Neoplasm Study Guide

📖 Core Concepts Neoplasm: abnormal, excessive tissue growth; the process is neoplasia. Tumour vs. Cancer: “tumour” = any mass (benign, precancerous, malignant). Cancer = malignant neoplasm that invades, metastasizes, and is usually fatal if untreated. ICD‑10 Classification: Benign neoplasms – circumscribed, never become cancer. In‑situ neoplasms – localized, no invasion yet, can progress. Malignant neoplasms – invasive, metastatic. Neoplasms of uncertain/unknown behavior – secondary or unknown primary. Clonality: Tumours arise from a monoclonal population (same genetic/epigenetic abnormality). In lymphoid cancers, proven by a single Ig or T‑cell receptor gene rearrangement. DNA Damage: Central cause of cancer; each cell incurs >$10{,}000$ DNA lesions daily from normal metabolism. Field Cancerization (Field Defects): Histologically normal tissue that already harbors multiple genetic/epigenetic alterations, creating a pre‑malignant “patch.” --- 📌 Must Remember Benign ≠ Cancer; benign tumours never transform. In‑situ lesions are precancerous but not yet invasive. Driver mutations ≈ 3–4 per tumour; the rest are passenger mutations. Mutation burden: 60–70 protein‑altering mutations (exome) in breast/colon cancer; 80 000 total mutations in melanoma. Germline DNA‑repair gene mutations (e.g., TP53) → very high lifetime cancer risk. Epigenetic silencing (promoter methylation of MGMT, MLH1, PMS2) is common in sporadic cancers. Field defects arise when a mutant stem cell outcompetes neighbours, forming a clone that later acquires additional hits. Secondary neoplasm = metastasis from a known primary; cancer of unknown primary = metastatic tumour with no identifiable source. --- 🔄 Key Processes DNA Damage → Repair Deficiency → Genomic Instability Normal metabolism → >$10{,}000$ lesions/day → DNA‑repair pathways (e.g., mismatch repair). Germline or somatic loss of repair genes → lesions persist → error‑prone repair (translesion synthesis) → mutation accumulation. Clonal Evolution in a Field Defect A single mutant stem cell → clonal expansion → patch of altered epithelium. Subsequent independent mutations → sub‑clones → adenoma → invasive carcinoma. Demonstrating Monoclonality in Lymphoid Tumours Extract DNA → PCR amplify Ig heavy‑chain or T‑cell receptor (TCR) loci. Single dominant band = monoclonal → neoplastic label. Progression from In‑situ to Invasive Cancer Accumulation of additional driver mutations + loss of cell‑adhesion molecules → basement‑membrane breach → invasion. --- 🔍 Key Comparisons Benign vs. Malignant Benign: well‑circumscribed, no invasion, never metastasize. Malignant: infiltrative, destroys tissue, can metastasize. Tumour vs. Cancer Tumour = any mass (benign, in‑situ, malignant). Cancer = malignant tumour only. In‑situ vs. Invasive In‑situ: cells confined to epithelium, no stromal invasion. Invasive: cells breach basement membrane, can spread. Sporadic vs. Hereditary Cancer Sporadic (≈70 %): no germline mutation; often epigenetic silencing of repair genes. Hereditary: germline mutation in DNA‑repair gene (e.g., TP53, BRCA1/2). Driver vs. Passenger Mutations Drivers: confer growth advantage, few per tumour. Passengers: neutral, make up the bulk of mutations. --- ⚠️ Common Misunderstandings “All tumours are cancerous.” – False; many are benign. “In‑situ carcinoma always becomes invasive.” – Not inevitable; progression requires additional hits. “Only exogenous factors cause DNA damage.” – Endogenous metabolic processes cause >10 000 lesions/day. “Field defects are visible on routine histology.” – They appear normal; molecular testing reveals the alterations. “High mutation count means the tumour is more aggressive.” – Not necessarily; many are passenger mutations. --- 🧠 Mental Models / Intuition “Cancer as a mutational avalanche.” Imagine a snowball (a single mutant stem cell) rolling downhill, picking up more snow (mutations) and growing larger (clonal expansion). “Repair genes are the cell’s “spell‑check.” When spell‑check fails, typos (mutations) accumulate, leading to a garbled document (cancer genome). “Field defect = polluted neighborhood.” The area looks normal but the soil (DNA) is contaminated, making any new seed (cell) likely to grow a weed (tumour). --- 🚩 Exceptions & Edge Cases Secondary neoplasms – Metastatic lesions, not a new primary. Cancers without a palpable tumour – e.g., leukemia, carcinoma in situ. Unknown primary – Metastatic disease with no identifiable source; requires broad molecular profiling. Epigenetic silencing vs. mutation – Gene can be inactivated without sequence change (e.g., promoter methylation of MLH1). --- 📍 When to Use Which Classify neoplasm → Use ICD‑10 categories based on invasion & metastasis. Determine neoplastic vs. reactive lymphoid proliferation → Order clonality assay (Ig/TCR gene rearrangement). Assess hereditary cancer risk → Test for germline mutations in DNA‑repair genes if family history or early‑onset disease. Interpret high mutation burden → Consider melanoma or UV‑related cancers; prioritize immunotherapy eligibility. Investigate field cancerization → Use molecular mapping (e.g., methylation panels) around a lesion to guide surveillance. --- 👀 Patterns to Recognize High total mutation count + UV signature → Likely melanoma. 3–4 driver mutations with many passengers → Typical solid tumour (breast, colon). Promoter methylation of MLH1 / PMS2 → Microsatellite instability phenotype. Monoclonal Ig/TCR rearrangement → Lymphoid neoplasm. Patchy, genetically altered epithelium surrounding a tumour → Field defect. --- 🗂️ Exam Traps Choosing “benign” for any non‑painful mass – Remember benign tumours never become cancerous; “benign” must be based on histology, not symptoms. Assuming all in‑situ lesions will progress – Progression requires additional mutations; many remain indolent. Confusing “secondary neoplasm” with “new primary.” – Secondary = metastasis from known primary; treat as stage IV disease. Over‑valuing mutation numbers – A high passenger load does not equal aggressiveness; focus on driver genes. Attributing all DNA damage to lifestyle – Endogenous metabolic damage is a major, constant source. ---