General Pathology

Comprehensive study resource covering cell injury, inflammation, hemodynamics, immunopathology, neoplasia, environmental pathology, genetic disorders, systemic pathology, bone/soft tissue, neuropathology, and clinical laboratory medicine. Every concept, every stain, every high-yield fact you need to know.

1. Cell Injury, Adaptation and Death

Causes and bull; Reversible/Irreversible and bull; Necrosis Types and bull; Apoptosis and bull; Autophagy and bull; Adaptations and bull; Accumulations and bull; Calcification and bull; Aging

Causes and Mechanisms of Cell Injury
  • 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 vs Irreversible Injury
  • 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).
Necrosis Types
  • 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.
Apoptosis
  • 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, Necroptosis and Pyroptosis
  • 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.
Cellular Adaptations
  • 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).
Intracellular Accumulations
  • 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).
Pathologic Calcification and Aging
  • 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).
High-Yield Pearls
  • Coagulative necrosis = heart, kidney, spleen (architecture preserved). Liquefactive = brain. Caseous = TB. Fat = pancreas. Gangrenous = limb + bacteria.
  • Apoptosis: intrinsic (mitochondrial, BCL-2 family, caspase-9) vs extrinsic (death receptor, caspase-8). Both converge on executioner caspases 3/6/7.
  • p53 ↑ BAX, PUMA -> apoptosis. BCL-2 blocks BAX/BAK. Overexpressed in follicular lymphoma t(14;18).
  • Metaplasia is reversible; dysplasia is pre-neoplastic; CIS = full-thickness dysplasia.
  • Dystrophic calcification = dead tissue + normal Ca2+. Metastatic = normal tissue + high Ca2+.
  • Lipofuscin = wear-and-tear pigment (brown atrophy). Hemosiderin = iron overload (Prussian blue+).
Red Flags
  • Wet gangrene: rapid spread, sepsis, gas (Clostridium). Emergent surgical debridement + antibiotics.
  • Microvesicular steatosis (fatty liver of pregnancy, Reye): liver failure, encephalopathy, hypoglycemia.
  • Caseous necrosis + cough + hemoptysis + night sweats = active TB. AFB smear, culture, GeneXpert. Airborne isolation.
  • Acute pancreatitis with saponification -> hypocalcemia (Ca2+ binds FFA). CT abdomen, aggressive IVF, ICU.
  • Mallory bodies (alcoholic hepatitis): hepatocyte ballooning, eosinophilic perinuclear inclusions. Severe: MELD >= 20, steroids.

2. Inflammation and Repair

Acute Inflammatory Response and bull; Chemical Mediators and bull; Chronic Inflammation and bull; Granulomas and bull; Wound Healing and bull; Angiogenesis and bull; ECM and bull; MMPs

Acute Inflammation: Vascular Events
  • 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, high SG > 1. 020, inflammatory, cellular).
Acute Inflammation: Cellular Events
  • 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.
Chemical Mediators of Inflammation
  • 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.
Chronic Inflammation
  • 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.
Wound Healing and Repair
  • Regeneration: labile cells (skin, GI, BM) and 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, ECM and MMPs
  • 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.
High-Yield Pearls
  • Classic signs: rubor, calor, tumor, dolor, functio laesa. All from vascular changes + chemical mediators.
  • COX-1 constitutive (GI, platelet TXA2). COX-2 induced (inflammation). NSAIDs inhibit both. COX-2 selective (celecoxib) spares GI.
  • Complement: Classical (IgM/IgG), Alternative (microbes), Lectin (MBL). C3a/C5a = anaphylatoxins, C5a = chemotaxis, C3b = opsonin, C5b-9 = MAC.
  • Granulomatous: TB (caseating, Langhans), sarcoidosis (non-caseating, Schaumann), Crohn (non-caseating), fungal, foreign body.
  • Wound healing: primary (clean, linear, minimal scar) vs secondary (gaping, more granulation, contraction). Keloid extends beyond scar boundary.
  • IL-1/TNF -> fever, acute phase, cachexia. IL-6 -> CRP. TGF-β -> fibrosis, immunosuppression.
Red Flags
  • SIRS: >= 2 of temp > 38 or < 36, HR > 90, RR > 20/PaCO2 < 32, WBC > 12k or < 4k or > 10% bands. Sepsis = SIRS + infection.
  • Anaphylaxis: rapid urticaria + angioedema + hypotension + bronchospasm. Epinephrine IM first-line. H1/H2 blockers, steroids, IV fluids.
  • HLH: uncontrolled macrophage activation, fever, cytopenias, ferritin ↑↑, sCD25 ↑. Dexamethasone + etoposide + cyclosporine.
  • Keloid: risk in dark skin, young. Intralesional steroids, cryotherapy, excision + RT (high recurrence).
  • Non-healing wound: infection, ischemia (PAD), diabetes, malignancy (Marjolin ulcer SCC). Biopsy.

