Neoplasia Overview

Neoplasia

• Neoplasia is unregulated, irreversible, new tissue growth, distinct from hyperplasia and repair.
• Monoclonal: Neoplastic cells originate from a single parent cell.
• Clonality Determination:
• Glucose-6-phosphate dehydrogenase (G6PD) isoforms: Different isoforms exist (e.g., G6PDA, G6PD8, G6PDc), inherited one frgom each parent. Females randomly inactivate one isoform per cell. The normal ratio in cells is 1:1 (e.g., 50% of cells have G6PD A' and 50% G6PD8). This 1:1 ratio is maintained in polyclonal hyperplasia, whereas only one isoform characterizes monoclonal neoplasia.
• Androgen receptor isoforms are also useful for assessing clonality; located on the X chromosome.
• Immunoglobulin (Ig) light chain phenotype (B lymphocytes): B cells express either kappa or lambda light chains. The normal ratio is kappa:lambda=3:1. This ratio is maintained in polyclonal hyperplasia, but increases to >6:1 or inverts (e.g., 1:3) in monoclonal lymphoma.
• Tumor types: Neoplastic tumors can be benign or malignant.
• Benign tumors: Localized, non-metastatic.
• Malignant tumors (cancer): Invade locally and can metastasize.
• Tumor nomenclature: Based on tissue lineage and benign/malignant status (e.g., adenoma vs. adenocarcinoma).

Epidemiology of Cancer

• Cancer: Second leading cause of death in adults and children.
• Adult causes (leading to death): 1) Cardiovascular disease; 2) Cancer; 3) Cerebrovascular disease.
• Child causes (leading to death): 1) Accidents; 2) Cancer; 3) Congenital defects.
• Common cancers (adult incidence): Breast/prostate, lung, colorectal.
• Common cancer causes of death (adult): Lung, breast/prostate, colorectal.

Cancer Screening

• Cancer develops from a single mutated cell.
• Multiple divisions (doubling time) occur before detectable symptoms. Each doubling leads to increased mutations.
• Late detection cancers have more divisions and mutations; poorer prognosis.
• Screening goals detect precancerous changes (dysplasia) or cancers before symptoms.
• Common screening methods:
• Pap smear (cervical dysplasia).
• Mammography (breast cancer, in situ or invasive).
• PSA and DRE (prostate cancer).
• Hemoccult test and colonoscopy (colon cancer, adenomas).

Carcinogenesis

• Cancer formation: DNA damage in stem cells initiates the process. DNA damage overcomes repair but is not immediately lethal.

• Carcinogens: Agents that damage DNA, increase cancer risk (chemicals, oncogenic viruses, radiation).

• DNA mutations disrupt regulatory systems:

• Proto-oncogenes: Essential for cell growth/differentiation. Mutation creates oncogenes leading to uncontrolled growth. Categories include growth factors, receptors, signal transducers, nuclear regulators and cell cycle regulators.

• Tumor suppressor genes: Regulate cell growth, decrease tumor formation (e.g., p53, Rb).

• p53: Regulates cell cycle from G1 to S. DNA damage → slows cycle, upregulates repair enzymes. No repair possible → apoptosis. p53 upregulates BAX, disrupts Bcl2, cytochrome c leaks to initiate apoptosis Knudson two-hit hypothesis, both copies required for tumor formation.

• Rb: Also regulates G1 to S phase. Rb "holds" E2F transcription factor, releases when phosphorylated. Rb mutation creates constitutively free E2F = uncontrolled growth. Both copies of Rb gene require mutation for tumor formation. Knudson two-hit hypothesis, both copies needed for tumor formation.

• Regulators of apoptosis (e.g., Bcl2). Normal cells = prevents apoptosis; mutated cells = promote apoptosis as DNA cannot be repaired. Bcl2 stabilizes mitochondrial membrane inhibiting the release of cytochrome C. Bcl2 overexpression in Follicular lymphoma is a significant event as translocation t(14;18) places Bcl2 gene near an Ig heavy-chain locus leading to overexpression; this further stabilizes mitochondrial membrane prohibiting apoptosis, B cells accumulate in the germinal centers of the lymph node causing an eventual buildup into lymphoma.

• Other important features of tumor development:

• Telomerase: Necessary for cell immortality. Normal = telomere shortening, ultimately cell senescence. Cancer cells have upregulated telomerase.

• Angiogenesis: New blood vessel formation is needed for tumor survival & growth

• Immune evasion: Tumor cells avoid immune system surveillance. Mutations can cause abnormal proteins, expressed on MHC class I. CD8+ T cells target & destroy cells. Tumor cells can downregulate MHC class I expression. Immunodeficiency increases cancer risk.

Tumor Progression

• Tumor invasion & spread: Accumulation of mutations.

• Epithelial tumors: Normally attached by adhesion molecules like E-cadherin. Mutation leads to dissociation.

• Tissue invasion: Tumor cells attach to laminin, destroy basement membrane via collagenases. Cells attach to fibronectin in the extracellular matrix = local spread.

• Routes of metastasis:

• Lymphatic spread: Common in carcinomas. Initial spread to regional draining lymph nodes.

• Hematogenous spread: Predominantly in sarcomas. Also in renal, hepatocellular cancers; Follicular carcinoma of thyroid; and choriocarcinoma.

• Body cavity seeding: Common in ovarian carcinoma. Involves the peritoneum causing "omental caking."

Clinical Characterisitcs of Tumors

• Benign tumors: Slow growth, well-circumscribed, distinct borders; mobile.

• Malignant tumors: Rapid growth, poorly circumscribed, infiltrative, fixed to surrounding tissues.

• Diagnosis requires biopsy/excision

• Histologic features: Well-differentiated benign tumors (organized, uniform nuclei, low nuclear:cytoplasmic ratios, low mitosis). Poorly differentiated malignant tumors (disorganized growth, nuclear pleomorphism, high nuclear:cytoplasmic ratios, high atypical mitosis).

• Immunohistochemistry: Characterizes difficult-to-classify tumors.

• Serum tumor markers: Proteins released into serum from tumors. Useful for screening, monitoring treatment,/recurrence. Elevated levels require biopsy.

• Grading: Microscopic assessment of differentiation (how much cancer resembles parent tissue). Low/Well diff. better prognosis than high/poor diff.

• Staging: Assessment of size and spread. Uses TNM system (T-tumor, N-lymph nodes, M-metastasis). TNM staging important prognostic factor.