Tumors – Definition, Classification, and Theories of Tumorigenesis

1. Definition of a Tumor (Neoplasm)

• Tumor / Neoplasm: an abnormal mass of tissue

• Growth is:

  • Excessive

  • Uncoordinated with normal tissues

  • Persistent after removal of the initiating stimulus

• Term applies to both benign and malignant lesions

• Key concept: loss of normal growth control

Distinction

• Tumor ≠ inflammation, hyperplasia, or regeneration

• Hyperplasia: controlled, reversible increase in cell number

• Neoplasia: autonomous, irreversible growth

2. General Characteristics of Neoplasms

Cellular Characteristics

• Clonality: tumor arises from a single transformed cell

• Altered cell cycle regulation

• Genomic instability

• Progressive accumulation of mutations

Biological Behavior

• Benign tumors:

  • Localized growth

  • Well differentiated

  • No metastasis

• Malignant tumors:

  • Invasive growth

  • Destruction of surrounding tissues

  • Ability to metastasize

3. Classification of Tumors

A. Classification According to Biological Behavior

Benign Tumors

• Slow-growing

• Well circumscribed

• Often encapsulated

• Do not infiltrate adjacent tissues

• Do not metastasize

Malignant Tumors

• Rapid or uncontrolled growth

• Poorly circumscribed

• Infiltrative and destructive

• Metastatic potential

• Cause systemic effects (cachexia, anemia)

B. Classification According to Tissue of Origin

1. Epithelial Tumors

• Benign:

  • Papilloma

  • Adenoma

• Malignant (Carcinomas):

  • Squamous cell carcinoma

  • Adenocarcinoma

  • Basal cell carcinoma

  • Transitional cell carcinoma

2. Mesenchymal Tumors

• Benign:

  • Lipoma (adipose tissue)

  • Fibroma (fibrous tissue)

  • Chondroma (cartilage)

  • Osteoma (bone)

  • Leiomyoma (smooth muscle)

• Malignant (Sarcomas):

  • Liposarcoma

  • Fibrosarcoma

  • Chondrosarcoma

  • Osteosarcoma

  • Leiomyosarcoma

3. Hematopoietic and Lymphoid Tumors

• Leukemias

• Lymphomas

• Plasma cell tumors (multiple myeloma)

4. Neuroectodermal Tumors

• Gliomas

• Neuroblastoma

• Melanoma

C. Classification According to Degree of Differentiation

• Well differentiated: resembles tissue of origin

• Moderately differentiated

• Poorly differentiated

• Anaplastic:

  • Severe pleomorphism

  • High mitotic activity

  • Loss of normal tissue architecture

D. Classification According to Growth Pattern

• Expansive (pushing margins)

• Infiltrative (finger-like invasion)

• Exophytic (growing outward)

• Endophytic (growing inward)

4. Nomenclature of Tumors

General Rules

• Benign mesenchymal tumors: tissue + "-oma"

• Malignant epithelial tumors: carcinoma

• Malignant mesenchymal tumors: sarcoma

Important Exceptions

• Lymphoma – malignant

• Melanoma – malignant

• Seminoma – malignant

• Hepatoma (hepatocellular carcinoma)

5. Theories of Tumorigenesis (Carcinogenesis)

A. Genetic Mutation Theory (Modern Central Theory)

• Cancer is a genetic disease at the cellular level

• Caused by accumulation of non-lethal mutations affecting genes controlling:

  • Cell proliferation

  • Cell differentiation

  • DNA repair

  • Apoptosis

Main Gene Groups Involved

• Oncogenes

• Tumor suppressor genes

• DNA repair genes

B. Oncogenes

Definition

• Oncogenes are mutated or overexpressed forms of normal genes (proto-oncogenes)

• They promote uncontrolled cell proliferation

• Mutation leads to gain of function

Mechanisms of Activation

• Point mutation

• Gene amplification

• Chromosomal translocation

• Increased gene expression

Important Examples of Oncogenes

• RAS

  • Encodes GTP-binding signal transduction protein

  • Constant activation → continuous growth signaling

  • Common in colon, pancreatic, lung cancers

• MYC

  • Transcription factor

  • Increases cell proliferation and metabolism

  • Amplified in lymphomas and solid tumors

• HER2/neu (ERBB2)

  • Growth factor receptor

  • Amplified in breast and gastric cancer

• BCR-ABL

  • Fusion gene from t(9;22) Philadelphia chromosome

  • Constitutive tyrosine kinase activity

  • Chronic myeloid leukemia

C. Tumor Suppressor Genes

Definition

• Genes that inhibit cell proliferation or promote apoptosis

• Loss of function mutations

• Both alleles usually need to be inactivated ("two-hit hypothesis")

Important Tumor Suppressor Genes

• TP53 (p53)

  • "Guardian of the genome"

