, VEGF delayed), direct injury (burns, toxins), leukocyte-mediated. Exudation → edema (tumor). Stasis → margination. Transudate vs exudate: transudate (low protein <3g/dL, low SG <1.012, HF/cirrhosis/nephrotic). Exudate (high protein >3g/dL, high SG >1.020, inflammatory, cellular).

Leukocyte cascade: Margination → Rolling (selectins: P-selectin, E-selectin, L-selectin) → Adhesion (integrins LFA-1/Mac-1 bind ICAM-1/VCAM-1) → Transmigration (PECAM-1/CD31) → Chemotaxis (IL-8/CXCL8, C5a, LTB4). Phagocytosis: opsonization (IgG, C3b) → engulfment → killing (ROS via NADPH oxidase, MPO → HOCl; iNOS → NO; lysosomal enzymes, defensins, NETs). Leukocyte-mediated injury: ARDS, GN, reperfusion injury, RA.

Histamine: mast cells, basophils, platelets. Vasodilation, permeability (immediate). Arachidonic acid metabolites: COX pathway (COX-1 constitutive, COX-2 induced) → PGs (PGE2 pain/fever, PGI2 vasodilation, TXA2 platelet aggregation). LOX pathway → LTB4 (chemotaxis), LTC4/D4/E4 (bronchospasm, permeability). NSAIDs inhibit COX. Corticosteroids inhibit phospholipase A2. Complement: Classical (IgM/IgG + C1, C4, C2, C3). Alternative (microbial LPS, properdin). Lectin (MBL + MASP). C3a/C5a (anaphylatoxins), C5a (chemotaxis), C3b (opsonization), C5b-9 (MAC lysis). Plasma proteases: Kinin system (bradykinin → vasodilation, pain, permeability). Coagulation/fibrinolytic. Cytokines: IL-1/TNF (fever, acute phase, cachexia, endothelial activation). IL-6 (CRP, SAA). IL-8 (neutrophil chemotaxis). IL-12 (Th1). TGF-β (anti-inflammatory, fibrosis). NO: eNOS (vasodilation), iNOS (killing). PAF: platelet aggregation, permeability. Lysosomal enzymes: elastase, collagenase, cathepsin. ROS: killing + tissue damage.

Prolonged (weeks-months). Simultaneous destruction + repair. Causes: persistent infection (TB, syphilis, fungi, viruses), autoimmune (RA, SLE, IBD, Hashimoto), toxins (silica, asbestos), hypersensitivity, allograft, atherosclerosis, obesity, Alzheimer. Cells: Macrophages (M1 pro-inflammatory, IL-12hi, iNOS; M2 anti-inflammatory, IL-10hi, arginase). Epithelioid macrophages, giant cells (Langhans TB, foreign body, Touton/xanthelasma, Aschoff/rheumatic). Lymphocytes (Th1 → IFN-γ, Th2 → IL-4/IL-5/IL-13, Th17 → IL-17, Treg → IL-10/TGF-β). Plasma cells (Russell bodies). Eosinophils (parasites, allergy). Granulomatous inflammation: epithelioid macrophages + giant cells + lymphocytes. Caseating (TB, fungal) vs non-caseating (sarcoidosis, Crohn, foreign body, berylliosis, leprosy, syphilis, cat-scratch, brucellosis, rheumatoid). Sarcoid: Schaumann bodies, asteroid bodies. TB: Langhans, caseation, Ghon complex.

Regeneration: labile cells (skin, GI, BM) & stable cells (liver, kidney, pancreas) can divide. Permanent (cardiac, neurons, skeletal) cannot. Phases: (1) Hemostasis (platelet plug, fibrin, PDGF, TGF-β). (2) Inflammation (neutrophils 24-48h, macrophages). (3) Proliferation (angiogenesis, granulation tissue, fibroblasts, ECM, re-epithelialization). (4) Remodeling (collagen cross-linking, contraction myofibroblasts, scar). Primary intention: clean, approximated, minimal scar. Secondary: large, gaping, more granulation/contraction. Tertiary: delayed primary closure. Growth factors: EGF, FGF, PDGF, VEGF, TGF-β, HGF, KGF. Complications: dehiscence, ulceration, fistula, keloid (beyond wound, genetic), hypertrophic (within wound), contracture, desmoid, proud flesh, Marjolin ulcer (SCC in chronic wound).

Angiogenesis: VEGF-A (HIF-1α), FGF, Ang-1/Tie2 (stabilize), Ang-2 (destabilize), Notch/Dll4 (tip vs stalk). Steps: vasodilation → BM degradation (MMPs) → EC migration/proliferation → tube → pericyte maturation. ECM: Collagens (I, III, IV), elastin, proteoglycans (heparan, chondroitin, hyaluronic acid), fibronectin, laminin. Integrins: αβ transmembrane linking ECM to cytoskeleton. MMPs: collagenases (MMP-1,8,13), gelatinases (MMP-2,9), stromelysins (MMP-3,10), MT-MMP (MMP-14). Activated by plasmin. Inhibited by TIMPs. Balance → ECM turnover. Excess → tissue destruction (RA, invasion, aneurysm). Deficient → fibrosis.

Hydrostatic edema: increased capillary pressure. Systemic (HF, renal failure, fluid overload, cirrhosis ascites). Local (venous thrombosis, constrictive pericarditis). Oncotic (hypoproteinemic): decreased albumin <2.5. Nephrotic syndrome (>3.5g/d proteinuria), cirrhosis (decreased synthesis), malnutrition, protein-losing enteropathy, burns. Lymphedema: impaired drainage. Filariasis (elephantiasis), neoplastic/surgical obstruction, radiation, congenital (Milroy, Noonan). Inflammatory edema: increased permeability (exudate). Myxedema: non-pitting, GAG deposition in hypothyroidism. Pulmonary edema: cardiogenic (LVF, MS) vs non-cardiogenic (ARDS). Cerebral edema: vasogenic (BBB, tumors), cytotoxic (ischemia, toxins), interstitial (hydrocephalus).

Hyperemia: active arteriolar dilation → ↑ blood flow. Red tissue. Inflammation, exercise, blushing. Congestion: passive impaired venous outflow. Blue-red. HF, venous obstruction. Chronic passive congestion: lung (brown induration heart failure cells, fibrous thickening). Liver (nutmeg liver centrilobular necrosis, sinusoidal dilation, hemorrhage, cardiac cirrhosis). Spleen (congestive splenomegaly, Gamma-Gandy bodies).

Primary hemostasis: platelet plug. Adhesion (vWF bridges GPIb to collagen), activation (ADP, TXA2, serotonin), aggregation (fibrinogen bridges GPIIb/IIIa). Secondary hemostasis: coagulation cascade. Extrinsic (TF + VIIa → X, IX). Intrinsic (XII → XI → IX + VIIIa → X). Common (Xa + Va → thrombin → fibrinogen → fibrin, crosslinked by XIIIa). Anticoagulants: ATIII (heparin cofactor), protein C/S (inactivate Va, VIIIa), TFPI. Virchow triad: endothelial injury, stasis/turbulence, hypercoagulability. Arterial thrombus: platelet-rich (white). Venous thrombus: fibrin/RBC-rich (red). Lines of Zahn: alternating platelet/fibrin + RBC layers (antemortem vs postmortem). Hypercoagulable states: Primary (Factor V Leiden, Prothrombin G20210A, ATIII def, Protein C/S def). Secondary (pregnancy, OCP, malignancy/Trousseau, surgery, immobilization, DIC, HIT, APS, nephrotic).

Thromboembolism: 90%. PE (DVT → pulmonary artery → dyspnea, pleuritic pain, hemoptysis, shock/RV strain). CT pulmonary angiogram. Anticoagulation. Thrombolysis if massive. Paradoxical embolus via ASD/PFO. Systemic: LV thrombus (MI, AFib, IE). Fat embolism: long bone fracture, orthopedic surgery. Fat globules → pulmonary microvasculature + ARDS + petechiae + thrombocytopenia. 1-3d post-injury. Supportive. Air embolism: neck/cardiac surgery, central line, decompression sickness. >100mL fatal. Left lateral decubitus (Durant), hyperbaric O2. Amniotic fluid embolism: during labor. Fetal cells in pulmonary vessels. Sudden dyspnea, shock, DIC. Mortality >60%. Supportive, delivery. Tumor embolism: RCC (IVC), HCC (portal vein). Septic embolism: IE vegetations.

