📊 Overview & epidemiology high-yield
- Neoplasm = abnormal mass of tissue; growth exceeds normal, persists after stimulus removed
- Cancer = malignant neoplasm with invasive and metastatic potential
- Malignant subtypes by origin:
- Carcinoma – epithelial origin (∼90% of all cancers)
- Sarcoma – mesenchymal origin (bone, muscle, fat, cartilage)
- Leukemia/lymphoma – hematopoietic/lymphoid
- Second leading cause of death in the US (∼600,000 deaths/year)
- Most common cancers (US, all sexes): breast, lung, prostate
- Men (incidence ↓): prostate → lung/bronchus → colon/rectum
- Women (incidence ↓): breast → lung/bronchus → colon/rectum
- Children: ALL, CNS tumors, neuroblastoma, NHL
- Geographic/racial trends:
- Gastric cancer ↑ Japan; breast cancer ↑ US
- Hepatocellular carcinoma ↑ Asia
- Prostate cancer ↑ African American men
🧬 Causes & carcinogens
- Chemical carcinogens – direct (mutagen) or indirect (pro-carcinogen, need metabolic activation)
- Notable agents:
- Nitrosamines → gastric
- Cigarette smoke → multiple (lung, bladder, etc.)
- Asbestos → bronchogenic carcinoma, mesothelioma
- Vinyl chloride → hepatic angiosarcoma
- Aromatic amines / azo dyes → bladder, liver
- Benzene → leukemia
- Ames test – bacterial mutagenicity screen; correlates with carcinogenicity
- Radiation:
- UVB → pyrimidine dimers; Xeroderma pigmentosum (DNA repair defect) → ↑ skin cancer
- Ionizing radiation (X-ray, γ, α/β) → DNA crosslinks/breaks; ↑ leukemia, thyroid cancer
- Chronic inflammation – e.g., colitis → colorectal carcinoma
- Oncogenic viruses:
- RNA: HTLV-1 → adult T-cell leukemia/lymphoma
- DNA: HBV (hepatocellular), EBV (Burkitt, B-cell lymphomas, NPC), HPV (cervical, anogenital), HHV-8 (Kaposi sarcoma)
- Immunosurveillance failure – ↑ lymphomas in immunosuppressed
⚛️ Cancer biology & genetics
- Multistep carcinogenesis: initiation (mutation) → promotion (proliferation) → progression (additional mutations)
- Key mutated gene classes:
- Proto-oncogenes → oncogenes (gain-of-function)
- Tumor suppressors (loss-of-function; need two hits)
- Apoptosis regulators (e.g., Bcl-2)
- DNA repair genes (e.g., BRCA1/2)
Initiation→Promotion→Progression→Malignant phenotype
- Oncogene activation mechanisms: point mutation, translocation, amplification, insertional mutagenesis
- Examples: ERBB2 amplification (breast), BCR-ABL t(9;22) (CML), MYC t(8;14) (Burkitt)
- Tumor suppressors: Rb (cell cycle), p53 (DNA damage response, apoptosis), APC (colon), NF1/NF2
- Knudson two-hit: inherited germline mutation + somatic second hit → e.g., RB1 (retinoblastoma), TP53 (Li-Fraumeni)
- Apoptosis: Bcl-2 overexpression (t(14;18) in follicular lymphoma) → survival advantage
- Telomerase → limitless replication; Notch → angiogenesis
- Invasion/metastasis: loss of E-cadherin, ECM degradation, hematogenous/lymphatic spread
| Oncogene | Mechanism | Tumor |
|---|---|---|
| ERBB2 | amplification | breast, ovary |
| BCR-ABL | translocation t(9;22) | CML, ALL |
| KRAS | point mutation | lung, pancreas, colon |
| MYC | translocation t(8;14) | Burkitt lymphoma |
| CCND1 | translocation t(11;14) | mantle cell lymphoma |
🔬 Diagnosis & tumor markers
- Histology/cytology – gold standard; biopsy, FNA, Pap smear
- Immunohistochemistry (IHC) – lineage markers:
- Keratin → carcinoma
- Vimentin → sarcoma
- Desmin → muscle tumors
- GFAP → astrocytoma
- S100 → melanoma, neural tumors
- Benign vs malignant – benign: small, well-demarcated, noninvasive, no metastasis; malignant: invasive, pleomorphic, high mitotic rate, necrosis
- Anaplasia – loss of differentiation; hallmark of high-grade malignancy
- Serum tumor markers (screening, monitoring, recurrence):
- AFP – hepatoma, nonseminomatous germ cell
- β-hCG – choriocarcinoma, trophoblastic
- Calcitonin – medullary thyroid carcinoma
- CEA – colorectal, lung, breast, pancreas
- CA-125 – ovarian epithelial
- PSA – prostate
- Ancillary: flow cytometry, cytogenetics, PCR
⚠️ Paraneoplastic syndromes
- Symptoms from remote tumor effects, not direct invasion or metastasis
- May precede cancer diagnosis
- Most commonly associated with small cell lung cancer (Lambert-Eaton, SIADH, Cushing)
- Endocrine/metabolic:
- Cushing syndrome (ACTH) – neuroendocrine lung tumors, SCLC
- SIADH (ADH) – SCLC
- Hypercalcemia (PTHrP) – squamous cell lung, head/neck, esophagus, cervix
- Neurologic: Lambert-Eaton myasthenic syndrome (SCLC)
- Dermatologic: acanthosis nigricans (GI cancer)
- Skeletal: hypertrophic osteoarthropathy (clubbing, periostitis) – squamous cell lung
- Paraneoplastic hypercalcemia is most often caused by PTHrP, not bone metastasis
📌 Staging & grading
- Grade – histologic degree of differentiation (low → well-diff; high → anaplastic) and mitotic count
- Stage – clinical extent of disease (TNM)
- TNM: T = primary tumor size/extent; N = regional lymph nodes; M = distant metastasis
- Staging is generally a better prognostic predictor than grade
| Stage component | Meaning |
|---|---|
| Tis | carcinoma in situ |
| T1–T4 | increasing size/local invasion |
| N0–N3 | regional node involvement |
| M0/M1 | no / distant metastasis |
- Metastasis routes:
- Carcinomas → lymphatic (common)
- Sarcomas, renal cell, HCC, choriocarcinoma → hematogenous (early)
- Ovarian → peritoneal seeding