Colorectal polyps, polyposis and Lynch syndrome

• A colorectal polyp is a growth projecting from the bowel lining. Most are harmless, but adenomatous and serrated polyps are the precursors of nearly all colorectal cancers, and removing them prevents cancer.
• Risk rises with size, number and villous features. One or two small tubular adenomas carry a low future risk; larger or villous lesions, or more than a handful, demand earlier repeat colonoscopy.
• After a high-quality examination, guidelines disagree on how soon to look again: one European guideline returns many patients to screening, whereas the US task force still favours 3 to 10 years depending on the findings.
• Polyposis syndromes are genetic conditions that flood the colon with adenomas. Familial adenomatous polyposis (FAP) produces hundreds to thousands, usually from adolescence, and cancer is inevitable without colectomy. MUTYH-associated polyposis is recessive and milder. ^[4]
• Lynch syndrome is the commonest hereditary colorectal cancer syndrome. It comes from a faulty mismatch-repair gene, speeds up the adenoma-to-cancer step, and also raises risk of endometrial, ovarian and other cancers.^[5]

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

1. Classify colorectal polyps by histology and explain which types are precursors of cancer.
2. Outline the adenoma-carcinoma sequence, including its molecular steps and why serrated and Lynch lesions move faster.
3. Assign a post-polypectomy surveillance interval from a colonoscopy report, using both US and European guidance.
4. Recognise FAP and MUTYH-associated polyposis, and state their genetic basis, screening start ages and treatment.
5. Name the Amsterdam II and revised Bethesda criteria and explain the modern universal tumour-screening pathway.
6. Choose a sensible management plan for a person with a mismatch-repair gene mutation, including gynaecological surveillance and surgical options.

A polyp is a discrete mass protruding into the lumen of the bowel. The relevant question is not "is it a polyp?" but "what kind?", because histology determines cancer risk.

Adenomatous (neoplastic) polyps are the classic precursors. Their dysplastic epithelium and disturbed architecture place them on the adenoma-carcinoma pathway.

• Tubular adenoma: the commonest type; dense small tubules, low-grade dysplasia, low malignant potential on its own.
• Tubulovillous adenoma: mixed glands and villous fronds.
• Villous adenoma: broad, leaf-like fronds with a higher rate of high-grade dysplasia and invasive change; often larger and more prolifically secretory.

Serrated lesions look saw-toothed under the microscope. They were once called hyperplastic polyps and ignored; we now know three subtypes.

• Hyperplastic polyp: small, usually in the rectum and sigmoid; very low risk when under 10 mm.
• Sessile serrated polyp/lesion (SSP or SSL): flat, pale, often right-sided, harder to see; the main precursor of "serrated pathway" cancers.
• Traditional serrated adenoma (TSA): uncommon, often left-sided, with both dysplasia and serration.

Inflammatory polyps are regenerative, not neoplastic; they occur in ulcerative colitis and Crohn's disease and are markers of prior inflammation.

Hamartomatous polyps are disorganised native tissue. They occur sporadically and in inherited syndromes: Peutz-Jeghers, juvenile polyposis and Cowden syndromes.

Mesenchymal lesions such as lipomas and leiomyomas arise from the submucosa rather than the epithelium.

The clinically useful shorthand is "advanced adenoma": an adenoma that is at least 10 mm, has villous or tubulovillous histology, or shows high-grade dysplasia. These features predict a higher future risk and therefore shorter surveillance. The US task force coined this term precisely to drive surveillance, and it is the backbone of every interval table below.^[2]

Colorectal cancer is the third most common cancer worldwide. Most colorectal cancers develop from a polyp that sat in the bowel for years before invasion. Heritable factors account for roughly 35% of colorectal cancer risk, yet only 5 to 10% of all colorectal cancers come from a highly penetrant syndrome such as FAP or Lynch syndrome.^[1]

Polyps are common by middle age, and adenomas are more common in men and rise steeply with age.