White (anemic) infarct: solid organ with single end-artery (heart, kidney, spleen). Wedge-shaped. Red (hemorrhagic) infarct: venous occlusion (ovarian torsion), loose tissue (lung dual supply; liver), reperfusion. Factors: nature of vascular supply (single vs dual), rate of occlusion, tissue vulnerability (neurons 3-4min, myocytes 20-30min), O2 content. Healing: organization, granulation tissue, scar. Complications: arrhythmia, CHF, rupture, aneurysm, fibrosis.

Hypovolemic: hemorrhage, fluid loss. ↓Preload, ↓CO. Cardiogenic: pump failure (MI, arrhythmia, valvular, cardiomyopathy). ↑PCWP, ↓CO. Septic: infection → systemic inflammation → vasodilation, distributive. Warm (early) → cold (late). Cytokine storm (TNF, IL-1, NO). Most common ICU death. Neurogenic: loss of SNS tone (spinal cord injury). Bradycardia + vasodilation. Anaphylactic: IgE/mast cells → histamine, leukotrienes. Stages: compensated (tachycardia, vasoconstriction, ADH/aldosterone), progressive (lactic acidosis, vasodilation, DIC), irreversible (multi-organ failure, death). Pathology: Brain (red neurons), Heart (contraction band necrosis), Kidney (ATN), Lung (ARDS, hyaline membranes), Liver (centrilobular necrosis), Adrenal (lipid depletion). Management: ABCs, fluids, vasopressors (norepinephrine first for septic), treat cause, abx (sepsis), inotropes (cardiogenic). Surviving Sepsis Campaign 1h bundle.

Type I (IgE): IgE + allergen → mast cell degranulation → histamine, leukotrienes. Anaphylaxis, allergic rhinitis, asthma, urticaria. Phases: immediate (min) + late (4-8h, eosinophils). Type II (Antibody): IgG/IgM vs cell/ECM. Opsonization (AIHA, ITP), complement (ABO, Goodpasture), dysfunction (Graves, Myasthenia). Type III (Immune complex): complex deposition → complement → neutrophil damage. SLE, PAN, post-strep GN, serum sickness. Type IV (T-cell): DTH (CD4/Th1 → IFN-γ, macrophage activation PPD, contact dermatitis). CTL (CD8 → viral, tumor, allograft, type 1 DM).

SLE: ANA+ (98%), anti-dsDNA (nephritis), anti-Smith, anti-Ro/SSA, anti-La/SSB. Malar rash, discoid, photosensitivity, arthritis, serositis, lupus nephritis (I-VI). Drug-induced (procainamide, hydralazine, INH anti-histone). RA: symmetric polyarthritis (MCP, PIP, MTP). RF (IgM anti-Fc), anti-CCP (specific). Pannus → erosion. Extra: nodules, vasculitis, ILD, Felty (neutropenia + splenomegaly). Sjogren: anti-Ro/La, dry eyes/mouth, ↑ lymphoma (MALT). Scleroderma: limited (CREST anti-centromere). Diffuse (anti-Scl-70, skin + ILD + renal crisis + GI). Dermatomyositis: proximal weakness, CPK ↑, Gottron papules, heliotrope rash, anti-Jo-1 (ILD). Paraneoplastic (ovary, lung, breast, colon, NHL). Goodpasture: anti-GBM (collagen IV α3), crescentic GN + lung hemorrhage, linear IgG. ANCA vasculitis: GPA/Wegener (c-ANCA/PR3+, necrotizing granulomas). MPA (p-ANCA/MPO+, pauci-immune GN). Churg-Strauss (asthma, eosinophilia, p-ANCA). Amyloidosis: AL (light chains, MM, Congo red+ apple-green birefringence). AA (SAA, chronic inflammation RA, TB, FMF). ATTR (transthyretin, senile/hereditary). Organ: nephrotic, RCM, hepatomegaly, macroglossia (AL), carpal tunnel (ATTR).

SCID: T- B+/-, NK+/-, ADA deficiency, X-linked (γc). Early severe infections. DiGeorge: 22q11.2 deletion, thymic aplasia (T ↓), cardiac (conotruncal), cleft palate, hypocalcemia. CVID: low Ig, impaired antibody, sinopulmonary infections, autoimmunity, lymphoma. XLA: BTK mutation, absent B cells, low Ig, recurrent bacterial after 6mo. Hyper-IgM: CD40L/CD40 defect, normal/high IgM, low IgG/A/E, Pneumocystis, opportunistic. CGD: NADPH oxidase ↓, catalase+ infections (S. aureus, Serratia, Nocardia, Aspergillus). DHR test. LAD: CD18 integrin defect, delayed cord separation, no pus. Ataxia-telangiectasia: ATM mutation, ataxia, telangiectasias, IgA ↓, radiosensitivity, lymphoma. Wiskott-Aldrich: WAS mutation, eczema, thrombocytopenia (small platelets), recurrent infections, IgA/IgE ↑, IgM ↓.

HIV: Retrovirus (gp120 + CD4 + CCR5/CXCR4). Targets CD4+ T cells, macrophages, microglia. Acute retroviral syndrome (fever, lymphadenopathy, rash). Latency → AIDS (CD4 <200). OIs by CD4: <200: PCP (TMP-SMX), Toxoplasma (ring-enhancing, pyrimethamine + sulfadiazine). <100: Cryptococcus (CrAg, amphotericin + flucytosine), CMV (ganciclovir), MAC (clarithromycin + ethambutol + rifabutin). <50: PML (JC virus, no specific therapy). AIDS malignancies: Kaposi (HHV-8), NHL (DLBCL, primary CNS EBV+), cervical (HPV). ART: NRTI + INSTI (dolutegravir, bictegravir). Goal: undetectable (<20). PrEP: TDF/FTC. PEP: within 72h, 3 drugs, 28d. IRIS: paradoxical worsening after ART. Treat OI + steroids. HIVAN: collapsing FSGS, APOL1, Black race.

Benign: -oma (adenoma, papilloma, lipoma, leiomyoma, chondroma, osteoma, hemangioma, meningioma). Malignant: carcinoma (epithelial adenocarcinoma, SCC, TCC, BCC). Sarcoma (mesenchymal liposarcoma, leiomyosarcoma, osteosarcoma, chondrosarcoma, fibrosarcoma, rhabdomyosarcoma, angiosarcoma). Mixed (teratoma, fibroadenoma, carcinosarcoma). Blastoma (retinoblastoma, neuroblastoma, nephroblastoma/Wilms, hepatoblastoma, medulloblastoma). Anaplasia: loss of differentiation. Pleomorphism, hyperchromatic, high N:C, bizarre mitoses, loss of polarity. Key differences: benign (well-differentiated, encapsulated, pushing border, no metastasis, slow). Malignant (poorly differentiated, infiltrative, no capsule, metastasis, rapid, desmoplasia, angiogenesis, genomic instability).

Routes: Lymphatic (carcinomas breast, colon, lung, gastric. Sentinel LN). Hematogenous (sarcomas, RCC, HCC, choriocarcinoma. Veins → liver → lung → systemic). Bone: breast (lytic), prostate (blastic), lung, thyroid, kidney, melanoma. Seeding (peritoneal ovarian, gastric Krukenberg, colon, pancreas). Hallmarks: self-sufficiency in growth signals, insensitivity to anti-growth, evasion of apoptosis, limitless replication (telomerase), sustained angiogenesis (VEGF), invasion/metastasis (EMT, MMPs), immune evasion (PD-L1, Treg), metabolic reprogramming (Warburg aerobic glycolysis), genomic instability, tumor-promoting inflammation. EMT: loss of E-cadherin, gain of N-cadherin/vimentin, Twist, Snail, Slug. MET at distant site.

