12.1 Fundamentals of Pathology

Why cellular pathology is a scored Pathology topic

/practice/nbce-part1Practice questions with detailed explanations

Quick Answer: Reversible injury is hydropic swelling and fatty change. Irreversible injury is membrane and mitochondrial failure that produces necrosis (inflammation) or apoptosis (caspases, no inflammation). Acute inflammation is vascular leak plus neutrophils; repair is regeneration or fibrosis. Cancer is clonal, invades, and may metastasize. Edema follows Starling imbalance; thrombi follow Virchow triad; infarcts are ischemic necrosis; shock is inadequate perfusion.

Cell injury: hypoxia, ischemia, radicals, and calcium

A cell lives by ATP. Anything that collapses oxidative phosphorylation or floods the cytosol with calcium and reactive oxygen species (ROS) will injure it. Hypoxia is inadequate oxygen with perfusion still present (high altitude, anemia, carbon monoxide, cyanide at cytochrome oxidase). Ischemia is reduced blood flow: the cell loses oxygen and substrates and waste removal, so ischemia is worse than an equivalent isolated hypoxia. Reperfusion after ischemia can add a second hit: xanthine oxidase and leaking mitochondria generate superoxide, complement and neutrophils arrive, and the mitochondrial permeability transition pore opens.

Reversible injury on the slide is cellular swelling (hydropic or vacuolar change) and fatty change (steatosis). Swelling follows Na+/K+ ATPase failure: sodium and water enter, the ER dilates, and the cell looks pale and enlarged. Steatosis is triglyceride accumulation when the hepatocyte (or myocyte) cannot export lipoprotein, oxidize fatty acids, or keep up with delivery—alcohol, obesity, diabetes, hypoxia, carbon tetrachloride, and protein malnutrition are the named settings.

Irreversible injury is defined by severe plasma-membrane and mitochondrial damage. Enzymes leak; calcium floods; nuclear chromatin condenses. The three nuclear signs of necrosis are pyknosis (shrinkage and hyperchromasia), karyorrhexis (nuclear fragmentation), and karyolysis (fade-out of chromatin). Do not call those apoptosis; apoptotic nuclei are pyknotic and fragment into apoptotic bodies, but the tissue does not inflame.

Cellular adaptations

If the stress is survived rather than lethal, the cell adapts. Adaptations are reversible in principle; they become disease when the stimulus never stops or when the new phenotype is a platform for dysplasia.

Hypertrophy versus hyperplasia is a favorite discriminator. Cardiac myocytes and neurons cannot meaningfully divide, so the left ventricle thickens by hypertrophy. Epidermis, marrow, and glands can divide, so they hyperplastic. Prostate stroma and epithelium do both. Immobilization atrophy of paraspinal muscle is the same ubiquitin–proteasome program as denervation atrophy; the innervation is intact, the load is gone.

Metaplasia is not cancer, but it is a risk field. Barrett intestinal metaplasia can progress through dysplasia to adenocarcinoma. Squamous metaplasia of bronchi can progress to squamous dysplasia and carcinoma. The switch is driven by reprogramming of stem cells (cytokines, growth factors, vitamin A status), not by one cell morphing its already-made organelles.

Dysplasia is disordered growth: nuclear atypia, mitoses above the basal layer, loss of polarity. It is still confined by the basement membrane. Full-thickness dysplasia of epithelium is carcinoma in situ. Once cells cross the basement membrane, it is invasive carcinoma. Do not call metaplasia dysplasia; do not call dysplasia invasion.

Necrosis versus apoptosis

Necrosis is unregulated cell death in a living host. Membranes dissolve, contents spill, and inflammation follows. Apoptosis is programmed, energy-dependent, and noninflammatory: the cell shrinks, chromatin condenses, phosphatidylserine flips to the outer leaflet as an “eat-me” signal, and macrophages clear apoptotic bodies without a neutrophilic mess.

Patterns of necrosis (name the organ and the look):

A two-day-old left-anterior-descending infarct is coagulative: hypereosinophilic myocytes, pyknotic nuclei, preserved outlines, neutrophils arriving. A middle-cerebral-artery infarct is liquefactive even though the cause is still ischemia—the brain is lipid-rich and enzyme-rich. That pair is the highest-yield necrosis discriminator on a basic-science exam.

Apoptotic pathways. The intrinsic (mitochondrial) pathway is used for DNA damage, growth-factor withdrawal, and most chemotherapeutic injury. BH3-only sensors inhibit BCL-2. BAX and BAK oligomerize in the outer mitochondrial membrane. Cytochrome c enters the cytosol, binds Apaf-1, and forms the apoptosome that activates caspase-9. The extrinsic (death-receptor) pathway is Fas (CD95) or TNF receptor: ligand binding recruits FADD and activates caspase-8. Both streams meet executioner caspases 3, 6, and 7, which cut cytoskeleton, nuclear lamins, and DNA. Cytotoxic T cells can also inject granzyme B, which activates caspases directly. p53 links DNA damage to the intrinsic pathway (and to cell-cycle arrest via p21); loss of p53 is both a failure of apoptosis and a failure of genome guardianship.

