Neoplasia
1. What this chapter covers, and how NEET PG actually tests it
Neoplasia is the largest single topic in pathology and the one most often reduced to unstructured memorisation.
It has a structure. Cancer is the accumulation of a small number of acquired capabilities, and every fact in the subject attaches to one of them.
A cell becomes malignant when it can sustain its own growth signals, ignore signals to stop, evade death, divide without limit, build a blood supply, and invade.
Sort each gene, carcinogen and syndrome by the capability it provides, and the list becomes a structure you can reason from rather than recite.
| Area | What the exam asks | Typical stem |
|---|---|---|
| Nomenclature | Benign or malignant, which tissue | A tumour name |
| Oncogenes | Which pathway, which tumour | A named gene or translocation |
| Tumour suppressors | Why two hits are needed | An inherited cancer syndrome |
| Carcinogens | Which agent causes which tumour | An occupational exposure |
| Metastasis | Route and favoured site | A tumour plus a deposit site |
| Paraneoplastic | Which hormone, which tumour | An electrolyte or endocrine abnormality |
| Staging | What determines prognosis | A TNM description |
2. Benign versus malignant, and the words used
2.1 The four features that separate them
Differentiation, growth rate, local invasion and metastasis.
Metastasis is the only absolutely reliable criterion, since a tumour that has metastasised is malignant by definition, while every other feature exists on a spectrum.
Benign tumours are well differentiated, slow growing, encapsulated and non-invasive.
Malignant tumours vary from well differentiated to anaplastic, grow faster, invade locally and may metastasise.
Anaplasia is loss of differentiation, recognised by pleomorphism, large hyperchromatic nuclei, a high nuclear-to-cytoplasmic ratio, prominent nucleoli and atypical mitoses.
2.2 Nomenclature and its exceptions
Benign epithelial tumours are adenomas or papillomas; benign mesenchymal tumours take the suffix -oma.
Malignant epithelial tumours are carcinomas; malignant mesenchymal tumours are sarcomas.
Several tumours are named as if benign but are malignant, and these are examined precisely because the naming is misleading: lymphoma, melanoma, mesothelioma, seminoma and glioma.
Hamartoma is disorganised tissue native to the site; choristoma is normal tissue in an abnormal site.
Teratomas contain tissue from more than one germ layer, and in males any teratoma is treated as malignant.
2.3 Dysplasia and carcinoma in situ
Dysplasia is disordered growth with cytological atypia that does not cross the basement membrane, and it is reversible.
Carcinoma in situ is full-thickness dysplasia, still confined by the basement membrane.
Breaching the basement membrane is the single event that converts carcinoma in situ into invasive carcinoma, because only then can the tumour reach vessels and lymphatics.
3. The three classes of cancer gene
3.1 Oncogenes: gain of function
Proto-oncogenes become oncogenes through point mutation, amplification or translocation, and one mutated allele is sufficient because the effect is dominant.
| Gene | Function | Tumour |
|---|---|---|
| RAS | GTP-binding signal transducer | Colon, pancreas, lung |
| MYC | Transcription factor | Burkitt lymphoma |
| HER2 (ERBB2) | Growth factor receptor | Breast, gastric |
| BCR-ABL | Tyrosine kinase | Chronic myeloid leukaemia |
| BCL2 | Anti-apoptotic | Follicular lymphoma |
| RET | Receptor tyrosine kinase | MEN 2A and 2B, medullary thyroid |
| c-KIT | Receptor tyrosine kinase | Gastrointestinal stromal tumour |
| Cyclin D1 | Cell cycle | Mantle cell lymphoma |
RAS is the commonest mutated oncogene in human cancer, and the mutation impairs GTP hydrolysis so the protein remains permanently active.
BCL2 is the exception in this list because it does not drive proliferation at all; it prevents apoptosis, so cells accumulate because they fail to die.
3.2 Tumour suppressors: loss of function
Both alleles must be lost, which is Knudson's two-hit hypothesis.
