4.1 General & Systemic Pathology

1.3 General & Systemic Pathology

Cellular Adaptations, Cell Injury & Nuclear Morphologies

Cells respond to physiologic demands and stress by adapting. When stress exceeds adaptive capacity, cell injury occurs.

Cellular Adaptation Mechanisms

• Hypertrophy: Increase in cell size, resulting in increased organ size (e.g., left ventricular hypertrophy in systemic hypertension).
• Hyperplasia: Increase in cell number due to cellular proliferation (e.g., drug-induced gingival hyperplasia secondary to Phenytoin, Nifedipine, or Cyclosporine).
• Atrophy: Decrease in cell size and functional capacity due to reduced workload, loss of innervation, diminished blood supply, or inadequate nutrition.
• Metaplasia: Reversible replacement of one mature adult cell type by another adult cell type better able to withstand the adverse environment.
  • Barrett's Esophagus: Esophageal stratified squamous epithelium → intestinal columnar epithelium with goblet cells (due to chronic gastric acid reflux).
  • Smoker's Respiratory Tract: Ciliated pseudostratified columnar epithelium → stratified squamous epithelium.

Reversible vs. Irreversible Cell Injury

• Reversible Injury: Marked by cellular swelling (hydropic change due to Na+/K+-ATPase pump failure), plasma membrane blebbing, ribosome detachment, and fatty change (steatosis).
• Irreversible Injury (Cell Death): Defined by permanent mitochondrial dysfunction (inability to synthesize ATP) and massive loss of membrane integrity. Nuclear changes follow a strict progression:
  1. Pyknosis: Nuclear shrinkage and increased basophilia/hyperchromasia.
  2. Karyorrhexis: Fragmentation of the pyknotic nucleus.
  3. Karyolysis: Dissolution of the nucleus by endonucleases.

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Morphologic Patterns of Tissue Necrosis vs. Apoptosis

Mechanisms of Apoptosis

Apoptosis is an energy-dependent programmed cell death affecting single cells without eliciting an inflammatory response.

INTRINSIC (MITOCHONDRIAL) PATHWAY:
Cell Stress / DNA Damage → Pro-apoptotic proteins (Bax, Bak) → Cytochrome c release from Mitochondria → Activates Caspase-9

EXTRINSIC (DEATH RECEPTOR) PATHWAY:
FasL binding to Fas (CD95) or TNF binding to TNF-R → Recruits FADD → Activates Caspase-8

CONVERGENCE ON EXECUTIONER CASPASES:
Caspases-3 and 6 activated → Cleave cytoskeleton & activate Endonucleases → Apoptotic Bodies → Phagocytosis

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Acute vs. Chronic Inflammation & Chemical Mediators

Acute Inflammation Dynamics

Characterized by rapid onset, short duration, exudation of fluid/plasma proteins (edema), and predominantly neutrophil (PMN) emigration.

• Vascular Events: Transient vasoconstriction followed by arteriolar vasodilation (increased blood flow / rubor and calor) and increased microvascular permeability (protein-rich exudate / tumor).
• Leukocyte Extravasation Sequence: Marginations → Rolling (mediated by Selectins) → Firm Adhesion (mediated by Integrins) → Transmigration / Diapedesis (via PECAM-1 / CD31) → Chemotaxis (guided by LTB4, C5a, IL-8, bacterial N-formyl peptides).

Key Chemical Mediators

• Histamine: Released by mast cell degranulation; causes rapid arteriolar vasodilation and endothelial contraction producing interendothelial gaps.
• Arachidonic Acid Metabolites (Eicosanoids):
  • COX Pathway (Prostaglandins): PGE2 induces fever (hypothalamic reset), vasodilation, and sensitizes nerve endings to pain. PGI2 (Prostacyclin) inhibits platelet aggregation. Thromboxane A2 (TXA2) promotes platelet aggregation and vasoconstriction.
  • Lipoxygenase Pathway (Leukotrienes): LTB4 is a potent chemoattractant for neutrophils. LTC4, LTD4, LTE4 (slow-reacting substances of anaphylaxis) induce intense bronchospasm and increased vascular permeability.

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Granulomatous Inflammation: Tuberculosis & Sarcoidosis

Granulomatous inflammation is a specialized pattern of chronic inflammation characterized by microscopic aggregates of transformed, activated macrophages called epithelioid histiocytes, surrounded by a collar of lymphocytes, plasma cells, and multinucleated giant cells.

