Neoplasia Part Two Lecture Notes
Metastasis and Spread of Malignancy
Definition of Metastasis: The spread of a malignant neoplastic lesion or collection of cells beyond the original site of growth. Metastatic cells are discontinuous with the primary tumor site.
Significance: Metastasis is the unequivocal hallmark of malignancy. Benign tumors do not metastasize (with rare non-cancerous exceptions like endometriosis, which implants but is not malignant).
Diagnosis Statistics: Approximately of patients are diagnosed with metastasis at the time of initial discovery of their cancer. For a little less than a third of patients, metastasis is the first clinical evidence of the disease.
Patterns of Metastatic Spread:
Direct Seeding of Body Cavities or Surfaces: This occurs when a tumor is located in a cavity, such as ovarian cancer in the peritoneal cavity. Cells can grow directly onto surfaces or float in ascites fluid to latch onto distant viscera. This requires penetration of natural fields like the peritoneal lining.
Lymphatic Spread: The most common pathway for the initial spread of carcinomas. Tumor cells enter the lymphatic drainage and travel to regional lymph beds.
Sentinel Lymph Node: Defined as the first lymph node that receives blood or lymph flow from a particular tumor site.
Identification: Surgeons inject dye or radioactive material into the tumor; the first node to pick up the dye is the sentinel node.
Prognostic Value: If the sentinel node is negative for cancer under a microscope, it is a strong indicator that the tumor hasn't developed the capacity for regional spread.
Hematogenous Spread: Spread through arteries and veins; typical of sarcomas but also used by carcinomas. Cells enter the venous system and lodge in the first proximal capillary bed.
GI Tract Cancers: Drain via the portal system directly to the liver.
Caval Blood (Extremities/Head): Drains to the right side of the heart and lodges in the pulmonary capillary beds (lungs).
Unique Anatomical Pathways:
Vertebral Plexus (Batson Plexus/Veins): Deep pelvic cancers (prostate, rectum) can drain into the plexus surrounding the vertebral column, leading to lytic lesions in the spine.
Venous Propagation: Cancers of the liver, renal system, and adrenal cortex can grow directly inside the vein (e.g., Renal Cell Carcinoma growing up the IVC), propagating as a continuous column rather than a true embolus.
Microscopic Evidence: Seeing cancer cells invading a vessel (venous or arterial) is a poor prognostic indicator, signifying probable metastasis.
Iatrogenic/Surgical Planting: Accidental seeding can occur via needle biopsy tracks or surgical instruments if tumor cells stick to the tools during removal.
Biological Mechanisms of Metastasis
Necessary Mutations: Metastasis is a complex process requiring the cell to break free from regulatory constraints and gain specific functions:
Loosening Cell-to-Cell Interactions: Reducing sensing mechanisms that prevent growth upon contact with adjacent cells.
Degradation of Extracellular Matrix (ECM): Secreting enzymes to dissolve the basement membrane and connective tissue.
Locomotion: Gaining the ability to push through adjacent structures to reach the vascular system.
Intravasation and Survival: Entering the blood or lymph and surviving the journey as an embolus.
Extravasation: Exiting the vascular system at a distant site.
Angiogenesis: At the new site, the tumor must secrete factors to grow its own blood supply to provide nutrients for proliferation.
Comparison of Benign and Malignant Tumors
Differentiation: Benign tumors resemble the tissue of origin; malignant tumors range from well-differentiated to marked anaplasia.
Size: Benign tumors are typically larger than normal cells but uniform; malignant cells vary from normal to very large.
Pleomorphism: Minimal in benign; marked pleomorphism (variation in size/shape) in aggressive malignancies.
Rate of Growth: Benign is generally slow with few mitoses; malignant can be rapid with increased or atypical mitotic figures.
Invasion: Benign tumors do not invade and are often encapsulated/well-circumscribed; malignant tumors are locally invasive with indistinct, infiltrative borders.
Symmetry: Benign tumors are often symmetrical; malignant tumors are often asymmetrical.
Necrosis: Uncommon in benign; common in malignant due to outgrowing the blood supply.
Metastasis: Absent in benign; present in malignant (Gold Standard).
Clinical Examples: Benign vs. Malignant
Myometrium (Uterus):
Leiomyoma (Fibroids): Extremely common (found in over half of autopsied women); white, whorled, well-circumscribed nodules. They are non-malignant but can cause bleeding or pain.
Leiomyosarcoma: Large, poorly demarcated, hemorrhagic, necrotic, and locally invasive.
Breast:
Fibroadenoma: Well-circumscribed, round, symmetrical, and encapsulated. Glandular elements are benign in appearance.
Invasive Ductal Carcinoma: Infiltrating edges with finger-like "star-shaped" projections. High N:C ratio (appears blue at low power). Desmoplastic response (fibrous stroma) creates a hard, scarred, "speculated" look.
Cancer Epidemiology and Statistics
Incidence: The probability of being diagnosed during a specific time. Expressed as new cases per people.
