Neoplasia: Carcinogenesis & Tumor Markers
A board-focused tour of neoplasia: multistep carcinogenesis, oncogenes vs tumor-suppressor genes, high-yield chemical and viral carcinogens, and the tumor markers (with next-best-step decisions) the USMLE loves to test.
Big picture: what neoplasia is and how the boards test it
Neoplasia is an irreversible, monoclonal, unregulated proliferation that persists after the inciting stimulus is removed. Benign tumors are well-differentiated, slow-growing, encapsulated, and never metastasize (usually "-oma"); malignant tumors are anaplastic, invade the basement membrane, and metastasize (carcinoma = epithelial origin, sarcoma = mesenchymal).
Carcinogenesis is multistep: initiation (irreversible DNA mutation) → promotion (reversible clonal expansion) → progression (invasion, angiogenesis, metastasis). Cancer emerges from stepwise accumulation of driver mutations in oncogenes, tumor-suppressor genes, and DNA-repair genes.
Boards test three moves: (1) match a gene / chemical / virus / marker to its tumor; (2) pick the next best step — a tumor marker is for monitoring, a tissue biopsy is for diagnosis; and (3) prognosis — metastasis is the single most important prognostic factor, and stage > grade.
- Oncogenes = gain of function, dominant (one mutated allele is enough); arise from proto-oncogenes. Ex: RAS, MYC, HER2, BCR-ABL, BCL2, RET, KIT.
- Tumor-suppressor genes = loss of function, recessive — Knudson two-hit hypothesis (both alleles must be inactivated). Ex: RB1, TP53, APC, BRCA1/2, VHL, WT1, NF1.
- RB1 and TP53 guard the G1→S checkpoint. TP53 = "guardian of the genome" — triggers arrest (via p21), repair, or apoptosis (via BAX); TP53 is the most commonly mutated gene in human cancers.
- Hallmarks of cancer: evade apoptosis, self-sufficient growth signals, insensitivity to growth inhibitors, limitless replication (telomerase), sustained angiogenesis (VEGF), invasion/metastasis, altered metabolism (Warburg effect).
- Grade = degree of differentiation (histology); Stage = size + spread (TNM). Stage carries greater prognostic weight than grade.
- Tumor markers monitor treatment response/recurrence — they are not screening or definitive diagnostic tests.
Oncogenes vs tumor-suppressor genes
| Gene | Type | Key tumor(s) |
|---|---|---|
| RAS | oncogene (GTPase) | many carcinomas |
| MYC | oncogene | Burkitt lymphoma, t(8;14) |
| HER2/ERBB2 | oncogene | breast, gastric |
| BCR-ABL | oncogene, t(9;22) | CML, ALL |
| BCL2 | oncogene (anti-apoptotic), t(14;18) | follicular lymphoma |
| RET | oncogene | MEN2A/2B, medullary thyroid |
| KIT | oncogene | GIST |
| RB1 | suppressor | retinoblastoma, osteosarcoma |
| TP53 | suppressor | Li-Fraumeni, most cancers |
| APC | suppressor | FAP, colorectal |
| BRCA1/2 | suppressor (DNA repair) | breast, ovarian |
| VHL | suppressor | clear-cell RCC, hemangioblastoma |
| WT1 | suppressor | Wilms tumor |
Chemical & microbial carcinogens
| Agent | Associated cancer |
|---|---|
| Aflatoxin (Aspergillus) | HCC (TP53 mutation) |
| Vinyl chloride | hepatic angiosarcoma |
| Arsenic | angiosarcoma, squamous skin, lung |
| Asbestos | bronchogenic carcinoma > mesothelioma |
| Aromatic amines (naphthylamine) | urothelial (bladder) |
| Benzene, alkylating agents | leukemia (AML) |
| Nitrosamines | gastric adenocarcinoma |
| HPV 16/18 (E6→p53, E7→Rb) | cervical, anal, oropharyngeal |
| HBV / HCV | hepatocellular carcinoma |
| EBV | Burkitt, nasopharyngeal, Hodgkin |
| HHV-8 | Kaposi sarcoma |
| H. pylori | gastric adenocarcinoma, MALT lymphoma |
| HTLV-1 | adult T-cell leukemia/lymphoma |
| Schistosoma haematobium | squamous cell bladder cancer |
- Tumor markers are best for tracking treatment response and detecting recurrence, not screening — biopsy is definitive.
- AFP ↑ in HCC and yolk sac (endodermal sinus) tumors; also rises in pregnancy and neural tube defects.
- β-hCG ↑ in choriocarcinoma, hydatidiform mole, and germ cell tumors.
- Germ cell nuance: yolk sac/embryonal tumors raise AFP; pure seminoma has a NORMAL AFP (may have mildly ↑ β-hCG). An elevated AFP means the tumor is nonseminomatous.
- PSA is prostate-specific, not cancer-specific (↑ in BPH, prostatitis).
- CA-125 (ovarian) can be falsely ↑ by endometriosis, PID, pregnancy.
- Calcitonin → medullary thyroid carcinoma (parafollicular C cells; linked to RET / MEN2).
- LDH reflects tumor burden (lymphoma, testicular).
Key tumor markers → tumor
| Marker | Associated tumor |
|---|---|
| AFP | HCC, yolk sac tumor |
| CEA | colorectal (also pancreatic, gastric) |
| CA 19-9 | pancreatic adenocarcinoma |
| CA-125 | ovarian (surface epithelial) |
| CA 15-3 / 27-29 | breast |
| PSA | prostate |
| β-hCG | choriocarcinoma, mole, germ cell |
| Calcitonin | medullary thyroid carcinoma |
| Chromogranin A | neuroendocrine tumors |
| S-100 (IHC stain) | melanoma, schwannoma, Langerhans cell |
| TRAP (cytochemical stain) | hairy cell leukemia |
| Alkaline phosphatase | bone metastases, Paget, liver |
Vignette: A 58-year-old man with chronic hepatitis B and cirrhosis undergoes surveillance ultrasound, which reveals a new 3-cm hepatic mass; serum AFP is markedly elevated.
Diagnosis: Hepatocellular carcinoma (HCC).
Next best step: Obtain multiphasic contrast CT or MRI of the liver. Classic HCC shows arterial-phase hyperenhancement with venous "washout," which is diagnostic in a cirrhotic liver — biopsy is often unnecessary and is avoided when imaging is characteristic (seeding risk).
Buzz link: risk factors = HBV/HCV, cirrhosis, aflatoxin (TP53), alcohol. AFP here is used to monitor, not to make the diagnosis.
Vignette: A 27-year-old man has a painless, firm testicular mass; scrotal ultrasound shows a solid intratesticular lesion.
Next best step: Draw serum AFP, β-hCG, and LDH, then proceed to radical INGUINAL orchiectomy for diagnosis and treatment. NEVER perform a trans-scrotal biopsy — it risks tumor seeding and disrupts lymphatic drainage.
Interpretation: ↑ AFP → nonseminomatous germ cell tumor (yolk sac/embryonal); pure seminoma has a normal AFP. Stage with CT abdomen/pelvis — germ cell tumors spread to retroperitoneal para-aortic nodes.
"PSaMMoma bodies" — concentric, laminated calcifications on histology. Classic in:
- Papillary thyroid carcinoma
- Serous papillary cystadenocarcinoma of the ovary
- Meningioma
- Mesothelioma
Also seen in papillary renal cell carcinoma. Their presence signals a papillary/serous growth pattern.
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