3. Hemodynamic Disorders

Edema and bull; Hyperemia vs Congestion and bull; Hemostasis/Thrombosis and bull; Embolism and bull; Infarction and bull; Shock

Edema
  • Hydrostatic edema: increased capillary pressure.
  • Systemic (HF, renal failure, fluid overload, cirrhosis ascites).
  • Local (venous thrombosis, constrictive pericarditis).
  • Oncotic (hypoproteinemic): decreased albumin 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 vs Congestion
  • 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).
Hemostasis and Thrombosis
  • 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).
Embolism
  • 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.
Infarction
  • 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.
Shock
  • 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.
High-Yield Pearls
  • Virchow: endothelial injury (most important), stasis, hypercoagulability. Arterial = white (platelet). Venous = red (fibrin/RBC).
  • Lines of Zahn = antemortem. Postmortem clot = dark, gelatinous, no lines.
  • Red infarct: lung, liver, bowel (dual supply or venous). White infarct: heart, kidney, spleen (end-artery).
  • Shock types: hypovolemic (↓preload), cardiogenic (↑PCWP), septic (↓SVR), neurogenic (↓SNS), anaphylactic (IgE).
  • DIC: microthrombi + consumption + bleeding. PT/aPTT ↑, ↓fibrinogen, ↑D-dimer. Treat underlying cause.
  • Massive PE: SBP < 90 + RV strain. Thrombolysis unless contraindicated. Embolectomy if failed.
Red Flags
  • Cardiogenic shock: SBP < 90, CI < 2.2, PCWP > 15. Urgent echo + revascularization. Inotropes + MCS (IABP, Impella, VA-ECMO).
  • Amniotic fluid embolism: sudden collapse during labor + DIC. Immediate CPR, delivery, supportive care. Massive transfusion protocol.
  • Fat embolism syndrome: long bone fracture + petechiae + confusion + hypoxemia. Supportive care. Early fracture fixation.
  • HIT: platelets ↓ > 50% 5-10d post-heparin. Stop heparin, direct thrombin inhibitor (argatroban, bivalirudin). No warfarin alone.

4. Immunopathology

Hypersensitivity I-IV and bull; Autoimmune and bull; SLE and bull; RA and bull; Vasculitis and bull; Amyloidosis and bull; Immunodeficiency and bull; HIV/AIDS

Hypersensitivity Reactions (Types I-IV)
  • 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).
Autoimmune Diseases
  • 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).
Primary Immunodeficiency
  • 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/AIDS
  • HIV: Retrovirus (gp120 + CD4 + CCR5/CXCR4).
  • Targets CD4+ T cells, macrophages, microglia.
  • Acute retroviral syndrome (fever, lymphadenopathy, rash).
  • Latency -> AIDS (CD4 OIs by CD4: AIDS malignancies: Kaposi (HHV-8), NHL (DLBCL, primary CNS EBV+), cervical (HPV). ART: NRTI + INSTI (dolutegravir, bictegravir).
  • Goal: undetectable ( IRIS: paradoxical worsening after ART.
  • Treat OI + steroids.
  • HIVAN: collapsing FSGS, APOL1, Black race.
High-Yield Pearls
  • Hypersensitivity: I (IgE/mast cell), II (IgG/IgM vs cell), III (immune complex), IV (T-cell/DTH).
  • SLE: ANA (98%), anti-dsDNA (specific, nephritis), anti-Smith (specific). Drug-induced: anti-histone, resolves.
  • RA: anti-CCP specific. Pannus = synovitis + erosion. Felty = RA + neutropenia + splenomegaly.
  • ANCA: c-ANCA/PR3 = GPA. p-ANCA/MPO = MPA, Churg-Strauss. Pauci-immune GN.
  • Amyloid: AL (light chain, Congo red+), AA (SAA, chronic inflammation), ATTR (transthyretin).
  • HIV: ART all regardless CD4. U=U. PrEP for high risk. PEP within 72h.
Red Flags
  • Anaphylaxis: epinephrine IM 0.3-0.5mg, repeat q5-15min. H1/H2 blockers, steroids, IV fluids. Biphasic reaction risk up to 8h.
  • Goodpasture: RPGN + hemoptysis. Anti-GBM. Plasmapheresis + cyclophosphamide + steroids. Urgent.
  • SLE cerebritis: headache, seizure, psychosis, stroke. High-dose steroids, cyclophosphamide, mycophenolate. Rule out infection.
  • SJS/TEN: > 30% BSA = TEN. Stop drug, ICU/burn unit, supportive. IVIG/cyclosporine controversial.
  • HIV + CD4 < 50 + neuro symptoms: PML (JC virus). MRI brain. Optimize ART. IRIS may worsen.