Prevalence: The total number of existing cases in a population at a given time per .
Mortality Rate: The number of deaths per year per .
Correlation: High incidence usually leads to high prevalence, unless the mortality rate is extremely high (the patient dies before being counted in prevalence).
Sex-Specific Trends:
Men: #1 Incidence is Prostate; #1 Mortality is Lung.
Women: #1 Incidence is Breast; #1 Mortality is Lung.
Lung Cancer Significance: It is the second most common cancer by incidence but the most lethal because it presents late and has less effective treatments compared to breast or prostate cancer.
Skin Cancer: Excluded from most stats because basal cell carcinoma is nearly universal but rarely fatal.
Infectious Agents Associated with Malignancy
HTLV-1: Adult T-cell leukemia/lymphoma.
HPV (Human Papillomavirus):
High Risk (Types 16, 18): Carcinoma of the cervix, penis, and oropharynx.
Low Risk: Warty growths (papillomas).
HHV-8: Kaposi Sarcoma (AIDS-associated).
Epstein-Barr Virus (EBV): Burkitt Lymphoma.
Aspergillus (Aflatoxin B1): Hepatocellular carcinoma, associated with mutations.
Schistosoma haematobium: Bladder cancer (via chronic inflammation from the parasite).
H. pylori: Gastric adenocarcinoma and MALT lymphoma (Extra-nodal marginal zone lymphoma).
Hepatitis B & C: Hepatocellular carcinoma (via chronic inflammation/cirrhosis).
Environmental and Chemical Carcinogenesis
Historical Example (Scrotal Cancer): Chimney sweeps in London developed high rates of scrotal skin cancer due to exposure to soot (Benzo(a)pyrene). Percival Pott discovered that washing/bathing drastically reduced incidence.
Migration Studies: Japanese populations have high stomach cancer rates. When they migrate to California, their stomach cancer rates drop, and their rates of "Western" cancers rise, highlighting environmental over genetic triggers.
Iatrogenic Carcinogenesis: Some chemotherapy drugs (e.g., alkylating agents) used to kill cancer can cause secondary cancers years later by damaging DNA in healthy cells.
Specific Chemical Links:
Vinyl Chloride: Associated with hepatic angiosarcoma (vascular liver cancer). Note: Polyvinyl Chloride (PVC) pipes are inert and safe; the risk is to factory workers in manufacturing.
Arsenic: Skin and lung carcinoma.
Benzene: Acute Myeloid Leukemia (AML).
Asbestos: Associated with Malignant Mesothelioma (pleural lining) and Lung Carcinoma.
Mechanism: Chronic inflammation in alveolar walls. Occupational risk for shipyard workers, demolition workers, and old auto mechanics (brake linings).
Radon: Spontaneous decay of uranium results in alpha particles. Historically linked to uranium miners; currently mitigated in homes of smokers to prevent lung cancer.
Radiation Carcinogenesis
Ultraviolet (UV) Rays: UVB and UVC rays cause pyrimidine dimers in DNA. Prolonged exposure leads to melanoma, squamous cell carcinoma, and basal cell carcinoma.
Ionizing Radiation (X-rays, Gamma Rays): Causes DNA fractures. Increased risk of AML and thyroid cancer (especially in children).
Historical Context: Atomic bomb survivors (Japan) and early scientists like Marie Curie.
General Risk Factors for Cancer
Age: Risk increases dramatically with age. Cancers result from an accumulation of mutations.
Leading cause of death in females (ages ) and males (ages ).
Childhood Cancers: Account for of cancer deaths (under 15 years old).
Primitive neoplasms: Neuroblastoma, Wilms Tumor (nephroblastoma), Retinoblastoma.
Survival rates for ages have reached approximately .
Chronic Inflammation: Sites of constant injury/repair have increased mutation risk.
IBD: Colorectal carcinoma.
Reflux Esophagitis (Barrett's): Esophageal adenocarcinoma (squamous to glandular metaplasia).
Alcoholic Pancreatitis: Pancreatic carcinoma.
Osteomyelitis: Squamous cell carcinoma in chronic skin fistulas.
Multi-Step Carcinogenesis:
Initiator: Causes permanent DNA damage/mutation.
Promoter: Stimulates replication of the mutated cell.
Clonal Evolution: Once growth is unregulated, cells accumulate further "passenger mutations."
Molecular Hallmarks of Cancer
DNA Repair Defects: Loss of function in genes that fix mutations, leading to genetic instability.
Growth Signal Self-Sufficiency: Gain-of-function in proto-oncogenes; receptors are "stuck on."
Insensitivity to Anti-growth Signals: Inactivation of tumor suppressor genes.
Evasion of Apoptosis: Especially through mutation; cells resist programmed death.
Limitless Replication: Resistance to senescence.
Angiogenesis: Ability to recruit blood vessels.