Tuberculosis (TB)

• Etiology: Infection by Mycobacterium tuberculosis (acid-fast bacillus detected via Ziehl-Neelsen stain).
• Histopathology: Caseating granulomas featuring central caseous necrosis surrounded by epithelioid macrophages and Langhans giant cells (nuclei arranged in a horseshoe pattern at the cell periphery).
• Oral Lesions: Chronic, painful, non-healing indurated ulcer, most commonly found on the dorsum of the tongue.

Sarcoidosis

• Etiology: Systemic non-infectious autoimmune disease of unknown origin.
• Histopathology: Non-caseating granulomas (lacking central necrosis) containing Schaumann bodies and asteroid bodies.
• Clinical Presentation: Pulmonary hilar lymphadenopathy and lung involvement.
• Heerfordt Syndrome (Uveoparotid Fever): Classic sarcoidosis triad featuring bilateral parotid enlargement, anterior uveitis, facial nerve palsy (CN VII), and low-grade fever.

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Neoplasia Principles, Dysplasia & TNM Staging

Benign vs. Malignant Neoplasms

• Benign: Well-differentiated, slow growing, expansive, encapsulated, non-invasive, never metastasizes.
• Malignant: Poorly differentiated to anaplastic, rapid growth, infiltrative border, locally invasive, capable of metastasis.

Dysplasia & Carcinoma In Situ (CIS)

• Dysplasia: Disordered epithelial growth and maturation without breaching the basement membrane. Characterized by cellular atypia: hyperchromasia, pleomorphism, increased N/C ratio, loss of polarity, and abnormal mitoses.
• Carcinoma In Situ (CIS): Severe full-thickness dysplasia encompassing the entire thickness of the epithelium without invasion through the basement membrane.

Normal Epithelium → Mild/Moderate Dysplasia → Carcinoma In Situ (Full-thickness, Intact Basement Membrane) → Invasive Carcinoma (Breaches Basement Membrane)

TNM Staging System

• T (Tumor): Size and local extent of primary tumor (T1 to T4).
• N (Node): Presence and extent of regional lymph node metastasis (N0 to N3).
• M (Metastasis): Presence of distant metastasis (M0 or M1).
• Clinical Significance: Stage (extent of spread) is a far more reliable indicator of prognosis and survival in oral squamous cell carcinoma than Grade (degree of histologic differentiation).

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Atherosclerosis, Hypertension & Diabetes Mellitus

Atherosclerosis Pathogenesis

Initiated by chronic endothelial injury (from smoking, hypertension, hyperlipidemia) → endothelial dysfunction → monocyte adhesion and LDL entrapment in intima → oxidation of LDL → macrophages engulf ox-LDL, becoming Foam Cells → smooth muscle proliferation and collagen deposition forming a fibrous plaque. Rupture of unstable plaque induces acute arterial thrombosis.

Hypertension Guidelines & Dental Safety Protocols

• Classification: Normal (<120/<80 mmHg), Elevated (120-129/<80), Stage 1 (130-139/80-89), Stage 2 (>=140 or >=90).
• Hypertensive Crisis: BP >180 and/or >120 mmHg. Elective dental care MUST be deferred.
• Vasoconstrictor Limit: For patients with Stage 2 hypertension or ischemic heart disease, limit epinephrine to 0.04 mg (maximum 2 cartridges of 1:100,000 epinephrine).

Diabetes Mellitus Complications & Oral Pathology

• Type 1 DM: Autoimmune destruction of pancreatic beta cells → absolute insulin deficiency; prone to Diabetic Ketoacidosis (DKA).
• Type 2 DM: Peripheral insulin resistance and relative insulin deficiency; prone to Hyperosmolar Hyperglycemic State (HHS).
• Diagnostic Threshold: HbA1c >= 6.5% or fasting blood glucose >= 126 mg/dL. Target HbA1c for controlled diabetics is < 7.0%.
• Complications: Microvascular (Retinopathy, Nephropathy [Kimmelstiel-Wilson nodular glomerulosclerosis], Neuropathy) and Macrovascular (CAD, Stroke, Peripheral Artery Disease).
• Oral Manifestations: Periodontal disease is considered the 6th classic complication of diabetes. Diabetic patients present with impaired PMN chemotaxis, delayed wound healing, severe accelerated periodontitis, xerostomia, burning mouth syndrome, and oral candidiasis.