Gastrointestinal aspects of Peutz-Jeghers syndrome.

There are two main problems in the clinical management of the gastrointestinal (GI) tract in patients with Peutz-Jeghers syndrome (PJS), namely long-term cancer risk and managing polyp related complications (of which the most important clinically is intussusception). Given the rarity of this condition, the evidence base upon which to make recommendations is small. Furthermore, controversies persist regarding the relationship between PJ polyps, cancer development and cancer risk. In this article we will explore some of these controversies, to put into context the recommendations for clinical management of these patients. We will provide an overview, particularly focusing on clinical data, and on the recommendations for clinical management and surveillance of the GI tract in PJS. We highlight knowledge gaps which need to be addressed by further research.

Risk of colorectal adenomas and cancer in monoallelic carriers of MUTYH pathogenic variants: a single-centre experience.

PURPOSE: The carrier frequency of MUTYH pathogenic variants in the population may be as high as one in 45. Some studies have found an increased risk of colorectal cancer (CRC) in monoallelic carriers of MUTYH pathogenic variants, but the role of early surveillance colonoscopy is not conclusive. This study aimed to assess the outcomes of colonoscopy surveillance in MUTYH carriers. METHODS: Patients, with a monoallelic pathogenic variant in MUTYH, found at cascade testing, were identified from the St Mark's Hospital Polyposis Registry database. Findings at surveillance colonoscopy were reviewed. RESULTS: Two hundred and forty-nine carriers were identified, of whom 125 had undergone at least one surveillance colonoscopy. Twenty-eight patients (22%) developed at least one adenoma; all adenomas had low-grade dysplasia (LGD). The median age at first colonoscopy was 36 years (range 16-75 years). The median age at first adenoma detection was 43 years (range 22-75 years). The cumulative incidence of adenoma development by age 30, 40, 50, 60 and 70 years was 3.2%, 8.8%, 15.2%, 18.4% and 20.8%, respectively. No CRCs were observed. CONCLUSIONS: Our cohort of monoallelic carriers of MUTYH pathogenic variants is a relatively younger group than adults entering population screening colonoscopy, but a high adenoma rate was not observed. No CRCs were detected, suggesting that current guidance that these individuals should be managed in the same way as the general population is reasonable.

European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.

BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. METHODS: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. RESULTS: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. CONCLUSION: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.

MUTYH-associated polyposis - colorectal phenotype and management.

AIM: The aim was to determine the presentation, management and outcomes of MUTYH-associated polyposis (MAP). METHOD: A prospectively maintained database was used to identify patients with MAP. Demographic data and data on germline mutation, surgical management, histopathology of tumours and endoscopic surveillance were collected. RESULTS: In all, 134 patients with MAP were identified. The majority presented symptomatically (n = 83). Sixty-eight patients developed cancer (seven synchronous, 12 metachronous). The median age at diagnosis of first colorectal cancer was 47 years (range 33-74 years). Cancers occurred in the context of a few adenomas (< 10). The majority of patients (n = 108) had surgery as the first line management. One patient received palliative care. Twenty-five patients had endoscopic surveillance as first line management; no cancers occurred in this group. Patients who had segmental resection and postoperative surveillance still appeared to be at risk of metachronous cancer (5/30, 17%). CONCLUSIONS: MUTYH testing should be considered even in the context of cancers occurring with fewer than 10 adenomas. In cases of primary colorectal cancers, extended surgery should be considered if patients do not have access to high quality endoscopic surveillance postoperatively. For some patients, endoscopic therapy is an appropriate and safe option in expert hands.

Safety and efficacy of laparoscopic near-total colectomy and ileo-distal sigmoid anastomosis as a modification of total colectomy and ileorectal anastomosis for prophylactic surgery in patients with adenomatous polyposis syndromes: a comparative study.

