Pathology of Neoplasia
Neoplasia is the uncontrolled proliferation of cells forming a neoplasm (tumour). Understanding tumour biology, classification, and staging is fundamental to cancer management.
Key Facts
Benign tumours: Well-differentiated, encapsulated, slow-growing, no metastasis; malignant: Poorly differentiated, invasive, metastasise Hallmarks of cancer (Hanahan & Weinberg): Self-sufficiency in growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replication, sustained angiogenesis, tissue invasion/metastasis Oncogenes (gain-of-function): HER2, RAS, MYC, BCR-ABL; tumour suppressors (loss-of-function): p53, RB, APC, BRCA1/2 Two-hit hypothesis (Knudson): Both alleles of a tumour suppressor must be inactivated for tumour development TNM staging: T = tumour size/invasion, N = lymph node involvement, M = distant metastasis Tumour markers: PSA (prostate), CA-125 (ovarian), CEA (colorectal), AFP (hepatocellular, testicular), CA 19-9 (pancreatic) Metastasis occurs via lymphatic (carcinomas) or haematogenous (sarcomas) spread; common sites: liver, lung, bone, brain Cancer is the leading cause of death in the UK, accounting for ~28% of all deaths (~167,000/year)
Overview
Key Facts
Neoplasia literally means "new growth." Tumours are classified by their cell of origin: carcinomas (epithelial), sarcomas (mesenchymal), lymphomas (lymphoid), leukaemias (haematopoietic). Understanding the molecular basis of cancer drives modern targeted therapy.
Epidemiology
Cancer affects 1 in 2 people in the UK during their lifetime. The most common cancers are breast (55,000/year), lung (48,000), prostate (52,000), and bowel (42,000). Cancer causes approximately 167,000 deaths per year in the UK. Overall cancer survival has doubled in the last 40 years.
Aetiology
Carcinogenesis is a multistep process requiring accumulation of genetic mutations:
- Chemical: Smoking (polycyclic aromatic hydrocarbons), aflatoxins (hepatocellular), asbestos (mesothelioma)
- Physical: UV radiation (melanoma), ionising radiation (leukaemia, thyroid)
- Biological: HPV (cervical), EBV (Burkitt's, nasopharyngeal), H. pylori (gastric MALT lymphoma), HBV/HCV (hepatocellular)
- Genetic: Li-Fraumeni (p53), FAP (APC), Lynch syndrome (mismatch repair), BRCA1/2 (breast/ovarian)
Pathophysiology
The adenoma-carcinoma sequence (colorectal cancer model):
- Normal epithelium → APC loss → hyperproliferation → KRAS activation → adenoma → p53 loss → carcinoma → metastasis
Tumour grading: Based on differentiation (G1 well-differentiated to G3/G4 poorly differentiated) Tumour staging: TNM is the most widely used system; stage determines prognosis and treatment
Metastatic cascade: Local invasion → intravasation → survival in circulation → extravasation → colonisation of distant site
Tumour microenvironment: Immune cells, fibroblasts, angiogenesis, extracellular matrix interactions — influences treatment response
Clinical Presentation
General Cancer Presentations
- Unexplained weight loss >5% in 3 months
- Fatigue, night sweats, fever
- Lymphadenopathy (>2cm, hard, non-tender, fixed)
- Paraneoplastic syndromes: Hypercalcaemia (PTHrP), SIADH, Cushing's (ectopic ACTH)
Site-Specific Presentations
- Lung: Cough, haemoptysis, Pancoast syndrome, SVC obstruction
- Breast: Painless lump, skin tethering, peau d'orange, nipple retraction
- Colorectal: Change in bowel habit, rectal bleeding, iron deficiency anaemia
- Prostate: LUTS, bone pain (metastatic)
Red Flags (NICE NG12 — 2-Week Wait Referral)
- Unexplained lump
- Unexplained bleeding
- Unexplained weight loss
- Persistent change in bowel habit (>3 weeks)
- Post-menopausal bleeding
- Dysphagia
- Haematuria
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| Benign tumour | Encapsulated, slow-growing, no invasion | Imaging, biopsy if uncertain |
| Malignant tumour (primary) | Invasion, metastasis, weight loss | Biopsy (histology), staging CT |
| Metastatic disease | Multiple lesions, known primary, weight loss | CT TAP, tumour markers, biopsy |
