Cancer biology: precursor lesions and tumour associations

• Cancer is not one disease but many; what the cancers share is uncontrolled growth and spread, acquired step by step through genetic and epigenetic change.
• Most cancers arise from normal tissue through a visible intermediate: a precursor such as Barrett oesophagus, a tubular adenoma or cervical intraepithelial neoplasia, which is where screening earns its living.
• A precursor is not a sentence of cancer: most never progress, and some regress, so finding one raises a risk, it does not settle it.
• Paraneoplastic syndromes are remote effects of a cancer: fever, hormone excess, neurological syndromes and clots that can appear before the tumour is found.
• Tumour markers help monitor known cancer and its treatment; they are poor screening tests because they are neither sensitive nor specific enough on their own.
• Screening works best where the precursor is slow, stereotyped and removable - cervical and colorectal cancer are the success stories.
• In a low-resource setting, visual inspection, basic pathology and clinical follow-up of persistent symptoms do most of the work.

By the end of this page you should be able to:

1. Explain carcinogenesis as a multistep process involving oncogenes, tumour suppressor genes, DNA repair genes and the hallmarks of cancer.
2. Distinguish hyperplasia, dysplasia, carcinoma in situ and invasive cancer.
3. List the common precursor lesions and name the cancer each tends to lead to.
4. Recognise the typical paraneoplastic syndromes, the cancers behind them and the clues that separate them from non-paraneoplastic disease.
5. State what tumour markers can do in practice and why they are not used for mass screening.
6. Outline the principles a screening programme must satisfy before it is introduced.
7. Adapt precursor and marker work to a setting with limited tests or drugs.

Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body. ^[1] It starts almost anywhere, because the damaged instructions are inside the cell's own DNA. The body usually eliminates damaged cells before they turn cancerous, but that ability weakens with age, which is one reason cancer becomes commoner later in life. ^[1] Tumours can be benign or malignant; only malignant ones invade and spread.

A precursor lesion is an abnormal tissue change that is known to sit on the pathway to a particular cancer and that raises a person's risk of that cancer. ^[3] The word is broader than it sounds: it covers metaplasia (one mature cell type replacing another after chronic injury), hyperplasia, dysplasia and carcinoma in situ. A paraneoplastic syndrome is a set of signs and symptoms produced at a distance from the tumour by something the tumour secretes or by the immune response it triggers, not by invasion or metastasis. ^[4] A tumour marker is anything present in or produced by cancer cells, or made by the body in response to them, that gives information about the cancer. ^[2]

Cancers are usually named for the cell type and the organ: carcinomas from epithelial cells (by far the most common), sarcomas from bone and soft tissues, leukaemias from blood-forming marrow, lymphomas from lymphocytes, melanoma from melanocytes. ^[1] Precursors matter mainly for the carcinomas and for melanoma, because those are the cancers that pass through recognisable non-invasive stages.

Cancer is the second leading cause of death worldwide after cardiovascular disease; the global figures quoted in the premalignant-disease literature (more than 14 million deaths in 2012) refer to an older data set and are only a context. ^[3] Precursor lesions are diagnosed far more often than the cancers they could become: physicians diagnose premalignant disease at frequencies that substantially exceed those of clinical cancers. ^[3] That single observation explains the two big pitfalls of precursor medicine - overdiagnosis (finding lesions that would never have caused harm) and overtreatment (treating them anyway). Most precancerous lesions remain benign through life. ^[3]

Geography matters. Cervical and colorectal cancer screening has driven large falls where it is organised; elsewhere the same numbers still rise. Low-resource settings carry a disproportionate share of cancers that are curable if found early, because the curable precursor is reached late or never.

Carcinogenesis is the accumulation of genetic and epigenetic change in a single cell lineage over time. ^[1][3] Three families of gene are the usual targets. Risk factors that push this process along are the familiar ones: ageing, tobacco, alcohol, chronic inflammation, persistent viral infection (human papillomavirus, hepatitis B and C, Helicobacter pylori, Epstein-Barr virus), radiation and many chemical carcinogens. Specific mechanism links matter more than lists:

• HPV high-risk strains drive most cervical precursor lesions. ^[3]
• H. pylori drives intestinal metaplasia of the stomach. ^[3]
• Chronic reflux drives Barrett oesophagus.
• Chronic ultraviolet exposure drives actinic keratosis and Bowen disease of the skin.
• HIV-related immunosuppression favours Kaposi sarcoma and non-Hodgkin lymphoma; this is an association through immune failure rather than a fixed precursor.

