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Pathology Overview

27 min read

Introduction #

Pathology is the study of disease, encompassing the structural and functional changes in cells, tissues, and organs that underlie illness. Understanding fundamental pathologic processes is essential for clinical medicine, as these mechanisms form the basis for diagnosis, prognosis, and therapeutic intervention [1]. This review synthesizes high-yield concepts in general pathology relevant to USMLE Step 1 preparation.

Cellular Adaptations #

Cells respond to stress through various adaptive mechanisms that allow survival under adverse conditions. Hypertrophy represents an increase in cell size and functional capacity, commonly occurring in cardiac myocytes subjected to increased workload [2]. Hyperplasia involves an increase in cell number, typically seen in hormonally responsive tissues such as endometrium or in compensatory responses like hepatic regeneration [3]. Atrophy describes cellular shrinkage resulting from decreased workload, denervation, ischemia, or nutritional deprivation, with affected cells showing decreased protein synthesis and increased autophagy [4]. Metaplasia is the reversible replacement of one differentiated cell type with another, exemplified by the transformation of respiratory epithelium from ciliated columnar to squamous cells in chronic smokers [5].

Cellular Injury and Death #

Mechanisms of Cellular Injury

Cellular injury occurs when adaptive capacity is exceeded, resulting from hypoxia, oxidative stress, chemical toxins, infectious agents, or immunologic reactions [6]. Hypoxia impairs oxidative phosphorylation, leading to ATP depletion, failure of sodium-potassium ATPase pumps, cellular swelling, and disruption of calcium homeostasis [7]. Reactive oxygen species cause lipid peroxidation of cellular membranes, protein oxidation, and DNA damage through formation of superoxide, hydrogen peroxide, and hydroxyl radicals [8].

Reversible versus Irreversible Injury

Reversible injury manifests as cellular swelling, fatty change, and plasma membrane blebbing, with preservation of nuclear integrity [9]. Irreversible injury is characterized by severe mitochondrial dysfunction, extensive membrane damage, lysosomal rupture, and nuclear pyknosis, karyorrhexis, or karyolysis [10]. The “point of no return” involves severe mitochondrial calcium accumulation and extensive plasma membrane damage that cannot be repaired [11].

Necrosis

Necrosis represents cell death characterized by cellular swelling, membrane rupture, and inflammatory response [12]. Coagulative necrosis, the most common form, occurs in ischemic injury to solid organs where tissue architecture is preserved initially due to denaturation of structural proteins and enzymes [13]. Liquefactive necrosis occurs in bacterial infections and brain infarction, where complete digestion of dead cells results in liquid debris [14]. Caseous necrosis, characteristic of tuberculosis, shows cheese-like gross appearance with granulomatous inflammation microscopically [15]. Fat necrosis occurs in acute pancreatitis and traumatic injury to adipose tissue, with saponification of fat by lipases [16]. Gangrenous necrosis represents coagulative necrosis with superimposed bacterial infection [17]. Fibrinoid necrosis occurs in immune-mediated vasculitis and malignant hypertension, with vessel wall deposition of immune complexes and fibrin [18].

Apoptosis

Apoptosis is programmed cell death characterized by cell shrinkage, chromatin condensation, formation of apoptotic bodies, and absence of inflammation [19]. The intrinsic pathway involves mitochondrial outer membrane permeabilization regulated by BCL-2 family proteins, with release of cytochrome c activating caspase-9 and downstream executioner caspases [20]. The extrinsic pathway is initiated by death receptors such as FAS (CD95) binding FAS ligand, recruiting adaptor proteins and activating caspase-8 [21]. Apoptosis occurs physiologically in embryonic development, hormone-dependent involution, and elimination of immune cells, and pathologically in DNA damage, viral infections, and cytotoxic T-cell killing [22].

Autophagy

Autophagy is an adaptive catabolic process involving lysosomal degradation of cellular components, providing nutrients during starvation and removing damaged organelles [23]. Dysregulated autophagy contributes to neurodegenerative diseases, cancer, and metabolic disorders [24].

Inflammation #

Acute Inflammation

Acute inflammation represents the immediate response to injury, characterized by vascular changes, neutrophil recruitment, and mediator release [25]. Vascular changes include transient vasoconstriction followed by vasodilation, increased vascular permeability mediated by endothelial gap formation, and fluid exudation [26]. Cardinal signs include rubor (redness), calor (heat), tumor (swelling), dolor (pain), and functio laesa (loss of function) [27].

