Master Pathology
for USMLE Step 1

Core Concepts

• Cellular Adaptation: Atrophy (decrease in cell size/number), Hypertrophy (increase in cell size), Hyperplasia (increase in cell number), Metaplasia (reversible change from one mature cell type to another), Dysplasia (disordered cellular growth, often pre-malignant), Anaplasia (loss of differentiation, characteristic of malignancy).
• Cell Injury & Death:
  • Reversible: Cell swelling (hydropic change), fatty change.
  • Irreversible: Membrane damage (leads to Ca2+ influx), mitochondrial dysfunction, nuclear changes (pyknosis - condensation, karyorrhexis - fragmentation, karyolysis - dissolution).
  • Necrosis: Uncontrolled cell death with inflammation. Types: Coagulative (ischemia/infarcts in most solid organs, not brain), Liquefactive (brain infarcts, bacterial abscesses), Caseous (TB, fungi, granulomas), Fat (pancreatitis, trauma), Fibrinoid (vasculitis, malignant hypertension), Gangrenous (ischemia of limb/GI tract).
  • Apoptosis: Programmed cell death (intrinsic or extrinsic pathways) without inflammation.
• Inflammation:
  • Acute: Rapid onset, short duration, neutrophils predominant, exudate formation, cardinal signs (rubor, tumor, calor, dolor, functio laesa). Key mediators: Histamine, Bradykinin, Prostaglandins, Leukotrienes, Complement, IL-1, TNF-alpha.
  • Chronic: Prolonged, lymphocytes, macrophages, plasma cells, fibrosis, often involves granuloma formation (e.g., TB, sarcoidosis, Crohn's).
  • Leukocyte Extravasation: Rolling (selectins), Adhesion (integrins), Transmigration (PECAM-1/CD31).
• Tissue Repair: Regeneration (complete restoration) vs. Scarring (collagen deposition). Phases: Inflammation, Proliferation (granulation tissue, angiogenesis, re-epithelialization), Remodeling.
• Hemodynamics:
  • Edema: Fluid accumulation (↑ hydrostatic pressure, ↓ oncotic pressure, ↑ vascular permeability, lymphatic obstruction). Transudate (protein-poor) vs. Exudate (protein-rich).
  • Thrombosis: Intravascular clot formation (Virchow's Triad: endothelial injury, stasis, hypercoagulability).
  • Embolism: Detached intravascular mass (thromboembolism, fat, air, amniotic fluid, tumor). Pulmonary embolism (PE) and Systemic Embolism (stroke).
  • Infarction: Ischemic necrosis (wedge-shaped). Red infarcts (venous occlusion, reperfusion) vs. White infarcts (arterial occlusion in solid organs).
  • Shock: Systemic hypoperfusion. Types: Hypovolemic, Cardiogenic, Obstructive, Distributive (septic, anaphylactic, neurogenic).
• Immunopathology:
  • Hypersensitivity Reactions: Type I (IgE-mediated, immediate), Type II (IgG/IgM, cytotoxic), Type III (Immune complex-mediated), Type IV (T-cell mediated, delayed).
  • Autoimmunity: Loss of self-tolerance, immune attack on host tissues.
• Neoplasia: Benign vs. Malignant tumors. Hallmarks of Cancer (e.g., uncontrolled growth, evade apoptosis, angiogenesis, invasion, metastasis). Oncogenes (gain-of-function) vs. Tumor Suppressor Genes (loss-of-function). TNM staging.

Clinical Presentation

• Inflammation: Localized redness, swelling, heat, pain; systemic symptoms like fever, fatigue.
• Ischemia/Infarction: Acute organ dysfunction (e.g., chest pain in MI, sudden neurological deficit in stroke, limb pain/pallor).
• Edema: Visible swelling, pitting vs. non-pitting; impaired organ function (e.g., dyspnea in pulmonary edema).
• Thrombosis/Embolism: Acute pain, swelling (DVT), sudden dyspnea/pleuritic chest pain (PE), focal neurological deficits (stroke).
• Genetic Disorders: Syndromic features, developmental delay, congenital anomalies, characteristic physical findings, family history.
• Autoimmune Diseases: Chronic, fluctuating systemic symptoms (fatigue, fever, weight loss) and/or organ-specific manifestations (e.g., joint pain in RA, rash in SLE).
• Neoplasia: Palpable mass, unexplained weight loss, fatigue, pain, bleeding, constitutional symptoms, paraneoplastic syndromes.

Diagnosis (Gold Standard)

• Biopsy & Histopathology: Microscopic examination of tissue sections (e.g., H&E stain) is the cornerstone for diagnosing most pathological conditions, identifying cellular and architectural changes.
• Immunohistochemistry (IHC): Crucial for identifying specific cell types, tumor origin, and prognostic markers based on protein expression.
• Molecular Diagnostics: PCR, FISH, Next-Generation Sequencing (NGS) to detect specific genetic mutations, chromosomal translocations, or gene amplifications, vital for personalized medicine and prognostication in cancer.
• Flow Cytometry: Essential for classifying hematologic malignancies (leukemias/lymphomas) and evaluating immune cell populations.
• Electron Microscopy: Used for ultrastructural analysis in specific conditions (e.g., renal diseases, ciliary dyskinesia).

Management (First Line)

• Addressing Underlying Cause: Removing etiologic agents (e.g., infection, toxin), surgical resection of tumors.
• Supportive Care: Managing symptoms and complications, fluid resuscitation for shock, pain control, oxygen therapy.
• Anti-inflammatory/Immunosuppressive Therapy: NSAIDs, corticosteroids for acute inflammation; DMARDs, biologics for chronic autoimmune diseases.
• Anticoagulation/Thrombolysis: For thrombotic disorders to prevent clot extension or dissolve existing clots.
• Cancer-Specific Therapies: Surgery, chemotherapy, radiation therapy, targeted therapies, immunotherapy based on tumor type and stage.
• Genetic Counseling & Symptomatic Treatment: For hereditary conditions to manage symptoms and provide reproductive guidance.

Exam Red Flags