Risk factors for adenomatous polyps

• Older age (screening begins in middle age in many programmes)
• Male sex
• A family history of colorectal cancer or advanced polyps
• Diet high in red and processed meat, low in fibre; alcohol and smoking
• Obesity, diabetes and the metabolic syndrome
• Inflammatory bowel disease of long duration
• A personal history of adenomas or colorectal cancer

Risk factors for serrated neoplasia overlap but are distinct: smoking, obesity, alcohol and female sex are all prominent, and a right-sided family pattern is common.

The unifying theme is exposure of the colorectal mucosa to carcinogens. Faecal bile acids and short-chain products of red-meat digestion bathe the epithelium, and slow colonic transit in low-fibre diets prolongs exposure. In hereditary disease the substrate is the same, the sponge is faster, because the mucosa already carries the first hit in every cell.

The classical model is Fearon and Vogelstein's adenoma-carcinoma sequence:

1. Initiation. Loss of the APC tumour-suppressor gene on 5q21 allows a single crypt cell to persist and form a microadenoma. Almost all colorectal adenomas carry an APC mutation. This is the "gatekeeper" step.
2. Promotion. An activating K-ras mutation on 12p drives growth and villous change. The lesion enlarges into a small tubular adenoma.
3. Accumulation. Loss of further tumour suppressors (DCC/SMAD4 on 18q, TP53 on 17p) pushes the adenoma through high-grade dysplasia.
4. Invasion. The epithelium breaches the basement membrane and becomes carcinoma, with subsequent spread to nodes and liver.

Each step takes years. That long latency is the entire reason screening polypectomy works.

Serrated cancers do not start with APC loss. Instead:

• an activating BRAF mutation (or, less often, KRAS) produces a hyperplastic polyp;
• widespread CpG island methylation (the CIMP phenotype) silences tumour-suppressor promoters;
• if MLH1 is methylated and silenced, the lesion loses mismatch repair and becomes microsatellite unstable (MSI-high), with the rapid, mucus-rich, right-sided cancer typical of this route.

The two pathways look different down the microscope and produce different cancers, but both are interrupted by complete polypectomy.

In Lynch syndrome every cell already lacks one copy of a mismatch-repair gene (MLH1, MSH2, MSH6, PMS2, or EPCAM, whose deletion silences MSH2). A somatic "second hit" removes the other copy, producing MSI-high tumours with frameshift mutations and the characteristic dense lymphocytic infiltrate. Adenomas that arise here are fewer but progress faster: high-grade dysplasia and villous change are over-represented, and the interval between a clean colonoscopy and cancer can be under three years.^{[5] [2]}

Gross. Pedunculated, sessile or flat; size measured in millimetres. Villous lesions have a shaggy "briar" surface and may secrete large volumes of potassium-rich fluid.

Microscopic. Dysplasia is graded low or high. The World Health Organization definition of high-grade dysplasia replaces the old "carcinoma in situ", which is no longer used as a stage.

Invasion is diagnosed when malignant glands cross the muscularis mucosae into the submucosa. A "malignant polyp" is an adenoma harbouring invasive cancer; if completely excised with favourable histology, local treatment may suffice, but this decision is made by a multidisciplinary team.

Most polyps are silent. This is the central clinical fact of the topic: cancers are prevented by finding polyps before they bleed or obstruct.

When a polyp does declare itself:

• Occult gastrointestinal bleeding with iron-deficiency anaemia; the commonest presentation of a large right-sided lesion.
• Overt rectal bleeding or melaena from a left-sided or rectal lesion.
• Change in bowel habit, constipation or tenesmus from a low rectal or sigmoid mass.
• Abdominal pain or obstruction is rare unless the lesion is large.
• Mucus and potassium-rich diarrhoea from a large villous adenoma, occasionally causing hypokalaemia and dehydration.

Polyposis syndromes may present with rectal bleeding or iron deficiency in adolescence, or be found through cascade testing after a relative's diagnosis. Lynch syndrome is most often discovered only when a cancer develops, which is why universal tumour screening now exists.