Oncogenes: RAS (KRAS colon/pancreas/lung, NRAS melanoma/AML, HRAS bladder 30% cancers). MYC (t(8;14) Burkitt, amplified breast/lung). HER2/ERBB2 (breast → trastuzumab). EGFR (NSCLC, GBM → gefitinib, erlotinib, osimertinib). BRAF V600E (melanoma, hairy cell, colon, thyroid → vemurafenib, dabrafenib). BCR-ABL (t(9;22) CML → imatinib). ALK (NSCLC → crizotinib, alectinib). RET (MEN2, papillary thyroid → selpercatinib). Tumor suppressors: RB (cell cycle, E2F, lost in retinoblastoma, osteosarcoma, SCLC, breast). TP53 (guardian, p21/BAX/PUMA, lost >50% cancers, Li-Fraumeni). APC (Wnt, FAP, colon). BRCA1/2 (DNA repair, breast/ovarian). PTEN (PI3K/Akt, Cowden). VHL (HIF, RCC/hemangioblastoma). CDKN2A/p16 (many cancers). SMAD4 (pancreatic). NF1 (Ras-GAP, neurofibromas). WT1 (Wilms). DNA repair: MMR (MSH2/MLH1 Lynch/MSI-H). NER (XPA-XPG xeroderma pigmentosum). BER (MUTYH).

Chemical: Direct (alkylating). Indirect (need P450: PAH, aflatoxin, aromatic amines, nitrosamines). Initiation (permanent DNA damage) + promotion (reversible, proliferation). Radiation: UVB (pyrimidine dimers, p53 mutations → BCC, SCC, melanoma). Ionizing (DNA breaks → leukemia, thyroid, breast, lung). Microbial: HPV (E6/E7 → p53/RB loss → cervical, oropharyngeal, anal types 16,18). HBV/HCV (HCC). EBV (Burkitt, Hodgkin, nasopharyngeal, PTLD, gastric). HHV-8 (Kaposi, PEL, Castleman). H. pylori (gastric MALT, adenocarcinoma). Schistosoma (bladder SCC). Liver flukes (cholangiocarcinoma).

Grading: histologic differentiation (grade 1-4). Gleason (prostate: 2 patterns, e.g., 3+4=7). TNM staging: T (tumor size/extent), N (node involvement), M (metastasis). Markers: CEA (colon, pancreas), AFP (HCC, yolk sac), CA-125 (ovary), CA 19-9 (pancreas), PSA (prostate), β-HCG (choriocarcinoma, germ cell), calcitonin (medullary thyroid), thyroglobulin (thyroid), LDH (germ cell, lymphoma tumor burden), Bence-Jones (myeloma urine), SPEP (M spike). IHC: cytokeratin (epithelial), vimentin (mesenchymal), S100 (melanoma, neural, Schwann, chondroid), HMB-45 (melanoma), CD3 (T), CD20 (B), CD34 (vascular), desmin (muscle), myogenin (rhabdo), TTF-1 (lung, thyroid), GATA3 (breast, urothelial), ER/PR (breast), HER2 (breast, gastric), Ki-67 (proliferation).

Endocrine: Cushing (ACTH SCLC), SIADH (ADH SCLC), hypercalcemia (PTHrP SCC lung), hypoglycemia (IGF-2 fibrous tumors), carcinoid (serotonin). Neuro: Lambert-Eaton (VGCC SCLC), myasthenia (AChR thymoma), cerebellar degeneration (Yo ovary/breast), encephalitis (Hu SCLC). Cutaneous: acanthosis nigricans (gastric), dermatomyositis (breast/ovary), Trousseau (pancreatic), necrolytic migratory erythema (glucagonoma). Hematologic: polycythemia (Epo RCC), DIC (APML).

Lynch (HNPCC): MLH1/MSH2/MSH6/PMS2, MSI-H. Right colon, endometrial, ovarian, gastric, urothelial. IHC + MSI testing. FAP: APC mutation, hundreds polyps, cancer by 40s. Gardner (+ osteomas, desmoids). Turcot (+ medulloblastoma). BRCA1/2: breast/ovarian. BRCA1 → triple-negative. PARP inhibitors. Li-Fraumeni: TP53 → breast, sarcoma, brain, leukemia, adrenal. VHL: hemangioblastoma, RCC, pheochromocytoma, pancreatic NET. MEN: MEN1 (parathyroid, pituitary, pancreatic). MEN2A (RET medullary thyroid, pheochromocytoma, parathyroid). MEN2B (same + marfanoid, neuromas). NF1: neurofibromas, cafe-au-lait, Lisch nodules, optic glioma, MPNST. NF2: bilateral acoustic schwannoma, meningioma. TSC: cortical tubers, SEGA, cardiac rhabdomyoma, AML, LAM. Retinoblastoma: RB1, bilateral (heritable) vs unilateral (sporadic). Cowden: PTEN → breast, thyroid, endometrial, trichilemmomas. Beckwith-Wiedemann: IGF2 → Wilms, hepatoblastoma, omphalocele, macrosomia. CDH1: hereditary diffuse gastric + lobular breast.

Tobacco: #1 preventable death. 60 carcinogens (PAH, NNK/NNN, benzene, cadmium). Lung (90% SCLC/squamous), COPD, CVD, oropharyngeal, bladder, kidney, pancreatic, cervical, AML, premature aging. Alcohol: Steatosis → steatohepatitis → cirrhosis → HCC. Acute/chronic pancreatitis. Dilated cardiomyopathy. Wernicke (thiamine), Korsakoff, fetal alcohol syndrome. Oropharyngeal, esophageal, liver, breast, colorectal cancers. Obesity (BMI ≥30): Metabolic syndrome. DM2, HTN, IHD, OSA, NAFLD/NASH/HCC, cholelithiasis, osteoarthritis, GERD/Barrett, PCOS, breast/colon/endometrial/renal/esophageal/pancreatic cancers. Leptin resistance, ↑TNF/IL-6, ↓adiponectin.

Marasmus: total calorie deficit. Wasting, no edema. Kwashiorkor: protein deficit. Edema, fatty liver, flaky paint skin, hair changes. Vitamin A: night blindness, xerophthalmia, Bitot spots, keratomalacia. B1 (thiamine): beriberi (dry/wet), Wernicke-Korsakoff. B2 (riboflavin): angular stomatitis, cheilosis, glossitis. B3 (niacin): pellagra (dermatitis, diarrhea, dementia). Hartnup, carcinoid. B6 (pyridoxine): microcytic/sideroblastic anemia, dermatitis, neuropathy. INH causes deficiency. B7 (biotin): dermatitis, alopecia, neuro. Raw egg white (avidin). B9 (folate): megaloblastic anemia (NO neuro), homocysteine ↑, NTD. Deficiency: poor diet, pregnancy, methotrexate, alcohol, phenytoin. B12 (cobalamin): megaloblastic anemia + subacute combined degeneration (peripheral + posterior column + corticospinal). Pernicious anemia (anti-parietal/IF). MMA + homocysteine ↑. Vitamin C: scurvy (gingival hyperplasia, petechiae, poor wound healing, subperiosteal hemorrhage). Vitamin D: rickets (children bowing, rachitic rosary, craniotabes, tetany). Osteomalacia (adults bone pain, Looser zones, pseudofractures). Vitamin E: hemolytic anemia (premies), ataxia, neuropathy. Vitamin K: bleeding (PT ↑). Newborn prophylaxis IM. Warfarin inhibits recycling. Minerals: Iodine (goiter, cretinism). Iron (microcytic anemia, koilonychia, pica, Plummer-Vinson). Zinc (acrodermatitis enteropathica, hypogonadism). Selenium (Keshan CMP, Kashin-Beck). Copper (Menkes, Wilson).

