Difficult scientific evaluation of rare disease management: Peutz–Jeghers syndrome

Peutz–Jeghers syndrome (PJS) is a very rare (probably < 1 person per 100 000) autosomal dominant polyposis syndrome first described as a case report in the early 1920 s by Dutch internist Jan Peutz. The main diagnostic features of the syndrome are polyposis of the upper and lower digestive tract, with small-bowel predominance, and the presence of pigmented macules on lips and oral mucosa (melanosis). The rarity of PJS justifies the management of patients in a few expert centers, as recommended by the most recent European Society of Gastrointestinal Endoscopy (ESGE) guidelines published in 2019 [1].

“...this study illustrates the difficulty of improving knowledge in rare diseases”

Medical management of PJS reflects the high risk of mechanical complications arising from digestive polyps (i. e. intussusception) that may begin in early childhood, and a cumulative risk of cancer, which is estimated at 93 % between the ages of 15 and 64 years [2]. This high risk of cancer, especially in women, is explained by the numerous cancer sites related to the syndrome, not only the whole digestive tract, from esophagus to colon, but also gynecological tumors (adenoma malignum, ovarian granulosa tumors), breast adenocarcinoma, pancreatic adenocarcinoma, pulmonary adenocarcinoma, and Leydig cell tumor.

In this issue of Endoscopy, Khurelbaatar et al. report their experience of endoscopic management of small-bowel hamartomas in nine patients with PJS [3]. This study contributes valuable information to the limited data available in the literature and evaluates a polypectomy technique in this patient cohort. There are two main reasons for performing hamartoma resection in the small bowel of PJS patients. The first reason relates to the significant risk of hemorrhage and intussusception in patients, which necessitates early detection of polyps during childhood (40 % cumulative risk of intussusception at 20 years of age) [4]. Follow-up by capsule endoscopy is recommended at or before 8 years of age [1], or even earlier (from 4 years) when symptoms are present according to European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) and UK recommendations [5] [6]. Thus, very early genetic diagnosis is proposed for PJS to identify the 50 % of children in a family who could bear the germline mutation. The second reason relates to the cumulative risk of cancer, which although lower in the small bowel (13 % risk for 15 – 64 years) is much higher for the stomach (29 %) and colon (39 %) [2]. The risk of cancer in each small-bowel polyp is low, with only 16 % of hamartomas presenting foci of dysplasia; however, there is a 30 % risk of high grade dysplasia or cancer in polyps > 20 mm compared with 1.3 % in polyps < 20 mm [7] [8].

The best way to reduce the risk of both intussusception and cancer in patients with PJS is probably the surveillance (capsule endoscopy, magnetic resonance imaging) and clearance of large polyps, as recommended by the ESGE working group [1]. The size thresholds justifying resection have been estimated to be 20 mm for prevention of dysplasia and cancer, and 15 mm to avoid intussusception (mean size 34 mm, range 15 – 50 mm) [8]. Safe and efficient management of small-bowel polyposis using double-balloon enteroscopy in PJS has been reported, and intraoperative enteroscopy is an alternative in difficult cases [7] [8] [9]. The reported risk of complications is very low (0 /82 polypectomies in 13 patients, 1 perforation in 387 polypectomies from 18 patients).

The study by Khurebaatar et al. presents the feasibility and safety of ischemic polypectomy, defined as strangulation of the polyp base (by loop or clips), leading to polyp destruction without histological analysis [3]. A total of 67 procedures in nine patients were analyzed retrospectively and reported. The advantages of such a procedure could be to gain time (yet to be demonstrated) and the low risk of complications (1 out of 67 procedures, which is within the range of complication rates of therapeutic enteroscopy in this indication according to the literature). Disadvantages are the risk of incomplete polyp destruction and the lack of histology, especially for polyps > 20 mm in maximum diameter. As admitted by the authors, evaluation of polyp destruction could not be estimated for a defined polyp. Moreover, despite the low risk of cancer in hamartomas, this method does not allow the necessary evaluation of polyp histology, at least for large (> 20 mm) polyps. In this setting, only a close prospective follow-up for a very long period could validate the safety of this approach.

In summary, this study illustrates the difficulty of improving knowledge in rare diseases. The recent recommendations of ESGE, ESPGHAN, and UK societies are mostly based on expert opinion and a few long-term follow-up cohorts representing valuable but medium-quality resources. Cases from a single, albeit expert, center, do not provide the critical number of patients needed to evaluate care. Randomized studies are usually not feasible owing to the rarity of the syndrome, or would require excessively long follow-up periods. In addition, very few prospective databases worldwide facilitate detailed and structured recording. Thus, the time has probably come for the development of such prospective database with structured reporting and international, or at least national, prospective collaborative studies. This would be the best way to improve decision making in rare syndromes such as PJS polyposis.

Publication History

Article published online:
24 June 2021

• References

• 1 van Leerdam ME, Roos VH, van Hooft JE. et al. Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2019; 51: 877-895
• 2 Giardiello FM, Brensinger JD, Tersmette AC. et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 2000; 119: 1447-1453
• 3 Khurelbaatar T, Sakamoto H, Yano T. et al. Endoscopic ischemic polypectomy for small-bowel polyps in patients with Peutz-Jeghers syndrome. Endoscopy 2020; 53: 744-748
• 4 van Lier MG, Mathus-Vliegen EM, Wagner A. et al. High cumulative risk of intussusception in patients with Peutz–Jeghers syndrome: time to update surveillance guidelines?. Am J Gastroenterol 2011; 106: 940-945
• 5 Latchford A, Cohen S, Auth M. 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; 68: 442-452
• 6 Monahan KJ, Bradshaw N, Dolwani S. et al. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut 2020; 69: 411-444
• 7 Gao H, van Lier MG, Poley JW. et al. Endoscopic therapy of small-bowel polyps by double-balloon enteroscopy in patients with Peutz–Jeghers syndrome. Gastrointest Endosc 2010; 71: 768-773
• 8 Ohmiya N, Nakamura M, Takenaka H. et al. Management of small-bowel polyps in Peutz–Jeghers syndrome by using enteroclysis, double-balloon enteroscopy, and videocapsule endoscopy. Gastrointest Endosc 2010; 72: 1209-1216
• 9 Edwards DP, Khosraviani K, Stafferton R. et al. Long-term results of polyp clearance by intraoperative enteroscopy in the Peutz–Jeghers syndrome. Dis Colon Rectum 2003; 46: 48-50