_Patho_A_Lec__Neoplasia_I__MR_Ganir_

Page 1: Introduction to Neoplasia

• Neoplasia: New growth (tumor/swelling).

• Oncology: Study of tumors/neoplasms.

  • Abnormal mass of tissue.

  • Growth exceeds and is uncoordinated with normal tissue.

  • Persists after stimuli cessation.

  • Autonomous

  • Clonal: Arises from a single cell with genetic damage.

Types of Neoplasia

• Benign Neoplasms:

  • Generally innocent, localized, does not spread.

  • Amenable to surgical removal; patients generally survive.

  • Types:

    1. Mesenchymal: Suffix "oma" (e.g., osteoma, chondroma).

    2. Epithelial: Suffix "oma" based on origin or structure (e.g., adenoma, papilloma).

    3. Exceptions with “oma”: hepatoma, lymphoma, seminoma, melanoma, mesothelioma (malignant).

• Malignant Neoplasms:

  • Cancerous, invade and destroy adjacent structures.

  • Spread to distant sites causing death.

  • Types:

    1. Carcinoma: Epithelial origin (e.g., adenocarcinoma, squamous cell carcinoma).

    2. Sarcoma: Mesenchymal origin (e.g., liposarcoma, osteosarcoma).

Basic Components of Tumors

• Parenchyma: Clonal neoplastic cells; determines behavior & pathology.

• Stroma: Supportive tissue (e.g., blood supply).

  • Types:

    • Scant (e.g., lymphoma, fibrosarcoma).

    • Abundant desmoplasia (e.g., scirrhous carcinoma).

Mixed Tumor & Characteristics

• Mixed Tumor: Divergent differentiation of a single neoplastic clone.

  • Example: Pleomorphic adenoma (salivary gland).

• Teratoma: Totipotential cells differentiate along germ cell layers (benign or malignant).

• Hamartomas: Disorganized but benign masses of mature specialized cells.

• Choristomas: Heterotopic normal tissue.

Characteristics of Benign vs. Malignant

Page 2: Cellular Characteristics of Neoplasia

Features of Malignant Cells

1. Pleomorphism: Variation in size and shape.

2. Abnormal Nuclear Morphology: Increased nuclear/cytoplasmic ratio, hyperchromatic.

3. Mitoses: Increased, atypical mitoses.

4. Loss of Polarity: Disturbed orientation of cells.

5. Tumor Giant Cells: Not macrophages.

6. Dysplasia: Loss of uniformity and architectural orientation; "carcinoma in situ".

7. Metastasis: Discontinuous tumor implants.

Rate of Growth in Tumors

1. Doubling Time: Not shortened cell cycle.

2. Growth Fraction: Variability among tumors; correlates with differentiation.

   • High in some leukemias, low in breast & colon cancers.

3. Cell Shedding/Dying Rate.

Cancer Stem Cells & Cell Lineages

• Cancer may arise from:

  • Normal tissue stem cells or more differentiated cells acquiring self-renewal properties.

  • Tumor initiating cells (T-ICs) allow indefinite growth.

Local Invasion

• Benign tumors develop a rim of compressed connective tissue (capsule).

• Cancers invade surrounding tissue; infiltration is key to differentiate benign from malignant.

Metastasis

• Marks tumor as malignant, present in most malignant tumors.

• Pathways of Spread:

  • Seeding of Cavities: E.g., carcinomas from ovaries.

  • Lymphatics: First affected nodes (sentinel nodes).

  • Hematogenous Spread: Commonly affects lungs and liver.

Epidemiology of Cancer

• Study of cancer patterns contributes to knowledge of cancer origins.

• Contributors to Cancer Incidence: Environmental, racial, cultural influences.

Cancer Incidence Trends

• Increased Death Rate: Hepatocellular carcinoma from hepatitis C.

• Decreased Death Rates: Significant declines in breast & colorectal cancers in women & lung/prostate cancers in men.

