Introduction to Pathology

• Pathology is the study of disease.
• Pathology bridges science and medicine.
• Pathology supports patient care through diagnosis, prognosis, and treatment strategies.

Areas of Pathology

• Anatomic pathology involves diagnosing disease through macroscopic, microscopic, and molecular examination of organs and tissues.
• Clinical pathology involves diagnosing disease through laboratory analysis of bodily fluids and tissues like blood, urine, and CSF.
• Molecular pathology involves diagnosing disease through studying molecules in organs, tissues, or bodily fluids.

Anatomic Pathology Subspecialties

• Surgical pathology diagnoses tissue specimens obtained during surgery.
• Cytopathology diagnoses disease through examination of single cells or small clusters of cells.
• Autopsy pathology examines the body after death to determine the cause and extent of disease.
• Forensic pathology applies pathology to legal issues, like determining the cause of death in suspicious circumstances.

Clinical Pathology Subspecialties

• Clinical chemistry analyzes blood and other bodily fluids for chemical constituents.
• Hematology studies blood cells and blood-forming tissues.
• Medical microbiology identifies microorganisms responsible for causing disease.
• Blood bank/transfusion medicine handles the collection, processing, and transfusion of blood and blood products.
• Immunology studies the immune system and its role in disease.

Molecular Pathology Techniques

• Polymerase chain reaction (PCR) amplifies specific DNA sequences.
• Next-generation sequencing (NGS) is high-throughput sequencing of DNA or RNA.
• Fluorescence in situ hybridization (FISH) detects specific DNA sequences in cells or tissues.
• Immunohistochemistry (IHC) detects specific proteins in cells or tissues.

Basic Concepts in Pathology: Cellular Injury

• Cellular injury occurs when cells face stress exceeding their adaptation capacity.
• Cellular injury can be reversible or irreversible.

Causes of Cellular Injury

• Hypoxia is a lack of oxygen.
• Ischemia is reduced blood flow.
• Chemical agents include toxins and drugs.
• Physical agents include trauma, radiation, and temperature extremes.
• Infectious agents include bacteria, viruses, and fungi.
• Immunologic reactions include autoimmunity and hypersensitivity.
• Genetic defects include mutations.
• Nutritional imbalances include deficiencies or excesses.

Mechanisms of Cellular Injury

• ATP depletion reduces energy production.
• Mitochondrial damage impairs oxidative phosphorylation.
• Influx of calcium activates enzymes.
• Oxidative stress leads to an accumulation of free radicals.
• Membrane damage causes loss of cellular integrity.
• DNA damage activates apoptosis.

Reversible Cellular Injury

• Cellular swelling increases cell volume because of the influx of water.
• Fatty change (steatosis) involves the accumulation of lipid droplets within cells.

Irreversible Cellular Injury

• Necrosis is cell death because of external injury.
• Apoptosis is programmed cell death.

Necrosis

• Necrosis is characterized by cell swelling, membrane rupture, and inflammation.
• Types of necrosis include coagulative, liquefactive, caseous, fat, fibrinoid, and gangrenous.
  • Coagulative necrosis preserves tissue architecture.
  • Liquefactive necrosis involves tissue being digested by enzymes.
  • Caseous necrosis has a cheese-like appearance.
  • Fat necrosis involves saponification of fat.
  • Fibrinoid necrosis involves the deposition of fibrin-like material in vessel walls.
  • Gangrenous necrosis involves the death of tissue because of ischemia and infection.

Apoptosis

• Apoptosis involves cell shrinkage, chromatin condensation, and the formation of apoptotic bodies.
• Apoptosis does not elicit inflammation.
• Apoptosis is initiated by intrinsic or extrinsic pathways.
• Apoptosis is important for development, tissue homeostasis, and eliminating damaged cells.

Basic Concepts in Pathology: Inflammation

• Inflammation is a protective response to injury or infection.
• It eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiates tissue repair

Cardinal Signs of Inflammation

• Heat (calor)
• Redness (rubor)
• Swelling (tumor)
• Pain (dolor)
• Loss of function (functio laesa)

Components of Inflammation

• Vascular changes: Increased blood flow and vascular permeability
• Cellular events: Recruitment and activation of leukocytes
• Mediators of inflammation: Cytokines, chemokines, lipid mediators

Vascular Changes in Acute Inflammation

• Vasodilation: Increased blood flow, causing redness and heat
• Increased vascular permeability: Fluid and plasma proteins leak into tissues, causing swelling

Cellular Events in Acute Inflammation

• Leukocyte recruitment:
  • Margination: Leukocytes move to vessel wall
  • Rolling: Leukocytes loosely bind to endothelium
  • Adhesion: Leukocytes firmly bind to endothelium
  • Transmigration: Leukocytes squeeze between endothelial cells
  • Chemotaxis: Leukocytes migrate toward site of injury
• Leukocyte activation:
  • Phagocytosis: Ingestion and destruction of microbes and debris
  • Degranulation: Release of enzymes and toxic substances
  • Production of inflammatory mediators: Amplification of inflammatory response