5. Neoplasia

Nomenclature and bull; Benign vs Malignant and bull; Metastasis and bull; Hallmarks and bull; Oncogenes/Tumor Suppressors and bull; Carcinogenesis and bull; TNM and bull; Tumor Markers and bull; Cancer Genetics

Nomenclature and Benign vs Malignant
  • 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).
Metastasis and Hallmarks
  • 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 and Tumor Suppressors
  • 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).
Carcinogenesis
  • 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, Staging and Tumor Markers
  • 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).
Paraneoplastic Syndromes
  • 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).
Cancer Genetics
  • 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.
High-Yield Pearls
  • RAS: 30% cancers. MYC: t(8;14) Burkitt. HER2: breast. BCR-ABL: t(9;22) CML -> imatinib.
  • TP53: guardian, lost in > 50%. Li-Fraumeni = germline p53 -> breast, sarcoma, brain.
  • Lynch (MSI-H): MLH1/MSH2, right colon, endometrial. IHC/MSI. Prophylactic colectomy/hysterectomy.
  • BRCA1 -> triple-negative breast, ovarian, PARPi. BRCA2 -> breast, ovarian, pancreatic, melanoma.
  • Paraneoplastic: SCLC (ACTH, ADH, Lambert-Eaton). SCC lung (PTHrP). Midgut carcinoid (serotonin, valvular).
  • HPV: E6 (p53), E7 (RB). Types 16,18 -> cervical, oropharyngeal. Vaccine (Gardasil 9).
Red Flags
  • Tumor lysis syndrome: aggressive NHL/ALL post-chemo. Hyperuricemia, hyperK, hyperPhos, hypoCa. Rasburicase, allopurinol, fluids.
  • SVCS: lung cancer/lymphoma. Face/neck swelling, dyspnea. Urgent stenting vs RT/chemo.
  • Spinal cord compression: back pain + neurologic deficit. Epidural mets (breast, lung, prostate). Urgent MRI + dexamethasone + RT/surgery.
  • Febrile neutropenia: ANC < 500 + fever. Empiric broad-spectrum abx. G-CSF if high risk.

6. Environmental and Nutritional Pathology

Tobacco and bull; Alcohol and bull; Obesity and bull; Malnutrition and bull; Vitamin Deficiencies and bull; Heavy Metals and bull; Radiation and bull; Occupational Lung

Tobacco, Alcohol and Obesity
  • 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.
Malnutrition and Vitamin Deficiencies
  • 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).
Heavy Metals and Occupational Lung
  • 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.
High-Yield Pearls
  • Tobacco: #1 preventable. Lung (SCLC/squamous), COPD, CVD. Quit any age.
  • Megaloblastic: B12 (NEURO + macrocytic) vs folate (only macrocytic). MMA + homocysteine. Pernicious = anti-parietal/IF.
  • Asbestos: ferruginous bodies, pleural plaques, lower lobe fibrosis. Lung CA (x smoking), mesothelioma (no).
  • Silicosis: upper lobe nodules, eggshell LN, ↑TB. Coal worker: macules -> PMF. Caplan = +RA.
  • Lead: basophilic stippling, wrist drop, colic. DMSA chelation.
Red Flags
  • Wernicke: give thiamine BEFORE glucose. Korsakoff preventable. Empiric thiamine in all altered + alcoholism.
  • Lead encephalopathy: seizures, AMS. Urgent BAL + EDTA. CT for cerebral edema.
  • Methemoglobinemia: chocolate blood, O2 gap. Methylene blue 1-2mg/kg.
  • Mesothelioma: dyspnea, pleural effusion, latency 30-40y. Palliative cisplatin + pemetrexed.

7. Genetic and Pediatric Pathology

Birth Defects and bull; Prematurity and bull; TORCH and bull; SIDS and bull; Chromosomal and bull; Single Gene and bull; Inborn Errors

Birth Defects, Prematurity and Perinatal
  • 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 ( RDS/HMD (surfactant deficiency, betamethasone, CPAP, surfactant).
  • BPD (chronic O2/vent injury).
  • IVH (germinal matrix, neovascularization).
  • SIDS: peak 2-4mo, prone sleep, Triple-risk.
  • Prevention: supine, firm mattress, no smoking.
Chromosomal Disorders
  • Down (trisomy 21): flat facies, upslant, epicanthal, single palmar, clinodactyly, sandal gap, ID.
  • AVSD, duodenal atresia, Hirschsprung, hypothyroid, celiac, Alzheimer (APP x 3), ALL/AML (GATA1). ↑ risk maternal age.
  • Edwards (18): micrognathia, overlapping fingers, rocker-bottom, CHD, severe ID.
  • Patau (13): holoprosencephaly, cleft lip/palate, polydactyly, cutis aplasia, CHD.
  • 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.
Single-Gene Disorders
  • 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 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.
Inborn Errors of Metabolism
  • 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 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.
High-Yield Pearls
  • Down: AVSD, duodenal atresia, Hirschsprung, ALL/AML, Alzheimer (APP). Maternal age risk.
  • DiGeorge (22q11.2): conotruncal cardiac, thymic aplasia (T ↓), hypocalcemia, cleft palate.
  • CF: ΔF508, sweat Cl- > 60, P. aeruginosa. CFTR modulators (Trikafta).
  • Sickle: Glu6Val, hydroxyurea (↑HbF), acute chest syndrome, parvovirus aplastic crisis, hyposplenism.
  • Gaucher: glucocerebrosidase, crumpled paper cells, bone pain. Enzyme replacement (imiglucerase).
  • PKU: newborn screen, low-Phe diet. Maternal PKU must control before pregnancy.
Red Flags
  • RDS newborn: surfactant deficiency -> CPAP, surfactant. Antenatal betamethasone.
  • Sickle acute chest: fever + chest pain + infiltrates. O2, abx, incentive spirometry, transfusion.
  • NEC: premie + abdominal distension + bloody stools + pneumatosis. NPO, abx, surgery if perforation.
  • PKU: start low-Phe diet immediately to prevent brain damage.

