Neoplasia and carcinogenesis

From normal cell to cancer

• Metaplasia: one adult cell type replaced by another better suited to stress, such as columnar epithelium with goblet cells in the lower oesophagus after years of reflux (Barrett oesophagus). It is reversible, but cells dividing under continued injury can acquire mutations, so metaplasia can progress to dysplasia and adenocarcinoma.
• Dysplasia: disordered growth with nuclear atypia and loss of maturation. Mild to moderate dysplasia may regress if the cause (smoking, HPV) is removed.
• Carcinoma in situ: full-thickness atypia with the basement membrane intact; no metastatic potential yet. Invasive carcinoma has crossed the basement membrane.
• Premalignant lesions: leukoplakia (commonest oral premalignant lesion) and erythroplakia (highest malignant risk), oral submucous fibrosis (areca nut), Barrett oesophagus, ulcerative colitis, large sessile villous adenoma (the colonic polyp most likely to turn malignant), endometrial hyperplasia with atypia, actinic keratosis, CIN, cirrhosis, Marjolin ulcer in a chronic scar.

Benign versus malignant, and naming

• Benign tumours end in -oma; malignant epithelial tumours are carcinomas and malignant mesenchymal tumours sarcomas. Lymphoma, melanoma, seminoma, mesothelioma and hepatoma are malignant despite the name.
• Locally malignant tumours invade and recur but rarely metastasise: basal cell carcinoma and ameloblastoma (multilocular "soap-bubble" lesion of the posterior mandible).
• Hamartoma: disorganised mass of tissue native to the site; capillary haemangioma (thin-walled anastomosing channels lined by one layer of endothelium) is the commonest. Choristoma: normal tissue in the wrong place. Teratoma: tissue from all three germ layers; the mature cystic teratoma (dermoid) of the ovary contains hair, sebum and teeth.
• Follicular thyroid carcinoma is told from adenoma only by capsular or vascular invasion on histology, not by cytology, so fine needle aspiration cannot separate them.

The genetic basis

• Cell-cycle control: growth signals raise cyclin D, and cyclin D–CDK4/6 phosphorylates Rb; phosphorylated Rb releases E2F, which drives the cell past the G1/S checkpoint. When DNA is damaged, p53 rises and either arrests the cycle (through p21, which blocks CDKs) for repair or triggers apoptosis (through BAX). Lose p53 and cells with damaged DNA keep dividing.
• Oncogenes (gain of function; one mutant allele is enough): KRAS (commonest mutated oncogene; pancreas, colon, lung), MYC (Burkitt t(8;14)), N-MYC amplification (neuroblastoma: small round blue cells secreting catecholamines), HER2 (breast), BCR–ABL (CML), RET (MEN 2: medullary thyroid carcinoma, phaeochromocytoma, hyperparathyroidism), KIT (GIST), BRAF (melanoma, papillary thyroid), EGFR (lung adenocarcinoma), JAK2 (polycythaemia vera).
• Tumour suppressors (loss of function; both alleles must go): TP53 (mutated in over half of cancers; Li–Fraumeni), RB1, APC, BRCA1/2, VHL on 3p (clear cell renal carcinoma, sporadic and familial), WT1 on 11p13 (Wilms tumour; the WAGR deletion also removes neighbouring PAX6, causing aniridia), NF1, PTEN.
• Knudson two-hit hypothesis: in hereditary retinoblastoma every cell already carries one mutant RB1, so one more hit is enough: tumours are bilateral, multiple and early. Sporadic cases need two somatic hits in the same cell: one tumour, later.
• Apoptosis genes: BCL2 is anti-apoptotic; overexpressed in follicular lymphoma, t(14;18).
• DNA repair genes: mismatch repair (Lynch syndrome), nucleotide excision repair (xeroderma pigmentosum), BRCA (homologous recombination).
• Colorectal cancer, chromosomal instability pathway: loss of APC, then KRAS mutation, then loss of p53 (adenoma–carcinoma sequence). The other route is microsatellite instability from mismatch repair loss.
• Hallmarks: self-sufficient growth signals, insensitivity to inhibitors, evasion of apoptosis, limitless replication (telomerase), angiogenesis (VEGF), invasion and metastasis, Warburg metabolism, immune evasion.

Carcinogens

• Chemical carcinogenesis has two steps. An initiator causes permanent, non-lethal DNA damage (a dead cell cannot become a tumour). A promoter (classically croton oil, also hormones) then makes the initiated cell proliferate; promoters are not mutagenic, their effect is reversible, and they cause tumours only when applied after the initiator.
• UV light forms pyrimidine (thymine) dimers (basal cell, squamous cell carcinoma, melanoma); ionising radiation causes strand breaks.

