Small bowel polyp resection using device-assisted enteroscopy in Peutz-Jeghers Syndrome: Results of a specialised tertiary care centre

Abstract

Introduction

Enteroscopy resection of small bowel polyps in Peutz-Jeghers syndrome has only been described in small case series. Herein, we aimed to assess the efficacy of enteroscopy resection of small bowel polyps within a specialised tertiary care centre and the impact on intraoperative enteroscopy.

Methods

This was an observational single-centre study. All adult Peutz-Jeghers syndrome patients followed in the Predisposition Digestive Ile-de-France network who underwent an endoscopic resection of at least one small bowel polyp ≥ 1 cm by enteroscopy between 2002–2015 were included. Small bowel polyps were detected under a dedicated screening programme by previous capsule endoscopy and/or magnetic resonance enterography, performed every 2–3 years. Complete treatment was defined as the absence of polyps ≥ 1 cm after conventional endoscopic resection. Intraoperative enteroscopy or surgical resection were indicated in incomplete treatments. The overall complete treatment rate including conventional enteroscopy and intraoperative enteroscopy was also considered.

Results

Endoscopic resection of 216 small bowel polyps (median: 8.6 per patient, size: 6–60 mm) was performed by 50 enteroscopies in 25 patients (mean age: 36 years, range: 18–71, 56% male) with small bowel polyp ≥ 1 cm. Twenty-three patients (92%) underwent 42 screening capsule endoscopies and 14 (57%) had 23 magnetic resonance enterographies during a median follow-up of 60 months. Complete treatment was achieved in 76%. Intraoperative enteroscopy and surgical resection were performed in four (16%) and two (8%) patients. Intraoperative enteroscopy improved by 16% the complete treatment rate and the overall rate was 92%. The complication rate was 6%.

Conclusion

This long-term study confirmed the efficacy and safety of endoscopic resection of small bowel polyps in Peutz-Jeghers syndrome. Intraoperative enteroscopy can be a complementary approach in selected cases.

Key summary

Established knowledge on this subject

• • In the Peutz-Jeghers syndrome, small bowel (SB) polyps are associated with severe mechanical complications and risk of neoplastic transformation.

• • Device-assisted enteroscopy has been reported as an innovative alternative to surgery for the management of SB polyposis.

What are the new findings of this study?

• • Device-assisted enteroscopy is an efficient and safe technique for SB polyp removal in Peutz-Jeghers syndrome.

• • Surgical resection should be preferred for complex and challenging small bowel polyps.

Introduction

Peutz-Jeghers syndrome (PJS) is a rare genetic disorder that is characterised by multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation and an increased risk of gastrointestinal and non-gastrointestinal cancers.¹ It is an inherited autosomal dominant disease with incomplete penetrance, often due to a germline mutation of the serine theorine kinase 11 (STK11) gene.² The incidence is estimated to be from one per 50,000 to one per 200,000 births, with males and females equally affected.

PJS polyps occur mostly in the small bowel (SB; 60–90%),³ most specifically in the jejunum. Their size can vary from several millimetres to several centimetres. Indeed, most patients become symptomatic between the age of 10–30 years due to growth of the polyps. They can lead to severe mechanical complications such as occlusion, gastrointestinal necrosis or perforation, and haemorrhage and/or anaemia in about two-thirds of patients. The presence of PJS polyps in the SB is also associated with an increased risk of cancer. The lifetime SB cancer risk in PJS is estimated to be around 13%,^4,5 with a relative risk ratio of 520 compared to the general population. The pathophysiological mechanism of gastrointestinal cancer transformation is not completely understood and might be due either to dysplastic changes within the hamartomas or to a conventional neoplastic accelerated pathway,^6–8

Management of SB polyps in PJS has evolved over the past decade. The latest international and experts’ guidelines recommend SB polyp screening starting at the age of eight years, repeated every two to three years. Polypectomy is recommended for polyps larger than 1 cm in order to prevent mechanical or malignant complications.^5,9

Capsule endoscopy (CE) and magnetic resonance enterography (MRE) are relatively new techniques that allow less invasive screening and are therefore well accepted by the patients.^10,11 Polypectomy or mucosectomy by double-balloon enteroscopy (DBE), spiral enteroscopy (SE) or single balloon enteroscopy have become the first-line treatments for SB polyps, as they are efficient, safe and cost-effective.^12–14 Nevertheless, intraoperative enteroscopy (IOE) may be needed in some cases to explore the full length of the SB.^15,16 In this study, we aimed to evaluate the treatment profitability of enteroscopy in PJS within our specialised centre (a member of the Predisposition Digestive Ile-de-France (PRED-IdF) network), including the need for IOE.

