GI Polyps and Polyposis in Individuals Harboring Germline CHEK2 Mutations.

BACKGROUND: Checkpoint kinase 2 is a tumor suppressor gene in the DNA damage checkpoint system that may be mutated in several cancers. Patients with germline checkpoint kinase 2 mutations and multiple colon polyps were noted during routine care, and genetic testing is recommended for patients with as few as 10 lifetime polyps. OBJECTIVE: This study assessed whether checkpoint kinase 2 is associated with attenuated or oligopolyposis and characterized the GI clinicopathologic profile. DESIGN: Retrospective observational study. SETTINGS: Records from patients harboring germline checkpoint kinase 2 mutations from 1999 to 2020 were reviewed. PATIENTS: A total of 45 patients with germline checkpoint kinase 2 mutations with endoscopic examinations. MAIN OUTCOME MEASURES: Description of clinicopathologic variables. RESULTS: Twenty-five of 45 patients had polyps: 3 with only upper GI polyps, 17 with only lower GI polyps, and 5 with both upper and lower GI polyps. The most common germline checkpoint kinase 2 mutations in patients with polyps were p.S428F (n = 10), p.I157T (n = 4), and p.T476M (n = 2), with other mutations present in 1 patient each. Among patients with lower GI polyps, 9 had adenomas, 6 had serrated polyps, 1 had an inflammatory polyp, and 6 had both adenomatous and serrated polyps. Three patients (p.I157T, n = 2; p.R117G, n = 1) had more than 10 adenomas and 1 (p.G259fs) had 18 serrated polyps. Five patients (11.1%) developed colorectal adenocarcinoma, including 2 with more than 10 adenomas. Five patients with p.S428F (50%) exclusively had right-sided adenomas. LIMITATIONS: Single-center descriptive study. CONCLUSIONS: Germline checkpoint kinase 2 mutations should be considered in patients with polyposis. The preponderance of right-sided adenomas in patients with p.S428F mutations suggests the importance of right-sided colonoscopy in these patients. See Video Abstract . PLIPOS Y POLIPOSIS GASTROINTESTINALES EN INDIVIDUOS QUE ALBERGAN MUTACIONES EN LA LNEA GERMINAL DEL GEN CHEK: ANTECEDENTES:El punto de control quinasa 2 (CHEK2) es un gen supresor de tumores en el sistema de puntos de control de daño del ácido desoxirribonucleico (ADN) que puede mutar en varios cánceres. Durante la atención de rutina se observaron pacientes con mutaciones de la línea germinal CHEK2 y múltiples pólipos en el colon, y se recomiendan pruebas genéticas para pacientes con al menos 10 pólipos en su vida.OBJETIVO:Este estudio evaluó si CHEK2 está asociado con poliposis atenuada u oligopoliposis y caracterizó el perfil clínico-patológico gastrointestinal (GI).DISEÑO:Estudio observacional retrospectivo.ESCENARIO:Se revisaron los registros de pacientes que albergaban mutaciones de la línea germinal CHEK2 de 1999 a 2020.PACIENTES:45 pacientes con mutaciones de la línea germinal CHEK2 con exámenes endoscópicos.PRINCIPALES MEDIDAS DE RESULTADO:Descripción de variables clínico-patológicas.RESULTADOS:25 de 45 pacientes tenían pólipos: 3 sólo con pólipos GI superiores, 17 sólo con pólipos GI inferiores y 5 con pólipos GI superiores e inferiores. Las mutaciones de la línea germinal CHEK2 más comunes en pacientes con pólipos fueron p.S428F (n = 10), p.I157T (n = 4) y p.T476M (n = 2), con otras mutaciones presentes en 1 paciente cada una. Entre los pacientes con pólipos gastrointestinales inferiores, 9 tenían adenomas, 6 tenían pólipos serrados, 1 tenía un pólipo inflamatorio y 6 tenían pólipos tanto adenomatosos como serrados. Tres pacientes (p.I157T, n=2; p.R117G, n = 1) tenían >10 adenomas y 1 (p.G259fs) tenía 18 pólipos serrados. Cinco pacientes (11,1%) desarrollaron adenocarcinoma colorrectal, incluidos 2 con >10 adenomas. Cinco pacientes con p.S428F (50%) tenían exclusivamente adenomas del lado derecho.LIMITACIONES:Estudio descriptivo unicéntrico.CONCLUSIONES:Las mutaciones de la línea germinal CHEK2 deben considerarse en pacientes con poliposis. La preponderancia de adenomas del lado derecho en pacientes con mutaciones p.S428F sugiere la importancia de la colonoscopia del lado derecho en estos pacientes. (Traducción-Dr. Felipe Bellolio ).

Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models.

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.

Surgeon assessment of significant rectal polyps using white light endoscopy alone and in comparison to fluorescence-augmented AI lesion classification.

PURPOSE: Perioperative decision making for large (> 2 cm) rectal polyps with ambiguous features is complex. The most common intraprocedural assessment is clinician judgement alone while radiological and endoscopic biopsy can provide periprocedural detail. Fluorescence-augmented machine learning (FA-ML) methods may optimise local treatment strategy. METHODS: Surgeons of varying grades, all performing colonoscopies independently, were asked to visually judge endoscopic videos of large benign and early-stage malignant (potentially suitable for local excision) rectal lesions on an interactive video platform (Mindstamp) with results compared with and between final pathology, radiology and a novel FA-ML classifier. Statistical analyses of data used Fleiss Multi-rater Kappa scoring, Spearman Coefficient and Frequency tables. RESULTS: Thirty-two surgeons judged 14 ambiguous polyp videos (7 benign, 7 malignant). In all cancers, initial endoscopic biopsy had yielded false-negative results. Five of each lesion type had had a pre-excision MRI with a 60% false-positive malignancy prediction in benign lesions and a 60% over-staging and 40% equivocal rate in cancers. Average clinical visual cancer judgement accuracy was 49% (with only 'fair' inter-rater agreement), many reporting uncertainty and higher reported decision confidence did not correspond to higher accuracy. This compared to 86% ML accuracy. Size was misjudged visually by a mean of 20% with polyp size underestimated in 4/6 and overestimated in 2/6. Subjective narratives regarding decision-making requested for 7/14 lesions revealed wide rationale variation between participants. CONCLUSION: Current available clinical means of ambiguous rectal lesion assessment is suboptimal with wide inter-observer variation. Fluorescence based AI augmentation may advance this field via objective, explainable ML methods.

Substratifying the risk of covert malignancy in significant rectal polyps: Outcomes from a specialist multidisciplinary team (MDT).

AIM: A treatment strategy for patients with a significant polyp or early colon cancer (SPECC) of the rectum presents a challenge due to the significant rate of covert malignancy and lack of standardized assessment. For this reason, NICE recommends multidisciplinary meetings to improve outcomes. The primary aim of the present study was to report the performance of our specialist early rectal cancer (SERC) multidisciplinary team (MDT) in correctly substratifying the risk of cancer and to discuss the limitations of staging investigations in those patients with "poor outcomes". METHOD: This was a retrospective review of patients referred to our SERC MDT from 2014 to 2019. Lesions were assigned by the MDT to three pre-resection categories (low, intermediate, high) according to the risk of covert malignancy. Resection method and final histology were compared to the pre-resection categories. RESULTS: Of 350 SPECC lesions, 174 were assessed as low-risk, 108 intermediate-risk and 68 high-risk. The cancer incidence was 4.8%, 8.3% and 53%, respectively (15.5% overall). Eight lesions were categorized as low-risk but following piecemeal resection were found to be malignant. Five lesions, three of which were categorized as high-risk, were ultimately benign following conventional surgery. One pT1sm1 cancer, removed by anterior resection, may have been treated by local excision. CONCLUSION: A total of 83% of malignant polyps were triaged to an en bloc resection technique and surgical resection avoided for nearly all benign lesions. However, 12 patients from this cohort were deemed to have a poor outcome because of miscategorization. Further comparative research is needed to establish the optimum strategy for rectal SPECC lesion assessment. ORIGINALITY STATEMENT: There is currently no consensus for staging significant polyps of the rectum. This paper reports the effectiveness of a specialist early rectal cancer MDT to correctly risk-stratify significant rectal polyps. It underscores the importance of accurate categorization for treatment decision-making, while acknowledging the limitations of current staging modalities.