Named physiologic apoptosis: digital web resorption, endometrial breakdown, deletion of self-reactive lymphocytes, neutrophil death after an acute pneumonia resolves. Named pathologic apoptosis: Councilman bodies in viral hepatitis, follicle collapse after hormone withdrawal, lymphocyte depletion in HIV, chondrocyte loss in a degenerating nucleus pulposus. The disc’s limited vascularity means annular tears heal by fibrosis, not by regenerating native fibrocartilage—an adaptation/repair fact that matters when you later read musculoskeletal pathology.

Acute inflammation: vessels, leukocytes, outcomes

Inflammation is the vascularized-tissue response to injury. Acute inflammation lasts hours to a few days and is neutrophil-dominated. Chronic inflammation lasts weeks or more and is macrophage- and lymphocyte-dominated, with angiogenesis and fibrosis. Cardinal signs: rubor (redness), calor (heat), tumor (swelling), dolor (pain), functio laesa (loss of function).

Vascular events. A fleeting arteriolar constriction is followed by arteriolar dilation (histamine, nitric oxide, prostacyclin) → increased flow → redness and heat. Increased permeability of postcapillary venules (histamine, bradykinin, leukotrienes C4/D4/E4, C3a/C5a, substance P) leaks protein-rich exudate. The resulting concentrated red-cell mass raises viscosity and produces stasis, which lets leukocytes marginate.

Leukocyte events (memorize the molecules):

Outcomes of acute inflammation: (1) resolution if the tissue is labile or stable and the stimulus is gone; (2) abscess if neutrophils and liquefaction persist; (3) scarring if stroma is destroyed; (4) chronic inflammation if the stimulus remains (foreign body, autoantigen, mycobacteria).

Chemical mediators

COX-1 is constitutive (gastric mucosa, platelets, kidney). COX-2 is induced at inflammatory sites. That is why nonselective COX blockade hits stomach and platelets, and why PGE2 is the fever/pain mediator you should name on a stem that mentions hypothalamus or bradykinin-plus-prostaglandin synergy. Phospholipase A2 in herniated nucleus pulposus can generate these eicosanoids locally—chemical radiculitis without a huge mechanical dent on the thecal sac.

Chronic inflammation and granulomas

Chronic inflammation mixes mononuclear cells (macrophages, lymphocytes, plasma cells), tissue destruction, and attempts at healing (angiogenesis, fibrosis). Macrophages activate via IFN-γ from Th1 cells (classic M1, microbicidal, IL-1/TNF/ROS) or via IL-4/IL-13 (M2, TGF-β, repair and fibrosis). Granulomatous inflammation is a distinctive chronic pattern: aggregates of epithelioid macrophages, often with multinucleated giant cells, rimmed by lymphocytes.

Foreign-body giant cells wrap indigestible material (suture, splinter). Immune granulomas wrap persistent microbes or antigens that T cells cannot clear. A chiropractic-relevant foreign-body story is rare; the exam-relevant story is TB versus sarcoid versus Crohn on a stem that mentions epithelioid macrophages.

Repair, granulation tissue, and fibrosis

Repair restores tissue by regeneration (same cell type) or by scar (collagen). Regenerative capacity:

Granulation tissue is the provisional organ of healing: leaky new capillaries, fibroblasts, loose extracellular matrix (fibronectin, proteoglycans, type III collagen), and macrophages. TGF-β is the master fibrotic cytokine: it recruits fibroblasts, induces collagen, and inhibits metalloproteinases. Vitamin C is required for prolyl/lysyl hydroxylation of collagen; copper for lysyl oxidase crosslinking; zinc for metalloproteinases that remodel. Without vitamin C you get wound failure and bleeding gums (scurvy), not a vitamin trivia item for its own sake—connect it to collagen.

Timeline of a clean incised wound (primary intention): 24 h, neutrophils and fibrin; day 3, macrophages and granulation; day 5, collagen bridges the wound; week 2, fading inflammation; months, type III remodeled toward type I. Tensile strength is about 10% of normal at one week and plateaus near 70–80% by three months—never 100%. Secondary intention (gaping wounds, abscess cavities, infarcts) fills from the base, contracts via myofibroblasts, and scars more. Keloids overgrow the original wound and are collagen-rich; hypertrophic scars stay within the wound borders. Both are TGF-β/collagen excess, not infection.

Bone heals by hematoma → soft callus → hard callus → remodeling (woven then lamellar). Intervertebral disc inner annulus and nucleus have almost no vessels: annular tears scar; the nucleus does not regenerate a youthful proteoglycan gel. That is repair biology, not an adjustment protocol.