The dominant theory is multistep carcinogenesis: a sequential accumulation of DNA damage and epigenetic modification that gradually hands a cell the capabilities it needs to become a cancer. ^[1][3] Large studies of skin cells show that even healthy, sun-exposed tissue carries putative driver mutations at densities of around 140 per square centimetre, and 10 per cent of adults over 65 carry multiple somatic mutations in blood cells. ^[3] A clone carrying these changes is not the same as cancer; selection, context and further events decide the outcome. In ulcerative colitis, driver mutations in TP53 can be found in tissue that has not yet become dysplastic, but they exert a selective advantage mainly in a chronically inflamed microenvironment. ^[3]

Proto-oncogenes control normal cell growth and division. When altered, or more active than normal, they can become oncogenes: cancer-causing genes that let cells grow and survive when they should not. ^[1] Activation is usually dominant at the cellular level: a single altered allele is enough, through point mutation, gene amplification, chromosomal translocation or rearrangement. RAS and MYC are the textbook examples. The practical point for a student is that an oncogene is not a new, foreign gene; it is a normal growth gene stuck in the "on" position.

Tumour suppressor genes are also involved in controlling cell growth and division; cells with certain alterations in these genes may divide in an uncontrolled manner. ^[1] They usually work recessively at the cellular level, fitting the classic two-hit model built from retinoblastoma: both copies must be inactivated by mutation or deletion before the brake is lost. TP53 and RB1 are the familiar ones. In normal cells, tumour suppressor genes prevent cancer by slowing or stopping cell growth, so DNA changes that inactivate them lead to uncontrolled cell growth and cancer. ^[1]

The third class is the DNA repair genes. When they fail, the cell accumulates extra mutations and chromosome abnormalities (duplications, deletions), which can then hit oncogenes and tumour suppressors; mismatches in these genes are why some families develop cancer early. ^[1] Genomic instability is often called an enabling hallmark, because it makes all the others possible.

Cancer cells differ from normal cells in many ways, and these differences are the hallmarks: they grow without external growth signals, ignore stop and death signals (apoptosis), invade and spread, recruit blood vessels, hide from or subvert the immune system, accumulate chromosome changes and alter their metabolism. ^[1] Seeing cancer as the gradual acquisition of these capabilities, rather than as a single jump, is what makes precursors intelligible: a low-grade dysplasia has some of the changes, a high-grade lesion more, and invasive cancer most, although the order is not as tidy as the classroom diagram implies. ^[3]

Not every change is cancer, and these labels are worth keeping straight. ^[1]

• Hyperplasia: extra cells that still look normal and are organised normally; often a response to chronic irritation.
• Dysplasia: extra cells that look abnormal, with disordered tissue architecture. The more abnormal they look, the greater the chance that cancer will form.
• Carcinoma in situ: a full-thickness replacement by abnormal cells that have not invaded the basement membrane. It is sometimes called stage 0 cancer, but it is not cancer; because some cases progress, it is usually treated.

Field cancerisation is an important related idea: a whole patch of mucosa or skin can carry early changes, so a new tumour can appear next to a treated one even when the first was removed completely. ^[3]

A robust and honest table is the heart of this topic. The left column is the precursor state; the right is the cancer it most often feeds. Local anatomy sections sit behind each row, and sections of this page pull them together.

A few rows deserve comment rather than silence.

• Cervical dysplasia. Cervical cells infected by oncogenic HPV can become cervical intraepithelial neoplasia (CIN), which can progress to cervical cancer if untreated; many lower-grade lesions are cleared by the immune system, and 40 per cent of CIN grade 2 lesions regress. ^[3][6] Precursor, not verdict.
• Colonic adenoma. Adenomas are the classic precursor of colorectal cancer. The progression time is long enough that removing one prevents a future cancer; correspondingly perhaps 30 per cent of small polyps never progress and may regress. ^[3][6]
• Chronic atrophic gastritis. The usual chain is chronic H. pylori gastritis to atrophy to intestinal metaplasia to dysplasia to gastric adenocarcinoma (intestinal type), which is why treating the infection and surveillance are both useful. ^[3]
• Barrett oesophagus. Nondysplastic Barrett metaplasia progresses to adenocarcinoma in roughly 0.25 per cent of patients a year; high-grade dysplasia inside Barrett tissue carries around 6 per cent per year. ^[3] That is a tenfold or greater jump, and it is why high-grade dysplasia is treated, not just watched.
• Actinic keratosis. The annual risk of squamous skin cancer in a person with actinic keratosis has been estimated anywhere from under 1 per cent to 80 per cent depending on the study, a spread that should make anyone cautious about a single number; actinic keratosis is nonetheless a real precursor. ^[3]
• Cirrhosis and hepatitis B or C. Hepatocellular carcinoma usually arises in an already damaged liver; the virus and the cirrhosis act together. Antiviral treatment lowers risk but does not remove it, because the field of damaged liver remains.
• Ulcerative colitis. Risk rises with duration and extent of disease and is higher with a damaged segment; Crohn colitis is a weaker but real association. ^[3]
• HIV. The link to Kaposi sarcoma and non-Hodgkin lymphoma is via immune failure; restoration of immunity changes the picture.
• Thymoma. Not a precursor lesion in the usual sense, but it earns its place here because it is the tumour most students first meet in an associations list: myasthenia gravis, red cell aplasia and hypogammaglobulinaemia cluster with it.