The effect of implementing a transanal minimally invasive surgical programme for the local excision of early rectal neoplasia on outcomes in a tertiary referral rectal cancer centre.

Transanal minimally invasive surgery (TAMIS) is a surgical alternative to proctectomy in the management of complex rectal polyps and early rectal cancers. In 2016, our institution introduced a TAMIS programme. The purpose of this study was to evaluate changes in practice and outcomes in our institution in the 3 years before and after the implementation of TAMIS. We conducted a retrospective analysis of a prospective database of patients who underwent proctectomy or TAMIS for the management of complex rectal polyps or early rectal cancers at our institution between 2013 and 2018. 96 patients were included in this study (41 proctectomy vs 55 TAMIS). A significant reduction was noted in the number of proctectomies performed in the 3 years after the implementation of TAMIS as compared to the 3 years before (13 vs 28) ( P  < 0.001); 43% of patients ( n  = 12) who underwent proctectomy in the period prior to implementation of TAMIS were American Society of Anaesthesiologists grade III, as compared to only 15% ( n  = 2) of patients during the period following TAMIS implementation ( P  = 0.02). TAMIS was associated with a significant reduction in length of inpatient stay ( P  < 0.001). Oncological outcomes were comparable between groups (log rank P  = 0.83). Our findings support TAMIS as a safe and effective alternative to radical resection. The availability of TAMIS has resulted in a significant reduction in the number of comorbid patients undergoing proctectomy at our institution. Consequently, we have observed a significant reduction in postoperative complications over this time period.

Pediatric Rectosigmoid Atypical Juvenile Polyps Presenting With Rectal Prolapse and Acute Bleeding: A Case Report and a Comprehensive Literature Review.

Rectosigmoid solitary juvenile polyps are benign lesions, relatively frequent in childhood. The clinical debut of a pediatric polyp with bleeding is relatively frequent, but there are very few reports of rectal prolapse of polyps. We present the case of a 7-year-old female patient with no previous history who presented with rectal prolapse of a polyp with acute bleeding. An urgent endoscopic examination was performed and 2 rectosigmoid polypoid lesions were found and resected. The anatomopathological study showed that these were 2 hamartomatous polyps with mild dysplasia. The patient is asymptomatic and is being followed up. The literature concerning rectal prolapse of polyps in the pediatric population is scarce. In a pediatric patient with a rectal prolapse, this entity should be considered in the differential diagnosis.

The role of advanced endoscopy in appendiceal polyp management and outcomes.

BACKGROUND: Appendiceal orifice lesions are often managed operatively with limited or oncologic resections. The aim is to report the management of appendiceal orifice mucosal neoplasms using advanced endoscopic interventions. METHODS: Patients with appendiceal orifice mucosal neoplasms who underwent advanced endoscopic resections between 2011 and 2021 with either endoscopic mucosal resection (EMR), endoscopic mucosal dissection (ESD), hybrid ESD, or combined endoscopic laparoscopic surgery (CELS) were included from a prospectively collected dataset. Patient and lesion details and procedure outcomes are reported. RESULTS: Out of 1005 lesions resected with advanced endoscopic techniques, 41 patients (4%) underwent appendiceal orifice mucosal neoplasm resection, including 39% by hybrid ESD, 34% by ESD, 15% by EMR, and 12% by CELS. The median age was 65, and 54% were male. The median lesion size was 20 mm. The dissection was completed piecemeal in 49% of patients. Post-procedure, one patient had a complication within 30 days and was admitted with post-polypectomy abdominal pain treated with observation for 2 days with no intervention. Pathology revealed 49% sessile-serrated lesions, 24% tubular adenomas, and 15% tubulovillous adenomas. Patients were followed up for a median of 8 (0-48) months. One patient with a sessile-serrated lesion experienced a recurrence after EMR which was re-resected with EMR. CONCLUSION: Advanced endoscopic interventions for appendiceal orifice mucosal neoplasms can be performed with a low rate of complications and early recurrence. While conventionally lesions at the appendiceal orifice are often treated with surgical resection, advanced endoscopic interventions are an alternative approach with promising results which allow for cecal preservation.