Neoplasia: names, hallmarks, invasion, grade versus stage

A neoplasm is a clonal proliferation of transformed cells that persist after the stimulus is gone. Benign tumors are usually well differentiated, slow, often encapsulated, and do not metastasize—though they can kill by location (meningioma compressing brainstem). Malignant tumors invade and can metastasize.

Hallmarks of malignancy (use the named genes):

Invasion cascade: loosen junctions (E-cadherin down) → degrade basement membrane (matrix metalloproteinases) → attach to ECM (integrins) → migrate. Metastasis is survival in blood or lymph, arrest, and colonization. Carcinomas typically seed lymph nodes first (sentinel-node logic). Sarcomas typically seed lung and other organs via blood. Exceptions you should know: follicular thyroid carcinoma, renal-cell carcinoma, and hepatocellular carcinoma have a hematogenous habit; renal-cell carcinoma can snake into the inferior vena cava. Seeding of body cavities is classic for ovarian carcinoma (omental cake) and CNS tumors via CSF.

Grade is how much the tumor resembles its tissue of origin (well / moderate / poor / anaplastic; Gleason for prostate; Nottingham for breast). Stage is how far it has spread: TNM = Tumor size/invasion, Nodes, Metastasis. Stage generally beats grade for prognosis. Carcinoma in situ is Tis: high-grade cytology, basement membrane intact, no access to lymphatics yet.

Carcinogens worth naming because they illustrate mechanism: aflatoxin B1 → hepatocellular carcinoma (p53 mutation); vinyl chloride → hepatic angiosarcoma; asbestos → mesothelioma and lung carcinoma; HPV E6/E7 → degrade p53 and RB; EBV → Burkitt lymphoma, nasopharyngeal carcinoma, some Hodgkin; HBV/HCV → HCC; H. pylori → gastric adenocarcinoma and MALT lymphoma. Paraneoplastic teaching set: PTHrP in squamous lung carcinoma (hypercalcemia); ACTH or ADH in small-cell lung carcinoma; erythropoietin in renal-cell carcinoma.

Hemodynamic disorders

Edema is excess interstitial (or body-cavity) fluid. Starling forces are taught in physiology (/study-guides/nbce-part1/physiology-neural-cardiovascular/cardiovascular-physiology); pathology asks which force moved.

Transudate is protein-poor, specific gravity typically <1.012, from hydrostatic or oncotic imbalance. Exudate is protein-rich, specific gravity typically >1.020, from leaky vessels and inflammation (use Light criteria in pleural fluid when a stem gives LDH and protein ratios). Hyperemia is active arteriolar dilation (exercising muscle, acute inflammation). Congestion is passive venous backup: acute pulmonary congestion is alveolar capillaries packed with blood; chronic passive congestion of liver is nutmeg liver (centrilobular necrosis plus hemorrhage). Hemorrhage vocabulary: petechiae <2 mm, purpura 3–10 mm, ecchymoses >1 cm.

Thrombosis is pathologic clot in a living vessel. Virchow triad: (1) endothelial injury, (2) stasis or turbulence, (3) hypercoagulability. Intact endothelium is antithrombotic (prostacyclin, nitric oxide, ADPase, thrombomodulin–protein C, heparin-like antithrombin sites, tPA). Denuded or inflamed endothelium is the opposite.

Fates of a thrombus: propagation, embolization, dissolution (fibrinolysis), organization and recanalization. Postmortem clots are chicken-fat and currant-jelly, not attached, without lines of Zahn.

Embolism is a detached intravascular mass carried downstream.

Infarction is ischemic necrosis. White (anemic) infarcts occur in solid organs with end-arterial supply: heart, spleen, kidney. Red (hemorrhagic) infarcts occur where there is dual supply or reperfusion or venous occlusion: lung, intestine, testis. Shape is often wedge-shaped, apex at the occluded vessel. Histology follows the coagulative (or brain liquefactive) clock: 4–12 h, early hypereosinophilia; 1–3 days, neutrophils; 3–7 days, macrophages; thereafter granulation and scar.

Shock is systemic hypoperfusion. Stages: compensated (tachycardia, vasoconstriction, cool skin except in distributive shock), progressive (lactic acidosis, hypoxic injury), irreversible (membrane injury, death despite restored pressure).

Watershed infarcts of brain (ACA–MCA zone), heart (subendocardium), and colon (splenic flexure) are the anatomic signature of hypotensive shock once pressure is restored or the patient survives long enough to declare the lesion.

These four bullets—cell injury, inflammation/repair, neoplasia, hemodynamics—are the 15% fundamentals block. Genetic disease and hypersensitivity are the next two sections of this chapter; named organ diseases wait for the systems chapter.