Lead: children (IQ ↓, abdominal pain, basophilic stippling, lead lines, encephalopathy). Adults (wrist drop, HTN, nephropathy, gout). DMSA/EDTA/BAL chelation. Mercury: organic (Minamata paresthesias, ataxia, dysarthria, visual field). Inorganic (acrodynia). Arsenic: hyperpigmentation, hyperkeratosis, SCC/BCC, neuropathy, Blackfoot disease (PAD), garlic breath. Cadmium: Itai-itai (osteomalacia, renal tubular, lung/prostate cancer). Air pollution: PM2.5 → COPD, asthma, CVD, lung cancer. Radiation: UVB (pyrimidine dimers → BCC/SCC/melanoma). Ionizing (leukemia, thyroid, breast, lung). Radon (lung #2 cause). CWP: coal macules, PMF (upper lobes). Caplan + RA. Silicosis: upper lobe nodules, eggshell LN, TB risk. Asbestosis: lower lobe fibrosis, ferruginous bodies, pleural plaques. Lung CA (x smoking) + mesothelioma (no relation smoking). Berylliosis: non-caseating granulomas (LPT test). Hypersensitivity pneumonitis: farmer lung (thermophilic actinomycetes), bird fancier. IgG, DTH. Remove exposure, steroids.

Defects: Malformation (spina bifida, cleft, CHD). Deformation (oligohydramnios, Potter). Disruption (amniotic bands). Teratogens: Alcohol (FAS), retinoic acid, valproate (NTD), warfarin (nasal hypoplasia), ACEi (renal), lithium (Ebstein). TORCH: Toxoplasma (hydrocephalus, calcifications, chorioretinitis). Rubella (PDA, cataracts, deafness, blueberry muffin MMR vaccine). CMV (most common congenital microcephaly, periventricular calcifications, hearing loss, IUGR). HSV (disseminated, encephalitis). Syphilis (pneumonia alba, saddle nose, Hutchinson teeth, keratitis, deafness). Parvovirus B19 (hydrops fetalis). Zika (microcephaly). Prematurity (<37wk): RDS/HMD (surfactant deficiency, betamethasone, CPAP, surfactant). BPD (chronic O2/vent injury). IVH (germinal matrix, <32wk). NEC (pneumatosis, perforation). PDA (indomethacin/ibuprofen). ROP (O2 → neovascularization). SIDS: peak 2-4mo, prone sleep, Triple-risk. Prevention: supine, firm mattress, no smoking.

Down (trisomy 21): flat facies, upslant, epicanthal, single palmar, clinodactyly, sandal gap, ID. AVSD, duodenal atresia, Hirschsprung, hypothyroid, celiac, Alzheimer (APP ×3), ALL/AML (GATA1). ↑ risk maternal age. Edwards (18): micrognathia, overlapping fingers, rocker-bottom, CHD, severe ID. <10% survive 1yr. Patau (13): holoprosencephaly, cleft lip/palate, polydactyly, cutis aplasia, CHD. <5% survive 1yr. Turner (45,X): short stature, webbed neck, shield chest, lymphedema, coarctation, bicuspid AV, horseshoe kidney, streak gonads, infertility. Klinefelter (47,XXY): tall, eunuchoid, gynecomastia, hypogonadism, infertility, ↑breast CA, mediastinal germ cell. DiGeorge (22q11.2): CATCH-22 (conotruncal cardiac, abnormal facies, thymic aplasia/T ↓, cleft palate, hypocalcemia). Williams (7q11.23): elfin facies, hypercalcemia, supravalvular AS, gregarious, ID. Prader-Willi (15q11-13 paternal): hypotonia, hyperphagia/obesity, small hands/feet, hypogonadism. Angelman (maternal 15q11-13): severe ID, seizures, ataxia, frequent laughing. UBE3A. Cri-du-chat (5p-): cat-like cry, microcephaly, ID.

CF (CFTR, AR): ΔF508. Thick secretions. Lungs (S. aureus, P. aeruginosa, bronchiectasis). Pancreas (exocrine insufficiency, CF-related DM). Meconium ileus, CBAVD. Sweat Cl- >60. CFTR modulators (ivacaftor, lumacaftor, elexacaftor-tezacaftor-ivacaftor). Sickle cell (β-globin, AR): Glu6Val, HbS. Hemolytic anemia, vaso-occlusive crises, acute chest syndrome, stroke, priapism, dactylitis, splenic sequestration/autoinfarction (encapsulated organism risk), aplastic crisis (parvovirus B19), leg ulcers. Hydroxyurea (↑HbF), L-glutamine, crizanlizumab, voxelotor, chronic transfusions, BMT. Thalassemia: α (HbH β4, Bart γ4 hydrops). β (minor mild, major Cooley anemia transfusion-dependent, extramedullary hematopoiesis, iron overload). Hemophilia A (F8, XR): ↓FVIII. Joint bleeds, prolonged aPTT, normal PT. Factor VIII, DDAVP (mild A), emicizumab. vWD: most common inherited bleeding. Type 1 (mild, AD), 2 (qualitative), 3 (severe, AR). Epistaxis, menorrhagia, prolonged bleeding time/aPTT, ↓vWF. DMD (XR): absent dystrophin. Proximal <5y, Gowers, calf pseudohypertrophy, CMP, ID, CPK ↑↑. Becker milder. NF1 (AD): cafe-au-lait (>6 >5mm), neurofibromas, Lisch nodules, optic glioma, freckling, MPNST. Marfan (FBN1, AD): arachnodactyly, tall, ectopia lentis, aortic root dilation/dissection, MVP. Ehlers-Danlos: hyperextensible skin, hypermobile joints, fragile vessels (COL3A1 vascular type → rupture). Huntington (HTT, AD): CAG >40. Chorea, dementia, caudate atrophy. Anticipation. Myotonic dystrophy (DM1): CTG repeat, myotonia, frontal balding, cataract, cardiac conduction, insulin resistance.

PKU (AR): PAH def → ↑Phe → ID, microcephaly, fair skin, musty odor. Newborn screen. Low-Phe diet. Maternal PKU → microcephaly, CHD. MSUD (AR): branched-chain KAD def. Maple syrup urine, vomiting, lethargy, coma. OTC (X-linked): urea cycle, ↑NH3, ↑orotic acid. GSD: von Gierke (G6Pase, I hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia). Pompe (α-glucosidase, II cardiomegaly, hypotonia, death <1y). McArdle (muscle phosphorylase, V exercise intolerance, myoglobinuria). Lysosomal storage: Gaucher (glucocerebrosidase, crumpled paper cells, bone pain, cytopenia. Enzyme replacement). Niemann-Pick (sphingomyelinase, foam cells, cherry-red spot). Tay-Sachs (Hex A, GM2, cherry-red spot, neurodegeneration, blind/death 2-3y. Ashkenazi). Metachromatic leukodystrophy (arylsulfatase A, demyelination). Krabbe (globoid). Hurler (MPS I, corneas, ID). Hunter (MPS II, XR, no corneal clouding). Fabry (α-gal A, XR, angiokeratomas, acroparesthesias, renal, stroke, cornea verticillata). Peroxisomal: Zellweger (absent, dysmorphic, hypotonia). Adrenoleukodystrophy (VLCFA, adrenal, cerebral demyelination). Mitochondrial: MELAS (3243A>G, stroke-like, lactic acidosis). MERRF (myoclonus, RRFs). Kearns-Sayre (ophthalmoplegia, CMP, heart block). LHON (blindness). Maternal inheritance.