AIM: Colectomy in patients with adenomatous polyposis (AP) syndromes demands good oncological and surgical outcome. Total colectomy with ileorectal anastomosis (TC-IRA) is one surgical option for these patients. Anastomotic leakage rates of 11% have been reported following TC-IRA. Ileo-distal sigmoid anastomosis (IDSA) is a recent modification of our practice. Our aim was to compare postoperative outcome in patients with AP following near-total colectomy with IDSA (NT-IDSA) and TC-IRA at a single institution. METHOD: A prospectively maintained database was reviewed to identify patients with AP who underwent laparoscopic NT-IDSA and TC-IRA. Patient demographics, early morbidity and mortality and outcome of endoscopic surveillance were evaluated. RESULTS: A total of 191 patients with AP underwent laparoscopic colectomy between 2006 and 2017, of whom 139 (72.8%) underwent TC-IRA and 52 (27.2%) NT-IDSA. The median age at surgery in the TC-IRA and NT-IDSA groups was 20 years (IQR 17-45) and 27 years (IQR 19-50), respectively. Grade II complications were comparable between the two groups. There were no anastomotic leakages in the NT-IDSA group compared with 15 (10.8%) in the TC-IRA group (P = 0.0125) and no reoperation in the NT-IDSA group compared with 17 (12.2%) in the TC-IRA group (P = 0.008). The frequency of polypectomies per flexible sigmoidoscopy was comparable between the two groups. CONCLUSION: This study demonstrates that laparoscopic NT-IDSA for polyposis is associated with a significant improvement in anastomotic leakage rates and surgical outcome. It is too soon to tell whether NT-IDSA alters the need for further intervention, either endoscopic polypectomy or further surgery.

The association of age with the clinicopathological characteristics and prognosis of colorectal cancer: a UK single-centre retrospective study.

INTRODUCTION: Colorectal cancer (CRC) is uncommon in patients under the age of 40 years and its association with poor histological features and survival is uncertain. This study aimed to evaluate age-related differences in clinicopathological features and prognosis in patients diagnosed with CRC. METHOD: A single-centre retrospective review of all patients diagnosed with CRC between 2004 and 2013 was performed. Patients were stratified into three age groups: (1) 18-40 years, (2) 41-60 years and (3)> 60 years. Clinicopathological characteristics and outcomes were compared between the three groups. RESULTS: A total of 1328 patients were included, of whom 57.2% were men. There were 28 (2.1%) patients in group 1, 287 (21.6%) in group 2 and 1013 (76.3%) in group 3. Group 1 had the highest proportion of rectal tumours (57.1% in group 1, 50.2% in group 2 and 31.9% in group 3; P < 0.001). Tumour histology and disease stage were comparable between the groups. Group 1 had significantly worse disease-free survival (DFS) than the two older groups (44%, 78% and 77%, respectively; P = 0.022). Multivariate analysis demonstrated that age was not an independent prognostic factor whereas Stage III disease [hazard ratio (HR) 4.42; 95% CI 2.81-6.94; P < 0.001] and neoadjuvant chemotherapy (HR 1.65; 95% CI 1.06-2.58; P = 0.026) were associated with increased risk of recurrence. CONCLUSION: Patients under the age of 40 are more likely to present with rectal cancer and have comparable histological features than the older groups. Despite higher rates of adjuvant and neoadjuvant treatment, the young group were found to have worse DFS.

Risk of desmoid formation after laparoscopic versus open colectomy and ileorectal anastomosis for familial adenomatous polyposis.

BACKGROUND: Laparoscopy is used increasingly in prophylactic surgery for patients with familial adenomatous polyposis (FAP) undergoing colectomy with ileorectal anastomosis (IRA). Little is known about the impact of laparoscopy on subsequent desmoid risk. This study documented the risk of desmoid in patients undergoing laparoscopic and open IRA. METHODS: This was an observational study of patients with FAP and known germline APC mutation, undergoing IRA at a tertiary referral centre between 1996 and 2016. Patients were retrieved from a prospectively maintained polyposis registry. Data included genotype, family history of desmoid, sex, surgical approach at IRA and postoperative complications. The main outcome was development of either a clinically or radiologically significant desmoid. RESULTS: Some 112 patients (61 female) underwent colectomy and IRA. A laparoscopic approach was used in 69 patients (61·6 per cent). Baseline characteristics did not differ between patients having an open or laparoscopic approach. Median follow-up was 5·8 (i.q.r. 2·4-11·2) years. Patients who underwent laparoscopic IRA had a reduced risk of desmoid formation (3 of 69 (4 per cent) versus 7 of 43 (16 per cent) in the open group; P = 0·043). DISCUSSION: Laparoscopic IRA may reduce risk of subsequent desmoid formation in patients with FAP.

Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis.

AIM: Lynch syndrome (LS) accounts for 2-4% of all colorectal cancer (CRC) cases, and is associated with an increased risk of developing metachronous colorectal cancer (mCRC). The role of extended colectomy in LS CRC is controversial. There are limited studies comparing the risk of mCRC following segmental colectomy and extended colectomy. The objective of this systematic review is to evaluate the risk of developing mCRC following segmental and extended colectomy for LS CRC and endoscopic compliance. METHOD: A systematic review of major databases was performed using predefined terms. All original articles published in English comparing the risk of mCRC in LS patients after segmental and extended colectomy from 1950 to January 2016 were included. RESULTS: The search retrieved 324 studies. Six studies involving 871 patients met the inclusion criteria. Of these, 705 (80.9%) underwent segmental colectomy and 166 (19.1%) extended colectomy. Average follow-up was 91.2 months. The mCRC rate was 22.8% and 6% in the segmental and extended colectomy groups, respectively. The segmental group were over four times more likely to develop mCRC (OR 4.02, 95% CI: 2.01-8.04, P < 0.0001). mCRC occurred in patients after segmental colectomy despite 1-2-yearly postoperative endoscopic surveillance. CONCLUSION: This result suggests that extended colectomy reduces the risk of mCRC by over four-fold compared with segmental colectomy. mCRC occurred in the segmental group despite postoperative endoscopic surveillance. This needs to be borne in mind when deciding on the appropriate surgical management of LS patients with CRC. We recommend that extended colectomy should be considered for patients with confirmed LS CRC.

Clinical risk factors of colorectal cancer in patients with serrated polyposis syndrome: a multicentre cohort analysis.

OBJECTIVE: Serrated polyposis syndrome (SPS) is accompanied by an increased risk of colorectal cancer (CRC). Patients fulfilling the clinical criteria, as defined by the WHO, have a wide variation in CRC risk. We aimed to assess risk factors for CRC in a large cohort of patients with SPS and to evaluate the risk of CRC during surveillance. DESIGN: In this retrospective cohort analysis, all patients with SPS from seven centres in the Netherlands and two in the UK were enrolled. WHO criteria were used to diagnose SPS. Patients who only fulfilled WHO criterion-2, with IBD and/or a known hereditary CRC syndrome were excluded. RESULTS: In total, 434 patients with SPS were included for analysis; 127 (29.3%) were diagnosed with CRC. In a per-patient analysis ≥1 serrated polyp (SP) with dysplasia (OR 2.07; 95% CI 1.28 to 3.33), ≥1 advanced adenoma (OR 2.30; 95% CI 1.47 to 3.67) and the fulfilment of both WHO criteria 1 and 3 (OR 1.60; 95% CI 1.04 to 2.51) were associated with CRC, while a history of smoking was inversely associated with CRC (OR 0.36; 95% CI 0.23 to 0.56). Overall, 260 patients underwent surveillance after clearing of all relevant lesions, during which two patients were diagnosed with CRC, corresponding to 1.9 events/1000 person-years surveillance (95% CI 0.3 to 6.4). CONCLUSION: The presence of SPs containing dysplasia, advanced adenomas and/or combined WHO criteria 1 and 3 phenotype is associated with CRC in patients with SPS. Patients with a history of smoking show a lower risk of CRC, possibly due to a different pathogenesis of disease. The risk of developing CRC during surveillance is lower than previously reported in literature, which may reflect a more mature multicentre cohort with less selection bias.

