Guideline sources The following summarized guidelines for the evaluation and management of peutz-Jeghers syndrome (PJS) are prepared by our editorial team based on guidelines from the European Society of Gastrointestinal Endoscopy (ESGE 2023; 2019), the American Society for Gastrointestinal Endoscopy (ASGE 2022), the US Multi-Society Task Force on Colorectal Cancer (USMSTF 2022), the European Hereditary Tumour Group (EHTG 2021), the American Gastroenterological Association (AGA 2020), the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN 2019), the European Society of Medical Oncology (ESMO 2019), and the American College of Gastroenterology (ACG 2015). 1 2 3 4 5 6 7 8 9 Guidelines 1. Screening and diagnosis Indications for testing: As per USMSTF 2022 guidelines, evaluate for PJS in patients with characteristic mucocutaneous pigmentation and a family history of PJS. B https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 1/8 6/29/23, 11:08 PM Peutz-Jeghers syndrome Pathway As per EHTG 2021 guidelines, consider evaluating for PJS in adult patients with isolated typical perioral pigmentation or a confident diagnosis of a solitary polyp. C As per ACG 2015 guidelines, evaluate for PJS in patients with perioral or buccal pigmentation and/or 2 histologically characteristic gastrointestinal hamartomatous polyps or a family history of PJS. E 2. Diagnostic investigations Genetic testing: As per USMSTF 2022 guidelines, obtain genetic testing in patients with any of the following: 2 histologically confirmed Peutz-Jeghers polyps any number of Peutz-Jeghers polyps in the presence of a family history of PJS in a first- degree relative characteristic mucocutaneous pigmentation in the presence of a family history of PJS any number of Peutz-Jeghers polyps in the presence of characteristic mucocutaneous pigmentation. B As per EHTG 2021 guidelines, obtain genetic germline testing of the STK11 gene in patients meeting clinical diagnostic criteria for PJS, regardless of age. Diagnose PJS in patients meeting clinical criteria, even if an underlying causative germline variant is not identified. B Show 3 more As per ACG 2015 guidelines, obtain genetic testing for mutations in the STK11, SMAD4, and BMPR1A genes in patients with possible PJS. E Screening for hereditary hemorrhagic telangiectasia: consider obtaining cardiovascular assessment for and evaluation for HHT in SMAD4 mutation carriers. C 3. Diagnostic procedures Baseline upper and lower GI endoscopy: As per USMSTF 2022 guidelines, consider performing a baseline upper and lower gastrointestinal endoscopy between the ages of 8 and 10 years, at the time of capsule placement for small bowel surveillance or when polyps are identified on MR enterography. C As per ESGE 2019 guidelines, perform a baseline upper and lower gastrointestinal endoscopy at the age of 8 years in asymptomatic patients with PJS. B Baseline small bowel evaluation: obtain small bowel evaluation with video capsule endoscopy or MR enterography between the ages of 8 and 10 years, or earlier if symptomatic. B 4. Surgical interventions Indications for polypectomy: https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 2/8 6/29/23, 11:08 PM Peutz-Jeghers syndrome Pathway As per ESGE 2023 guidelines, perform device-assisted enteroscopy with polypectomy in patients with large (> 15 mm) or symptomatic polyps discovered on imaging or during small bowel capsule endoscopy. B As per USMSTF 2022 guidelines, perform polypectomy of symptomatic or 10 mm small bowel polyps to prevent intussusception and other complications, such as bleeding. B As per ESGE 2019 guidelines: Perform elective polypectomy of small bowel polyps > 15- 20 mm to prevent intussusception. Remove smaller polyps causing obstructive symptoms. B Perform device-assisted enteroscopy for the removal of polyps. Consider performing intraoperative enteroscopy depending on the phenotype. B Indications for colectomy: perform colectomy with ileorectal anastomosis or proctocolectomy with ileal pouch-anal anastomosis for polyp-related symptoms or when the polyps cannot be managed endoscopically. B Management of intussusception: Refer patients with an episode of acute severe abdominal pain and/or suspicion of intussusception to a surgical unit, preferably a dedicated