Pathology III — Neoplasia — USMLE Step 2 CK Notes
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Vocabulary
- Benign: well-differentiated, encapsulated, no invasion or metastasis; suffix -oma
- Malignant: anaplastic, invasive, metastasises; carcinoma (epithelial) or sarcoma (mesenchymal)
- Anaplasia: loss of differentiation, pleomorphism, high nuclear-to-cytoplasmic ratio, atypical mitoses
The two-hit logic
- Oncogenes — ONE activating hit, gain of function, dominant (RAS, MYC, HER2, ABL, RET)
- Tumour suppressors — TWO hits, loss of function (Knudson): TP53, RB, APC, BRCA, NF1/2, VHL, WT1
- TP53 (the 'guardian of the genome') is the most commonly mutated gene in human cancer; germline loss = Li-Fraumeni
Carcinogens and their cancers
- Aflatoxin → hepatocellular carcinoma (TP53) · vinyl chloride → hepatic angiosarcoma
- Aromatic amines → bladder · asbestos → mesothelioma and bronchogenic carcinoma
- Radiation → thyroid and leukaemia · alkylating agents → leukaemia
- HPV 16/18 → cervical (E6 degrades p53, E7 degrades Rb) · EBV → Burkitt, nasopharyngeal · HBV/HCV → hepatocellular
Tumour markers (for monitoring, not screening)
- AFP → hepatocellular, yolk sac · beta-hCG → choriocarcinoma, germ cell
- CEA → colorectal · CA-125 → ovarian · CA 19-9 → pancreatic · PSA → prostate
- Chromogranin → neuroendocrine · calcitonin → medullary thyroid
Paraneoplastic syndromes (small cell and squamous lead)
- Squamous cell lung → PTHrP → hypercalcaemia
- Small cell lung → ectopic ACTH (Cushing), ADH (SIADH), Lambert-Eaton
- Renal cell / hepatocellular → erythropoietin → polycythaemia
Metastasis and grade vs stage
- Carcinoma spreads via lymphatics; sarcoma via blood (haematogenous)
- Grade = differentiation; Stage = spread (TNM). Stage matters more for prognosis
- Commonest metastases to bone: prostate (blastic), breast (mixed), lung, kidney, thyroid
Nomenclature & hallmarks
- Benign (-oma) vs malignant (carcinoma = epithelial, sarcoma = mesenchymal). Hallmarks: self-sufficient growth signals, evade suppressors/apoptosis, limitless replication (telomerase), angiogenesis, invasion/metastasis.
- Anaplasia (loss of differentiation), pleomorphism, high nuclear:cytoplasmic ratio, mitoses. Dysplasia → carcinoma in situ → invasive (basement-membrane breach).
Oncogenes vs tumour suppressors
| Gene | Type | Association |
|---|---|---|
| RAS, MYC, HER2, BCR-ABL, BRAF | Oncogene (1 hit) | Many carcinomas, CML, breast, melanoma |
| p53, Rb, APC, BRCA1/2, VHL, NF1 | Suppressor (2 hits) | Li-Fraumeni, retinoblastoma, FAP, breast/ovary |
Chemical & microbial carcinogens
- Aflatoxin → HCC; vinyl chloride → hepatic angiosarcoma; aromatic amines/aniline dyes → bladder; benzene → leukaemia; asbestos → mesothelioma; nitrosamines → gastric; arsenic → skin.
- Microbes: HPV (cervical), HBV/HCV (HCC), EBV (Burkitt, nasopharyngeal), H. pylori (gastric/MALT), HTLV-1 (T-cell leukaemia).
Tumour markers
- AFP (HCC, yolk sac), CEA (colon), CA 19-9 (pancreas), CA-125 (ovary), PSA (prostate), beta-hCG (germ cell/choriocarcinoma), calcitonin (medullary thyroid), chromogranin (neuroendocrine).
Spread, grade, stage & paraneoplastic
- Grade = differentiation; Stage (TNM) = spread and the stronger prognostic factor. Carcinoma spreads via lymphatics, sarcoma via blood.
- Paraneoplastic: SIADH/ACTH (small cell lung), PTHrP (squamous lung, hypercalcaemia), polycythaemia (RCC/HCC via EPO), Lambert-Eaton, dermatomyositis.
- Cancer cachexia driven by TNF-alpha ('cachectin'), IL-6.
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