Warburg Effect (Aerobic Glycolysis):
Cells switch to anaerobic-style glycolysis even in the presence of oxygen to produce cellular intermediates (building blocks) needed for rapid division.
Clinical Use: PET scans use labeled glucose; cancer cells take it up at much higher rates than normal cells.
Immune Evasion: Reducing MHC Class I expression or secreting immunosuppressants.
Selected Oncogenes and Translocations
EGFR / HER2 (ERBB2): lung adenocarcinoma and breast carcinoma.
RET: Multiple Endocrine Neoplasia (MEN) 2A and 2B.
KIT (C-KIT): Gastrointestinal Stromal Tumor (GIST).
ALK: Lung adenocarcinoma ( for ).
N-RAS: Melanoma.
ABL: Acute Lymphoblastic Leukemia (ABL for , , and ).
N-MYC: Neuroblastoma ( for ).
C-MYC: Burkitt Lymphoma.
High Yield Translocations:
Chronic Myeloid Leukemia (CML): - Philadelphia Chromosome ().
Burkitt Lymphoma: - joined to Immunoglobulin heavy chain.
Ewing Sarcoma: - FLI-1/Ewing sarcoma gene.
Tumor Suppressor Genes and Hereditary Syndromes
Two-Hit Theory: For autosomal recessive genes, a person is born with one mutation (one "hit") and only needs a second somatic mutation for cancer to develop.
RB (Retinoblastoma): Prevents G1 to S transition. Defect leads to retinoblastoma and osteosarcoma.
p53: The "Guardian of the Genome"; stops the cell cycle for repair or triggers apoptosis. Defect leads to Li-Fraumeni Syndrome.
APC: Familial Adenomatous Polyposis (FAP); thousands of polyps in the colon.
Lynch Syndrome (HNPCC): DNA mismatch repair defect; high microsatellite instability (MSI). Targets for immunotherapy.
NF1 & NF2 (Neurofibromatosis):
NF1: Neurofibromas, malignant peripheral nerve sheath tumors, and Cafe au Lait spots (coffee-with-milk skin macules).
NF2: Acoustic neuromas (Cranial Nerve VIII), deafness, and meningiomas.
Cowden Syndrome (PTEN): Hamartomas of skin/lip, risk of breast/endometrial/thyroid cancer.
CDH1 (E-Cadherin): Adhesion loss leads to Diffuse Gastric Signet Ring Cell Carcinoma (cells infiltrate individually rather than in nests).
MEN 1: Three P's—Pituitary, Parathyroid, and Pancreas (islet cells).
MEN 2A: Medullary Thyroid Carcinoma (), Pheochromocytoma, Parathyroid.
MEN 2B: Medullary Thyroid Carcinoma, Pheochromocytoma, Marfanoid habitus, and mucosal neuromas.
VHL (Von Hippel-Lindau): Renal cell carcinoma.
Xeroderma Pigmentosum: Inability to repair pyrimidine dimers from UV light; multiple skin cancers in childhood.
Clinical Manifestations and Syndromes
Cachexia: Progressive loss of body fat/lean mass, weakness, and anemia. Mediated by TNF and other cytokines.
Paraneoplastic Syndromes: Symptoms not explained by local tumor effects (about of patients).
ACTH / SIADH: Small cell carcinoma of the lung.
Hypercalcemia: Squamous cell carcinoma of the lung (secreting PTHRP).
Trousseau Phenomenon: Hypercoagulability/migratory venous thrombosis, often associated with Pancreatic Carcinoma.
Acanthosis Nigricans: Hyperpigmented skin in non-sun-exposed areas (armpits); sign of occult GI or lung cancer.
Carcinoid Syndrome: Serotonin release causes facial flushing and diarrhea.
Staging and Grading
Grade: Measures differentiation (histologic and nuclear). Small cells, high N:C ratio, and anaplasia mean high grade.
Stage: The GOLD STANDARD for prognosis. Based on the TNM system:
T: Size of primary tumor.
N: Regional lymph node involvement.
M: Metastasis.
Gleason Pattern: Specific grading system for Prostate Cancer.
Laboratory Diagnosis of Cancer
Cytology: Looking at individual cells (Pap smears, Fine Needle Aspiration).
IHC (Immunohistochemistry): Using labeled antibodies to find antigens (e.g., Cytokeratin for carcinomas).
Flow Cytometry: Running cells through fluid streams to count receptor ratios (crucial for Leukemias/Lymphomas).
FISH: Fluorescent in situ hybridization to find translocations.
Microarray Analysis: A qualitative indicator of the number of copies of a gene variant compared to normal tissue (Red = overexpressed in tumor; Green = underexpressed; Black = normal).
Tumor Markers (Proteins in Fluid):
PSA: Prostate.
CEA: Colon, Pancreas.
CA-125: Ovary.
AFP (Alpha-fetoprotein): Liver (Hepatocellular Carcinoma).
HCG: Trophoblastic tumors, Testicular cancer.