Neoplasia and Cancer Biology
🟢 Lite — Quick Review (1h–1d)
Benign vs Malignant Tumors:
| Feature | Benign | Malignant |
|---|---|---|
| Differentiation | Well differentiated | Poorly/undifferentiated |
| Growth rate | Slow | Rapid |
| Margin | Encapsulated, pushing | Infiltrative, irregular |
| Capsular involvement | Confined | Invades through capsule |
| Necrosis/Hemorrhage | Rare | Common |
| Metastasis | Absent | Present |
| Recurrence | Rare | Common |
| Nuclear features | Uniform | Pleomorphism, ↑ N:C ratio |
Grading vs Staging:
- Grading — histological differentiation (Grade I-IV); based on microscopy
- Staging — extent of spread (TNM: Tumor size, Nodes, Metastases); based on clinical/imaging/pathology
🟡 Standard — Regular Study (2d–2mo)
Carcinogenesis — Two-Hit Hypothesis (Knudson):
- First hit — inherited or somatic mutation
- Second hit — somatic mutation (loss of heterozygosis)
- Explains familial cancers (RB, p53, BRCA1/2, APC)
Oncogenes — Common Examples:
| Oncogene | Normal Function | Cancer Association |
|---|---|---|
| RAS | GTPase (growth signal) | Pancreatic, colorectal, lung |
| MYC | Transcription factor | Burkitt lymphoma, neuroblastoma |
| BCL-2 | Anti-apoptotic | Follicular lymphoma |
| HER2/neu (ERBB2) | Growth factor receptor | Breast cancer |
| BCR-ABL | Tyrosine kinase (fusion) | CML, Philadelphia chromosome |
| KRAS | GTPase | Colorectal, pancreatic |
| EGFR | Growth factor receptor | Lung adenocarcinoma |
| ALK | Tyrosine kinase | Lung adenocarcinoma, lymphoma |
| N-MYC | Transcription factor | Neuroblastoma |
Tumor Suppressor Genes:
| Gene | Function | Cancer Association |
|---|---|---|
| RB | Inhibits E2F (cell cycle) | Retinoblastoma, osteosarcoma |
| p53 | ”Guardian of genome”; apoptosis | Li-Fraumeni syndrome; most human cancers |
| BRCA1/BRCA2 | DNA repair (homologous recombination) | Breast, ovarian cancer |
| APC | Inhibits Wnt signaling | Familial adenomatous polyposis (FAP) |
| WT1 | Transcription factor | Wilms tumor |
| NF1/NF2 | Ras GTPase regulator / cytoskeletal | Neurofibromatosis 1/2 |
| VHL | Ubiquitin ligase (HIF degradation) | Von Hippel-Lindau disease; renal cell carcinoma |
| PTEN | PI3K/AKT inhibitor | Cowden syndrome |
DNA Repair Genes: MSH2, MLH1 (mismatch repair) → Lynch syndrome (HNPCC)
Carcinogenic Agents:
- Chemical: Aflatoxin B1 (liver cancer), asbestos (mesothelioma, lung cancer), vinyl chloride (angiosarcoma of liver), benzidine (bladder cancer), betel nut (oral cancer), smokeless tobacco
- Physical: UV radiation (BCC, SCC, melanoma), ionizing radiation (leukemia, solid tumors)
- Biological/Viral: HPV (cervical cancer — types 16, 18), HBV/HCV (hepatocellular carcinoma), EBV (Burkitt lymphoma, nasopharyngeal carcinoma), HTLV-1 (Adult T-cell leukemia/lymphoma), H. pylori (gastric MALT lymphoma), Kaposi’s sarcoma (HHV-8)
Metastasis — Routes:
- Direct seeding — body cavities (peritoneum, pleura)
- Lymphatic spread — carcinomas (most common route)
- Hematogenous spread — sarcomas, carcinomas (liver, lung most common secondary sites)
- Transcoelomic — across serosal surfaces
Metastatic Patterns:
- Breast cancer → bone, brain, liver, lung
- Prostate cancer → bone (osteoblastic metastases)
- Lung cancer → adrenal glands, brain, bone, liver