Atherosclerosis: Endothelial injury → LDL oxidation → monocyte recruitment (MCP-1) → foam cells → fatty streak → fibrous cap (SMC, collagen) → complicated plaque (calcification, hemorrhage, ulceration, thrombosis). Risk: age, male, FH, smoking, HTN, DM, hyperlipidemia (LDL ↑, HDL ↓), obesity, Lp(a). IHD: stable angina (fixed). UA/NSTEMI (plaque rupture, subocclusive). STEMI (occlusive). Pathology: coagulative necrosis (24-72h), neutrophils (2-4d), macrophages, granulation (7-14d), scar (4-6wk). Mechanical complications: free wall rupture, papillary muscle, VSD, LV aneurysm, mural thrombus, Dressler pericarditis. HTN heart: concentric LVH, fibrosis, diastolic dysfunction → HF. Valvular: Rheumatic (molecular mimicry, Aschoff bodies, Anitschkow cells, McCallum patch). Acute RF (migratory polyarthritis, erythema marginatum, chorea, subcutaneous nodules, carditis). Chronic: MS most common. IE: vegetation (S. aureus, viridans, Enterococcus, HACEK). Prosthetic: early <1yr (coag-neg staph), late >1yr (similar native). Cardiomyopathies: DCM (dilated + systolic). HCM (LVH, disarray, SAM, sarcomere). RCM (infiltrative amyloid, sarcoid, hemochromatosis). Myocarditis (viral, giant cell, eosinophilic). Pericarditis: acute (viral, uremic, TB, neoplastic, SLE, Dressler). Tamponade (Beck triad, pulsus paradoxus, electrical alternans). Constrictive (TB, radiation). Cardiac tumors: Myxoma (LA, ball-valve, tumor plop). Rhabdomyoma (TSC). Papillary fibroelastoma (valvular). Metastatic (lung, breast, melanoma, lymphoma more common). Aortic aneurysm/dissection: AAA (atherosclerotic, infrarenal, >5.5cm risk). Cystic medial degeneration (Marfan, Ehlers-Danlos). Syphilitic aortitis (tree bark). Vasculitis: Giant cell (>50y, headache, jaw claudication, ↑ESR, blindness). Takayasu (<40y, pulseless, aortic arch). PAN (medium, microaneurysms, renal/nerve/GI). Kawasaki (<5y, coronary aneurysm). GPA (c-ANCA, necrotizing granulomas, lung/kidney). MPA (p-ANCA, pauci-immune GN). Churg-Strauss (asthma, eosinophilia, p-ANCA). HSP/IgA vasculitis (skin, joints, GI, kidney). Behcet (oral/genital ulcer, uveitis, pathergy). Buerger (smokers, distal extremities).

COPD: Chronic bronchitis (Reid index >0.4, mucous gland hypertrophy, goblet cell metaplasia, blue bloater, cor pulmonale). Emphysema (centriacinar upper smokers; panacinar lower α1-AT deficiency; paraseptal blebs). Pink puffer. Asthma: reversible obstruction, Th2 (IL-4,5,13, eosinophils). Curschmann spirals, Charcot-Leyden crystals, BM thickening, SM hypertrophy, mucous plugs. Pneumonia: CAP (S. pneumoniae, H. influenzae, Mycoplasma, Legionella). HAP (≥48h, P. aeruginosa, MRSA). Atypical (Mycoplasma, Chlamydia, Legionella). Aspiration (anaerobes, RLL). Lobar (4 stages: congestion, red/gray hepatization, resolution). Bronchopneumonia (patchy, S. aureus). PCP (HIV <200, silver stain, foamy exudate). TB: Ghon complex (primary). Secondary (apical cavitary, caseous, AFB+). Miliary (hematogenous). Lung cancer: Squamous (central, cavity, PTHrP → hyperCa, P63+). Adenocarcinoma (peripheral, TTF-1+, EGFR/ALK). SCLC (central, aggressive, NE markers, ACTH/SIADH/Lambert-Eaton). Large cell (anaplastic). Carcinoid (low-grade NET). Mesothelioma (pleural, asbestos, calretinin+, WT1+). ARDS: DAD, hyaline membranes, exudative → proliferative → fibrotic. Sepsis, aspiration, pneumonia, pancreatitis. IPF: UIP pattern (subpleural, honeycombing, fibroblastic foci). Pulmonary HTN: PAH (BMPR2, plexiform lesions). Secondary (left heart, lung disease, CTD, HIV, drugs). Cor pulmonale. Sarcoidosis: non-caseating granulomas, BHL, uveitis, erythema nodosum, hypercalcemia, ACE ↑. Schaumann bodies. Bronchiectasis: permanent airway dilation. CF, post-infection (TB, pertussis), ABPA, ciliary dyskinesia (Kartagener).

Peptic ulcer: Duodenal (H. pylori, hyperacidity, pain 2-3h after meals, relieved by food). Gastric (NSAIDs, H. pylori, impaired mucosal defense, pain with food). H. pylori: urease+, CagA/VacA, → chronic gastritis, PUD, MALT lymphoma, adenocarcinoma. Colorectal cancer: Adenoma-carcinoma sequence (APC → KRAS → SMAD4 → TP53). Lynch (MSI-H, right-sided, <50y). FAP (APC, hundreds polyps). Sessile serrated pathway (BRAF, CIMP). Screening: colonoscopy, FIT, Cologuard. IBD: Crohn (transmural, skip lesions, cobblestone, fissures, fistulas, granulomas, anywhere from mouth to anus). UC (mucosal, continuous from rectum, crypt abscesses, pseudopolyps, backwash ileitis). Both → colon cancer risk (UC > Crohn). Hepatitis: A (fecal-oral, acute, no chronic). B (blood/sexual/perinatal, chronic in 5% adults/90% neonates, cirrhosis/HCC. Vaccination. Serology: HBsAg (active), anti-HBs (immune), HBeAg (replication), anti-HBc (past/current). C (blood, chronic 80%, cirrhosis/HCC, DAAs cure >95%). D (HDV requires HBV). E (fecal-oral, pregnancy severe). Alcoholic liver disease: steatosis → steatohepatitis (Mallory bodies, ballooning, neutrophils) → cirrhosis. NAFLD/NASH: metabolic syndrome, ≥5% fat, NASH = steatosis + inflammation + ballooning, → cirrhosis/HCC. PBC: anti-mitochondrial (AMA), florid bile duct lesions, chronic cholestasis, cirrhosis. PSC: periductal concentric fibrosis, onion skin, ↑CCA risk. Associated with UC. Hemochromatosis: HFE C282Y, ↑Fe, bronze diabetes, cirrhosis, HCC, CMP, arthropathy. Wilson: ATP7B, Cu accumulation, Kayser-Fleischer rings, cirrhosis, neurologic. Autoimmune hepatitis: ANA/anti-SMA/anti-LKM, interface hepatitis. Pancreatic adenocarcinoma: head > body/tail. Painless jaundice, Courvoisier, weight loss, CA 19-9. KRAS, SMAD4, p53.

ATN: ischemic (shock, sepsis) or toxic (aminoglycosides, cisplatin, contrast, myoglobin, hemoglobin). Tubular necrosis, casts. → AKI. Acute interstitial nephritis: drug-induced (NSAIDs, penicillins, PPIs, rifampin). Fever, rash, eosinophilia, sterile pyuria. Glomerulonephritis: Post-strep (IC, subepithelial humps, ↓C3, ↓C4, diffuse proliferative, treat supportive). Crescentic (RPGN, crescents, Goodpasture linear IgG, ANCA pauci-immune, IC). IgA nephropathy (Berger, mesangial IgA, post-infection hematuria, most common GN worldwide). Membranous (subepithelial spikes, PLA2R, nephrotic, anti-PLA2R). MCD (foot process effacement, selective nephrotic, steroid-sensitive). FSGS (segmental sclerosis, nephrotic, ↓response to steroids). MPGN (mesangial + capillary wall, tram-track, low C3). Lupus nephritis (I-VI, classes I-V). Diabetic nephropathy: mesangial expansion, Kimmelstiel-Wilson nodules, GBM thickening, nodular GS. Hypertensive nephrosclerosis: arteriolar hyalinosis, GFR ↓. ADPKD: PKD1/PKD2, bilateral cysts, HTN, renal failure, berry aneurysms, hepatic cysts, mitral valve prolapse. RCC: Clear cell (VHL, 3p deletion, most common). Papillary (MET, PRCC). Chromophobe (better prognosis). Bladder: Urothelial (TCC, most common). Squamous (schistosoma). Risk: smoking, aniline dyes, cyclophosphamide, radiation. Hematuria, painless.