center. Perform emergency surgery (even in diagnostic intent) if small bowel intussusception is not ruled out after clinical and diagnostic evaluation. B Dessuscept, if safe to do so, for the treatment of intussusception. Perform enterotomy with resection of the (pedunculated) polyp at the base to remove the polyp acting as a hypomochlion. Inspect the entire small bowel for further relevant polyps and remove all polyps > 15 mm by enterotomy or intraoperative enteroscopy. Prefer an enterotomy in between polyps, depending on the distance between the polyps, allowing for the removal of multiple polyps via one enterotomy. B 5. Specific circumstances Pediatric patients (clinical assessment): Do not diagnose PJS solely based on the presence of lip and mucosal freckling. Refer patients with lip and mucosal freckling suggestive of PJS to a geneticist for diagnostic genetic testing. D Assess male patients with PJS for signs of large-cell calcifying Sertoli cell tumors of the testes, including gynecomastia. Refer patients with large-cell calcifying Sertoli cell tumors to a pediatric endocrinologist. B Pediatric patients, genetic testing: As per EHTG 2021 guidelines, obtain genetic germline testing of the STK11 gene in pediatric and adolescent patients with typical perioral pigmentation or one Peutz-Jeghers polyp. B As per ESPGHAN 2019 guidelines, obtain predictive genetic testing in asymptomatic at-risk patients from the age of 3 years, and earlier in symptomatic at-risk patients. B Pediatric patients, upper and lower GI evaluation: As per EHTG 2021 guidelines: https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 3/8 6/29/23, 11:08 PM Peutz-Jeghers syndrome Pathway Perform a baseline upper and lower gastrointestinal endoscopy at the age of 8 years in asymptomatic patients with PJS. Repeat these investigations every 1-3 years, depending on the phenotype, if polyps are detected at baseline endoscopy. Perform routine upper and lower gastrointestinal endoscopy at the age of 18 if the baseline endoscopy is negative. B Obtain small bowel surveillance either MRI or video capsule enteroscopy every 1-3 years, depending on the phenotype, starting from the age of 8 years in asymptomatic patients with PJS. B As per ESPGHAN 2019 guidelines, obtain gastrointestinal surveillance with upper and lower gastrointestinal endoscopy and video capsule endoscopy no later than 8 years in asymptomatic patients with PJS, unless symptoms arise earlier. Repeat these investigations every 3 years, or earlier in case of symptoms. Individualize timing for gastrointestinal surveillance and provide adequate counseling regarding the age to commence gastrointestinal surveillance. B Pediatric patients (screening for anemia): do not obtain routine Hgb testing in pediatric patients with PJS. Consider obtaining Hgb testing in symptomatic patients. D Pediatric patients (pharmacotherapy): do not offer pharmacological agents for the treatment or chemoprevention of PJS. D Pediatric patients (indications for polypectomy): perform elective polypectomy to prevent polyp-related complications. Remove small bowel polyps > 1.5-2 cm in size (or smaller if symptomatic) electively to prevent intussusception. Use endoscopic, surgical, or combined approaches on a case-by-case basis, depending on the site and size of the polyp and available endoscopic expertise. B Pediatric patients (management of intussusception): refer patients with symptomatic intussusception urgently for surgical reduction. B Show 2 more Pediatric patients (surveillance for malignancy): recognize that cancer in pediatric patients with PJS is an extremely rare event. Obtain routine assessment for features of sex cord tumors. B 6. Preventative measures Prophylactic pancreatectomy: do not perform prophylactic pancreatectomy because of its significant morbidity and potential mortality, even in experienced hands. D Show 2 more Prophylactic mastectomy: do not perform prophylactic mastectomy in female patients with PJS. Discuss risk-reducing mastectomy in a multidisciplinary setting, taking the family history and other clinical factors into consideration. D 7. Follow-up and surveillance Setting of surveillance: As per ESGE 2019 guidelines, conduct surveillance of patients with hereditary gastrointestinal