Dysplasia, Anaplasia and Malignant Cell Hallmarks

Dysplasia

• Involves disordered, non-neoplastic tissue growth
• Precedes neoplasia and can progress to cancer
• Typically found in epithelial tissues
• Can lead to carcinoma in situ
• Affects the entire epithelial layer
• Does not involve invasion of the basement membrane, remaining contained

Anaplasia

• Characterized by undifferentiated cell growth where cell origins non-discernible
• Features high metabolic activity
• Cells have minimal to no normal functions
• Often seen in aggressive, malignant tumors
• Usually indicates a poor prognosis
• Well-differentiated tumors resemble the tissue of origin, whereas anaplastic tumors lack distinguishing features

Hallmarks of Malignant Cells

• Autonomous, uncontrolled growth
• Insensitivity to growth factors or inhibitors
• Evasion of cell death pathways
• Resistance to apoptosis
• Ability to evade the immune system
• Unlimited replication potential
• Normal cells become senescent after a certain number of replications, but malignant cells do not
• Angiogenesis, or the formation of new blood vessels to support tumor growth, occurs
• Invasion of tissues and distant spread

Telomerase

• Normal cells divide about 60-70 times before becoming senescent
• Shortening of telomeres causes cellular senescence
• Telomeres are nucleotides found at the end of chromosomes
• Telomerase prevents gene loss during cell duplication
• Telomerase shows high activity in stem cells, but low activity in other cells
• Telomerase upregulation is common in various cancers

Grade

• Refers to the degree of cell differentiation
• Determined by a pathologist through microscopic tissue analysis of a biopsy
• Grades are classified from I to IV
• Well-differentiated tumors are classified as low grade
• Anaplastic or undifferentiated tumors are classified as high grade

Stage

• Refers to the extent and spread of a tumor
• This includes local spread, involvement of lymph nodes, and distant metastasis
• Determined using radiology and imaging
• Early stage means the growth is localized
• Advanced stage means the cancer has spread or metastasized

TNM Staging System

• A cancer staging system that uses letters and numbers to determine progression
• T signifies of the primary tumor size; T1-T4 are used
• N signifies the degree of regional lymph node spread: N0-N3 are used
• M signifies metastases
• M0 indicates no metastases, while M1 indicates the presence of metastases

Nomenclature

• Benign tumors: remain localized without spread, can be surgically removed, may cause problems through compression, tend to be well-differentiated with low mitotic activity
• Malignant tumors: invade and spread, may cause death

Tumor Naming

• Benign tumors: named by adding "-oma" to the cell or tissue of origin
  • Fibroma is a benign fibrous tumor
  • Chondroma is a benign cartilage tumor
• Adenomas: benign epithelial tumors often forming gland structures
• Papillomas: benign epithelial tumors on surfaces with "finger-like" projections

Malignant Tumor Naming

• Mesenchymal tissues cancers: form from connective tissue, bones, blood, or lymph
  • Solid tumors are called sarcomas
  • Blood/lymph cancers are leukemias or lymphomas
• Epithelial cells cancers: known as carcinomas
  • Glandular tumors are adenocarcinomas
  • Colon or lung adenocarcinomas can also occur
  • Squamous cell carcinoma is found in the skin

Tumor Spread

• Sarcomas typically spread through the blood (hematogenous spread)
• Arteries have thick walls hard to penetrate, veins are easily penetrated
• The liver and lungs are the sites of hematogenous spread
• Carcinomas usually spread through the lymphatic system
• Key exceptions: four carcinomas spread via the bloodstream
• These include choriocarcinoma (early hematogenous spread), renal cell carcinoma (renal vein), hepatocellular carcinoma (portal vein), and follicular thyroid carcinoma

Epidemiology

• Cancer is the second leading cause of death
• Heart disease is the number one cause of death
• Respiratory disease is the number three cause of death
• Accidents/trauma is the number four cause of death
• Lung cancer mortality is declining in men, but not women

Epidemiology in Children

• Accidents are the leading cause of death in children, followed by cancer and congenital disorders
• Leukemia is most common, followed by CNS tumors and neuroblastoma

Carcinogenesis

• Involves nonlethal DNA damage that leads to cancer
• Caused by mutations in two types of genes, tumor suppressor genes and oncogenes

Tumor Suppressor Genes

• Limit cell growth
• Classic examples: P53 and retinoblastoma genes
• P53 gene blocks progression through the cell cycle
• The retinoblastoma gene inhibits transcription factors
• Mutations in both alleles of a tumor suppressor gene are needed to shut down its activity

Germline Mutations

• One gene is mutated in all cells from birth
• Occurs in some tumor suppressor genes
• Leads to an increased risk of cancer at an early age
• Examples include: BRCA1/BRCA2 (breast cancer), hereditary retinoblastoma, HNPCC (Lynch syndrome), familial adenomatous polyposis (FAP), and Li-Fraumeni syndrome

Oncogenes

• Promote uncontrolled cell growth
• Proto-oncogenes regulate normal cellular functions
  • Growth factors, growth factor receptors, and signal transducers
• Proto-oncogene mutations transforms it into oncogene which progress to cancer
• A single gene mutation is sufficient to cause malignancy

Carcinogens

• Substances that cause cancer
  • Asbestos leads to mesothelioma
  • HPV leads to cervical cancer
  • Sunlight leads to skin cancer

Stem Cells and Cancer

• Stem cells have 2 defining features: Their ability to self renew and ability to differentiate cell types of one or more cell lineages
• During cell division of a stem cell, one daughter cell becomes a stem cell and has self-renewal ability and the other daughter cell can commit to differentiating
• Tumor cells share the self-renewal feature of stem cells
• Self renewal with stem cells provides increased opportunities for carcinogenic changes to occur
• When cancer occurs, altered regulation of self-renewal directly underlies carcinogenesis