Breast: Fibroadenoma (most common benign). DCIS (comedo most aggressive, calcifications on mammo). LCIS (risk marker). Invasive ductal (most common, 80%). Invasive lobular (loss of E-cadherin, diffuse, bilateral). ER/PR/HER2 subtypes: luminal A (ER+ PR+ HER2-, best), luminal B (ER+ HER2+/-), HER2-enriched (ER-PR-HER2+, trastuzumab), triple-negative (ER-PR-HER2-, worst, BRCA1, chemo). Paget disease (eczematous nipple + DCIS). Inflammatory (dermal lymphatic invasion, peau d’orange, aggressive). Cervical: HPV (16,18) → CIN I → II → III → invasive SCC. Koilocytosis (HPV effect). Screening: Pap smear, HPV test. Vaccine: Gardasil 9. Endometrial: Endometrioid (type I, estrogen-driven, good). Serous (type II, p53, poor). Risk: obesity, PCOS, tamoxifen, Lynch. Ovarian: HGSC (most common, p53, BRCA, serous). Mucinous. Germ cell (teratoma/dermoid most common, dysgerminoma, yolk sac → AFP, choriocarcinoma → β-HCG). Sex cord (granulosa → inhibin, Calretinin+, estrogen → precocious pseudopuberty). Prostate: BPH (periurethral, nodular hyperplasia, ↑PSA). Adenocarcinoma (peripheral zone, PIN → cancer, Gleason score, PSA screening). Bone metastases (osteoblastic). Androgen deprivation (LHRH agonists/antagonists, anti-androgens). Testicular: Seminoma (most common, radiosensitive, ↑LDH, PLAP+). Non-seminoma (embryonal, teratoma, yolk sac, choriocarcinoma). ↑AFP (yolk sac), ↑β-HCG (choriocarcinoma, embryonal).

Osteosarcoma: Malignant bone tumor producing osteoid. Metaphysis of long bones (distal femur, proximal tibia, proximal humerus). Peak: 10-20y (growth spurt). Codman triangle, sunburst appearance, ↑ALP. Variants: conventional, telangiectatic, parosteal (low-grade, better), periosteal. Treatment: neoadjuvant chemo + wide resection. Chondrosarcoma: Cartilage-producing, pain, central (pelvis, femur, humerus) or peripheral (osteochondroma malignant transformation). >40y. Rings-and-arcs calcification. Grade 1-3. Surgery (chemo/RT resistant). Ewing sarcoma/PNET: t(11;22) EWSR1-FLI1. Small round blue cell, CD99/MIC2+, PAS+ (glycogen). Diaphysis of long bones, pelvis, ribs. <20y. Onion skin periosteal reaction. Treatment: chemo + surgery/RT. Giant cell tumor (GCT/osteoclastoma): Epiphysis extending to subchondral bone. >20y (closed epiphysis). Soap bubble appearance. Numerous osteoclast-like giant cells. β treatment: denosumab (RANKL inhibitor). Recurrence ~20-50%, rarely malignant. Osteoid osteoma: <2cm, painful at night, relieved by NSAIDs (prostaglandin-mediated). Nidus with surrounding sclerosis. Femur, tibia. Radiofrequency ablation. Osteoblastoma: >2cm, similar histology, spine, less pain response to NSAIDs. Enchondroma: Benign cartilage in medullary cavity. Hands (most common). Ollier (multiple enchondromas, ↑risk of chondrosarcoma). Maffucci (enchondromas + hemangiomas, ↑↑risk). Osteochondroma: Most common benign bone tumor. Cartilage-capped bony projection (metaphysis, away from joint). Solitary vs multiple (Hereditary multiple exostoses EXT1/EXT2, ↑risk malignant transformation). Fibrous dysplasia: Bone replaced by fibrous tissue + irregular trabeculae (Chinese letters). Monostotic (femur, ribs, craniofacial). Polyostotic (McCune-Albright polyostotic + cafe-au-lait (coast of Maine) + precocious puberty + GNAS mutation). Aneurysmal bone cyst (ABC): Blood-filled cavities, fluid-fluid levels. <20y, metaphysis of long bones, posterior elements of spine. Reactive, not neoplastic. Simple bone cyst (unicameral): Fallen leaf sign, proximal humerus, femur. Fluid-filled.

Desmoid (aggressive fibromatosis): CTNNB1 (β-catenin) or APC mutation. Locally aggressive, no metastasis. Infiltrates muscle, high recurrence. NSAIDs, anti-estrogen, chemo, RT, surgery. Liposarcoma: Most common soft tissue sarcoma. Well-differentiated (12q13-15 amplification, MDM2+, low risk). Myxoid (t(12;16) FUS-DDIT3). Pleomorphic (high grade, aggressive). Leiomyosarcoma: Smooth muscle. Uterus, retroperitoneum, vessels (IVC). Desmin+, SMA+. Rhabdomyosarcoma: Skeletal muscle, <20y, head/neck, genitourinary, extremities. Embryonal (most common, botryoid variant sarcoma botryoides, vagina/bladder grapelike). Alveolar (t(2;13) PAX3-FOXO1, worse prognosis). Pleomorphic (adults). Myogenin+, MyoD1+, desmin+. Synovial sarcoma: t(X;18) SS18-SSX. Young adults, parameningeal, near joints (knee). Biphasic (epithelial + spindle) vs monophasic. TLE1+, cytokeratin+, EMA+. DFSP (Dermatofibrosarcoma protuberans): t(17;22) COL1A1-PDGFB. Dermal, slow-growing, locally aggressive, high recurrence, rarely mets. CD34+, storiform pattern. Imatinib (PDGFR inhibitor). Kaposi sarcoma: HHV-8. Endothelial-derived. Classic (older men, legs, indolent). Endemic (Africa). Iatrogenic (transplant). AIDS-associated (aggressive, cutaneous+visceral). Malignant peripheral nerve sheath tumor (MPNST): NF1, neurofibroma → MPNST. Pain, rapid growth. Angiosarcoma: Vascular, head/scalp, breast (post-RT), liver (vinyl chloride, Thorotrast). GIST: GI tract, CD117 (c-Kit)+, DOG1+. Imatinib (KIT/PDGFRA inhibitor). Clear cell sarcoma (melanoma of soft parts): t(12;22) EWSR1-ATF1. Alveolar soft part sarcoma: t(X;17) ASPSCR1-TFE3. Epithelioid sarcoma: INI1/SMARCB1 loss. Upper extremity. Undifferentiated pleomorphic sarcoma (UPS, formerly MFH): Diagnosis of exclusion.

Glioblastoma (GBM, WHO grade 4): Most common primary malignant brain tumor. IDH-wildtype (>90%, primary, >55y, worse) vs IDH-mutant (secondary from lower-grade). Pseudopalisading necrosis, microvascular proliferation. GFAP+. Treatment: maximal safe resection, RT + temozolomide (Stupp protocol). MGMT methylation → better response. Astrocytoma (diffuse, IDH-mutant, WHO 2-4): Low-grade (WHO 2, IDH-mutant, ATRX loss, p53+). Anaplastic (WHO 3). GBM (WHO 4). Oligodendroglioma: IDH-mutant, 1p/19q codeletion (diagnostic). Chicken-wire vessels, perinuclear halo (fried egg). WHO 2-3. Better prognosis. Chemosensitive (PCV, temozolomide). Ependymoma: From ependymal lining. Perivascular pseudorosettes, true rosettes. 4th ventricle, spinal cord. RELA fusion (supratentorial). Medulloblastoma: Primitive neuroectodermal tumor (PNET). Posterior fossa/vermis, <20y. Small round blue cells, Homer-Wright rosettes. WNT (best prognosis), SHH, group 3 (worst), group 4. Treatment: resection + craniospinal RT + chemo. Meningioma: Meningothelial, extra-axial, dural-based. >40y, F > M. Psammoma bodies. WHO 1-3. Most benign. Simpson grade resection. Recurrence risk ↑ with WHO grade. Schwannoma: Cranial nerves (CN VIII most common, vestibular/ acoustic). Bilateral in NF2. Antoni A (palisading, Verocay bodies), Antoni B (loose). S100+. Pituitary adenoma: Prolactinoma (most common, galactorrhea, amenorrhea, impotence). GH (acromegaly). ACTH (Cushing). Null cell. Craniopharyngioma: Rathke pouch remnant, suprasellar, calcification, cholesterol clefts, wet keratin. → visual field, endocrine. Choroid plexus tumors: Papilloma (benign, 4th ventricle, ρprognosis). Carcinoma (malignant, <3y). Hemangioblastoma: Cerebellum, von Hippel-Lindau (VHL). Foamy stromal cells, extensive capillaries. Produces Epo → polycythemia.