Neutrophil recruitment involves a coordinated sequence of margination, rolling mediated by selectins, firm adhesion via integrins binding ICAM-1 and VCAM-1, and transmigration through endothelium following chemokine gradients [28]. Chemical mediators include vasoactive amines (histamine, serotonin), arachidonic acid metabolites (prostaglandins, leukotrienes), cytokines (IL-1, TNF-α, IL-6), complement components (C3a, C5a), and kinins (bradykinin) [29].

Acute inflammation outcomes include complete resolution, healing by scarring, abscess formation, or progression to chronic inflammation [30].

Chronic Inflammation

Chronic inflammation persists for weeks to months, characterized by mononuclear cell infiltration (macrophages, lymphocytes, plasma cells), tissue destruction, and attempted repair with angiogenesis and fibrosis [31]. Granulomatous inflammation represents a distinctive pattern with epithelioid macrophages forming nodular aggregates, often with multinucleated giant cells [32]. Caseating granulomas occur in tuberculosis and fungal infections, while non-caseating granulomas characterize sarcoidosis, Crohn disease, and foreign body reactions [33].

Systemic Effects of Inflammation

Acute phase response includes fever mediated by IL-1, IL-6, and TNF-α acting on hypothalamic thermoregulatory centers, leukocytosis driven by cytokine-induced bone marrow release and mobilization, and hepatic production of acute phase proteins including C-reactive protein, serum amyloid A, fibrinogen, and hepcidin [34].

Tissue Repair and Healing #

Regeneration

Regeneration is restoration of tissue architecture through cellular proliferation, occurring in labile tissues (epithelia, hematopoietic cells) with continuous cell division, stable tissues (hepatocytes, fibroblasts) with conditional proliferation, and permanent tissues (neurons, cardiac myocytes) with minimal or absent regenerative capacity [35]. Stem cells maintain tissue homeostasis through asymmetric division, providing self-renewal and differentiated progeny [36].

Wound Healing

Cutaneous wound healing progresses through overlapping phases [37]. Hemostasis involves platelet aggregation, fibrin clot formation, and release of growth factors from platelet granules [38]. The inflammatory phase features neutrophil infiltration followed by macrophage predominance, with phagocytosis of debris and secretion of growth factors and cytokines [39]. Proliferation involves re-epithelialization, granulation tissue formation with angiogenesis and fibroblast proliferation, and collagen deposition [40]. Remodeling continues for months, with collagen reorganization, increased tensile strength, and regression of vasculature [41].

Primary intention healing occurs in clean, closely approximated wounds with minimal tissue loss, showing rapid epithelial regeneration and minimal scarring [42]. Secondary intention healing occurs in wounds with significant tissue loss or infection, requiring extensive granulation tissue formation and wound contraction, resulting in larger scars [43].

Abnormal Wound Healing

Keloids represent excessive scar tissue extending beyond original wound boundaries, more common in individuals of African descent, while hypertrophic scars remain confined to wound margins [44]. Contractures occur when healing spans joints or large surface areas, with excessive wound contraction causing functional impairment [45]. Dehiscence represents wound rupture, particularly in abdominal surgeries, associated with increased intra-abdominal pressure, infection, or poor nutritional status [46].

Hemodynamic Disorders #

Edema

Edema is accumulation of interstitial fluid resulting from increased hydrostatic pressure (heart failure, venous obstruction), decreased plasma oncotic pressure (nephrotic syndrome, liver cirrhosis, malnutrition), lymphatic obstruction, or increased vascular permeability (inflammation) [47]. Anasarca represents severe generalized edema, while specific distributions include pulmonary edema, pleural effusion (hydrothorax), peritoneal effusion (ascites), and pericardial effusion [48].

Hyperemia and Congestion

Hyperemia is active process with arteriolar dilation increasing blood flow, causing tissue redness and warmth [49]. Congestion is passive process with impaired venous outflow, causing tissue bluish discoloration (cyanosis) and chronic congestion leading to tissue hypoxia and fibrosis [50]. Chronic passive congestion of liver produces “nutmeg liver” appearance with centrilobular necrosis and hemorrhage [51].