  • Induces cell cycle arrest or apoptosis after DNA damage

  • Mutated in >50% of human cancers

• RB (Retinoblastoma gene)

  • Controls G1 → S phase transition

  • Loss leads to uncontrolled cell cycle progression

• APC (Adenomatous polyposis coli)

  • Regulates β-catenin and Wnt signaling

  • Mutation leads to colorectal adenomas

• BRCA1 / BRCA2

  • DNA repair genes (homologous recombination)

  • Loss increases risk of breast and ovarian cancer

D. DNA Repair Gene Defects

• Not directly oncogenic

• Increase mutation rate

• Lead to genomic instability

Examples

• Mismatch repair genes (MLH1, MSH2)

• Defective in Lynch syndrome (HNPCC)

E. Clonal Evolution Theory

• Tumor originates from a single mutated cell

• Progressive genetic instability

• Selection of aggressive subclones

• Explains:

  • Tumor heterogeneity

  • Drug resistance

F. Viral Theory of Oncogenesis

• Certain viruses induce malignant transformation

• Mechanisms:

  • Integration into host genome

  • Viral oncogenes

  • Chronic inflammation

Examples

• HPV – cervical carcinoma

• EBV – Burkitt lymphoma, nasopharyngeal carcinoma

• HBV / HCV – hepatocellular carcinoma

G. Chemical Carcinogenesis

• Exposure to carcinogenic substances

Types of Carcinogens

• Direct-acting carcinogens

• Indirect-acting (procarcinogens)

Stages

• Initiation

• Promotion

• Progression

H. Physical Carcinogenesis

• Ionizing radiation

• Ultraviolet radiation

• Causes DNA damage and mutations

I. Immunologic Theory

• Immune system normally eliminates transformed cells

• Tumor development occurs when immune surveillance fails

• Tumor immune evasion mechanisms:

  • Reduced antigen expression

  • Immunosuppressive cytokines

J. Stem Cell Theory

• Tumors arise from tissue stem cells

• Stem cells have:

  • Long lifespan

  • High proliferative potential

• Explains tumor recurrence and resistance

6. Adenoma–Carcinoma Sequence (Polyp to Cancer Pathway)

Definition

• Stepwise progression from normal epithelium → adenoma → carcinoma

• Classic model for colorectal cancer development

Molecular Stages

• Normal epithelium

  • No mutations

• Early adenoma formation

  • APC gene mutation

  • Activation of Wnt signaling

  • Increased β-catenin activity

• Intermediate adenoma

  • KRAS oncogene activation

  • Increased proliferation

• Late adenoma (high-grade dysplasia)

  • Loss of tumor suppressor genes (e.g. SMAD, DCC)

• Carcinoma

  • TP53 mutation

  • Invasion through basement membrane

Clinical Significance

• Explains rationale for colonoscopic polypectomy

• Early detection interrupts cancer development

• High-yield exam topic

B. Clonal Evolution Theory

• Tumor originates from a single mutated cell

• Progressive genetic instability

• Selection of aggressive subclones

• Explains:

  • Tumor heterogeneity

  • Drug resistance

C. Viral Theory of Oncogenesis

• Certain viruses induce malignant transformation

• Mechanisms:

  • Integration into host genome

  • Viral oncogenes

  • Chronic inflammation

Examples

• HPV – cervical carcinoma

• EBV – Burkitt lymphoma, nasopharyngeal carcinoma

• HBV / HCV – hepatocellular carcinoma

D. Chemical Carcinogenesis

• Exposure to carcinogenic substances

Types of Carcinogens

• Direct-acting carcinogens

• Indirect-acting (procarcinogens)

Stages

• Initiation

• Promotion

• Progression

E. Physical Carcinogenesis

• Ionizing radiation

• Ultraviolet radiation

• Causes DNA damage and mutations

F. Immunologic Theory

• Immune system normally eliminates transformed cells

• Tumor development occurs when immune surveillance fails

• Tumor immune evasion mechanisms:

  • Reduced antigen expression

  • Immunosuppressive cytokines

G. Stem Cell Theory

• Tumors arise from tissue stem cells

• Stem cells have:

  • Long lifespan

  • High proliferative potential

• Explains tumor recurrence and resistance

6. Clinical Significance for Surgeons

• Basis for surgical oncology

• Determines:

  • Extent of resection

  • Margin requirements

  • Lymph node management

• Guides adjuvant therapy decisions

• Essential for exam and clinical reasoning

7. Exam-Oriented Key Points

• Tumor growth is autonomous and irreversible

• Carcinoma = epithelial malignancy

• Sarcoma = mesenchymal malignancy

• Metastasis defines malignancy (except locally aggressive tumors)

• Carcinogenesis is a multistep genetic process

8. Summary

• Tumors represent uncontrolled cell proliferation

• Classification is essential for diagnosis and treatment

• Tumorigenesis is multifactorial

• Understanding mechanisms underpins modern surgery and oncology