8. Systemic Pathology: CV and Respiratory

Atherosclerosis and bull; IHD and bull; HTN Heart and bull; Valvular and bull; Cardiomyopathies and bull; COPD and bull; Pneumonia and bull; TB and bull; Lung Cancer and bull; ARDS and bull; IPF and bull; PE and bull; Pulmonary HTN

Atherosclerosis and Ischemic Heart Disease
  • 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 (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).
Respiratory Pathology
  • 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 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).
High-Yield Pearls
  • Atherosclerosis: endothelial injury, LDL ox, foam cells, fatty streak -> fibrous plaque -> complicated (rupture -> thrombus).
  • COPD: chronic bronchitis (blue bloater, Reid > 0.4, cor pulmonale) vs emphysema (pink puffer, α1-AT def, centriacinar vs panacinar).
  • Lung cancer: squamous (central, cavity, hyperCa). Adeno (peripheral, EGFR/ALK). SCLC (central, aggressive, NE, paraneoplastic).
  • TB: Ghon complex (primary), apical cavitary (reactivation), miliary (disseminated). RIPE therapy.
  • ARDS: DAD, hyaline membranes. Low Vt ventilation (6mL/kg).
  • PAH: plexiform lesions. Sildenafil, prostacyclin, bosentan. Lung transplant.
Red Flags
  • Massive PE: SBP < 90, RV strain. Thrombolysis unless CI. Embolectomy if failed.
  • Aortic dissection: tearing pain, pulse differential, mediastinal widening. CT angio. Emergency surgery (type A) vs medical (type B).
  • Cardiac tamponade: Beck triad + pulsus paradoxus + electrical alternans. Emergent pericardiocentesis.
  • Tension pneumothorax: tracheal deviation, hyperresonance, JVD, hypotension. Needle decompression 2nd ICS midclavicular.
  • Massive hemoptysis ( > 400mL/24h): bronchial artery embolization, rigid bronchoscopy, surgery. Causes: TB, bronchiectasis, lung cancer, Aspergilloma.

9. Systemic Pathology: GI, Renal and Reproductive

Peptic Ulcer and bull; Colorectal Cancer and bull; IBD/Crohn/UC and bull; Hepatitis and bull; Cirrhosis and bull; GN and bull; RCC and bull; Bladder and bull; Breast and bull; Cervical and bull; Endometrial and bull; Ovarian and bull; Prostate and bull; Testicular

GI Pathology
  • 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, 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.
Renal Pathology
  • 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.
Reproductive and Breast Pathology
  • 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).
High-Yield Pearls
  • Colon CA: adenoma-carcinoma sequence (APC -> KRAS -> SMAD4 -> p53). Lynch = MSI-H, right-sided. FAP = hundreds polyps.
  • H. pylori: PUD, MALT lymphoma, gastric adeno. Test (urease breath, stool Ag). Triple therapy for eradication.
  • HBV: HBsAg (active), anti-HBs (immune), HBeAg (replication), anti-HBc (past). Vaccine prevents.
  • GN: post-strep (↓C3, subepithelial humps). IgA (mesangial IgA, post-infection hematuria). MCD (foot process effacement, steroid-sensitive).
  • RCC: clear cell (VHL, 3p deletion). Papillary (MET). Chromophobe (better prognosis).
  • Breast: luminal A (best), triple-negative (worst, BRCA1). HER2+ (trastuzumab). DCIS (comedo = worst).
Red Flags
  • Cirrhosis + new ascites: HCC vs decompensation. AFP, ultrasound. Screening q6mo.
  • Hepatorenal syndrome: cirrhosis + AKI + < 500 proteinuria + no improvement after IV albumin. Terlipressin + albumin.
  • Variceal bleed: urgent endoscopy + band ligation + octreotide. TIPS if refractory.
  • Testicular mass with ↑β-HCG: choriocarcinoma. Radical orchiectomy. Chemo (BEP).
  • Ovarian mass + ↑CA-125 + ascites: HGSC until proven otherwise. Surgical staging + debulking + carboplatin/paclitaxel.