Hemorrhage

Hemorrhage is extravasation of blood from vessels, classified by location as hematoma (tissue collection), hemothorax (pleural cavity), hemopericardium (pericardial cavity), hemarthrosis (joint), or hemoperitoneum (peritoneal cavity) [52]. Petechiae are pinpoint hemorrhages (1-2 mm) associated with thrombocytopenia or platelet dysfunction, purpura are larger (>3 mm) hemorrhages from vasculitis or coagulation disorders, and ecchymoses (bruises) result from trauma [53].

Thrombosis

Thrombosis is intravascular blood clot formation in living individuals, governed by Virchow’s triad: endothelial injury, abnormal blood flow (stasis or turbulence), and hypercoagulability [54]. Arterial thrombi typically form at sites of atherosclerotic plaque rupture or endothelial injury, composed primarily of platelets and fibrin (“white thrombi”) [55]. Venous thrombi form in conditions of stasis, containing predominantly red blood cells and fibrin (“red thrombi”), with deep venous thrombosis commonly originating in lower extremity veins [56].

Thrombus fate includes propagation, embolization, dissolution by fibrinolysis, or organization with recanalization [57]. Lines of Zahn represent laminations of platelets and fibrin (pale) alternating with red blood cells (dark), distinguishing antemortem thrombi from postmortem clots [58].

Embolism

Embolism is intravascular obstruction by detached material transported through circulation [59]. Pulmonary thromboembolism most commonly originates from deep venous thrombosis, with large emboli causing sudden death, medium emboli causing pulmonary infarction, or recurrent small emboli causing pulmonary hypertension [60]. Systemic thromboembolism arises from cardiac mural thrombi (atrial fibrillation, myocardial infarction) or atherosclerotic plaques, causing stroke, mesenteric ischemia, or limb ischemia [61].

Fat embolism occurs with long bone fractures or extensive soft tissue trauma, with fat globules entering circulation and potentially causing respiratory distress and neurologic symptoms [62]. Air embolism occurs with rapid decompression (decompression sickness) or iatrogenic causes (central venous catheter placement), with nitrogen bubbles forming in tissues and blood [63]. Amniotic fluid embolism is rare obstetric emergency with maternal circulation contamination by fetal cells, causing acute respiratory distress, disseminated intravascular coagulation, and cardiovascular collapse [64].

Infarction

Infarction is tissue necrosis resulting from ischemia, classified as white (anemic) infarcts in solid organs with end-arterial circulation (heart, kidney, spleen) showing pale, wedge-shaped areas, or red (hemorrhagic) infarcts in tissues with dual circulation or venous occlusion (lung, intestine, brain) showing hemorrhagic appearance [65]. Factors determining infarction include vascular anatomy (collateral circulation), tissue vulnerability to hypoxia (brain and heart most sensitive), oxygen content of blood, and rate of occlusion development [66].

Shock

Shock is systemic hypoperfusion causing cellular hypoxia and organ dysfunction [67]. Cardiogenic shock results from impaired cardiac output (myocardial infarction, arrhythmias, cardiac tamponade), hypovolemic shock from decreased blood volume (hemorrhage, fluid loss), septic shock from systemic infection with vasodilation and increased vascular permeability, neurogenic shock from loss of vascular tone (spinal cord injury), and anaphylactic shock from IgE-mediated systemic vasodilation [68].

Shock progresses through compensatory stage with preserved blood pressure through tachycardia and vasoconstriction, progressive stage with tissue hypoperfusion and lactic acidosis, and irreversible stage with extensive cellular injury culminating in multi-organ failure [69]. Systemic inflammatory response syndrome (SIRS) may occur in severe shock, characterized by widespread inflammatory mediator release causing endothelial injury, disseminated intravascular coagulation, and organ dysfunction [70].

Neoplasia #

Nomenclature and Classification

Neoplasms are abnormal tissue masses with unregulated, excessive cellular proliferation persisting after cessation of inciting stimulus [71]. Benign tumors remain localized, exhibit slow growth, and show well-differentiated histology with suffix “-oma” (lipoma, adenoma), while malignant tumors invade locally, metastasize distantly, and demonstrate variable differentiation with terms carcinoma (epithelial origin) or sarcoma (mesenchymal origin) [72].

Characteristics of Neoplasia

Differentiation describes morphologic and functional similarity to normal cells, with well-differentiated tumors resembling tissue of origin and anaplastic tumors showing poor differentiation with marked cellular and nuclear pleomorphism [73]. Dysplasia represents disordered cellular growth and maturation in epithelia, considered pre-malignant with potential for progression to carcinoma, graded as low-grade or high-grade [74]. Carcinoma in situ is full-thickness epithelial dysplasia without basement membrane invasion [75].