When a mass is seen at colonoscopy the main alternatives are colorectal cancer itself, a submucosal lesion (lipoma, carcinoid, GIST), a vascular malformation, or inflammation from diverticular disease or inflammatory bowel disease. A biopsy or complete endoscopic mucosal resection settles the question in almost every case. Where imaging suggests a mass but colonoscopy is normal, consider extraluminal or non-epithelial disease.

Colonoscopy is the diagnostic and therapeutic standard: it visualises the mucosa, allows polypectomy, and obtains histology. Key quality markers, agreed by all societies, are an adequate adenoma detection rate, cecal intubation with caecal photodocumentation, adequate bowel preparation, and complete resection. If the baseline examination is of poor quality, the safest management is to repeat it rather than to enter a surveillance programme built on sand.^[2]

• Faecal immunochemical test (FIT) and guaiac tests screen for cancer in averaged-risk populations; they are not a substitute for colonoscopy after a polyp has been found.
• CT colonography detects large lesions and suits patients who cannot undergo colonoscopy, but it does not permit polypectomy.
• Capsule colonoscopy is emerging for surveillance but is not yet routine.
• Histology is mandatory for every removed polyp; the pathology report dictates the interval.

The modern gateway to Lynch diagnosis is tumour-based. The BSG recommends that every person newly diagnosed with colorectal cancer be tested with immunohistochemistry (IHC) for the four mismatch-repair proteins, or with microsatellite instability (MSI) testing, to find tumours with deficient mismatch repair. Loss of expression on IHC points to the underlying gene, so a single stain panel can target germline testing. Where MLH1 expression is lost, testing the tumour for a BRAF V600E mutation or MLH1 promoter methylation is used to separate Lynch syndrome from sporadic MSI-high cancer due to methylation. Abnormal tumour testing is then followed by germline analysis of the implicated gene, usually after genetic counselling.^[1]

This universal approach has replaced reliance on family history alone, because clinical criteria miss a substantial fraction of carriers.

The US Multi-Society Task Force stratifies post-colonoscopy surveillance by the number, size and histology found on a high-quality baseline examination.^[2]

Serrated lesions carry their own table because their biology differs.^[2]

When the US guideline stratifies by adenoma count, the underlying principle is the same as usual clinical practice: adenoma count is treated as a marker of the whole mucosa's neoplastic tendency, not merely of the individual polyp.

The ESGE update is more restrictive about who needs surveillance at all.^[3]

• Complete removal of 1 to 4 adenomas under 10 mm (low-grade dysplasia, villous components included) or of any serrated polyp under 10 mm without dysplasia: no surveillance, return to screening; if organised screening is unavailable, colonoscopy at 10 years. ^[3]
• At least one adenoma at least 10 mm, high-grade dysplasia, five or more adenomas, a serrated polyp at least 10 mm, or a serrated polyp with dysplasia: surveillance at 3 years. ^[2]
• After a 3-year surveillance that is clean, a second surveillance at 5 years; then return to screening. ^[3]
• Piecemeal resection of a polyp at least 20 mm: early repeat colonoscopy at 3 to 6 months, then again at 12 months. ^[3]
• Stop surveillance from age 80 if life expectancy is reduced. ^[3]
• Surveillance intervals are unchanged by a family history of colorectal cancer.

Amsterdam II criteria (for a family with a hereditary colorectal cancer pattern): at least three relatives with colorectal cancer or another Lynch-associated cancer (endometrium, small bowel, ureter or renal pelvis), one a first-degree relative of the other two; cancer in at least two generations; at least one cancer diagnosed before age 50; familial adenomatous polyposis excluded; tumours verified histologically.^[5]

Revised Bethesda guidelines (to select tumours for MSI testing): colorectal cancer diagnosed in a patient under 50 years; synchronous or metachronous colorectal or other Lynch-associated tumour at any age; MSI-high tumour diagnosed under 60 years; colorectal cancer in a patient with a first-degree relative with a Lynch-associated tumour, one diagnosed under 50; colorectal cancer in a patient with two or more first- or second-degree relatives with Lynch-associated tumours at any age. Lynch-associated tumours include colorectal, endometrial, stomach, ovarian, pancreatic, ureteric, renal pelvic, biliary tract and brain tumours, sebaceous gland adenomas and keratoacanthomas, and small-bowel carcinoma.^[5]

Both sets of criteria are now used less often than universal tumour screening, but they still structure the family-history conversation and select patients for genetic referral when tumour tissue is unavailable.