polyposis syndromes, including PJS, in dedicated units providing monitoring https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 4/8 6/29/23, 11:08 PM Peutz-Jeghers syndrome Pathway of compliance and endoscopic performance measures. B As per ACG 2015 guidelines, conduct surveillance of patients with a genetic predisposition for pancreatic cancer, including PJS, ideally in experienced centers utilizing a multidisciplinary approach and under research conditions. B Surveillance for malignancy, upper and lower GI tract: As per USMSTF 2022 guidelines: Obtain upper and lower gastrointestinal endoscopy surveillance every 2-3 years if characteristic polyps are detected on baseline evaluation. B Obtain upper and lower gastrointestinal endoscopy surveillance at the age of 18 years, or sooner if symptoms occur, and then every 3 years if there are no Peutz-Jeghers polyps at baseline. B As per EHTG 2021 guidelines: Perform upper or lower gastrointestinal endoscopy earlier rather than waiting for routine surveillance in case of symptoms. B Do not obtain routine endoscopic surveillance in patients with a confident diagnosis of a solitary Peutz-Jeghers polyp. D As per ESGE 2019 guidelines: Obtain upper and lower gastrointestinal endoscopy surveillance starting at the age of 18, at an interval of 1 -3 years based on the phenotype, if the baseline endoscopy is negative. B Obtain upper and/or lower gastrointestinal endoscopy earlier than the planned surveillance procedure if the patient is symptomatic. B As per ESMO 2019 guidelines, obtain surveillance for gastric and colorectal cancer with upper and lower gastrointestinal endoscopy every 1-3 years, starting at the age of 8, in patients with PJS. B As per ACG 2015 guidelines, obtain surveillance for stomach and colon cancer in patients with or at risk of PJS. B Surveillance for malignancy, small bowel: As per ESGE 2023 guidelines, obtain small bowel surveillance with small bowel capsule endoscopy and/or MR enterography, depending on local availability and expertise and/or patient preference, in patients with PJS. B As per USMSTF 2022 guidelines: Obtain small bowel surveillance with video capsule endoscopy or MR enterography between the ages of 8 and 10 years. Resume surveillance at age 18 if no polyps are found at the initial evaluation. Continue small bowel surveillance in adulthood throughout life every 2-3 years because of the risk of small bowel intussusception. B Obtain small bowel evaluation earlier if the patient is symptomatic. B As per EHTG 2021 guidelines: Obtain small bowel evaluation earlier rather than waiting for routine surveillance in case of symptoms. B Do not obtain routine endoscopic surveillance in patients with a confident diagnosis of a solitary Peutz-Jeghers polyp. D As per ESGE 2019 guidelines: https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 5/8 6/29/23, 11:08 PM Peutz-Jeghers syndrome Pathway Obtain small bowel surveillance with either MRI studies or video capsule enteroscopy from the age of 8 years, at an interval of 1 - 3 years based on phenotype, in asymptomatic patients with PJS. B Obtain small bowel evaluation earlier than the planned surveillance procedure if the patient is symptomatic. B As per ESMO 2019 guidelines, obtain small bowel surveillance with capsule endoscopy or MRI enterography every 1-3 years, starting at the age of 8, in patients with PJS. B As per ACG 2015 guidelines, obtain surveillance for small bowel cancer in patients with or at risk of PJS. B Surveillance for malignancy, pancreas: As per ASGE 2022 guidelines, consider obtaining annual screening for pancreatic cancer with EUS, including when it can be combined with screening upper or lower gastrointestinal endoscopy, in patients with PJS, starting from the age of 35 years or 10 years earlier than the youngest relative with pancreatic cancer. Consider obtaining MRI when it can be combined with other imaging, such as enterography. C As per USMSTF 2022 guidelines, consider obtaining annual surveillance for pancreatic cancer with either MRCP or EUS starting at the age of 35 years. C As per AGA 2020 guidelines, consider obtaining surveillance for pancreatic cancer in patients with PJS. C As per ESMO 2019 guidelines, obtain annual surveillance for pancreatic cancer with