An inherited cancer syndrome means the patient was born with one hit already present, which is why familial tumours occur earlier and are more often bilateral or multifocal.
| Gene | Syndrome | Function |
|---|---|---|
| RB | Retinoblastoma | Restrains G1 to S transition |
| TP53 | Li-Fraumeni | Arrests cycle or triggers apoptosis after DNA damage |
| APC | Familial adenomatous polyposis | Regulates beta-catenin |
| BRCA1 and BRCA2 | Hereditary breast and ovarian cancer | Homologous recombination repair |
| VHL | Von Hippel-Lindau | Degrades hypoxia-inducible factor |
| NF1 and NF2 | Neurofibromatosis | RAS regulation, membrane organisation |
| WT1 | WAGR, Denys-Drash | Renal and gonadal development |
| PTEN | Cowden syndrome | Inhibits PI3K signalling |
TP53 is the most commonly mutated gene in human cancer, and its loss removes the checkpoint that would otherwise stop a damaged cell dividing.
Retinoblastoma illustrates the two-hit rule perfectly: the hereditary form is bilateral and early, the sporadic form unilateral and later, because two independent somatic hits in one cell are far less likely.
3.3 DNA repair genes
Loss of repair capacity does not itself transform a cell; it accelerates the accumulation of mutations in the other two gene classes.
Mismatch repair failure causes hereditary non-polyposis colorectal cancer, recognised by microsatellite instability.
Nucleotide excision repair failure causes xeroderma pigmentosum, with extreme ultraviolet sensitivity and early skin cancers.
Ataxia-telangiectasia and Fanconi anaemia are the double-strand break repair disorders.
3.4 How RB and p53 actually work
These two genes are examined constantly, and both become straightforward once the mechanism is clear.
RB protein in its hypophosphorylated state binds the E2F transcription factor and holds it inactive, which keeps the cell in G1.
Growth signals activate cyclin D with CDK4 and CDK6, which phosphorylate RB, release E2F, and allow entry into S phase.
So the G1 to S transition is a restraint being lifted rather than an accelerator being pressed, and losing RB removes the restraint permanently.
Cyclin D amplification and CDK4 mutation achieve the same result from the other direction, which is why they act as oncogenes.
The p53 protein is the checkpoint that responds to DNA damage, and it has three possible outputs: arrest the cycle, direct repair, or trigger apoptosis if damage is irreparable.
Arrest is achieved by inducing p21, which inhibits the cyclin-CDK complexes that would otherwise phosphorylate RB.
Losing p53 therefore allows a cell with damaged DNA to continue dividing, which is precisely how mutations accumulate.
Human papillomavirus disables both checkpoints simultaneously, with E6 degrading p53 and E7 inactivating RB, which is why a single virus is so efficiently carcinogenic.
4. Invasion, metastasis and angiogenesis
4.1 The invasion sequence
Loosening of intercellular junctions, degradation of matrix, attachment to new matrix, and migration.
Loss of E-cadherin is the key step in loosening, and its absence characterises lobular carcinoma of the breast and diffuse gastric carcinoma.
Matrix metalloproteinases degrade basement membrane and are the tumour's principal digestive tool.
4.2 Routes and destinations
Carcinomas spread predominantly by lymphatics, sarcomas predominantly by blood.
Transcoelomic spread across body cavities produces the Krukenberg tumour, a bilateral ovarian deposit from gastric signet ring carcinoma.
Metastasis is not random: the destination reflects both the venous drainage and the receptiveness of the target tissue, which is the seed and soil hypothesis.
Prostate cancer reaches the vertebrae through the valveless Batson venous plexus, which bypasses the lungs entirely and produces characteristically osteoblastic deposits.
Liver, lung, bone and brain are the commonest metastatic sites, and metastatic deposits far outnumber primary tumours at each.
Bone metastases are lytic in most tumours but osteoblastic in prostate cancer, which is why the alkaline phosphatase rises there.
4.3 Angiogenesis
A tumour cannot exceed one to two millimetres without a blood supply, because diffusion cannot reach further.
Vascular endothelial growth factor is the principal driver, and hypoxia-inducible factor is what switches it on.
Von Hippel-Lindau disease illustrates the pathway in reverse: the VHL protein normally degrades hypoxia-inducible factor, so losing it produces continuous angiogenic signalling and highly vascular tumours.
4.4 Immune evasion and checkpoint blockade
A tumour that has acquired every other capability still has to survive immune surveillance, and how it does so has become directly examinable.
Cytotoxic T cells recognise tumour antigens presented on MHC class I, so downregulating MHC class I is one common escape route.
Tumours also exploit the brakes the immune system uses on itself, expressing PD-L1 to engage the PD-1 receptor on T cells and switch them off.
CTLA-4 is a second brake, acting earlier during T cell priming rather than at the effector stage.