Methods

Patients

This was an observational retrospective monocentric study based on a prospective cohort of PJS patients under the PRED-IdF network at our tertiary care centre. Our centre coordinates the PRED-IDF programme, which is a dedicated regional network for counselling and follow-up of patients with genetic predispositions to gastrointestinal cancers. All adult patients (≥18 years) with a clinical or genetic diagnosis of PJS who underwent a SB polypectomy between January 2002–December 2015 were included. Patients characteristics, previous SB or gastrointestinal surgery and personal history of cancer were collected.

SB screening

Baseline SB polyp (SBP) screening was carried out by CE, MRE or both, and every two to three years thereafter. CE was performed using the PillCam device (Pillcam SB1-SB3, Medtronic, USA) and was read by two gastroenterologists experienced in capsule use (>500 CE exams, ES, GR). MRE was performed in the prone position one hour after the oral administration of an enteral contrast agent (in general 1.5–2 l). The follow-up was defined as the time interval between the baseline examination and the last screening examination during the period of study.

Enteroscopy procedure

Device-assisted enteroscopy (DAE) or push enteroscopy were indicated when a polyp ≥ 1 cm was found on baseline screening or follow-up. The antegrade or retrograde route was determined based on the location of the largest polyps. If they were located in the jejunum or in the proximal ileum, the antegrade route was chosen. If the polyps were found in the middle or distal ileum, the retrograde route was then preferred. The endoscopic approach (DBE, SE or push enteroscopy) was chosen according to the equipment available at the time of the examination, the endoscopist’s preference and the polyps’ locations and numbers. DBE (Fujifilm, Saitama, Japan) was used for all retrograde routes and for the majority of antegrade routes, especially when there were few polyps to remove. SE (Spirus Medical, Inc., Stoughton, Massachusetts, USA) was preferred when there was a large number of polyps, allowing multiple polyp retrieval during the examination without the need to remove the entire device. Push enteroscopy (PE) was rarely indicated unless the polyps were located proximal to the Treitz ligament. All enteroscopies were performed under general anaesthesia by a senior gastroenterologist with long experience in SB endoscopy (>100 enteroscopies) (ES, GR), assisted by a specialised nurse or a fellow.

Endoscopic resection by polypectomy or mucosectomy was performed with a symmetric snare (Olympus, Rungis, France) using monopolar current (VIO3/VIO300D generators, ERBE, Limonest, France) by endocut I/Q and forced/swift coagulation modes. Other techniques such as endoloop (Ethicon, Nanterre, France) or submucosal injection with diluted epinephrine (1:10,000) prior to endoscopic resection were performed on an individual basis. Prophylactic endoscopic closure to reduce the risk of delayed complications was performed using endoscopic clipping at the discretion of the endoscopist. Tattooing was carried out at the distal point reached by DAE in all cases.

Outcomes

Complete treatment was defined by the absence of residual polyps ≥ 1 cm after endoscopic resections. To reach that objective, the same patient could undergo as many DAEs as necessary. The absence of residual polyps was considered when all polyps detected at initial SB screening were removed. The description of incomplete treatment was retained in the remaining cases. In the case of endoscopic treatment failure or incomplete treatment, IOE or surgical resection (SR) were indicated. IOEs were performed after laparotomy, when not all polyps ≥1 cm were reached after both antegrade and retrograde enteroscopies. Access to the digestive lumen was possible after enterotomy and progression throughout the SB was manually ensured by the surgeon. SR was selected when endoscopic polyp resection was considered technically difficult, although the polyps could be reached. Overall, the complete treatment rate including SB polypectomy by conventional or intraoperative enteroscopy was also considered.

Acute and delayed complications related to enteroscopy with or without surgery such as bleeding, perforation and acute pancreatitis were noted. Delayed bleeding was defined as haematemesis or melaena requiring endoscopic haemostasis, readmission, blood transfusion or surgical intervention after the completion of the procedure.

Histopathological assessment was considered. According to the Vienne classification, adenomas were classified into low-grade dysplasia, high-grade dysplasia and adenocarcinoma when available. Polyp size in histopathological analysis was not considered.

Ethics

The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the institution’s human research committee. Written informed consent was obtained from all patients entering the PRED-IdF network, for both prospective and retrospective data analysis. The research proposal was reviewed by the local ethics committee (CNIL, 1779298; 3 July 2014).

Statistical analysis

Categorical variables were compared using the chi-squared test. Normally distributed continuous variables were presented as the mean (standard deviation) and analysed by the Student t test. Non-normally distributed variables were expressed with the median (range) and analysed by the U-Mann-Whitney test. Per-patient and per-procedure approaches were also considered. Values of p < 0.05 were considered statistically significant. SPSS version 24 was used (IBM, SPSS Inc., Illinois, USA).