Peutz-Jeghers syndrome: intriguing suggestion of gastrointestinal cancer prevention from surveillance.

BACKGROUND: Peutz-Jeghers syndrome is characterized by GI polyps and mucocutaneous pigmentation and carries an increased risk of GI cancer. GI polyps may bleed or cause intussusception. Luminal GI surveillance is recommended, but there are few data detailing outcomes from GI surveillance in Peutz-Jeghers syndrome. OBJECTIVE: This study aimed to assess outcomes from GI surveillance in patients with Peutz-Jeghers syndrome. DESIGN: This study is a retrospective review, using hospital and registry notes and endoscopy and histology reports. SETTING: The investigation was conducted at a tertiary referral center. PATIENTS: All patients with Peutz-Jeghers syndrome who were followed up at St Mark's hospital were included. MAIN OUTCOME MEASURES: The primary outcomes measured were surveillance procedures performed, complications, and long-term outcomes. RESULTS: Sixty-three patients from 48 pedigrees were included; the median age when patients were first seen was 20 years (range, 3-59). Only baseline investigations were performed in 12 patients. The remaining patients were followed up for 683 patient years, a median of 10 years (range, 2-41). Seven hundred seventy-six procedures were performed to assess the GI tract. These led to 5 double-balloon enteroscopies, 1 push enteroscopy, and 71 surgical procedures. Of the surgical procedures, 20 were performed as a result of baseline investigations, 12 arose from investigations of symptoms, and 39 were due to surveillance of asymptomatic patients. No emergency surgical interventions were performed. No luminal GI cancers were diagnosed. Of the 2461 polypectomies performed, 6 polyps contained atypia or dysplasia. Six complications arose from endoscopy or surgical intervention, requiring 5 laparotomies to manage these complications. CONCLUSION: GI surveillance in Peutz-Jeghers syndrome is relatively safe and avoids the need for emergency surgery for small-bowel polyps. The lack of GI cancers may reflect that surveillance and polypectomy have prevented cancer from developing, although the detection of neoplasia or dysplasia is uncommon.

Gastrointestinal polyps and cancer in Peutz-Jeghers syndrome: clinical aspects.

The two main problems in the management of the gastrointestinal tract in patients with Peutz-Jeghers syndrome (PJS) are the long term cancer risk and managing polyp related complications, such as intussusception and bleeding. In this article we will focus mainly on the clinical management of these problems. We will highlight some of the controversies regarding gastrointestinal PJS polyps, cancer development and cancer risk. We will review the available literature, particularly focusing on clinical data, to provide insights into these controversies. We describe guidelines for the surveillance and management of gastrointestinal polyps in PJS and review the data behind current recommendations.

Peutz-Jeghers syndrome: a systematic review and recommendations for management.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.

Feasibility of video capsule endoscopy in the management of children with Peutz-Jeghers syndrome: a blinded comparison with barium enterography for the detection of small bowel polyps.

OBJECTIVES: Peutz-Jeghers syndrome (PJS) in children may present with anaemia, intussusception, or obstruction from an early age and surgery is common. Prophylactic polypectomy may reduce subsequent complications. Traditional barium enterography (BE) has poor sensitivity and requires significant radiation. We compared the performance of capsule endoscopy (CE) with BE in children with PJS. MATERIALS AND METHODS: Children with PJS (ages 6.0-16.5 years) were prospectively recruited and underwent BE followed by CE, each reported by expert reviewers blinded to the alternate modality. Number of "significant" (>10 mm) and total number of polyps were recorded. Child preference was assessed using a visual analogue questionnaire. Definitive findings were assessed at laparotomy or enteroscopy, when performed. RESULTS: There was no significant difference for >10 mm polyp detection. Six polyps were found in 3 children by both modalities: 3 polyps in 2 children at CE, 3 polyps in 1 child at BE (P=0.50). Re-review of 1 CE identified 3 polyps that were missed in 1 child at initial reading. Significantly more <10 mm polyps were identified by CE than BE: 61 vs 6 (P=0.02). CE was significantly more comfortable than BE (median score CE 76 [interquartile range 69-87] vs BE 37 [interquartile range 31-68], P=0.03) and was the preferred investigation in 90% (P=0.02). CONCLUSIONS: CE is a feasible, safe, and sensitive test for small bowel polyp surveillance in children with PJS. It is significantly more comfortable than BE and is the preferred test of most children for future surveillance. There is a learning curve for reporting CE studies in PJS and appropriate training is essential.

