For education and revision only. Not individual medical advice; check current NICE/BNF and local guidance before clinical use. Clinical safety and terms.
Pathology: Neoplasia - tumour biology, spread, staging and markers
🩻 Neoplasia - tumour biology, spread, staging and markers. About 1 in 2 people in the UK will develop cancer in their lifetime. Understanding how tumours arise (carcinogens, oncogenes and tumour suppressors), how they are classified, how they invade and spread, and how they are graded and staged underpins early diagnosis, the interpretation of pathology reports, and the logic of treatment and screening. Your four questions: Is the lesion benign or malignant? What is its cell of origin (carcinoma, sarcoma, lymphoma, melanoma, germ cell)? What are its grade and stage (TNM)? Which molecular features predict prognosis and guide treatment?
Definitions and Nomenclature
Neoplasm - "an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of normal tissue, and persists after cessation of the stimulus" (Willis). Monoclonal - derived from a single cell.
Tumour (swelling) is used interchangeably; cancer means a malignant neoplasm.
Tissue of origin
Benign
Malignant
Glandular epithelium
Adenoma
Adenocarcinoma
Squamous epithelium
Squamous papilloma
Squamous cell carcinoma
Transitional epithelium (urothelium)
Transitional papilloma
Urothelial carcinoma
Fibrous tissue
Fibroma
Fibrosarcoma
Fat
Lipoma
Liposarcoma
Smooth muscle
Leiomyoma (fibroid)
Leiomyosarcoma
Skeletal muscle
Rhabdomyoma
Rhabdomyosarcoma (children)
Bone
Osteoma
Osteosarcoma (adolescents)
Cartilage
Chondroma
Chondrosarcoma
Blood vessels
Haemangioma
Angiosarcoma
Melanocytes
Naevus
Melanoma
Germ cells
Mature teratoma (dermoid cyst)
Seminoma, embryonal carcinoma, immature teratoma
Haematopoietic
-
Leukaemia, lymphoma, myeloma
Misleading names - lymphoma, melanoma, seminoma, mesothelioma and glioma are all malignant despite "-oma".
Hamartoma - disorganised mass of mature tissue native to the site (lung hamartoma - popcorn calcification; Peutz–Jeghers polyps); choristoma - normal tissue in the wrong place (ectopic pancreas).
Benign tumours can still be dangerous - by location (meningioma compressing the brain, pituitary adenoma), hormone secretion (insulinoma, phaeochromocytoma, parathyroid adenoma), obstruction (intussusception from a polyp), haemorrhage, or malignant transformation (colorectal adenoma).
Mesothelioma (latency 30–50 years), lung cancer (multiplicative with smoking)
Aflatoxin (Aspergillus on stored grain and nuts)
Hepatocellular carcinoma
Vinyl chloride
Hepatic angiosarcoma
Benzene
AML
Arsenic
Skin, lung, bladder, liver angiosarcoma
Nitrosamines (processed meat, smoked foods)
Stomach, colorectal
Alkylating chemotherapy, etoposide
Secondary leukaemia (MDS/AML)
Oestrogen (unopposed, HRT, obesity)
Endometrium, breast
Physical carcinogens:UV radiation (UVB - basal cell carcinoma, SCC, melanoma - the commonest cancers in the UK), ionising radiation (atomic bombs and Chernobyl - leukaemia, thyroid cancer in children; radiotherapy - secondary breast cancer after mantle radiotherapy for Hodgkin lymphoma, sarcomas; radon - lung cancer).
Biological carcinogens: HPV, EBV, HHV-8, hepatitis B and C, HTLV-1 (viruses - see Virology); H. pylori (gastric adenocarcinoma, MALT lymphoma); Schistosoma haematobium (bladder SCC); liver flukes (Clonorchis, Opisthorchis - cholangiocarcinoma).
Chronic inflammation - ulcerative colitis, chronic hepatitis, Barrett's, Marjolin's ulcer (SCC in a chronic scar or ulcer), PSC (cholangiocarcinoma).
Obesity - the second biggest preventable cause in the UK (endometrium, oesophageal adenocarcinoma, kidney, colorectal, postmenopausal breast, pancreas, liver).
Proto-oncogenes - normal genes promoting growth; activated to oncogenes by point mutation, amplification or translocation; gain of function - one allele is enough (dominant at cellular level).
Tumour suppressor genes - normally restrain growth or repair DNA; loss of function - both alleles must be inactivated (Knudson two-hit hypothesis): TP53 (about 50% of cancers; Li–Fraumeni), RB1 (retinoblastoma, osteosarcoma), APC (FAP and most sporadic colorectal cancers - first step in the adenoma–carcinoma sequence), BRCA1/2, VHL (von Hippel–Lindau - renal clear cell carcinoma, haemangioblastoma, phaeochromocytoma), NF1/NF2, PTEN (Cowden), WT1 (Wilms'), CDKN2A/p16 (familial melanoma, pancreatic), MEN1, CDH1 (E-cadherin - hereditary diffuse gastric and lobular breast cancer), SMAD4/DPC4 (pancreatic, juvenile polyposis), STK11 (Peutz–Jeghers).