10. Bone and Soft Tissue Pathology

Osteosarcoma and bull; Chondrosarcoma and bull; Ewing and bull; GCT and bull; Osteoid Osteoma and bull; Fibrous Dysplasia and bull; Liposarcoma and bull; Rhabdomyosarcoma and bull; Synovial Sarcoma and bull; DFSP and bull; Kaposi

Bone Tumors
  • 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.
  • 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: 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.
  • Simple bone cyst (unicameral): Fallen leaf sign, proximal humerus, femur. Fluid-filled.
Soft Tissue Tumors
  • 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, 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.
High-Yield Pearls
  • Osteosarcoma: metaphysis, Codman triangle, sunburst, ↑ALP, < 20y. Neoadjuvant chemo + surgery.
  • Ewing: t(11;22), small round blue, CD99+, diaphysis, onion skin. Chemo + surgery/RT.
  • GCT: epiphysis, soap bubble, giant cells, > 20y. Denosumab. Recurrence high.
  • Chondrosarcoma: > 40y, pelvis, rings-and-arcs. Surgery (chemo/RT resistant).
  • Rhabdomyosarcoma: < 20y, embryonal (botryoid) vs alveolar (PAX3-FOXO1, worse). Myogenin+.
  • Liposarcoma: most common STS. MDM2+ well-diff. Myxoid t(12;16). Pleomorphic worst.
  • Synovial sarcoma: t(X;18), biphasic, TLE1+, near knee. Young adults.
Red Flags
  • Pathologic fracture: bone lesion (tumor, infection, metabolic). Suspect primary malignant vs metastatic.
  • Rapid growth + pain in known neurofibroma -> MPNST. MRI, PET, biopsy. Wide excision + RT.
  • Retroperitoneal mass: liposarcoma, leiomyosarcoma. CT/MRI, core biopsy. Surgical resection + RT.
  • Desmoid: aggressive recurrence. NSAIDs, tamoxifen, chemo, RT. Avoid R1/R2 resection if morbidity high.

11. Neuropathology

CNS Tumors and bull; Demyelinating and bull; Neurodegenerative and bull; Stroke and bull; CNS Infections and bull; Trauma

CNS Tumors
  • 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, 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, Hemangioblastoma: Cerebellum, von Hippel-Lindau (VHL).
  • Foamy stromal cells, extensive capillaries.
  • Produces Epo -> polycythemia.
Demyelinating and Neurodegenerative
  • 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 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.
Stroke, CNS Infections and Trauma
  • Ischemic stroke (85%): Thrombotic (atherosclerosis, lipohyalinosis lacunar, 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).
High-Yield Pearls
  • GBM: IDH-wt (primary, > 55y, worse) vs IDH-mutant (secondary). MGMT methylation -> temozolomide response.
  • Oligodendroglioma: IDH-mutant, 1p/19q codeletion. Better prognosis. PCV chemo.
  • Medulloblastoma: posterior fossa, < 20y. WNT (best), group 3 (worst). Craniospinal RT + chemo.
  • MS: Dawson fingers, oligoclonal bands, relapsing-remitting. Treat acute (IV steroids), prevent (DMTs).
  • Alzheimer: Aβ plaques + tau tangles. ApoE ε4 risk. Hippocampal atrophy. Cholinesterase inhibitors.
  • Parkinson: substantia nigra loss, Lewy bodies (α-synuclein), tremor, rigidity, bradykinesia. L-DOPA.
  • CJD: spongiform, rapid dementia, myoclonus, EEG PSWCs, 14-3-3. Fatal.
Red Flags
  • Subarachnoid hemorrhage: thunderclap headache, CT+, LP xanthochromia. Urgent neuro ICU, aneurysm clipping/coiling.
  • Ischemic stroke < 4.5h: tPA if no CI. < 24h: mechanical thrombectomy (proximal large vessel occlusion).
  • Bacterial meningitis: empiric abx (ceftriaxone + vancomycin) + dexamethasone before LP if suspected. Do not delay abx for LP.
  • Intracranial HTN: herniation (uncal, central, tonsillar). Emergent mannitol/hyperventilation, neurosurgery, decompressive craniectomy.
  • EDH: lucid interval -> rapid decline -> herniation. Emergent craniotomy + evacuation.

12. Clinical Pathology and Lab Medicine

CBC and bull; Coagulation and bull; Chemistry and bull; SPEP/UPEP and bull; Tumor Markers and bull; Microbiology and bull; Blood Bank and bull; Molecular and bull; Lab Errors

