Peutz-Jeghers Syndrome Management

Introduction to Peutz-Jeghers Syndrome

• Peutz-Jeghers Syndrome (PJS) is characterized by mutations in the STK11 gene, leading to dysregulation of the AKT-mTOR signaling pathway, with a family history of PJS found in 70% of cases and 30-70% of sporadic cases, as noted by the American Gastroenterological Association 1
• The American College of Medical Genetics recommends that PJS patients have a dramatically increased cancer risk, with an overall relative risk for all cancers of 15.2 times the general population and a lifetime risk of any cancer of 93% 1

Clinical Characteristics

• Patients with PJS often present with characteristic mucocutaneous pigmentation, hamartomatous polyps throughout the gastrointestinal tract, and onset of symptoms between ages 10-30 years, with common presenting complaints including intestinal obstruction, abdominal pain, and blood in stool 1
• Specific cancer risks include gastrointestinal cancers, breast cancer, gynecological cancers, and lung cancer, with breast cancer risk comparable to BRCA1/2 carriers 1

Diagnostic Approach

• The American College of Medical Genetics recommends complete sequencing of the STK11 gene coding area for diagnosis, with testing costs approximately $975-$1400 for proband identification 1

Surveillance and Screening

• The American Gastroenterological Association recommends upper endoscopy and colonoscopy beginning at age 8-10 years, repeated every 2-3 years, and small bowel surveillance starting at age 8-10 years using video capsule endoscopy or MRI enterography 1
• Breast cancer screening should begin at age 25-30 with annual mammography and breast MRI, and gynecologic cancer screening should begin at age 25-30 with annual pelvic examination, transvaginal ultrasound, and CA-125 1
• Annual testicular examination should begin at age 10, as recommended by the American Gastroenterological Association 1

Management of Polyps and Cancer

• Endoscopic removal of symptomatic polyps or polyps >1.5 cm is recommended, as well as intraoperative endoscopy during laparotomy for small bowel polyps, and standard cancer treatments based on cancer type and stage should be used, with consideration of mTOR inhibitors for STK11-related tumors 1, 2

Preventive Measures and Genetic Counseling

• Genetic counseling should be offered to all patients with PJS who are considering having children, addressing the high degree of intrafamilial variability in disease severity, and first-degree relatives of patients with PNETs associated with known hereditary syndromes should be offered genetic testing for the specific pathogenic variant identified in the affected family member, as recommended by the National Comprehensive Cancer Network 3, 4
• Consider prophylactic mastectomy for women with very high breast cancer risk and prophylactic hysterectomy and oophorectomy after childbearing is complete, as recommended by the American Gastroenterological Association 1
• The following table summarizes the recommended surveillance and screening for PJS patients:

3, 5

Risk-Reducing Strategies and Treatment

• Risk-reducing strategies for high-risk individuals include smoking cessation, weight management, and consideration of pancreatic cancer surveillance in specialized centers, as recommended by the National Comprehensive Cancer Network 6, 7
• The National Comprehensive Cancer Network recommends first-line platinum-based chemotherapy (FOLFIRINOX preferred) due to defects in DNA damage repair, with maintenance PARP inhibitors following response to platinum-based therapy, and consider immune checkpoint inhibitors (pembrolizumab) for patients with pancreatic cancer 3, 6
• Targeted therapies, such as TRK inhibitors for NTRK fusions, ROS1/ALK fusions, and BRAF inhibitor combinations for BRAF mutations, should be considered, as recommended by the Journal of Clinical Oncology 6