Results

Patients

A total number of 27 patients with PJS underwent the SB screening programme between 2002–2015. Two patients had no SBPs larger than 10 mm. Finally, 25 patients (92.6%) required SB polypectomy and were included in the study. The median age was 36 years (range: 18–71), with a male/female sex ratio of 14/11. Sixty-four percent (n = 16) had a personal history of SB surgery prior to joining the network, mainly for mechanical reasons. The median age at first SB surgery was 20 years (range: 13–40). In addition, two patients had a partial colectomy at the age of 18 years. Regarding the personal history of non-gastrointestinal cancer, there were patients with lung cancer (n = 2), breast cancer (n = 2), and intraductal papillary mucinous tumour of the pancreas (n = 1). Patient characteristics are summarised in Table 1.

Table 1.

Baseline characteristics of patients with Peutz-Jeghers syndrome who underwent the Predisposition Digestive Ile-de-France (PRED-IdF) screening programme and endoscopic treatment.

	Results
Demographics
Sex (male)	14 (56%)
Age (median, range, months)	36 (18–71)
Personal history of SB surgical resection
n (%)	16 (64%)
Age at surgery (median, range, months)	20 (13–40)
Screening
Follow-up (median, range, months)	60 (2–139)
Type of SB screening – n (%)
Capsule endoscopy	42 (64.6%)
MRE	23 (35.4%)

MRE: magnetic resonance enterography; SB: small bowel.

SBP screening

During the period of study, 23 patients (92%) underwent CE (n = 42) and 14 patients (57%) had MRE (n = 23). Thus, there were 11 patients without previous baseline MRE, and CE screening was not performed in two cases. However, at least one of these examinations was performed in all patients. The median number of CE and MRE per patient were 1.7 (range: 0–4) and 0.9 (range: 0–4) respectively.

All patients underwent DAE or push enteroscopy after a previous procedure confirming the presence of at least one SBP ≥ 1 cm. The median time of follow-up was 60 months (range: 2–139), and there were 14 cases (56%) who underwent only one baseline examination prior to endoscopic treatment.

Endoscopic resection

A total of 50 SB enteroscopies were performed as shown in Table 2, including antegrade (n = 42, 84%) and retrograde (n = 8, 16%) routes (median: two procedures/patient, range: 1–6). The mean delay between enteroscopies was 6.5 months (range: 1–19), and they were distributed as follows: DBE (n = 33, 66%), SE (n = 15, 30%) and PE (n = 2, 4%) (Figure 1).

Table 2.

Type of enteroscopic procedures and route performed in 25 patients with Peutz-Jeghers syndrome for small bowel polypectomy.

Type of enteroscopy	Number of patients, n (%)	Number of procedures, n (%)	Number of polyps, median (range)
Antegrade procedure	n = 25 (100)	n = 42 (84)	n = 202 (93.5)
DBE enteroscopy	25 (100)	25 (60)	2.5 (1–8)
Spiral enteroscopy	12 (48)	15 (36)	6 (1–30)
Push enteroscopy	2 (8)	2 (4)	2 (2–2)
Retrograde procedure	n = 7 (28)	n = 8 (16)	n = 14 (6.5)
DBE enteroscopy	7(28)	8 (100)	1 (1–8)
Spiral enteroscopy	0 (0)	0 (0)	0 (0–0)
Push enteroscopy	0 (0)	0 (0)	0 (0–0)

DBE: double-balloon enteroscopy.

Figure 1.

Study flow chart. Complete treatment was defined by the absence of residual polyps ≥ 1 cm after endoscopic resections. DBE: double balloon enteroscopy; PE: push enteroscopy; SE: spiral enteroscopy.

Endoscopic polypectomy or mucosectomy (Figure 2) resulted in the resection of 216 polyps with a median number of polyps per patient of 8.6 (range: 1–45). The median number of polyps per procedure was 4.3 polyps/procedure and at least one of them measured 1 cm or more. In addition, the concordance for the polyp size (< or ≥1 cm) between previous screening procedures and enteroscopy was 100%, as all polyps suspected to be equal or larger than 1 cm by CE/MRE were confirmed by enteroscopy.

Figure 2.

Snare polypectomy using double-balloon enteroscopy of a large hamartomatous jejunal polyp in a 42-year-old female presenting with Peutz-Jeghers syndrome.

Complete treatment was observed in 19 patients (76%) (Figure 1). Complications were reported after three DAE procedures (6%): two cases of delayed bleeding requiring blood transfusions (DBE) and one case of acute pancreatitis (SE). No complication occurred after IOE or SR. All complications were treated conservatively with a favourable outcome. Neither perforation nor death occurred.

For patients with incomplete treatment (n = 6, 24%), IOE and SR were performed in four (16%) and two cases (8%) respectively. An additional endoscopic resection of 58 polyps by IOE was performed (14.5 polyps/patient, range: 7–25). In addition, there was a statistically significant difference in the incomplete treatment rate between patients with SR before and after the introduction of DAE in our unit (64% vs 24%, p < 0.001).