Older guidance relied on Amsterdam and Bethesda criteria. Current genetics practice favours universal tumour screening, followed by germline testing directed by the IHC pattern, and the use of predictive models (PREMM, MMRpro, MMRpredict) that estimate the probability of a mismatch-repair mutation from personal and family history. A 10% or greater probability of carrying a pathogenic variant is used by some guidelines as the threshold for offering genetic testing, although cut-offs are acknowledged as arbitrary.^[1]

• FAP: classically 100 or more colorectal adenomas, with genetic diagnosis on an APC pathogenic variant. Attenuated forms have fewer, often 10 to under 100 adenomas, and present later. American guidance starts genetic testing at over 10 cumulative adenomas.^[4]
• MUTYH-associated polyposis: typically 10 to 100 adenomas, biallelic MUTYH pathogenic variants, recessive inheritance.
• Multiple colorectal adenomas without a syndrome: 10 or more adenomas prompts gene-panel testing in many pathways, particularly when under 60 or with a strong family history.^[1]

Most polyps are dealt with at the index colonoscopy. The important safety points:

• Complete resection matters more than the tool. A piecemeal approach to a large lesion must be followed by careful margin assessment and a documented short surveillance interval, because incomplete resection leaves substrate for cancer.
• Large sessile lesions should be removed completely; piecemeal resection of an adenoma at least 20 mm requires repeat colonoscopy at 6 months.^[2]
• Malignant polyps (invasive cancer within the adenoma) trigger a multidisciplinary review; whether simple polypectomy suffices depends on margin, grade and lymphovascular invasion.
• Complete removal of all visualised polypoid tissue is what allows surveillance tables to apply at all.^[2]

FAP. Prophylactic colectomy is the only reliable prevention of colorectal cancer. Ileorectal anastomosis (advisable when the rectum is relatively spared) or ileal pouch-anal anastomosis are chosen according to polyp burden in the rectum, sphincter status and patient preference. Timing is guided by polyp size and dysplasia rather than by age alone, because the average age of cancer without surgery is 39.^[4] After colectomy the retained rectum or pouch is surveyed every 1 to 3 years. Duodenal adenomas require lifelong endoscopic surveillance from age 25 with intervention guided by the Spigelman stage. Thyroid, desmoid, dental and retinal (congenital hypertrophy of the retinal pigment epithelium, CHRPE) manifestations require coordinated follow-up. Chemoprevention with COX inhibitors (sulindac, celecoxib) can reduce polyp burden but the BSG notes that the evidence for benefit from chemoprophylaxis in polyposis syndromes is insufficient, so it is not first-line.^[1]

Attenuated FAP behaves like a milder form of the same disease. Colonoscopic surveillance starts 12 to 14 years (or 18 to 20 in some guidance), at 1 to 3 year intervals, and colectomy is timed to polyp burden rather than to a fixed age.^[4]

MUTYH-associated polyposis. Because MAP is recessive, relatives of an affected patient who are themselves affected must inherit biallelic pathogenic variants; siblings and the patient's children may be at risk of being carriers, and carriers themselves need colonoscopic surveillance. The BSG recommends colonoscopy annually from age 18 to 20 years and upper gastrointestinal surveillance from age 35, graded by Spigelman stage.^[1]

Chemoprophylaxis. Daily aspirin reduces colorectal cancer risk in people with Lynch syndrome and is recommended by the BSG; exact dose is a decision for the patient and their clinician, given long-term safety trade-offs. In polyposis syndromes the evidence for chemoprophylaxis is insufficient.^[1]

Surveillance. The BSG and ESGE recommend that mismatch-repair mutation carriers have colonoscopic surveillance every 2 years, starting at age 25 for MLH1 and MSH2 carriers and age 35 for MSH6 and PMS2 carriers.^[1] This is tighter than older Mallorca guidance, which started at 20 to 25 years and favoured an interval of 1 to 2 years, and which found that advanced cancers arose when intervals stretched beyond two years.^[5]