EUS or MRI, starting at the age of 30, in patients with PJS. B As per ACG 2015 guidelines, obtain surveillance for pancreatic cancer in patients with or at risk of PJS. B Surveillance for malignancy, breast: As per EHTG 2021 guidelines, obtain surveillance for breast cancer in female patients with PJS, including the following: raising awareness at the age of 18 years, such as by starting breast self-examination clinical breast examination every 6-12 months starting at the age of 25 years annual breast contrast-enhanced MRI screening (or breast ultrasound if MRI is contraindicated or not available) at the age of 25-30 years annual mammogram with consideration of tomosynthesis and ultrasound for dense breast and annual breast contrast MRI at the age of 30-50 years annual mammogram with consideration of annual breast contrast MRI for dense breast pattern at the age of 50-75 years individualize further surveillance in patients aged > 75 years. B As per ACG 2015 guidelines, obtain surveillance for breast cancer in patients with or at risk of PJS. B Surveillance for malignancy, gynecological: As per EHTG 2021 guidelines, offer expert gynecological surveillance in female patients with PJS irrespective of the family history of gynecological cancer because the estimated lifetime risk of specific gynecological tumors is 18-50%. B Show 3 more https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 6/8 6/29/23, 11:08 PM Peutz-Jeghers syndrome Pathway As per ACG 2015 guidelines, obtain surveillance for ovarian, uterine, and cervical cancers in patients with or at risk of PJS. B Surveillance for malignancy, testes: obtain surveillance for testicular cancer in patients with or at risk of PJS. B Surveillance for malignancy, lung: insufficient evidence to recommend specific screening for lung cancer in patients with or at risk of PJS, although the risk for lung cancer is increased. Consider obtaining an annual CXR or chest CT in smokers. I Clinical findings Symptoms Past medical history Abdominal pain Breast cancer Cervical cancer Head and neck exam Colorectal cancer Endometrial cancer Oral pigmentation Lower gastrointestinal bleeding Perioral hyperpigmentation Ovarian cancer Integument exam Pancreatic cancer Sertoli cell tumor Palmar hyperpigmentation Small bowel cancer Pigmented macules Stomach cancer Plantar hyperpigmentation Abdominal exam Hematological findings Signs of bowel obstruction Anemia Lab findings Endoscopic findings FOBT Colorectal polyps Genetic testing Stk11 gene mutation References 1. Monique E van Leerdam, Victorine H Roos, Jeanin E van Hooft et al. Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy ESGE Guideline. Endoscopy. 2019 Sep;51 9 877 895. Open 2. Anja Wagner, Stefan Aretz, Annika Auranen et al. The Management of Peutz-Jeghers Syndrome: European Hereditary Tumour Group EHTG Guideline. J Clin Med. 2021 Jan 27;10 3 473. Open 3. Sapna Syngal, Randall E Brand, James M Church et al. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 Feb;110 2 223 62; quiz 263. Open https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 7/8 6/29/23, 11:08 PM Peutz-Jeghers syndrome Pathway 4. Andrew Latchford, Shlomi Cohen, Marcus Auth et al. Management of Peutz-Jeghers Syndrome in Children and Adolescents: A Position Paper From the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 2019 Mar;68 3 442 452. Open 5. Marco Pennazio, Emanuele Rondonotti, Edward J Despott et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy ESGE Guideline Update 2022. Endoscopy. 2023 Jan;55 1 58 95. Open 6. N Stjepanovic, L Moreira, F Carneiro et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019 Oct 1;30 10 1558 1571. Open 7. Mandeep S Sawhney, Audrey H Calderwood, Nirav C Thosani et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. Gastrointest Endosc. 2022 May;95 5 817 826. Open 8. C Richard Boland, Gregory E Idos, Carol Durno et al. Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi- Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2022 Jun 1;117 6 846 864. Open 9. Harry R Aslanian, Jeffrey H Lee, Marcia Irene Canto. AGA Clinical Practice Update on Pancreas Cancer Screening in High-Risk Individuals: Expert Review. Gastroenterology. 2020 Jul;159 1 358 362. Open https://web.pathway.md/diseases/recJ5MuisNFBsu8rH 8/8