Classification of polyposis syndromes two major groups. Adenomatous polyposis syndromes. Hamartomatous polyposis syndromes

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Bertram Wilkerson
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1 Hereditary polyposis syndromes Classification of polyposis syndromes two major groups adenomatous and non-adenomatous polyposis syndromes Adenomatous polyposis syndromes Familial adenomatous polyposis(fap) Attenuatedfamilial adenomatouspolyposis(afap) MUTYH (MYH)-associated polyposis(map) Hamartomatous polyposis syndromes Peutz-Jeghers syndrome(pjs) Juvenile polyposis(jp) Cowden syndrome(cs)

Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Prevalence: 1 in 10.

Extraintestinal manifestations Colonic manitestations Presence of > 100 colonic adenomatous polyps Polyp

2 Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Prevalence: 1 in individuals Clinical characteristics Colonic manifestations Extracolonic manifestations in the GI tract Extraintestinal manifestations Colonic manitestations Presence of > 100 colonic adenomatous polyps Polyp development usually starts in the distal colorectum at an average age of 15y Nearlyall patientswithuntreatedfap developcrc bytheageof40

adenomasoftheduodenum, partii an III) Lifetime risk for duodenal cancer 4-12 % Jejunal

3 Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Extracolonic manifestations Upto90 % ofpatientsdeveloppolypsin theupper GI tract (oftenflat adenomasoftheduodenum, partii an III) Lifetime risk for duodenal cancer 4-12 % Jejunal polyps in 55%, ileal polyps in 18% of patients Fundic gland polyposis (30-40%) Gastricadenomas (5-10%, antrum)

4 Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Extraintestinal manifestations Desmoid tumors(10-20 %) Epidermoid cysts(30-50%) Fibromas and osteomas Dental abnormalities Congenital hypertrophy of the retinal pigment epithelium(chrpe, 70%)

5 Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Gardner`s syndrome Combination of polyposis, epidermoid cysts and osteomas Turcot s syndrome Combination of polyposis and tumours of the CNS Genetics Autosomal dominant inherited disease Germline mutation of the APC gene in chromosome 5 mutations detectable in 80 % of patients with FAP New or de novo mutations are responsible for25 % offap cases

6 Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Surveillance Surveillance is recommended for first-degree relatives of index patients with FAP if the mutation has been verified or if the mutational status is unclear Screening procedures for polyposis of the lower gastrointestinal tract polyposis of the upper gastrointestinal tract extraintestinal manifestations Screening procedures for polyposis of the lower gastrointestinal tract AGArecommendscompletecolonoscopyevery1-2 y beginningattheageof10-12 Deutsche S3-Richtlinie: rectosigmoidoscopyannuallyinitiatedattheageof10-12; if adenomas are diagnosed complete colonoscopy annually

Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Screening procedures for polyposis of the upper gastrointestinal tract AGA: EGD (incl.

7 Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Screening procedures for polyposis of the upper gastrointestinal tract AGA: EGD (incl. side-viewing endoscopy) every 1-3 y starting at the age of Deutsche S3-Richtlinie: EGD every1-3 y startingattheageof30 Whenadenomasareobserved, screeningintervalsshouldbeshortenedto1-2 years depending on the severity of polyposis(spigelman staging criteria) Screening procedures for extraintestinal manifestations Annual ultrasoundofthethyroidglandan abdomenstartedattheageof10-12 years is recommend to screen for thyroid cancer and desmoid tumours

8 Hereditary polyposis syndromes- Familial adenomatous polyposis(fap) Treatment Polyposis of the lower GI tract Prophylactic surgery is performed in the majority of patients before the age of 20 Colectomy sould be considered when > 20 adenomas develop, when adenomas > 1 cm arefoundorwhenadvancedhistologyappear Polyposis of the upper GI tract(optimal treatment is unclear) Endoscopic resection(often limited by the number of polyps and their sessile formation) Surgical intervention