Multiple sclerosis (MS): Autoimmune, periventular demyelination. Relapsing-remitting (80%) → secondary progressive. Primary progressive (15%). MRI: Dawson fingers, periventricular plaques, T2 hyperintense. CSF: oligoclonal bands, IgG index ↑. Pathology: demyelination with relative axonal sparing, perivascular lymphocyte cuff, macrophages with myelin debris. PML (progressive multifocal leukoencephalopathy): JC virus in immunocompromised (HIV CD4 <50). Lytic infection of oligodendrocytes, demyelination, bizarre astrocytes. No specific therapy. GBS (Guillain-Barre): Acute inflammatory demyelinating polyneuropathy (AIDP). Post-infection (Campylobacter jejuni, CMV, EBV, Mycoplasma, Zika). Ascending paralysis, areflexia, albuminocytologic dissociation (↑CSF protein, normal cells). Plasmapheresis or IVIG. Alzheimer disease: Most common neurodegenerative (60-80%). β-amyloid plaques (Aβ40/42, APP/PSEN1/2 mutations in familial), neurofibrillary tangles (tau hyperphosphorylation). Hippocampal and parietal atrophy, widened sulci, enlarged ventricles. ApoE ε4 risk factor. Parkinson disease: Loss of substantia nigra dopaminergic neurons, Lewy bodies (α-synuclein). Tremor, rigidity, bradykinesia, postural instability. L-DOPA treatment. Huntington disease: CAG repeat, caudate atrophy, chorea, dementia. ALS (amyotrophic lateral sclerosis): Motor neuron degeneration (upper + lower). TDP-43 inclusions, Bunina bodies. Sporadic >90%. Riluzole, edaravone. Prion (CJD): Spongiform encephalopathy, misfolded prion protein (PrPSC). Rapid dementia, myoclonus, periodic sharp waves on EEG. 14-3-3 protein in CSF. Variant CJD (vCJD) from BSE (mad cow). Iatrogenic (growth hormone, grafts). Lewy body dementia: Cortical Lewy bodies, hallucinations, fluctuating cognition, Parkinsonism. FTD (frontotemporal dementia): Tau (Pick disease Pick bodies, Pick cells) or TDP-43. Personality change, aphasia.

Ischemic stroke (85%): Thrombotic (atherosclerosis, lipohyalinosis lacunar, <1.5cm, basal ganglia/thalamus/pons/internal capsule). Embolic (AFib, IE, valvular, LV thrombus, PFO). Watershed (border zone, hypotension, between ACA/MCA/PCA). Hemorrhagic transformation of ischemic infarct. Hemorrhagic stroke (15%): Intracerebral (HTN, amyloid angiopathy, AVM, aneurysm rupture, cavernoma, drugs/vasculitis, coagulopathy). Subarachnoid (berry aneurysm rupture Circle of Willis, thunderclap headache, sentinel bleed, CT+). Meningitis: Bacterial (purulent, neutrophils, ↓glucose, ↑protein. S. pneumoniae, N. meningitidis, H. influenzae, L. monocytogenes, Group B strep). Viral (lymphocytes, normal/ ↓glucose, enterovirus, HSV). Fungal (cryptococcus, India ink+, CrAg). TB (basal exudate). Encephalitis: HSV (temporal lobe, hemorrhagic, PCR +). Arboviruses, Rabies (Negri bodies, cytoplasmic inclusions in Purkinje cells/hippocampus). Brain abscess: Ring-enhancing with edema, from sinus/ear/dental infection, hematogenous (lung abscess, IE, CHD), trauma. Trauma: EDH (lens-shaped, middle meningeal artery, lucid interval). SDH (crescent-shaped, bridging veins, elderly/alcoholics, chronic). Contusion (coup/contrecoup, inferior frontal/temporal poles). DAI (diffuse axonal injury, shearing, microscopic axonal retraction balls, coma).

RBC indices: MCV (microcytic <80 iron deficiency, thalassemia, anemia of chronic disease, sideroblastic. Macrocytic >100 B12/folate, alcohol, liver, MDS, reticulocytosis, drugs). MCH, MCHC, RDW. Microcytic anemia: Iron deficiency (↓Fe, ↑TIBC, ↓ferritin). Thalassemia (normal Fe studies, ↑HbA2, HbF). Anemia of chronic disease (↓Fe, ↓TIBC, ↑ferritin). Sideroblastic (ring sideroblasts, normal/↑Fe). Macrocytic anemia: B12 (↓B12, ↑MMA, ↑homocysteine). Folate (↓folate, normal MMA, ↑homocysteine). Hemolytic anemia: Normocytic, ↑reticulocytes, ↑LDH, ↑indirect bilirubin, ↓haptoglobin. Fragments (schistocytes MAHA/DIC/TTP-HUS). Spherocytes (hereditary). Sickle (HbS). G6PD (Heinz bodies, bite cells). AIHA (direct Coombs+). WBC differential: Neutrophilia (infection, inflammation, steroids, stress, CML). Lymphocytosis (viral, CLL). Eosinophilia (allergy, parasites, drugs, Churg-Strauss). Monocytosis (TB, EBV, CMML, post-chemo recovery). Pancytopenia (aplastic, MDS, leukemia, B12/folate, hypersplenism, SLE, drugs).

PT (INR): Extrinsic + common pathway (factors VII, X, V, II, fibrinogen). Elevated in warfarin, liver disease, vitamin K deficiency, DIC. aPTT: Intrinsic + common pathway (XII, XI, IX, VIII, X, V, II, fibrinogen). Elevated in heparin, hemophilia (VIII, IX), vWD, lupus anticoagulant (not corrected with mixing), DIC, liver. Mixing studies: Corrects with normal plasma = factor deficiency. Does not correct = inhibitor (lupus anticoagulant, factor inhibitor). BMP: Na, K, Cl, HCO3, BUN, Cr, glucose, Ca. CMP: Adds liver tests, albumin, total protein. LFTs: AST/ALT (hepatocellular injury), ALP/GGT (cholestasis, note GGT confirms hepatobiliary origin), bilirubin (direct/indirect, conjugated vs unconjugated). CPK: Muscle injury (MM skeletal, MB cardiac, BB brain). Troponin I/T: Myocardial injury, onset 3-4h, peak 24-48h, duration 4-10d. BNP/NT-proBNP: Heart failure. >100 acute, >35 chronic. HbA1c: Diabetes control (glucose 2-3mo average). Urine dipstick: Blood (hematuria, hemoglobinuria, myoglobinuria). Protein (glomerular vs tubular). Glucose (diabetes). Ketones (DKA, starvation). Leukocyte esterase/nitrite (UTI). Urine microscopy: RBC casts (GN), WBC casts (AIN, pyelo), granular/waxy casts (ATN), fatty casts (nephrotic). ABG: pH, PaCO2, PaO2, HCO3. Respiratory acidosis (↑PaCO2), respiratory alkalosis (↓PaCO2), metabolic acidosis (↓HCO3), metabolic alkalosis (↑HCO3). Anion gap (Na - (Cl + HCO3). Normal 8-12. High AG = MUDPILES. Non-AG = HARDASS. Delta-delta for mixed.