Gentle Giant? Giant Gastric Solitary Peutz-Jeghers Polyp.

Solitary hamartomatous polyps with identical pathological features of the typical hamartomas of the Peutz-Jegher syndrome are extremely rare. These solitary lesions lack the associated intestinal polyposis, classic mucocutaneous pigmentation, and family history typifying the Peutz-Jegher syndrome. We describe the case of a 31-year-old woman with a giant solitary gastric hamartoma endoscopically diagnosed and laparoscopically resected.

Resectability of Small Duodenal Tumors: A Randomized Controlled Trial Comparing Underwater Endoscopic Mucosal Resection and Cold Snare Polypectomy.

INTRODUCTION: Underwater endoscopic mucosal resection (UEMR) and cold snare polypectomy (CSP) are novel endoscopic procedures for superficial nonampullary duodenal epithelial tumors (SNADET). However, consensus on how to use both procedures appropriately has not been established. In this study, we evaluated treatment outcomes of both procedures, including resectability. METHODS: In this single-center randomized controlled study conducted between January 2020 and June 2022, patients with SNADET ≤12 mm were randomly allocated to UEMR and CSP groups. The primary end point was sufficient vertical R0 resection (SVR0), which was defined as R0 resection including a sufficient submucosal layer. We compared treatment outcomes including SVR0 rate between groups. RESULTS: The SVR0 rate was significantly higher in the UEMR group than in the CSP group (65.6% vs 41.5%, P = 0.01). By contrast, the R0 resection rate was not significantly different between study groups (70.3% vs 61.5%, P = 0.29). The submucosal layer thickness was significantly greater in the UEMR group than in the CSP group (median 546 [range, 309-833] µm vs 69 [0-295] µm, P < 0.01). CSP had a shorter total procedure time (median 12 [range, 8-16] min vs 1 [1-3] min, P < 0.01) and fewer total bleeding events (9.4% vs 1.5%, P = 0.06). DISCUSSION: UEMR has superior vertical resectability compared with CSP, but CSP has a shorter procedure time and fewer bleeding events. Although CSP is preferable for most small SNADET, UEMR should be selected for lesions that cannot be definitively diagnosed as mucosal low-grade neoplasias.

Osseous metaplasia in a rectal polyp.

Rectal polyps are finger-like projections of the mucosal surface that generally present with complaints of bleeding or mass per rectum. Polyps are classified histopathologically as neoplastic and non-neoplastic. Here, we present one such rare case of a middle-childhood boy who presented with complaints of bleeding per-rectum and revealed a 1.5 cm long rectal polyp. Histopathological examination revealed an osseous change in the rectal polyp. A detailed literature review of reported cases of benign rectal polyps with osseous metaplasia was conducted and consolidated all postulated theories of pathogenesis. This case report shows an interesting incidental finding of osseous metaplasia of the rectal polyp.

Clinicopathologic comparison between sporadic and syndromic Peutz-Jeghers polyps.

