Screening

All patients with a personal and/or family history of Peutz-Jeghers syndrome (PJS) should be offered genetic counseling and genetic testing. Genetic testing should be utilized to confirm the clinical diagnosis in those patients who satisfy the diagnostic criteria for PJS.[18]​ Genetic testing is also recommended for those with a pathogenic or likely pathogenic (P/LP) STK11 variant detected by tumor genomic testing on any tumor type in the absence of germline analysis.[22]​ If there are existing genetic test results, repeated genetic testing is generally unneeded unless there is uncertainty about an existing result: for example, the result is inconsistent with the patient’s clinical presentation or the test methodology has changed or significantly advanced.[25][26]

Genetic testing for at-risk family members

After appropriate genetic counseling and informed consent, testing for at-risk family members may be performed for those individuals with a family history of PJS and an identified STK11 mutation. Given the pediatric manifestations of PJS, genetic testing of at-risk children should not be delayed until adulthood. It should be recognized that while most patients will have an affected parent, approximately 25% of patients have de novo mutations.[8] Even if the mutation is thought to be de novo, the first-degree relatives of patients with PJS should be carefully evaluated for features of PJS (gastrointestinal polyps or mucocutaneous pigmentation), and they should be offered genetic testing. Whether inherited or de novo, all children of the proband have a 50% risk of inheriting the mutation and should be offered genetic testing. If the familial pathogenic variant is not found in family members, then routine cancer surveillance should be offered. 

Cancer surveillance screening for patients with PJS

Cancer screening and surveillance is indicated in all individuals with PJS.

Limited data exist regarding the efficacy of the various cancer surveillance modalities for patients with PJS. Guidelines for cancer screening are largely based on expert opinion.

Gastrointestinal cancer

US and European guidelines, along with consensus statements, make the following recommendations regarding gastrointestinal surveillance:[17][18][22][27][28][30]​​[41][42]

  • Video capsule endoscopy (VCE) or computed tomography/magnetic resonance enterography (CTE or MRE) of the small bowel should begin by age 8 years (or earlier if the patient is symptomatic). Capsule endoscopy is safe to use in individuals with PJS and small bowel polyposis who do not have obstructive symptoms. If a concern for capsule retention is present, a patency capsule should be utilized. If no polyps are found at the initial exam, US guidelines recommend that small bowel surveillance should resume at age 18 years and continue every 2-3 years throughout life, whereas European guidelines advise repeating surveillance every 3 years from the outset.

  • Esophagogastroduodenoscopy (EGD) and colonoscopy to look for upper gastrointestinal and colorectal polyps should be done by age 8 years (or earlier if the patient is symptomatic). If polyps are found, both exams are repeated every 2-3 years; if no polyps are detected, a subsequent baseline exam is conducted at age 18 years, and every 2-3 years thereafter.

Breast cancer

The lifetime risk of breast cancer in women with PJS varies from 32% to 54% to as high as 40% to 85%, which is similar to rates seen with BRCA-1 and BRCA-2 mutations.[18][22]

The US Multi-Society Task Force on Colorectal Cancer advises monthly breast self-exam starting at age 18 years, biannual clinical breast exam starting at age 25 years, annual breast magnetic resonance imaging (MRI) starting from ages 25 to 29 years, and mammography with consideration of tomosynthesis (3-dimensional mammography) alternating every 6 months with breast MRI with contrast from ages 30 to 75 years.[18]​ The National Comprehensive Cancer Network (NCCN) recommends mammogram and MRI annually starting at approximately age 30 years.[22]​ Given the variance in the lifetime risk of breast cancer, guidelines differ regarding the frequency of clinical breast exams, with the US Multi-Society Task Force on Colorectal Cancer recommending them every 6 months from age 25 years and the NCCN recommending them every 6-12 months starting at age 30 years​.[18][22]​ Prophylactic mastectomy can be considered on a case-by-case basis.[18]