CBC and Anemia Workup
  • RBC indices: MCV (microcytic 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).
Coagulation and Chemistry
  • 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/UPEP, Microbiology and Blood Bank
  • SPEP: M spike = monoclonal gammopathy.
  • MGUS (asymptomatic, 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 and 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).
Molecular and Cytogenetics, Lab Errors
  • 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 160, K 6. 5, Ca 14, glucose 500, pH 7. 6, pO2 5, aPTT > 100, troponin positive, positive blood cultures, critical microbiology results (Gram stain, AFB, Cryptococcus, malaria).
High-Yield Pearls
  • Microcytic anemia: iron (↓Fe, ↑TIBC, ↓ferritin) vs thalassemia (normal Fe, ↑HbA2).
  • Hemolytic: ↑retic, ↑LDH, ↑indirect bili, ↓haptoglobin. Schistocytes = MAHA (DIC/TTP-HUS). Coombs+ = AIHA.
  • PT/aPTT mixing: corrects = deficiency; no correction = inhibitor (lupus anticoagulant, factor inhibitor).
  • Multiple myeloma: CRAB (hyperCa, renal, anemia, bone lesions). M spike, ↑FLC, SPEP/UPEP.
  • Transfusion reaction: ABO = acute hemolytic (stop transfusion, fluids, supportive). TRALI = hypoxemia + CXR infiltrates.
  • Lab errors: pre-analytical > analytical > post-analytical. Most errors are pre-analytical (patient ID, tube, hemolysis).
Red Flags
  • Acute hemolytic transfusion reaction: ABO mismatch. Stop transfusion immediately. Check Coombs, check for hemoglobinuria. Supportive care (fluids, vasopressors, dialysis if needed).
  • TTP: microangiopathic hemolytic anemia + thrombocytopenia + fever + renal + neuro. Schistocytes. ↓ADAMTS13. Plasma exchange (PEX) urgently.
  • DIC: PT/aPTT ↑, ↓fibrinogen, ↑D-dimer, ↓platelets. Treat underlying cause.
  • Spinal fluid: traumatic tap vs SAH (xanthochromia, decreasing RBC count). Glucose < 40 = meningitis (bacterial, TB, fungal).
  • Critical lab value: K > 6.5 EKG, calcium gluconate, insulin + D50, albuterol, kayexalate, dialysis.