Hereditary polyposis syndromes- attenuated FAP Approximately10% offap patientspresentwithan attenuatedform offap Clinical characteristics Colonic manifestations Extracolonic manifestations Colonic

9 Hereditary polyposis syndromes- attenuated FAP Approximately10% offap patientspresentwithan attenuatedform offap Clinical characteristics Colonic manifestations Extracolonic manifestations Colonic manifestations colorectal polyps with a predominance in the proximal colon Tendency to polyp and CRC development at a later age; AFAP is mostly diagnosed in patients older than 45 years Without therapeutic interventions the estimated CRC risk is 70-80% Extraintestinal manifestations Desmoid tumours Epidermoid cysts Fibromas and osteomas(mandibula) Dental abnormalities, CHRPE

10 Hereditary polyposis syndromes- attenuated FAP Genetics Mode of inheritance: Autosomal dominant inherited disease APC germline mutations are detected in % with AFAP Surveillance Polyposis of the lower gi tract: Patients should always be screened by colonoscopy(frequency of proximal colonic polyps) every 1-2 years, beginning in the late teenage years Polyposis of the upper gi tract: Patients EGD every 1-3 y starting at the age of (including side-viewing endoscopy) Screening procedures for extraintestinal manifestations Annual ultrasound of the thyroid gland an abdomen

11 Hereditarypolyposissyndromes-attenuatedFAP Treatment Approximately 33 % of patients with AFAP can be managed during the long-term with endoscopy and polypectomy(because of small polyp numbers) 66 % require colectomy (if polyposis cannot be controlled by repeated polypectomies)

12 Hereditary polyposis syndromes- MUTYH-associated polyposis(map) Accounts for< 10 % ofearly-onsetcrc Clinical characteristics Colonic manifestations Multiple colorectal adenomas and carcinoms(phenotype difficult to distinguish from FAP/AFAP) Negative family history Most patients older than 45 years at diagnosis(most patients detected by symptoms rather than screening, 50 % with CRC) Adenomatous polyps predominate, hyperplastic polyps are common Extracolonic manifestations Gastricandduodenal polyps in 11 and17 % FAP-associated extracolonic features do not occur Increased risk for ovarian, bladder, skin, sebaceous gland tumors, possible brest cancer

Hereditary polyposis syndromes- MUTYH-associated polyposis(map) Genetics Autosomal recessive inherited disease Biallelic mutations in MUTYH can be identified in 10-20% with APC-mutation-negative FAP

13 Hereditary polyposis syndromes- MUTYH-associated polyposis(map) Genetics Autosomal recessive inherited disease Biallelic mutations in MUTYH can be identified in 10-20% with APC-mutation-negative FAP and AFAP Twohotspotmutationsrepresenting80 % ofall mutations(y165c and G382d) Germline mutation testing is indicated in patients with 10 or more adenomas after exclusion of an APC mutation Surveillance Colonoscopyevery2-3 y, beginningatage25 y EGD every1-3 y startingattheageof20-25 y Treatment Prophylactic colectomy when endoscopic management becomes problematic (large polyps, high grade dysplasia)

14 Hereditary polyposis syndromes- Juvenile polyposis syndrome(jps) Rare polyposis syndrome characteried by multiple hamartomatous polyps of the colorectum(98%), stomach(13%) and the small bowel(6%) Definition Fiveormorejuvenile polypsin thecolonorrectum; or One juvenile polyp and postive family history of JP, or Juvenils polyps outside the colon or rectum(stomach or small bowel, any number) Clinical presentation Twoforms: - Juvenile polyposis of infancy -Congenitalabnormalities(cardiovascular, urogenital orcns abnormalities, 15 % of patients) - Diarrhoea, haemorrhage, malnutrition and intussusception - Generalized juvenile polyposis/juvenile polyposis coli - usuallypresentlaterin childhoodoradult life(median ageat diagnosis 35-40y)

Cancer risk -Life-time riskforcrc of39 % -Increasedriskforstomach, duodenal, pancreaticcancer(noformal