- Colon cancer → liver (portal circulation)
- Retinoblastoma/osteosarcoma → lung (hematogenous)
Tumor Markers:
| Marker | Associated Cancer |
|---|---|
| AFP | Hepatocellular carcinoma, yolk sac tumor |
| β-hCG | Choriocarcinoma, germ cell tumors |
| CEA | Colorectal carcinoma (also gastric, pancreatic, breast) |
| CA-125 | Ovarian serous carcinoma |
| CA 19-9 | Pancreatic adenocarcinoma |
| PSA | Prostate cancer |
| S-100 | Melanoma, nerve sheath tumors |
| Chromogranin | Neuroendocrine tumors |
| Calcitonin | Medullary thyroid carcinoma |
| Thyroglobulin | Follicular/papillary thyroid carcinoma |
| CA 15-3 | Breast cancer |
🔴 Extended — Deep Study (3mo+)
Hallmarks of Cancer (Hanahan & Weinberg):
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Evasion of apoptosis
- Limitless replicative potential (telomerase activation)
- Sustained angiogenesis
- Invasion and metastasis
- Reprogramming energy metabolism (Warburg effect)
- Evading immune destruction
- Genome instability and mutation
- Tumor-promoting inflammation
Tumor Microenvironment:
- Cancer-associated fibroblasts (CAFs) — secrete growth factors, remodel ECM
- Tumor-associated macrophages (TAMs) — M2 phenotype promotes tumor growth
- Regulatory T cells (Tregs) — suppress anti-tumor immunity
- Myeloid-derived suppressor cells (MDSCs)
- ECM remodeling — MMPs (matrix metalloproteinases) → invasion
Apoptosis Pathways:
Extrinsic (Death Receptor):
FasL (on cytotoxic T cells) → Fas (CD95) → FADD → Caspase 8 → Caspase 3 TNF-α → TNFR1 → TRADD → Caspase 8
Intrinsic (Mitochondrial):
DNA damage/ROS/TNF → BH3-only proteins (BIM, BAD, PUMA) → BAX/BAK → Mitochondrial outer membrane permeabilization → Cytochrome c release → Apoptosome (Apaf-1 + Caspase 9) → Caspase 3
Anti-apoptotic: BCL-2, BCL-XL, MCL-1 Pro-apoptotic: BAX, BAK, BIM, BAD, PUMA, NOXA
Tumor Invasion — Steps:
- Loss of E-cadherin (cell-cell adhesion)
- EMT (Epithelial-Mesenchymal Transition) — ↓ cytokeratin, ↑ vimentin
- Degradation of basement membrane (MMPs, cathepsins, uPA)
- Migration through ECM
- Intravasation → circulation → extravasation → colonization
Tumor Angiogenesis:
- VEGF — most important pro-angiogenic factor
- FGF — basic FGF
- Angiopoietins — Ang-1 (maturation), Ang-2 (destabilization)
- Tumor cells → hypoxia → HIF-1α stabilization → ↑ VEGF transcription
- Anti-angiogenic therapy: Bevacizumab (anti-VEGF antibody), sunitinib (VEGFR inhibitor)
Telomerase and Cancer:
- Normal somatic cells: Telomeres shorten with each division → senescence
- Cancer cells: Telomerase reactivation → limitless replicative potential
- hTERT (human telomerase reverse transcriptase) — re-expressed in 85-90% of cancers
Paraneoplastic Syndromes:
| Syndrome | Associated Cancer | Mechanism |
|---|---|---|
| Cushing syndrome | Small cell lung cancer | ACTH production |
| SIADH | Small cell lung cancer | ADH production |
| Hypercalcemia | SCC lung, breast, renal | PTHrP production |
| Polycythemia | Renal cell carcinoma, hepatocellular carcinoma | EPO production |
| Lambert-Eaton | Small cell lung cancer | Anti-VGCC antibodies |
| Trousseau syndrome | Pancreatic adenocarcinoma | Migratory thrombophlebitis |
| Acanthosis nigricans | Gastric adenocarcinoma | EGFR family activation |