Peutz-Jeghers syndrome and screening for pancreatic cancer.

BACKGROUND: Cancer risk, including pancreatic, is high in those with Peutz-Jeghers syndrome (PJS). It has been suggested that such patients should undergo screening for pancreatic cancer. METHODS: The risk of pancreatic cancer in PJS, pancreatic screening and potential screening strategies were reviewed. Cost-effectiveness was assessed according to American Gastroenterology Association guidelines and a risk stratification model proposed by the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer. RESULTS: The risk of pancreatic cancer is increased in PJS but screening would cost over US 35,000 dollars per life saved. Risk stratification reduces cost by 100,000 dollars and costs fall to 50,000 dollars per life saved if deaths from other forms of cancer are avoided. CONCLUSION: Screening should be performed only on a research basis to evaluate the benefit and cost-effectiveness in high-risk groups.

Genetic determinants modulate susceptibility to pregnancy-associated tumourigenesis in a recombinant line of Min mice.

Min mice provide a good model of human familial adenomatous polyposis. Recently, we have reported on two recombinant inbred lines (I and V) and the location of a modifier (Mom3) close to Apc, which altered polyp numbers in our mice possibly by modifying the frequency of wild-type (WT) allele loss at Apc; mice with severe disease (line V) showed elevated rates of loss. We now show that in line I only, a single pregnancy caused a significant increase in adenoma multiplicity compared with virgin controls (P<0.001) and that an additional pregnancy conferred a similar risk. Pregnancy was linked to both adenoma initiation and enhanced tumour growth in line I mice, and interline crosses indicated that susceptibility to pregnancy-associated adenomas was under genetic control. We found no evidence for the involvement of oestrodial metabolizing genes or the oestrogen receptors (Esr1 and 2) in tumour multiplicity. Importantly, a significantly elevated frequency of WT allele loss at Apc was observed in adenomas from parous mice (line and backcrossed) carrying the line I Min allele relative to equivalent virgin controls (P=0.015). Our results provide the first experimental evidence for genetic determinants controlling pregnancy-associated tumourigenesis; analogous genetic factors may exist in humans.

A 10-year review of surgery for desmoid disease associated with familial adenomatous polyposis.

BACKGROUND: Desmoid tumours affect 10-25 per cent of patients with familial adenomatous polyposis and represent a major cause of morbidity and mortality. Surgery for intra-abdominal desmoids has traditionally been used as a last resort or to manage obstructive complications. The aim was to review 10 years of desmoid surgery in patients with familial adenomatous polyposis from a single centre. METHODS: Patients who had surgery for desmoid disease between 1994 and 2004 were identified from the Polyposis Registry database and their hospital notes reviewed. RESULTS: Twenty patients had surgery to remove 32 desmoid tumours (16 intra-abdominal, 12 abdominal wall, four extra-abdominal). Complete clearance was achieved in 19 tumours and, of these, clinically significant recurrence occurred in eight. There was no difference in recurrence rates for site or sex. There was no operative mortality. Intra-abdominal desmoid resection was associated with a mean resection of 45.55 (range 10-200) cm of small bowel. One patient required long-term parenteral feeding. Median follow-up was 5 (range 0.6-10) years. During this period, one patient died (metastatic duodenal cancer); there was no mortality from desmoid disease. CONCLUSION: Surgery for intra-abdominal desmoids in selected patients is less hazardous than previously reported. Surgery for abdominal wall and extra-abdominal tumours is safe. However, disease recurrence remains a major problem.