13. Cheatsheets and Mnemonics

Quick Remembers and bull; Differential Tables and bull; Decision Aids

Necrosis Types Mnemonic
  • Coagulative: heart, kidney, spleen (architecture intact).
  • Liquefactive: brain (cyst), abscess (neutrophils).
  • Caseous: TB, fungi. Cheese-like, granulomas, Langhans.
  • Fat: pancreatitis (saponification, Ca2+).
  • Gangrenous: dry (line of demarcation) vs wet (+bacteria) vs gas (Clostridium, crepitus).
  • Fibrinoid: immune complex in vessels (PAN, malignant HTN).
Apoptosis Pathways
  • Intrinsic: Stress -> BAX/BAK -> Cytochrome c -> Apaf-1 + procaspase-9 -> Caspase-9 -> Caspase-3/6/7
  • Extrinsic: FasL/Fas, TNF/TNFR1 -> DISC -> Caspase-8 -> Caspase-3
  • Anti-apoptotic: BCL-2, BCL-XL (block BAX/BAK)
  • BH3-only sensors: BIM, BID, BAD, PUMA, NOXA
  • p53 -> BAX, PUMA (DNA damage -> apoptosis)
  • BCL-2 overexpressed: follicular lymphoma t(14;18)
Inflammatory Mediators
  • Histamine: mast cell, immediate vasodilation/permeability
  • Prostaglandins: PGE2 (pain, fever), PGI2 (vasodilation), TXA2 (platelet aggregation)
  • Leukotrienes: LTB4 (chemotaxis), LTC4/D4/E4 (bronchospasm)
  • Complement: C3a/C5a (anaphylatoxins), C5a (chemotaxis), C3b (opsonin), C5b-9 (MAC)
  • Cytokines: IL-1/TNF (fever, cachexia), IL-6 (CRP), IL-8 (chemotaxis), TGF-β (fibrosis)
  • NO: eNOS (vasodilation), iNOS (macrophage killing)
Virchow Triad and Thrombosis
  • Endothelial injury: HTN, smoking, atherosclerosis, vasculitis, trauma
  • Stasis/turbulence: AFib, LV aneurysm, immobilization, venous insufficiency
  • Hypercoagulability (Primary): Factor V Leiden, Prothrombin G20210A, ATIII def, Protein C/S def
  • Hypercoagulability (Secondary): pregnancy, OCP, malignancy, DIC, HIT, APS
  • Arterial (white): platelet-rich. Venous (red): fibrin/RBC-rich.
  • Lines of Zahn: antemortem (postmortem = gelatinous, no lines)
Shock Types Quick Reference
  • Hypovolemic: ↓Preload, ↓CVP, ↓CO. Hemorrhage, burns, dehydration.
  • Cardiogenic: ↑PCWP, ↓CO. MI, arrhythmia, valvular, CMP.
  • Septic (distributive): ↓SVR, ↑CO (early), ↓CO (late). Most common ICU death.
  • Neurogenic: ↓SVR, ↓HR. Spinal cord injury, spinal anesthesia.
  • Anaphylactic: IgE, mast cells, histamine, bronchospasm, vasodilation.
  • Treatment: Norepinephrine first for septic. Fluids. Surviving Sepsis 1h bundle.
Hypersensitivity Types
  • Type I: IgE + mast cell -> histamine, leukotrienes. Anaphylaxis, asthma, hay fever.
  • Type II: IgG/IgM vs cell/ECM. AIHA, ITP, Goodpasture, Graves, Myasthenia.
  • Type III: Immune complex -> complement -> neutrophil. SLE, PAN, post-strep GN.
  • Type IV: T-cell mediated. DTH (PPD, contact dermatitis). CTL (viral, tumor, allograft).
Oncogenes and Tumor Suppressors
  • RAS: 30% cancers (KRAS colon/pancreas/lung, NRAS melanoma, HRAS bladder)
  • MYC: t(8;14) Burkitt, amplified breast/lung
  • HER2/ERBB2: breast (trastuzumab)
  • EGFR: NSCLC, GBM (gefitinib, erlotinib, osimertinib)
  • BRAF V600E: melanoma, hairy cell, colon (vemurafenib)
  • BCR-ABL: t(9;22) CML (imatinib)
  • TP53: guardian, > 50% cancers. Li-Fraumeni germline.
  • RB: cell cycle. Retinoblastoma, SCLC, osteosarcoma.
  • APC: Wnt, FAP, colon. BRCA1/2: DNA repair, PARPi.
Tumor Markers Quick Reference
  • CEA: colon, pancreas, stomach, lung, breast
  • AFP: HCC, yolk sac tumor, NTD
  • CA-125: ovarian
  • CA 19-9: pancreatic, biliary
  • PSA: prostate
  • β-HCG: choriocarcinoma, germ cell
  • Calcitonin: medullary thyroid
  • Bence-Jones (urine): multiple myeloma
  • LDH: germ cell, lymphoma (tumor burden)
  • 5-HIAA (urine): carcinoid
Vitamin Deficiencies (A to K)
  • A: night blindness, xerophthalmia, Bitot spots, keratomalacia
  • B1 (thiamine): beriberi, Wernicke (confusion, ataxia, nystagmus), Korsakoff (amnesia)
  • B3 (niacin): pellagra (dermatitis, diarrhea, dementia)
  • B9 (folate): megaloblastic anemia (NO neuro), homocysteine ↑
  • B12 (cobalamin): megaloblastic + subacute combined degeneration. Pernicious anemia.
  • C: scurvy (gingival hyperplasia, petechiae, poor wound healing)
  • D: rickets (children), osteomalacia (adults), Looser zones
  • K: bleeding (PT ↑). Newborn prophylaxis. Warfarin.
Cancer Genetics Syndromes
  • Lynch: MLH1/MSH2, MSI-H, right colon, endometrial, ovarian
  • FAP: APC, hundreds polyps, cancer by 40s. Gardner (+ osteomas, desmoids).
  • BRCA1/2: breast, ovarian, pancreatic, PARP inhibitors
  • Li-Fraumeni: TP53, breast, sarcoma, brain, leukemia
  • VHL: hemangioblastoma, RCC, pheochromocytoma
  • MEN1/2: parathyroid, pituitary, pancreatic, medullary thyroid, pheo
  • NF1: neurofibromas, cafe-au-lait, Lisch nodules, MPNST
  • TSC: tubers, SEGA, cardiac rhabdomyoma, AML, LAM
  • Cowden (PTEN): breast, thyroid, endometrial, trichilemmomas
Anemia Differential
  • Microcytic: iron def (↓Fe, ↑TIBC, ↓ferritin), thalassemia (normal Fe, ↑HbA2), ACD, sideroblastic
  • Macrocytic: B12 (↑MMA, ↑homocysteine), folate (↑homocysteine), alcohol, MDS, liver
  • Normocytic: ACD, hemolytic (↑retics, ↑LDH, ↑indirect bili, ↓hapto), renal, aplastic
  • Hemolytic: schistocytes (MAHA/DIC/TTP-HUS), spherocytes (HS), sickle, G6PD, AIHA (Coombs+)
Transfusion Reactions
  • Acute hemolytic: ABO mismatch. Fever, pain, DIC, hemoglobinuria. Stop, fluids, supportive.
  • Febrile non-hemolytic: Anti-WBC. Fever, chills. Antipyretics. Leukoreduced.
  • Allergic: Urticaria, pruritus. Antihistamines.
  • Anaphylactic: IgA deficiency. Epinephrine, steroids.
  • TACO: Volume overload, ↑BP, dyspnea. Diuresis.
  • TRALI: Anti-HLA, acute lung injury, hypoxemia, CXR bilateral infiltrates.
Key Histology Stains and IHC Markers
Stain/MarkerTargetPositive In
H and EGeneral morphologyAll tissues
PASGlycogen, mucin, fungiGSD, fungal walls, basement membrane
Congo redAmyloidAL, AA, ATTR (apple-green birefringence)
Prussian blueIronHemochromatosis, hemosiderosis
Silver stainFungi, Pneumocystis, reticulinPCP, fungal walls, melanin
Ziehl-Neelsen (AFB)MycobacteriaM. tuberculosis, M. leprae
Gram stainBacterial cell wallGram+ (purple), Gram- (pink)
GiemsaParasites, DNAMalaria, Babesia, H. pylori, Chlamydia
Oil red O (frozen)LipidSteatosis, liposarcoma, fat embolism
IFIg, complementGN (linear vs granular), SLE, Goodpasture, IgA
Cytokeratin (CK7/20)EpithelialCarcinomas (organ of origin)
VimentinMesenchymalSarcomas, melanoma
S100Neural, melanocyticMelanoma, schwannoma, chondroid
HMB-45MelanosomeMelanoma (not desmoplastic)
CD3T-cellT-cell lymphoma, reactive T cells
CD20B-cellB-cell lymphoma (DLBCL, follicular)
CD34Hematopoietic, vascularVascular tumors, GIST, DFSP
CD45 (LCA)LeukocyteLymphoma/leukemia (not carcinoma)
DesminMuscleLeiomyoma/sarcoma, rhabdomyosarcoma
TTF-1Lung, thyroidLung adeno, SCLC, thyroid
GATA3Breast, urothelialBreast CA, urothelial CA
Ki-67ProliferationAggressive tumors, grading
PD-L1Immune checkpointCheckpoint inhibitor response