Gynaecological surveillance. Carriers of MMR mutations, and women from families with demonstrated mismatch repair deficiency, should be offered annual transvaginal ultrasound and aspiration biopsy, or at least annual gynaecological review, from age 30 to 35. Prophylactic hysterectomy and bilateral salpingo-oophorectomy should be offered after completion of childbearing, particularly for MSH6 carriers in whom endometrial cancer risk is highest; this substantially reduces site-specific cancer.^[5]

Gastric and urinary surveillance. These are offered where gastric or urinary cancer runs in the family, or in countries with high gastric cancer incidence. Pancreatic or small-bowel surveillance is not supported outside a clinical trial.^[1][5]

Surgical treatment of colorectal cancer. When cancer does arise, a subtotal colectomy with ileorectal anastomosis can be favoured over segmental resection in a young patient (roughly under 50), because the metachronous cancer risk after segmental surgery in an MMR carrier is substantial; the decision also balances bowel function and quality of life, and should be individualised. Rectal cancers can still be treated with standard low anterior resection when this can avoid an abdominoperineal excision.^[1][5]

Other sites. MLH1 and MSH2 carriers have the highest risks of the spectrum of Lynch cancers; MSH6 and PMS2 carriers have lower colorectal but still substantial endometrial risk. Gene-specific risks are described in the guideline.^[1]

• Lynch: colonoscopy every 2 years from the gene-appropriate age until 75; gynaecological review annually from 30 to 35; aspirin for chemoprevention when tolerated. Upper and urinary imaging only if the family history or country of residence warrants it. ^[1]
• After polypectomy in average-risk patients: as per the US and ESGE tables.
• After colectomy in FAP: retained rectum or pouch 1 to 3 years, with duodenal surveillance lifelong.

• Polyposis of unexplained cause, or any young patient with multiple adenomas.
• Tumour IHC showing loss of an MMR protein.
• A family reaching Amsterdam II or revised Bethesda criteria.
• A malignant polyp, or a sessile lesion over 20 mm, for removal by an expert.
• A FAP family needing genetic testing, colectomy or duodenal management.

• Organised colonoscopy may not be available, but FIT-based programmes can still detect cancer earlier, and high-quality colonoscopy with snare polypectomy is the capacity that prevents it.
• Where colonoscopy quality is variable, repeat a suboptimal examination before enrolling patients in surveillance; a poor examination followed by surveillance pretends to safety it cannot deliver.^[2]
• Genetic testing and IHC may be unavailable. The older clinical criteria (Amsterdam II, revised Bethesda) remain a practical sieve, and family-history-driven screening colonoscopy is better than nothing.
• Colectomy for FAP, subtotal colectomy for Lynch cancer and duodenal surveillance in FAP require surgical and endoscopic expertise; refer early, and counsel families about cascade testing.
• In regions where gastric cancer is common, add gastric surveillance to Lynch follow-up; where it is uncommon, do not.

Of adenomas and serrated lesions: bleeding (especially from stalked polyps), anaemia; obstruction if very large; malignant transformation to colorectal cancer.

Of polyposis syndromes: inevitable colorectal cancer in untreated FAP and most untreated MAP; duodenal and ampullary cancer in FAP (the leading cause of death after colectomy); desmoid tumours (sometimes aggravated by surgery), thyroid cancer, brain tumours in children with Turcot variant, osteomas and epidermoid cysts.

Of Lynch syndrome: colorectal cancer (with faster progression than sporadic disease), endometrial cancer, ovarian cancer and the broader tumour spectrum; a high rate of metachronous (second) colorectal cancer after a first cancer if the first operation is segmental.