Rate of growth varies, with benign tumors typically growing slowly through cellular mitosis, while malignant tumors grow more rapidly with correlation between growth rate and differentiation level [76]. Metastasis, the hallmark of malignancy, involves invasion through basement membrane, intravasation into vessels, survival in circulation, extravasation at distant sites, and colonization with growth in distant organs [77]. Common metastatic routes include lymphatic spread (carcinomas), hematogenous spread (sarcomas), and seeding of body cavities [78].

Molecular Basis of Cancer

Carcinogenesis is multistep process requiring accumulation of mutations in proto-oncogenes, tumor suppressor genes, and genes regulating apoptosis and DNA repair [79]. The hallmarks of cancer include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming energy metabolism, and evading immune destruction [80].

Proto-oncogenes promote cellular proliferation and survival, with gain-of-function mutations creating oncogenes that drive malignancy [81]. Examples include RAS (signal transduction), MYC (transcription factor), HER2/ERBB2 (growth factor receptor), and BCL2 (anti-apoptotic) [82]. Tumor suppressor genes normally inhibit cellular proliferation, requiring loss of both alleles for malignant transformation according to Knudson’s “two-hit hypothesis” [83]. RB (retinoblastoma) regulates G1/S transition, TP53 (p53) induces cell cycle arrest or apoptosis in response to DNA damage, APC regulates WNT signaling pathway, and BRCA1/BRCA2 participate in DNA repair [84].

Defective DNA repair increases mutation accumulation, with hereditary nonpolyposis colorectal cancer (Lynch syndrome) involving mismatch repair gene mutations and xeroderma pigmentosum involving nucleotide excision repair defects [85]. Telomerase reactivation maintains telomere length, conferring replicative immortality to cancer cells [86].

Carcinogenesis

Chemical carcinogens include direct-acting agents requiring no metabolic conversion and indirect-acting procarcinogens requiring metabolic activation [87]. Examples include polycyclic aromatic hydrocarbons (lung cancer), alkylating agents (leukemia), aromatic amines (bladder cancer), and aflatoxin (hepatocellular carcinoma) [88]. Radiation carcinogenesis involves ionizing radiation causing DNA damage (leukemia, thyroid cancer) and UV radiation causing pyrimidine dimer formation (skin cancer) [89].

Oncogenic viruses contribute to human cancers through various mechanisms [90]. DNA viruses include human papillomavirus (cervical carcinoma) producing E6 and E7 proteins that inactivate p53 and RB, Epstein-Barr virus (Burkitt lymphoma, nasopharyngeal carcinoma), hepatitis B virus (hepatocellular carcinoma), and human herpesvirus-8 (Kaposi sarcoma) [91]. RNA retroviruses include human T-cell leukemia virus-1 (adult T-cell leukemia/lymphoma) and HIV (lymphomas, Kaposi sarcoma) [92]. Helicobacter pylori is bacterial carcinogen associated with gastric adenocarcinoma and MALT lymphoma through chronic inflammation and genetic alterations [93].

Tumor Immunology

Immune surveillance involves recognition and elimination of neoplastic cells by innate and adaptive immunity [94]. Tumor antigens include tumor-specific antigens unique to cancer cells, tumor-associated antigens overexpressed in tumors, and viral antigens in virally-induced cancers [95]. Immune evasion mechanisms include downregulation of MHC expression, secretion of immunosuppressive factors (TGF-β, IL-10), expression of immune checkpoint molecules (PD-L1), and recruitment of regulatory T cells [96].

Paraneoplastic Syndromes

Paraneoplastic syndromes are symptom complexes occurring in cancer patients that cannot be explained by direct tumor effects or metastases [97]. Endocrine syndromes include Cushing syndrome from ectopic ACTH (small cell lung cancer), hypercalcemia from PTHrP (squamous cell carcinomas, renal cell carcinoma), SIADH from ectopic ADH (small cell lung cancer), and hypoglycemia from insulin-like growth factors (hepatocellular carcinoma) [98]. Neurologic syndromes include Lambert-Eaton myasthenic syndrome (small cell lung cancer), myasthenia gravis (thymoma), and cerebellar degeneration (ovarian cancer, small cell lung cancer) [99]. Hematologic syndromes include polycythemia from erythropoietin (renal cell carcinoma), thrombocytosis, and migratory thrombophlebitis (Trousseau syndrome) in pancreatic adenocarcinoma [100].