Pancreatic cancer

Pancreatic cancer is the third most common malignancy (after breast and colorectal) in people with PJS, with an 11% to 36% lifetime risk of pancreatic ductal adenocarcinoma.[18][22]​​ Surveillance via endoscopic ultrasound (EUS) and/or MRI or magnetic resonance cholangiopancreatography (MRCP) is recommended. The International Cancer of the Pancreas Screening Consortium recommends pancreatic imaging every 1-2 years starting from age 40 years.[18][43]​​ The NCCN recommends annual imaging of the pancreas with either EUS or MRI/MRCP beginning at age 30-35 years (with earlier initiation if there is a family history of pancreatic cancer; the NCCN suggests starting 10 years younger than earliest age of onset in the family).[22]​ The US Multi-Society Task Force on Colorectal Cancer also advises annual pancreatic imaging starting at age 35 years.[18]

Gynecological cancers

The lifetime risks for ovarian, uterine, and cervical cancer are estimated at 21%, 9%, and 10% to 23%, respectively.[18] Guidelines differ with regard to the recommended age at which screening with pelvic exam, cervical smear, and transvaginal ultrasound should start, with the NCCN advising a starting age of approximately 18-20 years and other societies a later starting age of 25 years.[8][22]

Almost all ovarian cancers in patients with PJS are sex cord tumors with annular tubules (SCTAT). These tumors can cause irregular menstruation and precocious puberty. Annual physical exam to check for precocious puberty is recommended, starting at the time of diagnosis, as well as yearly pelvic exam and pelvic ultrasound from the age of 18-20 years.[8][22]

For uterine cancer surveillance, annual pelvic exam is recommended from ages 18 to 25 years. The American College of Gastroenterology (ACG) advises annual transvaginal ultrasound beginning at age 25 years.[8] The NCCN does not recommend routine ultrasound screening, but advises annual pelvic exam from ages 18 to 20 years and endometrial biopsy in the presence of abnormal bleeding.[22]

A high proportion of cervical cancers in patients with PJS are minimal deviation adenocarcinoma (formerly known as adenoma malignum), a rare, well-differentiated adenocarcinoma that is difficult to detect with liquid-based cytology and has a poor prognosis. Guidelines recommend annual pelvic exam and liquid-based cytology from the age of 18-25 years (again, guidelines differ with regard to the age at which this should start).[8][18][22]​ The NCCN also advocates consideration of total hysterectomy once a woman has completed her family.[22]

Testicular cancer

Male patients with PJS have a 9% lifetime risk of developing Sertoli cell tumors, with a mean age at diagnosis of 9 years.[18][22]​​[41]​ Annual testicular exam and observation for feminizing changes is recommended, with follow-up testicular ultrasound if abnormalities are detected. The US Multi-Society Task Force on Colorectal Cancer advises screening from birth, whereas the NCCN recommends starting at the time of diagnosis.[18][22]

Lung cancer

The estimated lifetime risk of lung cancer in patients with PJS is 7% to 17%.[8] Guidelines differ in recommendations for surveillance. The US Multi-Society Task Force on Colorectal Cancer and NCCN simply recommend educating patients about symptoms and smoking cessation.[18][22] However, the American College of Chest Physicians, American Society of Clinical Oncology, and American Cancer Society advise low-dose computed tomography (CT) annually from ages 55 to 74 years (based on the level of cumulative risk in patients with PJS, which is similar to people with a more than 30 pack-year history of smoking who have quit for 10-15 years).[18]

The evidence to support these recommendations is not robust. It is the opinion of the authors that surveillance should be individualized based on phenotype, expected age and incidence of disease, and family history. [Figure caption and citation for the preceding image starts]: Small bowel hamartomatous polyp identified on capsule endoscopyFrom the collection of Dr Carol A. Burke, used with permission [Citation ends].com.bmj.content.model.Caption@50e4c288

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