Checkpoint inhibitors work by blocking these brakes rather than by attacking the tumour, which is why their toxicities are autoimmune in character.
Immune evasion is the reason a tumour with a high mutational burden can respond well to checkpoint blockade: more mutations mean more neoantigens for a released immune system to recognise.
That is also why microsatellite-unstable colorectal cancers, which carry very large numbers of mutations, are particularly responsive.
5. Carcinogens
5.1 Chemical
| Agent | Tumour |
|---|---|
| Aflatoxin B1 | Hepatocellular carcinoma |
| Vinyl chloride | Hepatic angiosarcoma |
| Aromatic amines, aniline dyes | Bladder transitional cell carcinoma |
| Benzene | Acute myeloid leukaemia |
| Asbestos | Bronchogenic carcinoma and mesothelioma |
| Arsenic | Skin, lung, angiosarcoma |
| Nitrosamines | Gastric carcinoma |
| Alkylating agents | Acute myeloid leukaemia |
Aflatoxin acts through a specific TP53 mutation, which is why the link is so tightly established.
Asbestos causes bronchogenic carcinoma more often than mesothelioma, although mesothelioma is the more specific association, and smoking multiplies the bronchogenic risk enormously while not affecting mesothelioma risk.
5.2 Radiation and viruses
Ionising radiation causes leukaemia, thyroid and breast cancer; ultraviolet radiation causes skin cancers through pyrimidine dimer formation.
| Virus | Tumour |
|---|---|
| Human papillomavirus 16, 18 | Cervical, oropharyngeal, anal |
| Epstein-Barr virus | Burkitt, nasopharyngeal, Hodgkin |
| Hepatitis B and C | Hepatocellular carcinoma |
| Human herpesvirus 8 | Kaposi sarcoma |
| HTLV-1 | Adult T cell leukaemia |
| Helicobacter pylori | Gastric carcinoma and MALT lymphoma |
Human papillomavirus works through the E6 and E7 proteins, which degrade p53 and inactivate RB respectively, disabling both major checkpoints at once.
Helicobacter pylori is a bacterium rather than a virus, and MALT lymphoma is notable for regressing after eradication therapy.
6. Paraneoplastic syndromes and staging
6.1 The syndromes worth knowing
| Syndrome | Usual tumour |
|---|---|
| Syndrome of inappropriate antidiuresis | Small cell lung carcinoma |
| Ectopic ACTH | Small cell lung carcinoma |
| Hypercalcaemia from PTH-related peptide | Squamous cell lung carcinoma |
| Polycythaemia from erythropoietin | Renal cell carcinoma |
| Lambert-Eaton syndrome | Small cell lung carcinoma |
| Acanthosis nigricans | Gastric adenocarcinoma |
| Trousseau migratory thrombophlebitis | Pancreatic adenocarcinoma |
| Dermatomyositis | Various visceral malignancies |
Small cell carcinoma produces the endocrine syndromes because it is neuroendocrine in origin, while squamous carcinoma produces hypercalcaemia through parathyroid hormone-related peptide.
Hypercalcaemia of malignancy is more often caused by that peptide than by bone metastases, which is a frequently reversed fact.
6.2 Grade and stage
Grade describes how differentiated the tumour is; stage describes how far it has spread.
Stage is far more important than grade for prognosis in almost every solid tumour, because spread determines what treatment can achieve.
TNM records tumour size or depth, nodal involvement and distant metastasis.
Lymph node status is usually the single strongest prognostic variable, which is why sentinel node biopsy has become central to breast and melanoma surgery.
The two important exceptions are worth holding, because they are the questions the examiner builds around the rule.
Soft tissue sarcomas are graded rather than staged for prognosis, since they metastasise by blood and rarely involve nodes, so grade carries the prognostic weight instead.
Melanoma depth, measured as the Breslow thickness, predicts outcome better than any other single variable, and it is essentially a measure of how far invasion has progressed.
Clark level, which describes the anatomical layer reached, has largely been abandoned in favour of the millimetre measurement because thickness is more reproducible.
6.3 Cancer epidemiology in India
The Indian pattern differs from Western data in ways the exam tests directly, and quoting Western frequencies is a common way to lose a mark.
Oral cavity cancer is far commoner in India than in Western populations, driven by tobacco chewing, areca nut and gutkha.