Genetic and Pediatric Diseases #

Single-Gene Disorders

Autosomal dominant disorders require only one mutant allele for phenotypic expression, often affecting structural proteins, with variable expressivity and incomplete penetrance [101]. Examples include familial hypercholesterolemia (LDL receptor deficiency), Marfan syndrome (fibrillin-1 mutation affecting connective tissue), neurofibromatosis type 1 (tumor suppressor gene mutation), and achondroplasia (FGFR3 mutation) [102].

Autosomal recessive disorders require two mutant alleles for disease manifestation, typically involving enzyme deficiencies [103]. Cystic fibrosis results from CFTR mutations causing abnormal chloride channel function, leading to thick secretions affecting lungs, pancreas, and other organs [104]. Sickle cell disease involves point mutation in β-globin gene producing hemoglobin S, causing red blood cell sickling under hypoxic conditions [105]. Phenylketonuria results from phenylalanine hydroxylase deficiency causing intellectual disability if untreated [106]. Tay-Sachs disease involves hexosaminidase A deficiency causing GM2 ganglioside accumulation in neurons [107].

X-linked recessive disorders predominantly affect males, with carrier females usually unaffected due to lyonization [108]. Duchenne muscular dystrophy results from dystrophin gene mutations causing progressive muscle weakness [109]. Hemophilia A involves factor VIII deficiency, while hemophilia B involves factor IX deficiency, both causing bleeding diathesis [110]. Glucose-6-phosphate dehydrogenase deficiency predisposes to hemolytic anemia with oxidative stress [111].

Chromosomal Disorders

Numerical abnormalities include aneuploidy (abnormal chromosome number) and polyploidy (multiples of haploid number) [112]. Down syndrome (trisomy 21) presents with intellectual disability, characteristic facies, congenital heart defects, and increased Alzheimer disease and leukemia risk [113]. Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13) are associated with severe malformations and early lethality [114]. Turner syndrome (45,X) in females causes short stature, webbed neck, and ovarian dysgenesis [115]. Klinefelter syndrome (47,XXY) in males causes hypogonadism, gynecomastia, and infertility [116].

Structural abnormalities include deletions, duplications, inversions, and translocations [117]. Cri-du-chat syndrome results from 5p deletion causing distinctive cat-like cry and intellectual disability [118]. Chronic myelogenous leukemia demonstrates Philadelphia chromosome t(9;22) creating BCR-ABL fusion gene [119].

Lysosomal Storage Diseases

These disorders involve lysosomal enzyme deficiencies causing substrate accumulation in various tissues [120]. Mucopolysaccharidoses result from glycosaminoglycan degradation defects, with Hurler syndrome (α-L-iduronidase deficiency) causing coarse facies, corneal clouding, and organomegaly [121]. Sphingolipidoses include Gaucher disease (glucocerebrosidase deficiency) causing hepatosplenomegaly and bone lesions, Niemann-Pick disease (sphingomyelinase deficiency), and Fabry disease (α-galactosidase A deficiency) [122].

Amyloidosis #

Amyloidosis involves extracellular deposition of insoluble fibrillar proteins with characteristic β-pleated sheet configuration, staining with Congo red and demonstrating apple-green birefringence under polarized light [123]. AL (light chain) amyloidosis is associated with plasma cell dyscrasias, depositing immunoglobulin light chains [124]. AA (serum amyloid A) amyloidosis occurs in chronic inflammatory conditions with deposition of acute phase protein SAA [125]. Aβ amyloidosis involves amyloid precursor protein deposition in Alzheimer disease [126]. Transthyretin (TTR) amyloidosis includes both hereditary and senile systemic forms [127]. Clinical manifestations depend on organs involved, with kidney involvement causing nephrotic syndrome, cardiac involvement causing restrictive cardiomyopathy, and liver involvement causing hepatomegaly [128].

Conclusion #

This overview encompasses fundamental pathologic processes including cellular adaptations, injury mechanisms, inflammation, repair, hemodynamic disorders, neoplasia, and genetic diseases. Mastery of these concepts provides essential foundation for understanding disease mechanisms and clinical manifestations across all medical specialties.

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