Paraneoplastic syndromes are remote effects of cancer. ^[4] They are not metastases: they are caused by tumour secretion (hormones, peptides, cytokines) or by immune cross-reactivity between the tumour and normal tissues. ^[4] They can precede the cancer diagnosis, especially the neurologic ones, which is why recognising them sometimes finds an otherwise occult tumour early. ^[4] They affect up to 8 per cent of cancer patients overall. ^[4]

The classic groupings are endocrine, neurologic, dermatologic, rheumatologic and haematologic. The first-line approach to most of them is to treat the underlying tumour; many improve or resolve when the tumour shrinks, although some neurologic damage is permanent.

Two sequencing points matter for exams. Paraneoplastic neurologic syndromes are detected before the cancer in 80 per cent of cases, and because onconeural damage can be permanent, treatment often stabilises rather than cures. ^[4] And Trousseau syndrome is the one paraneoplastic problem you treat with unfractionated or low-molecular-weight heparin while investigating the tumour, not with warfarin alone. ^[5]

A tumour marker is anything produced by cancer cells, or made by the body in response to them, that informs care: diagnosis confirmation, type, stage, prognosis, choice of targeted treatment, response to treatment, and detection of recurrence. ^[2] Some markers belong to one cancer (prostate-specific antigen for prostate cancer, thyroglobulin for thyroid cancer), others are raised in several (carcinoembryonic antigen, CA 19-9, CA 125). ^[2]

The central teaching point is their limits. An elevated marker does not mean cancer is present; non-cancerous conditions can raise it, and not everyone with a given cancer has a higher level. ^[2] Measurements are therefore combined with biopsy and imaging rather than used alone. ^[2] On top of that, early cancers usually release only tiny amounts, so sensitivity is poor at the stage where finding them matters, and many markers are elevated by benign conditions, so specificity is poor too. No single marker suits all, and in practice a panel is often needed to cover different tumour types. Levels also vary with age, sex, comorbidity and assay method.

One point about screening: circulating tumour markers have generally not worked as screening tests, because they are not sensitive enough (they miss people with disease) and not specific enough (they flag people without it). ^[2] That is why current practice combines them with clinical findings, imaging and tissue diagnosis, and why marker use in an asymptomatic person is a research question, not routine care. Multi-cancer detection blood tests are under study on exactly this problem. ^[2]

The goal of cancer screening is to find early-stage cancer or precursor lesions in people without symptoms, at a point in the disease course where treatment is more likely to cure. ^[6] That simple idea collides with a complex reality, and Wilson and Jungner's 1968 criteria (proposed for the WHO) still organise thinking about whether a screening programme should exist at all: ^[6]

1. The condition must be an important public-health problem.
2. There must be an accepted treatment, and facilities to deliver it.
3. There must be a recognisable early or latent stage.
4. There must be a suitable test that is acceptable to the people screened.
5. The natural history of the condition must be well understood.
6. There must be an agreed policy on whom to treat, and case-finding must be continuous rather than one-off.
7. Cost must be balanced against the whole health budget.
8. Benefit must outweigh harm, including the harms of false positives, false negatives, overdiagnosis and overtreatment.

Modern experience has added four lessons. ^[6] First, the biology of invasive cancer ranges from indolent to aggressive, so the test should target progressive, potentially lethal disease rather than anything it can find. Second, not every precursor is an obligate precursor - most are not; treating them all means overtreatment. Third, effective screening removes advanced disease, so population registries should track stage shift, not just case counts. Fourth, people do not benefit equally, so the target population should be defined by risk and expected lifespan rather than by age alone.