Page 3: Childhood Cancer and Genetic Predisposition

Common Neoplasms in Childhood

• Small round blue cell tumors (e.g., neuroblastoma, Wilms tumor).

• Acute leukemia: 60% of deaths in children.

Genetic Predisposition

• Autosomal Dominant Inherited Cancer Syndromes:

  • Inheritance of single mutant allele significantly increases tumor risk.

  • Examples:

    1. Retinoblastoma (RB gene).

    2. Familial adenomatous polyposis (APC gene).

    3. Li-Fraumeni syndrome (p53 gene).

    4. Multiple Endocrine Neoplasia (MEN) syndromes.

    5. Hereditary Nonpolyposis Colon Cancer (HNPCC).

Characteristics of Inherited Cancer Syndromes

• Tumors arise in specific sites and tissues.

• Associated with specific marker phenotypes (e.g., café-au-lait spots).

Defective DNA Repair Syndromes

• Generally autosomal recessive; lead to DNA instability (e.g., xeroderma pigmentosum).

Familial Cancers

• Include breast, ovary, pancreas cancers.

• Characteristics: early onset, multiple close relatives affected, multiple tumors.

Interactions Between Genetic & Nongenetic Factors

• Complex interplay influencing environmentally induced cancers.

Nonhereditary Predisposing Conditions

1. Chronic Inflammation: E.g., ulcerative colitis, H. pylori gastritis.

2. Precancerous Conditions: Non-neoplastic (e.g., chronic gastritis), neoplastic (e.g., villous adenoma).

Page 4: Molecular Basis of Cancer

Fundamental Principles

• Nonlethal genetic damage drives carcinogenesis through mutations acquired from environmental agents.

• Tumors arise from clonal expansion of single precursor cells.

• Four classes of regulatory genes targeted by genetic damage:

  1. Proto-oncogenes (growth promoting).

  2. Tumor suppressor genes (growth inhibiting).

  3. Genes that regulate apoptosis.

  4. Genes involved in DNA repair.

Steps in Cell Proliferation

1. Growth factor binding to receptor.

2. Activation of signal transducing proteins.

3. Signal transmission to nucleus.

4. Activation of nuclear factors & cell cycle entry.

Growth Factors

• Enhance cell proliferation in normal and cancerous cells through autocrine actions.

Involvement of Oncoproteins

• Mimic signal transducing proteins, altering proliferation.

• Example: RAS gene mutations are common in tumors, leading to excessive proliferation signals.

MYC Oncogene

• Enhances self-renewal and impedes differentiation, amplified in various carcinomas.

Page 5: Key Oncogenes and Tumor Suppressors

MYC Oncogene

• Reprograms somatic cells to pluripotent stem cells; enhances self-renewal.

CYCLINS

• Control orderly cell cycle progression; associated with genetic instability.

Growth Factor Signal Alterations

• Overexpression of growth factor genes alters signaling pathways.

Tumor Suppressors

• RB Gene: Regulates cell growth; mutations lead to retinoblastoma.

• p53 Gene: Most common target for genetic alterations; initiates apoptosis.

Knudson’s Hypothesis

• Two-hit model required for tumor development; heterozygotes no cancer, homozygotes develop cancer.

Common Tumor Suppressors

• NF1, NF2, VHL, PTEN involved in various cancers.

Page 6: Tumor Suppressor Mechanics

APC/β-Catenin Pathway

• APC regulates catenin; loss leads to continuous WNT signaling, driving cell proliferation.

Key Tumor Suppressor Genes and Their Implications

• NF1: Associated with neurofibroma & glioma;

• NF2: Schwannoma related;

• VHL: Renal cell carcinoma roles;

• PTEN: Associated with “Cowden Syndrome”;

• WT1: Wilms tumors related;

• PTCH: Linked to Gorlin syndrome and basal cell carcinoma.