| Peutz-Jeghers | Ovarian sex cord tumors, Sertoli cell tumors | STK11/LKB1 mutation |
Oncogenic Viruses — Details:
- HPV: E6 (inactivates p53), E7 (inactivates RB) → cervical, oropharyngeal, anal carcinoma
- HBV: X protein → promotes proliferation; chronic inflammation → cirrhosis → HCC
- HCV: Chronic inflammation → cirrhosis → HCC
- EBV: LMP-1 (constitutive NF-κB activation) → Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, post-transplant lymphoproliferative disorder
- HHV-8 (Kaposi’s sarcoma herpesvirus): vFLIP → activates NF-κB → Kaposi sarcoma, primary effusion lymphoma
Chemotherapy — Mechanism-Based Classification:
| Class | Mechanism | Examples |
|---|---|---|
| Alkylating agents | Crosslink DNA | Cyclophosphamide, cisplatin, nitrosoureas |
| Anti-metabolites | Mimic substrates | Methotrexate, 5-FU, cytarabine, mercaptopurine |
| Microtubule inhibitors | Mitosis arrest | Vincristine, paclitaxel |
| Topoisomerase inhibitors | DNA replication stress | Etoposide, irinotecan, doxorubicin |
| DNA crosslinkers | Platinum-based | Cisplatin, carboplatin |
| Antibiotics | Intercalation/free radical | Doxorubicin, bleomycin |
| Corticosteroids | Lymphocyte apoptosis | Prednisone |
| Biological/Targeted | Kinase inhibitors, antibodies | Imatinib, rituximab, trastuzumab |
Special Considerations:
- Bleomycin — pulmonary fibrosis (↑ risk with O₂ supplementation)
- Doxorubicin — cardiotoxicity (free radical generation); cumulative dose limit
- Cisplatin — nephrotoxicity, ototoxicity, peripheral neuropathy
- Cyclophosphamide — hemorrhagic cystitis (acrolein toxicity); prevent with MESNA
- Methotrexate — mucositis, myelosuppression; antidote: leucovorin (folinic acid)
- Vincristine — neurotoxicity (peripheral neuropathy); don’t give intrathecally (fatal)
Carcinoid Syndrome:
- Secretory product: Serotonin (5-HT), histamine, bradykinin
- Features: Flushing, diarrhea, wheezing, right-sided heart disease (carcinoid heart disease — tricuspid/pulmonic stenosis/regurgitation)
- Usually indicates liver metastases (because hepatic metabolism normally inactivates serotonin before systemic circulation)
- Urinary 5-HIAA — serotonin metabolite; diagnostic marker
Key NEET-PG Clinical Pearls:
- Philadelphia chromosome = t(9;22) BCR-ABL fusion → CML, ALL
- Li-Fraumeni syndrome = germline p53 mutation → multiple cancers (breast, sarcoma, brain, adrenocortical)
- Xeroderma pigmentosum = defective nucleotide excision repair → UV-induced skin cancers
- Ataxia telangiectasia = ATM mutation → ↑ sensitivity to ionizing radiation; lymphoid malignancies
- Bloom syndrome = BLM helicase defect → ↑ sister chromatid exchanges; AML, lymphomas
- BRCA1/BRCA2 = defective homologous recombination repair → breast, ovarian, pancreatic cancer
- MEN syndromes: MEN1 (pituitary, parathyroid, pancreatic tumors; menin gene), MEN2A/2B (medullary thyroid carcinoma, pheochromocytoma, parathyroid; RET proto-oncogene)
- Lynch syndrome (HNPCC) = mismatch repair defects → colorectal, endometrial, ovarian cancer
- Gardner syndrome = APC mutation → FAP + desmoid tumors, osteomas, sebaceous cysts
- Turcot syndrome = APC or MMR mutations → colorectal + brain tumors
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