15 Hereditary polyposis syndromes- Juvenile polyposis syndrome(jps) Pedunculated, smooth and lobulated polyps with an vulnerable surface Histology - Large cistically dilated mucus glands - Acutely inflamed lamina propria Cancer risk -Life-time riskforcrc of39 % -Increasedriskforstomach, duodenal, pancreaticcancer(noformal riskanalysis) Genetics - Autosomal dominant inherited disease -GermlinemutationsoftheSMAD4 andbmr1a in about50-60% ofpatients

16 Hereditary polyposis syndromes- Juvenile polyposis syndrome(jps) Surveillance and treatment (based on expert opinion) ColonoscopyandEGD in patientsatriskorwithhighsuspicionofjps at age15 orattime offirstsymptoms AtdiagnosisofJPS, theentiregi tractshouldbeexaminedforthe presence of polyps(capsule endoscopy, MR enteroclysis) In provenjps : EGD, colonoscopyandcapsuleendoscopy/mr enteroclysis every two years to detect and remove polyps Prophylactic surgery if polyposis unmanageable by endoscopy(number ofpolyps, dysplasia, severegi bleeding, diarrhoea) in patientswithstrong family history of cancer

Hereditary polyposis syndromes Peutz-Jeghers syndrome Incidence: 1/50000-1/120000 Definition and clinical

patients) PJ polyps: predilection for the small bowel Diagnostic criteria -twoormorepj polyps - one PJ polyp

Duodenum Histology: - extensive smooth muscle aborization throughout the polyp Symptoms occur in adolescence

17 Hereditary polyposis syndromes Peutz-Jeghers syndrome Incidence: 1/ / Definition and clinical characteristics Peutz-Jeghers polyps and mucocutaneous melanin pigmentation (pigment lesions in 95% of patients) PJ polyps: predilection for the small bowel Diagnostic criteria -twoormorepj polyps - one PJ polyp and mucocutaneous pigment lesion -onepj polypandpositive familyhistoryofpjs Jejunum Ileum Colon Rectum Stomach Duodenum Histology: - extensive smooth muscle aborization throughout the polyp Symptoms occur in adolescence and young adulthood - abdominal pain due to intussusception - occult bledding and iron-deficiency anemia - intestinal obstruction

18 Hereditary polyposis syndromes Peutz-Jeghers syndrome Cancerrisk: -85% bytheageof70-70% for gastrointestinal cancer(crc 39 %, panceratic cancer %, gastric cancer29%) - increased risk for gynaecologic neoplasia(breast 50 %), thyroid gland and lung Genetics - autosomal dominant inherited desease -germlinemutationofthestk 11 tumoursuppressorgene(detection rate 94%) Surveillance and treatment no evidence-based guidelines - Biannual EGD and colonoscopy and screening for small bowel polyps (startingattheageof12) - endoscopic resection of polyps - endoendovaginal ultrasound examination initiated at the age of 18 -screeningforbreastandpancreaticcancerstartedattheageof25

19 Hereditary polyposis syndromes Cowden syndrome(cs) Definition and clinical characteristics Intestinal hamartomatous polyposis(stomach, colon, oesophagus) -Juvenile polyps, lipomas, inflammatorypolyps, ganglioneuromas, lymphoid hyperplasia Cutaneous hamartomas(facial trichilemmomas, oral papillomas, hyperkeratotic skin lesions) and oesophageal glycogenic akanthosis Increased lifetime risk for breast cancer(50%) and thyroid cancer(10-20%) Gastrointestinal cancer risk is not increased Genetics Autosomal dominantly inherited disease Germline mutations of the tumour suppressor gene PTEN (approximately 80% of patients) Surveillance Should focus on breast and thyroid cancer

Familial Adenomatous Polyposis

Familial Adenomatous Polyposis 1 in 10,000 incidence 100 s to 1000 s of colonic adenomas by teens Cancer risk: colon, gastric, duodenum (periampulla), small bowel, pancreas, papillary thyroid, childhood