Mediators of Inflammation

• Cytokines: Proteins that regulate immune and inflammatory responses (e.g., TNF, IL-1, IL-6)
• Chemokines: Attract leukocytes to site of inflammation (e.g., IL-8, MCP-1)
• Lipid mediators:
  • Prostaglandins: Vasodilation, pain, fever
  • Leukotrienes: Increased vascular permeability, bronchospasm
  • Platelet-activating factor (PAF): Vasodilation, increased vascular permeability, leukocyte activation

Types of Inflammation

• Acute inflammation: Rapid onset, short duration, characterized by neutrophils
• Chronic inflammation: Slow onset, long duration, characterized by lymphocytes and macrophages

Outcomes of Acute Inflammation

• Resolution: Complete restoration of tissue structure and function
• Healing by fibrosis (scarring): Replacement of damaged tissue with collagen
• Chronic inflammation: Persistent inflammation and tissue damage

Chronic Inflammation

• Caused by persistent infections, prolonged exposure to toxins, or autoimmune diseases
• Characterized by infiltration of lymphocytes and macrophages, tissue destruction, and attempts at repair

Granulomatous Inflammation

• A type of chronic inflammation characterized by the formation of granulomas
• Granulomas are aggregates of macrophages surrounded by lymphocytes
• Causes of granulomatous inflammation:
  • Infections: Tuberculosis, fungal infections
  • Foreign bodies: Sutures, splinters
  • Autoimmune diseases: Sarcoidosis, Crohn's disease

Basic Concepts in Pathology: Tissue Repair

• Tissue repair is the process of restoring tissue structure and function after injury
• It involves regeneration and/or scar formation

Regeneration

• Replacement of damaged cells with cells of the same type
• Requires intact connective tissue scaffold and proliferative capacity of cells

Scar Formation

• Replacement of damaged tissue with collagen
• Occurs when regeneration is not possible or when there is extensive tissue damage
• Steps in scar formation:
  • Angiogenesis: Formation of new blood vessels
  • Fibroblast migration and proliferation: Deposition of extracellular matrix
  • Collagen synthesis: Production of collagen fibers
  • Wound contraction: Reduction in wound size
  • Remodeling: Reorganization of collagen fibers

Factors Influencing Tissue Repair

• Infection: Delays healing
• Nutrition: Protein deficiency impairs collagen synthesis
• Glucocorticoids: Inhibit inflammation and collagen synthesis
• Mechanical factors: Excessive movement disrupts healing
• Poor perfusion: Impairs delivery of oxygen and nutrients
• Foreign bodies: Delay healing
• Type and extent of injury: More extensive injuries heal more slowly
• Location of injury: Some tissues heal better than others

Complications of Wound Healing

• Deficient scar formation:
  • Dehiscence: Rupture of a wound
  • Ulceration: Inadequate vascularization
• Excessive scar formation:
  • Keloid: Excessive collagen deposition that extends beyond original wound boundaries
  • Hypertrophic scar: Excessive collagen deposition that remains within original wound boundaries
• Contractures: Deformities caused by excessive wound contraction

Key Concepts in Pathology: Genetic Disorders

• Genetic disorders result from abnormalities in an individual's genetic material
• Can be caused by mutations in single genes, multiple genes, or chromosomal abnormalities

Types of Genetic Disorders

• Single-gene disorders: Caused by mutations in a single gene
  • Autosomal dominant: One copy of the mutated gene is sufficient to cause the disorder
  • Autosomal recessive: Two copies of the mutated gene are required to cause the disorder
  • X-linked dominant: One copy of the mutated gene on the X chromosome is sufficient to cause the disorder in females
  • X-linked recessive: Two copies of the mutated gene on the X chromosome are required to cause the disorder in females; one copy is sufficient in males
• Multifactorial disorders: Caused by a combination of genetic and environmental factors
• Chromosomal disorders: Caused by abnormalities in the number or structure of chromosomes
  • Aneuploidy: Abnormal number of chromosomes
  • Translocation: Transfer of a piece of one chromosome to another chromosome
  • Deletion: Loss of a portion of a chromosome
  • Duplication: Presence of an extra copy of a portion of a chromosome

Basic Concepts in Pathology: Neoplasia

• Neoplasia is the uncontrolled proliferation of cells
• Neoplasms can be benign or malignant

Benign Neoplasms

• Well-differentiated cells
• Slow growth rate
• Localized
• Do not metastasize

Malignant Neoplasms (Cancer)

• Poorly differentiated or undifferentiated cells (anaplasia)
• Rapid growth rate
• Invasive
• Metastasize (spread to distant sites)

Nomenclature of Neoplasms

• Benign neoplasms:
  • Typically named by adding "-oma" to the cell type of origin (e.g., adenoma, fibroma)
• Malignant neoplasms:
  • Carcinomas: Arise from epithelial cells
  • Sarcomas: Arise from mesenchymal cells (e.g., bone, muscle, fat)
  • Lymphomas: Arise from lymphocytes
  • Leukemias: Arise from blood-forming cells

Hallmarks of Cancer

• Sustaining proliferative signaling
• Evading growth suppressors
• Resisting cell death
• Enabling replicative immortality
• Inducing angiogenesis
• Activating invasion and metastasis
• Deregulating cellular energetics
• Avoiding immune destruction
• Genome instability and mutation
• Tumor-promoting inflammation