CH 7 - Altered Cellular Proliferation and Differentiation

Cellular Proliferation & Differentiation

  • Proliferation: generation of new daughter cells through division of progenitor (parent) cells.
  • Differentiation: orderly maturation process that allows a cell to acquire a specific structure and function.
  • Stem cells: highly undifferentiated; provide a reservoir for regeneration and repair.
  • Genetic control normally governs both processes; cancer arises when cells ignore these controls.

Alterations in Cancer

  • Autonomy: unregulated, excessive proliferation.
  • Anaplasia: loss of differentiation ➔ cells lose specialized functions.
  • Epithelial cells (lining & glandular) most likely to form neoplasms; connective-tissue cells form sarcomas.

Carcinogenesis

  • Definition: origin & development of a cancerous neoplasm.
  • Two mutation sources affecting growth/division:
    • Inherited: 5\% of cancers.
    • Acquired: 95\% of cancers (dominant).

Common Carcinogens

  • Radiation, hormones, chemicals, tobacco, microbes (viral & bacterial).

Initiation–Promotion–Progression Theory

  • Initiation: first exposure to a carcinogenic agent ➔ irreversible DNA damage.
  • Promotion: promoter agent activates oncogenes; reversible if promoter removed.
  • Progression: autonomous, independent tumor growth & invasion.

Tissue / Organ Impact

  • Benign tumors
    • Localized, encapsulated; closely resemble tissue of origin; rarely lethal.
  • Malignant tumors
    • Invasive, destructive; rapid proliferation; metastasize; poor resemblance to origin tissue.

Cancer Spread

  • Local spread: confined to tissue of origin.
  • Direct extension: invasion of adjacent organs/tissues.
  • Seeding: shedding of neoplastic cells that implant within a cavity or nearby surface.
  • Metastasis: dissemination via lymphatic or vascular routes to distant sites ➔ worsened prognosis.

Tumor Nomenclature (selected examples)

  • Epithelial surface: benign = papilloma; malignant = squamous-cell carcinoma.
  • Glandular: adenoma vs. adenocarcinoma.
  • Connective fibrous: fibroma vs. fibrosarcoma.
  • Muscle smooth: leiomyoma vs. leiomyosarcoma.
  • Neural glial: glioma vs. glioblastoma.

TNM Classification (Table 7.2)

  • T (Primary Tumor)
    • T X = cannot evaluate
    • T 0 = no evidence
    • T is = carcinoma in situ
    • T 1{-}T 4 = increasing size/extent
  • N (Regional Lymph Nodes)
    • N X = cannot evaluate
    • N 0 = no node involvement
    • N 1{-}N 3 = escalating nodal spread
  • M (Distant Metastasis)
    • M X = cannot evaluate
    • M 0 = none
    • M 1 = present

General Manifestations of Cancer

  • Lymphadenopathy
  • Fever
  • Anorexia–cachexia syndrome (weight loss, muscle wasting)
  • Palpable mass
  • Site-specific loss of function

Diagnostic Tests

  • Comprehensive history & physical.
  • Imaging: radiographs, endoscopy, ultrasound, CT, MRI.
  • Biopsy / cytology (gold standard for definitive Dx).
  • Tumor markers in blood, urine, tissue.
  • Other labs (CBC, metabolic panels, organ-specific tests).

Treatment Modalities

  • Surgery: curative, debulking, palliative.
  • Chemotherapy: systemic cytotoxic drugs targeting fast-growing cells (healthy & malignant).
  • Radiation therapy: ionizing radiation to shrink/kill tumors.
  • Hormonal manipulation: remove/block hormones that fuel tumor growth.
  • Immunotherapy: boost or redirect immune system (e.g., checkpoint inhibitors).
  • Bone-marrow / stem-cell transplantation: replace diseased marrow.
  • Palliative care: symptom control, QOL improvement at any stage.

Applications (Major Malignancies)

Lung Cancer

Pathophysiology

  • Leading global cause of cancer death.
  • Top risk factor: cigarette smoking; industrial pollutants contribute.
  • Origin: epithelial lining of bronchi, bronchioles, alveoli.
  • Four subtypes: adenocarcinoma, squamous-cell, large-cell, small-cell carcinoma.

Clinical Manifestations

  • Persistent cough, hemoptysis, chest pain, dyspnea.

Diagnostics

  • Hx & physical, bronchoscopy, chest x-ray, CBC, tissue biopsy/cytology.

Treatment

  • Small-cell: chemotherapy primary.
  • Non-small-cell: surgery ± chemo; radiation if inoperable.

Colon Cancer

Risk Factors

  • Age, family history, bowel diseases, smoking, alcohol, obesity/inactivity, high-fat diet.

Pathogenesis

  • Sequence: non-neoplastic polyp ➔ neoplastic polyp ➔ adenocarcinoma.
  • Mutation pathways: chromosomal instability, DNA replication errors.

Clinical Manifestations

  • Altered bowel habits, occult/frank blood in stool, abdominal pain, obstruction, anemia.

Diagnostics

  • CBC, liver function, serum CEA, colonoscopy/sigmoidoscopy with biopsy.

Treatment

  • Surgery (segmental resection/colostomy), chemotherapy, biologic agents, radiation.

Brain Cancer

Pathophysiology

  • Metastatic lesions > primary brain tumors.
  • Primary forms: gliomas, meningiomas, pituitary adenomas, acoustic neuromas; various specific sites (astrocytoma, medulloblastoma, etc.).

Clinical Manifestations

  • Focal loss of motor/sensory function, cognitive/behavioral change, headache, vomiting, seizures.

Diagnostics

  • Neurologic exam (cranial nerves, reflexes, sensory, motor).
  • Imaging: brain scan, x-ray, CT, MRI, angiography, PET.

Treatment

  • Surgery, radiation, chemotherapy, palliative care.

Leukemia

Pathophysiology & Types

  • Malignant neoplasms of blood/blood-forming organs.
  • Acute: ALL (children), AML (adults).
  • Chronic: CLL (small dysfunctional B-cells), CML (granulocyte/erythrocyte/megakaryocyte over-production).

Clinical Manifestations

  • Anemia, bruising, bleeding (epistaxis), bone pain, headaches, visual changes, GI symptoms, weight loss, fever, lymph-organ enlargement.

Diagnostics

  • Hx & physical, CBC, bone-marrow biopsy, cytology.

Treatment

  • Chemotherapy (induction, consolidation, maintenance), radiation, bone-marrow/stem-cell transplant.

Lymphoma

Pathophysiology

  • Solid tumors from WBCs/lymph tissue; may extend to bone marrow.
  • Two classes: Hodgkin (HL) and Non-Hodgkin (NHL).

Clinical Manifestations

  • Hodgkin: painless progressive cervical node enlargement; B-symptoms (low-grade fever, night sweats, pruritus, weight loss, fatigue).
  • Non-Hodgkin: painless nodal enlargement; systemic symptoms possible.

Diagnostics

  • HL: presence of Reed–Sternberg cells.
  • NHL: Hx/physical, lymph-node biopsy, chest & abdominal CT.

Treatment

  • HL: chemotherapy, radiation, hematopoietic stem-cell transplant.
  • NHL: radiation ± chemotherapy (aggressive forms).