Examples from population experience show the spread. Cervical and colorectal screening work best, because their precursors are slow and removable; mammography and PSA find indolent disease as well as dangerous disease, and have therefore been followed by real debate and revised guidelines. ^[6] Lung cancer screening with low-dose CT in heavy smokers has shown a roughly 16 per cent relative reduction in lung-cancer-specific mortality in trial populations. ^[6]

A precursor page on its own is thin. These associations only become useful when they are read against the chapters on the organ systems named above:

• Hepatocellular carcinoma and chronic liver disease (cirrhosis, hepatitis B and C) - how surveillance ultrasound and alpha-fetoprotein fit with the degree of fibrosis.
• Gastric cancer and peptic disease - the H. pylori test-and-treat strategy, and how to manage intestinal metaplasia once it is found.
• Colorectal cancer and inflammatory bowel disease - colonoscopy intervals after a diagnosis of colitis, and how a polyp found at screening is managed.
• Cervical cancer and sexually transmitted infection - how HPV vaccination and cytology or HPV testing fit together.
• Oesophageal cancer and reflux disease - when a Barrett segment is treated endoscopically and when it is just watched.
• Skin and lip cancers and dermatology - cryotherapy, topical therapy or excision for actinic keratosis, and the biopsy rule for Bowen disease.
• Oral and head-and-neck cancer - the threshold for biopsy of a white or red patch that will not clear.
• Breast, prostate, lung, thyroid, bladder and gynaecological cancers - where screening tests sit in each, and where they do not.

Where the organ chapter makes a different staging or management point, the organ chapter wins on treatment; this page wins on the shared biology.

• Knowledge of the precursor chain is cheaper than any scanner. Recognising that a "mitral stenosis" murmur that changes with posture, or a cervical erosion that bleeds on contact, or a persistent throat white patch, might be the first step in a cancer chain costs nothing.
• VIA (visual inspection with acetic acid) and a simple colposcope, where they exist, can transform cervical outcomes; HPV testing on self-collected samples is expanding access. The principles, not a particular brand, are what matter here.
• H. pylori test and treat where testing is available; if only urea breath or stool antigen are present, use them.
• Basic pathology - biopsy for any persistent oral, cervical, gastric or skin lesion - is the backbone. The skill to take a biopsy and get it read is more valuable than a new marker.
• Clinical follow-up of symptoms that do not fit (persistent painless jaundice, progressive dysphagia, altered bowel habit after 50) brings patients to investigation earlier than screening in many settings.
• Cost is not just money: time to travel, a day's lost wages and anxiety about a positive test. Programmes that ignore these have low uptake and high loss to follow-up.
• Where treatment (endoscopic resection, surgery, radiotherapy) is not available locally, build the referral pathway first, then the screening programme.

• Cancer is a multistep genetic and epigenetic disease: oncogenes accelerate, tumour suppressor genes lose their braking function, DNA repair genes let mutations pile up.
• Hyperplasia, dysplasia and carcinoma in situ are the visible stages before invasion; carcinoma in situ is not cancer.
• Precursors are common and usually harmless: most never progress and some regress.
• The common precursors each have a favoured cancer - actinic keratosis and Bowen disease to squamous cell carcinoma, Barrett oesophagus to adenocarcinoma, atrophic gastritis to gastric adenocarcinoma, colonic adenoma to colorectal cancer, cirrhosis with hepatitis B or C to hepatocellular carcinoma, ulcerative colitis to colorectal cancer, cervical dysplasia to cervical cancer, oral leukoplakia to oral cancer.
• HIV-related immune failure predisposes to Kaposi sarcoma and non-Hodgkin lymphoma; thymoma clusters with myasthenia gravis.
• Paraneoplastic syndromes are remote effects: hypercalcaemia, SIADH, ectopic Cushing, Lambert-Eaton, dermatomyositis, Trousseau-type hypercoagulability, each with characteristic tumours.
• Tumour markers inform care in known cancer but are poor screening tests; an elevated result is not a diagnosis.
• Screening succeeds where the precursor is slow and removable; population criteria (Wilson and Jungner) still govern whether a programme should exist.
• Preview the organ chapters for what to do once a precursor is found.

Hepatocellular carcinoma; gastric cancer; colorectal cancer; cervical cancer; oesophageal and gastric disorders; skin cancers and melanoma; oral and head-and-neck cancers; breast cancer; prostate cancer; lung cancer; bladder and renal cancer; pancreatic cancer; hypercalcaemia; SIADH; hypercoagulable states; leukaemia; lymphoma; multiple myeloma; Kaposi sarcoma; HIV infection; thymoma; metastatic cancer overview.