Neoplasms: Benign vs. Malignant

Cellular Capabilities of Neoplasia

• Neoplasia is the new, uncontrolled growth of cells
• The objective is to discuss cellular capabilities enabling tissue invasion/metastasis, recognize benign from malignant neoplasms, and understand tumor progression

Morphologic Features of Benign vs. Malignant Neoplasms

Benign Neoplasms

• Slow-growing with controlled cell division
• Circumscribed borders remain localized without invading surrounding tissues
• Encapsulation is often present
• Encapsulation prevents invasion, which makes surgical excision more feasible

Malignant Neoplasms

• Invasive borders that are irregular and infiltrative into adjacent tissues
• Rapid, uncontrolled growth that leads to necrosis
• Angiogenesis is required, where tumor cells secrete vascular endothelial growth factor (VEGF) to recruit new blood vessels
• Capable of metastasis, which spreads to lymph nodes and distant organs
• A mnemonic device to remember Malignant Tumors is to think of a crab

Carcinogenesis

• Process of how normal cells become cancer cells
• Has three main steps: initiation, promotion, and progression

Initiation

• A normal cell accumulates irreversible DNA damage, leading to permanent genetic mutations
• Causes of DNA damage include exposure to carcinogens (radiation, toxins, viral infections), spontaneous mutations, and inherited genetic predispositions like BRCA1 and TP53 mutations
• Generates an initiated cell with altered genetic regulation
• Clinical significance includes that initiated cells may remain dormant for years
• Initiated cells may have damage to proto-oncogenes, tumor suppressor genes, or DNA repair genes

Promotion

• Repeated stimuli push the mutated cell to proliferate
• Promoting factors encourage growth of initiated cells, but do not cause new mutations
• Unlimited replicative potential, allowing for tumor expansion
• Mechanisms of tumor immortality include loss of cell-cycle regulation, self-sufficiency in growth signals, and evasion of apoptosis
• A loss of cell-cycle regulation can be Cyclins/CDKs
  • Cyclins are regulatory proteins that rise and fall at specific points of the cell cycle
  • Cyclin-dependent kinases (CDKs) are enzymes that, when bound to cyclins, phosphorylate target proteins to push the cell to the next phase of the cycle
  • Overexpression of cyclin D1 dysregulates Cyclin dependent kinase activity resulting in neoplastic growth
• Self-sufficiency in growth signals enable cancer cells to stimulate their own proliferation via oncogenic mutations
  • Epidermal growth factor receptor (EGFR) activates downstream signaling causing cell proliferation, survival, angiogenesis, and cancer invasion
• Evasion of apoptosis ensures tumor cells avoid programmed cell death and continue surviving despite genomic instability
• p53 is frequently mutated, preventing apoptosis

Progression

• Tumor continues expanding, requiring greater nutrient and oxygen supply
• Key progression events are angiogenesis, tissue invasion, and metastasis
  • Angiogenesis is when tumor cells secrete VEGF to recruit blood vessels
  • Tissue invasion is when tumor cells break through structural barriers
  • Metastasis is when tumor cells disseminate via blood or lymphatics

Concept of Tumor Invasion

• Loss of Intercellular Adhesion occurs with loss of E-Cadherin
  • Epithelial cells normally remain tightly bound via E-Cadherin proteins
  • Tumor cells downregulate E-Cadherin, detaching from surrounding epithelial cells to migrate freely
  • Loss of E-Cadherin correlates with aggressive tumor invasion
• Degradation of Extracellular Matrix (ECM) entails tumor cells secreting metalloproteinases (MMPs) and collagenases, breaking down structural barriers
  • Carcinomas invade basement membranes
  • Sarcomas invade adjacent connective tissue without needing basement membrane penetration
  • ECM disruption frees tumor cells, enabling migration and metastasis
• Locomotion refers to how cancer cells move through tissue to invade surrounding areas and metastasize
  • Cancer cells use receptors to detect and bind to molecules in the extracellular matrix to trigger migration pathways
  • Fibroblast fibronectin and laminin mediate migration
  • Autocrine effectors (EGF, TGF-β) promote mobility

Mechanisms of Tumor Migration & Dissemination

• There are three main metastatic pathways

Hematogenous Spread (Bloodstream)

• Common in sarcomas and aggressive carcinomas
• Tumor cells invade blood vessels, forming tumor emboli
• Colorectal cancer metastasizes to the liver, and lung cancer metastasizes to the brain

Lymphatic Spread

• Most common in carcinomas
• Tumor cells migrate via lymphatic channels, accumulating in regional lymph nodes
• Breast cancer metastasizes to axillary lymph nodes
• Sentinel Lymph Node is the first lymph node draining metastatic tumor cells
• Radioactive dye injection identifies the sentinel lymph node
• Presents as enlarged, painless lymph node

Cavitary Seeding

• Tumors directly invade body cavities, allowing serosal implantation
• Ovarian carcinoma deposits metastases onto peritoneal surfaces

Metastasis

• Indicates malignant behavior
• Metastasis is the spread of cancer cells from the primary tumor to distant sites
• Cancer cells often get trapped in the first capillary bed they encounter
• Angiogenesis allows tumors to receive oxygen and nutrients
  • Major pro-angiogenic factors are VEGF, FGF, and HIF-alpha
• Glioblastoma DOES NOT metastasize, but will invade adjacent tissue
• Leukemia cells are naturally spread in the blood, which does not count as metastasis

Key Takeaways

• Tumors progress through initiation, promotion, and progression, acquiring invasive and metastatic capabilities
• Carcinomas spread via lymphatics, while sarcomas spread hematogenously
• Loss of E-Cadherin, ECM degradation, and angiogenesis enable tumor invasion and migration
• Metastasis is a definitive marker of malignancy, making systemic therapy essential