14. Treatment Tables and Protocols

Sepsis and bull; DIC and bull; Anaphylaxis and bull; TB and bull; HIV ART and bull; Tumor Lysis and bull; GVHD

Sepsis and Septic Shock (SSC 2024)
  • 1-hour bundle: Measure lactate (repeat if > 2).
  • Blood cultures before abx.
  • Broad-spectrum abx within 1h. Crystalloid 30mL/kg.
  • Vasopressors if MAP 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.
DIC Management
  • ISTH DIC score >= 5: platelets 3s, fibrinogen Bleeding: Platelets if 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.
Anaphylaxis Protocol
  • 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.
TB Treatment Regimens
  • 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.
HIV ART
  • 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 Monitoring: Viral load at 4-6wk, then q3-6mo.
Tumor Lysis Syndrome (TLS)
  • 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.
GVHD Management
  • Acute ( 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).
Hemolytic Anemia Treatment
  • 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.
Key Drug Interactions
  • Rifampin: potent CYP450 inducer -> reduces OCPs, warfarin, ARVs, azoles, methadone, cyclosporine, steroids.
  • INH: B6 deficiency (give B6 25-50mg/d), hepatitis (avoid alcohol, monitor LFTs).
  • Allopurinol + azathioprine/6-MP: severe myelosuppression. Reduce azathioprine by 60-75%.
  • Digoxin + amiodarone/verapamil: ↑digoxin. Reduce dose by 50%.
  • Warfarin + amiodarone: ↑INR. Reduce warfarin by 25-50%.
  • Statins + CYP3A4 inhibitors (azoles, macrolides, amiodarone, grapefruit): ↑statin toxicity -> rhabdomyolysis.
  • TMP-SMX + warfarin: ↑INR. Monitor closely.
  • MTX + NSAIDs: ↓MTX clearance -> myelosuppression, nephrotoxicity.

15. Study Tips and Exam Preparation

Board Review and bull; High-Yield Topics and bull; Clinical Reasoning and bull; How to Succeed

How to Use This Guide
  • 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.
Top High-Yield Concepts
Cell Injury

Coagulative vs liquefactive vs caseous necrosis, apoptosis intrinsic/extrinsic pathways, BCL-2 family, p53, reversible vs irreversible injury, metaplasia vs dysplasia.

Inflammation

Vascular/cellular events, chemical mediators (histamine, COX/LOX, complement, cytokines), granulomatous inflammation (TB vs sarcoid), wound healing, keloid vs hypertrophic scar.

Hemodynamics

Virchow triad, arterial vs venous thrombus, lines of Zahn, PE, DIC, shock types, red vs white infarct, edema types.

Neoplasia

Hallmarks of cancer, RAS/MYC/HER2/BCR-ABL, TP53/RB/APC/BRCA, TNM staging, tumor markers, paraneoplastic syndromes, Lynch/FAP/BRCA/Li-Fraumeni.

Immunopathology

Hypersensitivity I-IV, SLE (ANA/anti-dsDNA/anti-Smith), RA (anti-CCP), ANCA vasculitis, amyloidosis (AL/AA/ATTR), HIV OIs by CD4.

Systemic Pathology

Atherosclerosis, lung cancer types, COPD, GN (post-strep, IgA, MCD, crescentic), breast CA subtypes, colon CA (adenoma-carcinoma sequence, Lynch vs FAP).

Bone and Soft Tissue

Osteosarcoma (Codman, sunburst), Ewing (t(11;22), CD99+), GCT (epiphysis), chondrosarcoma, liposarcoma (MDM2+), rhabdomyosarcoma (myogenin+), synovial sarcoma (t(X;18)).

Clinical Pathology

Microcytic vs macrocytic anemia, PT/aPTT mixing studies, tumor markers, Gram stain, transfusion reactions, lab errors (pre/analytical/post), critical values.

Clinical Reasoning Frameworks
  • 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.
Final Words

Pathology is the bridge between basic science and clinical medicine. Master the patterns of tissue injury, memorize the key stains and IHC markers, and understand the molecular basis of neoplasia - these are the foundations of every specialty. This guide covers the entire scope of general pathology for medical students, residents, and board review. Updated 2026. "The more you know pathology, the better clinician you become."

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