National Cancer Registry Programme data place lung and oral cavity as the two leading sites among Indian men, with oral cancer accounting for roughly 11 per cent of male cancers.
Among Indian women, breast cancer is now clearly the leading site at close to 29 per cent, with cervix uteri second at around 11 per cent.
The projected national burden is approximately 1.57 million cases for 2025, which is the figure usually quoted in public health questions.
Tobacco in all its forms accounts for roughly a third to a half of cancers in Indian men, which is why tobacco control is the single largest available intervention.
Gallbladder cancer shows a striking geographical concentration in the Gangetic belt, particularly in northern and eastern states.
Oesophageal cancer is disproportionately common in parts of Kashmir and the north-east, associated with dietary and tobacco practices.
Screening programmes under the national non-communicable disease framework target oral, cervical and breast cancer specifically, because these three are accessible to clinical examination.
7. Worked examples
Example 1
A 2-year-old presents with bilateral retinoblastoma. What does the bilaterality indicate?
Retinoblastoma requires both RB alleles to be lost in a single retinal cell.
In sporadic disease, two independent somatic hits must occur in the same cell, which is so unlikely that it happens once and produces one unilateral tumour.
Bilateral disease means the patient inherited one defective allele already present in every cell, so only one further hit is needed and it occurs independently in both eyes.
The same reasoning predicts the raised lifetime risk of osteosarcoma, since the inherited hit is present in bone cells too.
Example 2
A 55-year-old smoker with lung cancer has a serum sodium of 118 mmol/L with concentrated urine and normal volume status.
Hyponatraemia with inappropriately concentrated urine and euvolaemia is the syndrome of inappropriate antidiuresis.
The question is which histological type, and this is decided by cell of origin rather than by frequency.
Small cell carcinoma arises from neuroendocrine cells and therefore secretes peptide hormones, making it the cause of both inappropriate antidiuresis and ectopic ACTH.
Had the stem given hypercalcaemia instead, the answer would be squamous cell carcinoma acting through parathyroid hormone-related peptide.
Example 3
A woman with gastric signet ring carcinoma is found to have bilateral solid ovarian masses.
Bilaterality in ovarian masses raises the probability of metastatic rather than primary disease.
Gastric carcinoma reaches the ovaries by transcoelomic seeding across the peritoneal cavity.
This is a Krukenberg tumour, and the diagnostic feature is mucin-filled signet ring cells within an ovarian stroma.
The finding indicates disseminated disease, so it changes management from potentially curative to palliative.
8. Traps the exam sets repeatedly
Assuming tumours named with the -oma suffix are benign. Lymphoma, melanoma, mesothelioma, seminoma and glioma are all malignant, and the exam exploits the naming directly.
Attributing hypercalcaemia of malignancy to bone metastases by default. Parathyroid hormone-related peptide from a squamous tumour is the commoner mechanism.
Treating grade and stage as equally important. Stage dominates prognosis in nearly every solid tumour.
Forgetting that BCL2 is anti-apoptotic rather than proliferative. Follicular lymphoma cells accumulate because they do not die.
Confusing hamartoma with choristoma. A hamartoma is disorganised native tissue; a choristoma is normal tissue in the wrong place.
Summary
Cancer is the accumulation of a small number of acquired capabilities, and every fact in neoplasia attaches to one of them.
Metastasis is the only absolute criterion of malignancy; every other feature is a spectrum.
Several malignant tumours carry benign-sounding names, and the exam uses that deliberately.
Oncogenes act dominantly through one allele; tumour suppressors need both hits, which is why an inherited first hit produces earlier and bilateral disease.
TP53 is the most commonly mutated gene in cancer and RAS the most commonly mutated oncogene.
DNA repair genes do not transform cells directly but accelerate mutation in the other two classes.
Loss of E-cadherin loosens junctions and initiates invasion; matrix metalloproteinases perform the digestion.
Metastatic destination reflects venous drainage and target receptiveness, illustrated by Batson plexus spread to vertebrae and Krukenberg tumours of the ovary.
Angiogenesis limits tumours to one or two millimetres until vascular endothelial growth factor is switched on, which is why VHL loss produces such vascular tumours.
Small cell carcinoma causes the endocrine paraneoplastic syndromes because it is neuroendocrine, while squamous carcinoma causes hypercalcaemia through parathyroid hormone-related peptide.
Stage matters more than grade, and nodal status is usually the strongest single prognostic variable.