Thus, the overall complete treatment rate including both conventional enteroscopy and IOE approaches was 92% (n = 23), improving by 16%. Similarly, considering all procedures, a total of 274 polyps were removed (endoscopic size 5–60 mm), including hamartomas (n = 262, 95.6%), low-grade dysplasia adenomas (n = 11, 4%) and high-grade dysplasia adenoma (n = 1, 0.4%). The 12 adenomas were diagnosed in five patients. No SB cancer was detected.

Discussion

To the best of the authors’ knowledge, this study is one of the largest cohort reporting the efficacy and safety of endoscopic polypectomy of SBPs in Peutz-Jeghers patients. Herein, we report a 76% complete treatment rate in 25 patients with 216 SBPs. IOE and SR were required in respectively four and two patients. Notably, IOE improved by 16% the complete treatment rate leading to a 92% overall success rate.

Management of SBPs in PJS has evolved over the past decades. Before enteroscopy emergence, PJS patients often underwent laparotomy for elective intestinal resection. In our cohort, we found that 64% of PJS patients had a history of SB surgery due to mechanical complications, at a median age of 20 years. This rate and early age appear to be consistent with the data observed in the literature.^5,8,17 In the Saint Mark’s Hospital Polyposis Registry, one of the largest reported cohort, they demonstrated that 68% of adults with PJS had undergone a laparotomy for an episode of intestinal obstruction, mostly before the age of 18 years (median age: 10, range: 2–18 years).¹⁸

With the development of enteroscopy and related devices, polypectomy by DAE has been reported as an innovative alternative to surgery for the management of SB polyposis.¹⁹ Concerning endoscopy in PJS patients, only a few studies have been published in the field. Most of them are single-centre experiences with limited number of cases.^15,20 To our knowledge, the largest published cohort included 22 patients that underwent a total of 34 DAE procedures.^20,21 In our study, the success rates are comparable with previous studies performed at tertiary referral centres. We found that endoscopic treatment of SBP is feasible and complete in 76% of the patients but may require several techniques and multiple polypectomy sessions. The two patients who still needed SR despite endoscopic therapy, presented with technically challenging polyps: one 6 cm large polyp of the jejunum difficult to expose, and one large flat recurrent polyp arising from an anastomotic jejuno-ileal area. When comparing the actual surgical rate in our series (24% including IOE) to the historical one (64%), we identified a significant reduction of the need for surgery, suggesting that DAE may reduce the need for surgery in PJS.

The significant difference found in our study between the actual rate of surgery and the historical rate could be explained in several ways. First, DAE is a relatively recent technique described by Yamamoto et al. in 2001.²² This could explain the high surgical rate within the period before DAE. Second, early screening of SBPs in PJS to avoid mechanical complications is also recent. Thus, this could explain the high rate of surgery in adults who were not screened at a young age.²³ In our centre, 64% of PJS patients had undergone SB surgery before joining the screening programme. Third, with the mastery of SBP endoscopic polypectomy over the past decade at our centre, more challenging resections of large/difficult polyps were successfully attempted. For these reasons we think that, compared to surgery, real benefits can raise from endoscopic treatment of SBP for PJ patients followed in a specialised network. Indeed, the association of regular non-invasive screening starting in childhood in families with known PJS and the use of endoscopic treatment in polyps larger than one centimetre, can minimise complication occurrences and the need for more extensive surgery.

Concerning IOE, it has been described as a valuable tool in patients with tumours, Meckel's diverticulum²³ and Obscure gastrointestinal bleeding (OGIB), finding a bleeding source in about 80% of cases.²⁴ In addition, Edwards et al. described how this technique improves polyp clearance without the need for additional enterotomies and may help to reduce the frequency of laparotomies in PJS.²⁵ In our series, IOE improved the complete treatment rate in 19%, leading to an overall success rate of 92%.

Our study has some limitations. First, its retrospective nature and the long time period concerned make standardization of the follow-up and techniques difficult. Second, the relatively low number of subjects limits the study power but, as PJS is a very rare disease, it is difficult to have a large cohort. Third, the impact of previous SB surgeries is unknown and could artificially lower the rate of current surgeries, as described before.

Conclusion

In conclusion, this study demonstrated that endoscopic polypectomy using DAE is efficient and safe for eradication of significant SBPs in about three-quarters of patients with PJS. Notably, IOE can be a complementary approach in selected cases, but SR must be reserved for complex situations.

Declaration of conflicting interests

The authors declare that there is no conflict of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics approval

This study was approved by the ethics committee of our institution (CNIL 1779298 – 3 july 2014), and The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Georges Pompidou European hospital's human research committee.

Informed consent

Informed consent was obtained from each patient included in this study.