• Oncogenic organisms: HPV 16/18 (E6 inactivates p53, E7 inactivates Rb), EBV, HBV, HCV, HHV-8, HTLV-1, *H. pylori* (gastric adenocarcinoma, MALT lymphoma), *S. haematobium*, *Clonorchis* (cholangiocarcinoma). Koilocytes show HPV infection, not cancer.

Spread and metastasis

• Carcinomas spread first by lymphatics (regional nodes; sentinel node biopsy); sarcomas by blood. Follicular thyroid, renal cell (into the renal vein), hepatocellular carcinoma and choriocarcinoma also favour blood.
• GI tumours seed the liver through the portal vein; systemic venous drainage seeds the lungs. Transcoelomic spread: ovarian cancer over the peritoneum; Krukenberg tumours from gastric signet-ring carcinoma (diffuse type causes linitis plastica).
• Bone metastases: breast, prostate (sclerotic), lung, kidney, thyroid. Metastases outnumber primaries in liver, lung, brain and bone.
• Why prostate prefers bone and uveal melanoma the liver: blood flow alone does not explain it; the target organ's microenvironment must suit the tumour cells (the "seed and soil" idea: adhesion molecules, chemokines, growth factors).
• Carcinoid syndrome (flushing, diarrhoea, wheeze) from a gut neuroendocrine tumour appears only with liver metastases, because portal blood normally carries serotonin to the liver, where it is destroyed; hepatic secondaries release it straight into the systemic veins. A bronchial carcinoid drains systemically and can cause the syndrome without them.

Grading and staging

• Grade = how abnormal the tumour looks (differentiation, pleomorphism, mitoses). Stage = how far it has spread (TNM). Stage predicts prognosis better.

Tumour immunity

• Tumour antigens: neoantigens from mutated proteins, overexpressed normal proteins (HER2), oncofetal antigens (AFP, CEA), viral antigens.
• Effectors: CD8 cytotoxic T cells (main), NK cells (kill cells that have lost MHC class I), macrophages.
• Evasion: loss of MHC class I, TGF-β, regulatory T cells, and PD-L1 on tumour cells binding PD-1 on T cells to switch them off. Checkpoint inhibitors (anti-PD-1 such as pembrolizumab; anti-CTLA-4 such as ipilimumab) release the brake; side effects are autoimmune (colitis, thyroiditis, hepatitis).

Effects on the host

• Local: obstruction, bleeding, ulceration, pathological fracture. Right-sided colon cancers (wide lumen, liquid stool) bleed occultly and present with iron-deficiency anaemia; left-sided cancers obstruct (change in bowel habit, colicky pain).
• Cachexia from TNF-α, IL-1 and IL-6; fever; anaemia of chronic disease.

Diagnosis

• Histology is the gold standard (core, excision or incision biopsy; frozen section); FNAC gives cells but not architecture. Leukaemia is confirmed by bone marrow aspirate and trephine.
• Psammoma bodies (laminated concentric calcifications) suggest papillary thyroid carcinoma, serous ovarian tumours, meningioma and mesothelioma.

• Marker half-life matters: AFP falls by half every 5–7 days and hCG every 1–2 days after complete removal. An AFP that is still 600 three weeks after orchidectomy (expected well under 150 from 1,000) means residual tumour outside the testis. A raised AFP in a "seminoma" means a non-seminomatous element.
• Radiosensitive tumours: seminoma, dysgerminoma, lymphomas, Ewing sarcoma; melanoma and osteosarcoma are relatively resistant.

Remember Oncogenes need one hit and act like a stuck accelerator; tumour suppressors need two hits and act like failed brakes.

Exam trap Metastasis, not anaplasia, is the absolute proof of malignancy; grade and stage are different things.

Exam trap An initiator must cause non-lethal, permanent DNA damage; a promoter given before the initiator causes nothing.

How FCPS asks about this

• Inherited retinoblastoma is bilateral and early: the first hit is inherited (Knudson).
• G1/S checkpoint: cyclin D–CDK4/6 phosphorylates Rb; p53 arrests the cycle or causes apoptosis.
• Spread: carcinomas by lymph, sarcomas by blood; organ preference reflects the soil.
• Carcinogens: areca nut and oral cancer; nickel and nasal sinus cancer; aniline dyes and bladder; tamoxifen and oestrogen-only HRT and endometrial cancer.
• Small cell lung cancer: SIADH, ACTH, Lambert–Eaton; squamous gives PTHrP hypercalcaemia.
• Markers: CEA for recurrence; AFP in cirrhosis; persistent AFP after orchidectomy means residual disease.
• Grading: Gleason uses glandular architecture; Nottingham uses tubules, pleomorphism and mitoses; Breslow thickness for melanoma.