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).