SPEP: M spike = monoclonal gammopathy. MGUS (asymptomatic, <3g/dL, normal FLC ratio, no end-organ damage). Multiple myeloma (M spike, CRAB: hypercalcemia, renal failure, anemia, bone lesions. ↑FLC, ↓uninvolved Ig, ↑β2M). Waldenstrom (IgM, lymphoplasmacytic). AL amyloidosis (light chains). UPEP/urine immunofixation: Bence-Jones (free light chains). Gram stain: Gram+ cocci (S. aureus, Strep, Enterococcus). Gram- rods (E. coli, Klebsiella, Pseudomonas). Gram+ rods (Clostridium, Bacillus, Listeria, Corynebacterium). Culture & sensitivity: Identify pathogen + antibiotic susceptibility (MIC, MBC). Blood bank: ABO system (A, B, AB, O). Rh (D+/-). Type and screen (detect unexpected antibodies). Crossmatch (donor + recipient). Coombs test: Direct (DAT antibody on patient RBC → AIHA, HDN, transfusion reaction). Indirect (IAT antibody in serum → pretransfusion testing). Transfusion reaction: Acute hemolytic (ABO mismatch, fever, pain, DIC, → stop transfusion, check Coombs, supportive). Febrile (anti-WBC, common). Allergic (urticaria, treat antihistamine). Anaphylactic (IgA deficiency, anti-IgA). TACO (volume overload). TRALI (anti-HLA, acute lung injury, hypoxemia). Peripheral smear: Review for blasts, dysplasia, schistocytes, parasites (malaria, babesia, trypanosomes), abnormal WBC morphology (toxic granules, bands, hypersegmented neutrophils, smudge cells).

FISH (fluorescence in situ hybridization): Detect specific DNA sequences/translocations (BCR-ABL, HER2 amplification, 1p/19q codeletion). PCR: Amplify DNA/RNA for pathogen detection (HSV, CMV, EBV, HIV viral load, TB, COVID). NGS (next-generation sequencing): Simultaneous sequencing of many genes (cancer panels, exome, genome). Karyotype: Chromosome number/structure (trisomy 21, Philadelphia chromosome, translocations). Array CGH/SNP array: Genome-wide copy number analysis. IHC (immunohistochemistry): Protein expression in tissue (cancer markers, classification). Flow cytometry: Surface markers (leukemia/lymphoma phenotyping, CD4 counts). Liquid biopsy (ctDNA): Circulating tumor DNA for monitoring, mutations. Pre-analytical errors: Wrong patient, wrong tube, hemolysis, clotting, insufficient volume, delayed transport, improper storage, fasting status. Analytical errors: Instrument malfunction, reagent problems, calibration drift, interference (lipemia, icterus, hemolysis), hook effect, cross-reactivity. Post-analytical errors: Transcription/entry mistakes, incorrect reference range, delayed communication of critical values, misinterpretation. Reference ranges: Mean ± 2 SD (95% of healthy population). Interpreting with clinical context. Critical values: Immediately report: Na <120 or >160, K <2.5 or >6.5, Ca <6 or >14, glucose <50 or >500, pH <7.2 or >7.6, pO2 <40, platelets <20K, PT/INR >5, aPTT >100, troponin positive, positive blood cultures, critical microbiology results (Gram stain, AFB, Cryptococcus, malaria).

1-hour bundle: Measure lactate (repeat if >2). Blood cultures before abx. Broad-spectrum abx within 1h. Crystalloid 30mL/kg. Vasopressors if MAP <65 (norepinephrine first). Antibiotics: Vancomycin + piperacillin-tazobactam (or cefepime, carbapenem). De-escalate. Vasopressors: Norepinephrine 0.05-0.5 μg/kg/min. Add vasopressin (0.03 U/min). Epinephrine third. Avoid dopamine unless bradycardic. Steroids: Hydrocortisone 200mg/day if vasopressor-dependent. Source control: Drain abscess/empyema, remove infected devices. Lactate clearance: >20% decrease as resuscitation target.

ISTH DIC score ≥5: platelets <100, ↑D-dimer, PT >3s, fibrinogen <100. Treat underlying cause. Bleeding: Platelets if <50K + bleeding. Cryoprecipitate (fibrinogen >150). FFP if PT/aPTT ↑. Thrombotic: UFH if purpura fulminans. APML: ATRA + aggressive platelet/fibrinogen support. Trauma/obstetric: Massive transfusion protocol (1:1:1). Avoid tranexamic acid unless hyperfibrinolysis.

Epinephrine IM 0.3-0.5mg (1:1000), anterolateral thigh, repeat q5-15min. IV fluids 1-2L. Diphenhydramine 25-50mg IV/IM. Famotidine 20mg IV. Methylprednisolone 125mg IV. Albuterol nebulized. Glucagon if on β-blockers. Observe for biphasic (up to 8h). Prescribe auto-injector. Allergy referral.

Drug-sensitive: 2-month RIPE (rifampin 10mg/kg, INH 5mg/kg, PZA 25mg/kg, EMB 15mg/kg daily) + 4-month continuation (R + INH). Latent: INH 300mg daily x 9mo (or rifampin 4mo, or INH + rifapentine weekly x 3mo). MDR-TB: Fluoroquinolone + injectable + second-line (bedaquiline, linezolid) for 18-24mo. Monitoring: INH → LFTs, B6 25-50mg/d (neuropathy). Rifampin → orange secretions, CYP induction. EMB → optic neuritis (color vision monthly). PZA → hyperuricemia, hepatitis.

First-line: TAF/FTC + dolutegravir (or bictegravir). Start immediately. PEP: within 72h, TDF/FTC + raltegravir/dolutegravir x 28d. PrEP: TDF/FTC daily. Prophylaxis: TMP-SMX if CD4 <200 (PCP). Azithromycin if CD4 <50 (MAC). Monitoring: Viral load at 4-6wk, then q3-6mo.

Risk: ALL, Burkitt, AML with high WBC. Prophylaxis: IV fluids 3L/m2/day, allopurinol 300mg (or rasburicase 0.2mg/kg if high risk). Treatment: Monitor K, Ca, Phos, uric acid q6-8h. Rasburicase. Insulin + D50 for K >6.5. Calcium gluconate for EKG changes. Hemodialysis if refractory. Do not give rasburicase to G6PD deficiency.

Acute (<100d): Prophylaxis: MTX + cyclosporine/tacrolimus + MMF. Treatment: methylprednisolone 2mg/kg/d. Second-line: ruxolitinib (JAK inhibitor), ATG, basiliximab. Chronic (>100d): Prednisone + calcineurin inhibitor. Second-line: ruxolitinib, ibrutinib, ECP, rituximab. Prevention: T-cell depletion, post-transplant cyclophosphamide (haplo).

AIHA warm (IgG): Prednisone 1mg/kg/d first-line. Second-line: rituximab, splenectomy, immunosuppression. AIHA cold (IgM): Avoid cold. Rituximab first-line. TTP: ↓ADAMTS13. Daily PEX + steroids. Caplacizumab. PNH: Eculizumab/ravulizumab (anti-C5). HUS typical: Supportive (E. coli O157:H7). HUS atypical: Eculizumab.

Pathology is the foundation of all clinical medicine. Master these core topics in order: (1) Cell injury and death — understand necrosis vs apoptosis, as this framework recurs in every organ system. (2) Inflammation and repair — the mediators and cellular players are the same in every disease. (3) Neoplasia — the hallmarks, oncogenes, and tumor suppressors are the bedrock of oncology. (4) Hemodynamic disorders — shock, thrombosis, embolism are exam favorites. (5) Systemic pathology — apply your knowledge to each organ system. Use the cheat cards above for rapid recall before exams. Focus on understanding morphology and mechanisms, not just memorizing lists.

Anemia: Microcytic (iron def, thalassemia, ACD) vs macrocytic (B12, folate, alcohol, MDS) vs normocytic (hemolytic, renal, aplastic). Check MCV, reticulocytes, iron studies, peripheral smear. Bleeding: PT ↑ (warfarin, liver, vitamin K). aPTT ↑ (heparin, hemophilia, vWD, lupus anticoagulant). Both (DIC, liver). Mix corrects = deficiency; no correction = inhibitor. Jaundice: Pre-hepatic (hemolysis, indirect bili). Hepatic (direct + indirect). Post-hepatic (obstructive, direct bili, ALP/GGT). Lymphadenopathy: Infection (EBV, TB, HIV). Neoplastic (lymphoma, mets). Autoimmune (SLE, RA, sarcoid). Excisional biopsy for architecture. FUO: Infection (TB, abscess, IE, HIV), malignancy (lymphoma, RCC, HCC), autoimmune (SLE, Still, RA, vasculitis), drugs (DRESS). Workup: CBC, cultures, ESR/CRP, ANA, RF, SPEP, LDH, ferritin, CT chest/abdomen/pelvis, PET-CT, biopsy.