Of treatment: polypectomy bleeding and perforation; post-colectomy pouch dysfunction, pouchitis and incontinence; chemotherapy resistance of mismatch-repair-deficient tumours to 5-fluorouracil-based regimes (experimental evidence).^[5]

• Sporadic adenomas removed completely rarely recur as the same lesion; the field itself remains at risk, which is what surveillance addresses.
• Untreated FAP produces colorectal cancer in almost all carriers by mid-life; with colectomy and duodenal surveillance, life expectancy approaches but does not reach that of the general population because of duodenal cancer and desmoids.^[4]
• Lynch carriers who follow 2-yearly colonoscopy have a markedly reduced incidence of advanced colorectal cancer and a reduction in colorectal cancer mortality compared with those not under surveillance.^[5]
• For endometrial cancer, prophylactic hysterectomy largely removes the risk; for other Lynch cancers, screening remains imperfect.

• Average-risk screening detects and removes precursor lesions before invasion; colonoscopy is both diagnosis and prevention.
• Polyp removal is cancer prevention when it is complete. A polypectomy is a cheap operation against an expensive cancer.
• Hereditary cascade testing extends prevention to relatives at no extra biology.
• Lifestyle (avoidance of smoking, maintaining a healthy weight, physical activity and moderating red and processed meat) is advised to all at increased familial risk.^[1]
• Gender and gene. Risk-management discussions should be individualised by mutation type, age and family pattern.

Children. Juvenile polyposis presents in childhood with rectal bleeding. FAP surveillance begins in adolescence, because the polyps usually appear from the second decade. Genetic testing is offered only after genetic counselling and, for minors, within a family-based protocol.^[4]

Pregnancy. Colorectal polyps are not accelerated by pregnancy; when a large pedunculated polyp causes bleeding, endoscopic removal is safe in pregnancy with appropriate sedation. Lynch carriers who decline surveillance during pregnancy should resume afterwards.

Older adults. In patients over 80, or with reduced life expectancy, both screening and surveillance may be stopped; ESGE explicitly advises considering cessation from age 80 when life expectancy is reduced.^[3]

Immunocompromised patients, including organ-transplant recipients, have a higher burden of adenomas and a shorter adenoma-to-cancer interval; in practice they are surveyed as if they were high-risk, even without a named syndrome.

• Most colorectal cancers arise from adenomatous or serrated polyps; removing the polyp prevents the cancer.
• An advanced adenoma means size at least 10 mm, villous or tubulovillous histology, or high-grade dysplasia. These features shorten surveillance.^[2]
• Hyperplastic polyps under 10 mm are very low risk; sessile serrated and traditional serrated adenomas matter and are easily missed, especially in the right colon.^[2]
• US and European surveillance tables differ: one European guideline returns many small-polyp patients to screening, while the US task force keeps 3 to 10 year intervals.^[2][3]
• FAP gives hundreds to thousands of adenomas from adolescence, an APC mutation, and near-certain cancer without colectomy; relatives start colonoscopy at 12 to 14 years, at 1 to 3 year intervals, with duodenal surveillance from 25.^[1][4]
• MUTYH-associated polyposis is recessive, usually shows 10 to 100 adenomas, and is colonoscoped annually from 18 to 20 years.^[1]
• Lynch syndrome accounts for a substantial minority of hereditary colorectal cancer; mismatch-repair failure accelerates the adenoma-carcinoma sequence, so colonoscopy is 2-yearly, gene-stratified (25 years for MLH1/MSH2, 35 for MSH6/PMS2).^[1][5]
• Universal tumour immunohistochemistry or MSI testing of every colorectal cancer is now the gateway to Lynch diagnosis.^[1]
• Amsterdam II and revised Bethesda criteria still structure family-risk assessment and select tumours for MSI testing.^[5]
• Endometrial, ovarian and other cancers dominate women's risk in Lynch syndrome; hysterectomy and salpingo-oophorectomy after childbearing, plus aspirin, are the evidence-supported additions.^[1][5]
• Polyposis syndromes are managed by expert centres: colectomy in FAP, surveillance and surgery timed to polyp burden, duodenal staging, and counselling of relatives.

Colorectal cancer; colorectal cancer screening; inflammatory bowel disease; juvenile polyposis syndrome; Peutz-Jeghers syndrome; Cowden syndrome; Gardner syndrome; gastric cancer surveillance; endometrial cancer; chemoprevention of colorectal cancer.