| Lymphoma | Lymphadenopathy, B symptoms, hepatosplenomegaly | Excisional lymph node biopsy, CT/PET |
| Paraneoplastic syndrome | Hypercalcaemia, SIADH, cerebellar signs without tumour | Tumour markers, CT, antibodies |
| Reactive lymphadenopathy | Tender, soft, associated infection | Observation, biopsy if persistent >6 weeks |
Diagnosis / Investigation
Bedside
- Clinical examination: Lump assessment (site, size, shape, consistency, tethering, lymph nodes)
- Observations: Weight, performance status (ECOG/Karnofsky)
Bloods
- FBC: Anaemia (chronic disease, bone marrow infiltration)
- LFTs: Liver metastases, biliary obstruction
- Calcium: Hypercalcaemia of malignancy
- Tumour markers: PSA, CA-125, CEA, AFP, β-hCG, CA 19-9, LDH
- LDH: Raised in lymphoma, germ cell tumours, melanoma
Imaging
- CT TAP: Primary staging investigation for most solid tumours
- PET-CT: Staging lymphoma, lung cancer; response assessment
- MRI: Local staging (rectal, brain, sarcoma)
- Mammography: Breast cancer screening and diagnosis
- USS: Thyroid, testicular, breast lumps
Special Tests
- Histology/biopsy: Gold standard — core biopsy, excisional biopsy, FNA
- Immunohistochemistry: ER/PR, HER2 (breast), CD markers (lymphoma), Ki-67 (proliferation index)
- Molecular testing: EGFR, ALK, ROS1 (lung), BRAF (melanoma), KRAS (colorectal), microsatellite instability
- Genetic testing: BRCA1/2, Lynch syndrome mismatch repair genes
Management
Non-pharmacological
- MDT discussion (surgeon, oncologist, radiologist, pathologist, CNS)
- Cancer staging and performance status assessment
- Palliative care referral if appropriate
- Psychological support and CNS involvement
Pharmacological
- Chemotherapy: Cytotoxic agents — platinum-based (cisplatin, carboplatin), taxanes (paclitaxel), anthracyclines (doxorubicin), antimetabolites (5-FU, methotrexate)
- Targeted therapy: Trastuzumab (anti-HER2 — breast), imatinib (BCR-ABL — CML), rituximab (anti-CD20 — lymphoma), pembrolizumab (anti-PD-1 — melanoma, lung)
- Hormonal therapy: Tamoxifen (ER+ breast), letrozole (aromatase inhibitor), enzalutamide (prostate)
- Immunotherapy: Checkpoint inhibitors (anti-PD-1, anti-CTLA-4), CAR-T cell therapy
- Radiotherapy: Curative or palliative — external beam or brachytherapy
Surgical
- Curative resection with adequate margins
- Sentinel lymph node biopsy (melanoma, breast)
- Debulking surgery (ovarian)
- Palliative surgery (bypass, stenting)
Referral Criteria
- Any suspected cancer — 2-week-wait pathway (NICE NG12)
- All cancers discussed at MDT
- Genetic risk assessment if strong family history
Prognosis
- Overall cancer survival: 10-year survival approximately 50% (varies widely by cancer type)
- Breast cancer: 5-year survival ~85% (UK); stage I ~98%, stage IV ~15%
- Lung cancer: 5-year survival ~15% (often late presentation)
- Colorectal cancer: 5-year survival ~60%; Dukes A ~93%, Dukes D ~7%
- Prostate cancer: 5-year survival ~86% overall; 10-year ~84%
- Pancreatic cancer: 5-year survival ~7% — poorest of common cancers
- Early detection through screening programmes (breast, cervical, bowel) significantly improves survival
Other Relevant Information
Tumour Nomenclature
| Cell of Origin | Benign | Malignant |
|---|---|---|
| Epithelial (glandular) | Adenoma | Adenocarcinoma |
| Epithelial (squamous) | Papilloma | Squamous cell carcinoma |
| Mesenchymal (bone) | Osteoma | Osteosarcoma |
| Mesenchymal (fat) | Lipoma | Liposarcoma |
| Mesenchymal (smooth muscle) | Leiomyoma | Leiomyosarcoma |
| Lymphoid | — | Lymphoma |
| Haematopoietic | — | Leukaemia |
Paraneoplastic Syndromes
| Syndrome | Associated Cancer | Mechanism |
|---|---|---|
| Hypercalcaemia | Squamous cell lung, breast, myeloma | PTHrP, osteolysis |
| SIADH | Small cell lung | Ectopic ADH |
| Cushing's | Small cell lung, carcinoid | Ectopic ACTH |
| Lambert-Eaton | Small cell lung | Anti-VGCC antibodies |
| Polycythaemia | Renal cell, hepatocellular | Ectopic EPO |