Adenoma–carcinoma sequence (Vogelstein): normal mucosa → APC loss → early adenoma → KRAS activation → late adenoma → TP53 loss (and SMAD4) → carcinoma.
Breast (lifetime 60–85%), ovarian (BRCA1 about 40%), male breast and prostate (BRCA2), pancreatic; MRI surveillance, risk-reducing surgery; PARP inhibitors
Lynch syndrome
MLH1, MSH2, MSH6, PMS2
Colorectal, endometrial, ovarian, gastric, urothelial; MMR testing on all colorectal and endometrial cancers
Familial adenomatous polyposis
APC
Hundreds to thousands of colonic adenomas → near 100% colorectal cancer by 40 without prophylactic colectomy; duodenal cancer, desmoids, CHRPE (retinal pigment patches)
MUTYH-associated polyposis
MUTYH (recessive)
Attenuated polyposis
Li–Fraumeni
TP53
Sarcomas, breast, brain, adrenocortical carcinoma, leukaemia - avoid radiation where possible
Signet ring gastric cancer, lobular breast cancer - prophylactic gastrectomy
Clues to hereditary cancer - young age at diagnosis, multiple primaries, bilateral tumours, several affected relatives in successive generations, rare tumours (male breast cancer, adrenocortical carcinoma), specific ancestry (Ashkenazi Jewish BRCA founder variants).
Invasion - loss of cell adhesion (E-cadherin), breach of the basement membrane (matrix metalloproteinases), migration (epithelial–mesenchymal transition).
Routes of spread:
Local - direct invasion (perineural spread - head and neck, pancreas, prostate; adenoid cystic carcinoma).
Lymphatic - typical of carcinomas; to regional nodes - sentinel lymph node biopsy (breast, melanoma); Virchow's node (left supraclavicular - gastric cancer, Troisier's sign), Sister Mary Joseph nodule (umbilical - intra-abdominal cancer).
Haematogenous - typical of sarcomas (also renal cell carcinoma, HCC, follicular thyroid, choriocarcinoma); to the first capillary bed reached: lungs (from systemic veins), liver (from portal drainage - colorectal, gastric, pancreatic).
Transcoelomic - across body cavities (ovarian cancer → peritoneum, omentum - ascites; Krukenberg tumour - ovarian metastasis from signet ring gastric cancer; pleural spread; pseudomyxoma peritonei from appendiceal mucinous tumours).
Iatrogenic - needle tracts, port sites (rare).
"Seed and soil" - organ tropism: bone metastases from breast, prostate (sclerotic), lung, kidney and thyroid (lytic - "BLT with Kosher Pickle"); brain - lung, breast, melanoma, kidney, colorectal; liver - colorectal, pancreas, stomach, breast, lung; adrenal - lung.
Commonest tumours in some organs are metastases - liver, lung, bone, brain, adrenal.
Metastatic cancer of unknown primary - immunohistochemistry (CK7/CK20, TTF-1 lung and thyroid, CDX2 GI, PAX8 renal and gynae, GATA3 breast and urothelial, PSA prostate) and imaging guide the search.
Immune surveillance - T cells and NK cells recognise tumour antigens (neoantigens from mutations, viral antigens, cancer-testis antigens). Cancer is commoner with immunosuppression (transplant - skin SCC, post-transplant lymphoproliferative disorder; HIV - Kaposi, lymphoma, cervical and anal cancer).
Immune evasion - PD-L1 expression, loss of MHC I, regulatory T cells, immunosuppressive microenvironment. Checkpoint inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA-4) and CAR-T cells exploit immunity; tumours with high mutational burden or MSI-high respond best.
How tissue diagnosis is made:
Cytology - fine needle aspiration (thyroid nodules, lymph nodes, breast), fluid cytology (pleural effusion, ascites), cervical cytology (now after HPV-positive screen). Cells only - cannot confirm invasion.
Scenario. A colorectal cancer resection report reads: "moderately differentiated adenocarcinoma, pT3 pN1b (2/18) M0, R0, extramural venous invasion present, MMR proficient." Interpret.
Answer: Grade - moderately differentiated. Stage - tumour invades through the muscularis propria into pericolorectal tissue (T3), 2 of 18 nodes involved (N1b), no distant metastasis - stage III. Margins clear (R0). EMVI is an adverse feature. MMR proficient - Lynch unlikely and immunotherapy not indicated. Stage III → offer adjuvant chemotherapy (e.g. CAPOX).
Scenario. Why is a tumour's stage generally more important than its grade for prognosis?
Answer: Stage describes the extent of spread (local, nodal, distant), which largely determines curability and survival; grade reflects biological aggressiveness and influences treatment within a stage, but a low-grade cancer that has metastasised still has a worse prognosis than a high-grade localised one in most tumour types.
Scenario. A 35-year-old woman with breast cancer has a mother with ovarian cancer and a sister with breast cancer at 42. What should be offered?
Answer: Referral to clinical genetics for germline testing (BRCA1, BRCA2, PALB2 and related genes - NHS National Genomic Test Directory criteria met). A positive result affects her treatment (risk-reducing surgery, PARP inhibitors) and allows cascade testing of relatives.