Peutz-Jeghers polyps (PJPs) are hamartomatous polyps that may define patients with Peutz-Jeghers syndrome (PJS), a rare inherited polyposis syndrome with high cancer risk. However, the clinical significance of 1-2 sporadic PJPs (without other PJS stigmata) regarding malignant potential and identification of new PJS probands is still unclear. We identified 112 patients with 524 histologically confirmed PJPs and categorized them based on polyp number into syndromic (n = 38) if ≥3 PJPs or diagnosed PJS, solitary (1 PJP, n = 61), and intermediate (2 PJPs, n = 13). Clinicopathologic features, including presence of dysplasia in the polyp and development of neoplasia in the patient, were compared on a per-patient and per-polyp basis. Whereas patients with solitary and intermediate PJPs were not different from each other, patients with syndromic PJPs were, in multivariate analysis, younger (P = .001) and more likely to develop neoplasia (P = .02) over a 62.6-months median follow-up than patients with sporadic PJPs. On an individual polyp basis, syndromic PJPs were more likely, in multivariate analysis, to occur in the small intestine (P < .001), but less likely to harbor metaplasia (P = .03) or dysplasia (P = .001), than sporadic PJPs. Dysplasia and metaplasia were more likely in larger PJPs, by multivariate analysis (P = .007 and P < .001, respectively). These data suggest that strict criteria for PJS (including ≥3 PJPs), as currently used, stratify patients into distinct groups with significant differences in clinicopathologic parameters, particularly regarding risk of neoplasia. However, sporadic PJPs exhibit characteristics such as dysplasia and are thus important to recognize and diagnose but perhaps as heralding only a forme fruste PJS.

Management of malignant T1 colorectal cancer polyps: results from a 10-year prospective observational study.

AIM: The recurrence risk associated with residual malignant cells (bowel wall/regional nodes) following T1 colorectal cancer (CRC) polypectomy must be weighed against operative morbidity. Our aim was to describe the management and outcomes of a large prospective cohort of T1 CRCs. METHOD: All T1 CRCs diagnosed between March 2007 and March 2017 at the Glasgow Royal Infirmary were included. Patients were grouped by polypectomy, rectal local excision and formal resection status. χ2 testing, multivariate binary logistic and Cox regression were performed. RESULTS: Of 236 patients, 90 (38.1%) underwent polypectomy only, six (2.6%) polypectomy and then rectal excision, 57 (24.2%) polypectomy and then resection, 14 (5.9%) rectal excision only and 69 (29.2%) primary resection. Polypectomy only correlated with male sex (P = 0.028), older age (P < 0.001), distal CRCs (P < 0.001) and pedunculated polyps (P < 0.001); primary resection with larger polyps (P < 0.001); polypectomy then resection with piecemeal excision (P = 0.002) and involved polypectomy margin (P < 0.001). Poor differentiation (OR 7.860, 95% CI 1.117-55.328; P = 0.038) independently predicted lymph node involvement. Submucosal venous invasion (hazard ratio [HR] 10.154, 95% CI 2.087-49.396; P = 0.004) and mucinous subtype (HR 7.779, 95% CI 1.566-38.625; P = 0.012) independently predicted recurrence. Submucosal venous invasion (HR 5.792, 95% CI 1.056-31.754; P = 0.043) predicted CRC-specific survival. Although 64.4% of polypectomy-only patients had margin involvement/other risk factors, none developed recurrence. Of 94 with polypectomy margin involvement, five (5.3%) had confirmed residual tumour. Overall, lymph node metastases (7.1%), recurrence (4.2%) and cancer-specific mortality (3.0%) were rare. Cancer-specific 5-year survival was high: polypectomy only (100%), polypectomy and then resection (98.2%), primary resection (100%). CONCLUSION: Surveillance may be safe for more T1 CRC polyp patients. Multidisciplinary team discussion and informed patient choice are critical.

Familial intestinal polyposis and device assisted enteroscopy: where do we stand?

INTRODUCTION: Hereditary polyposis syndromes are a group of inherited disorders associated with a high risk of developing colorectal cancer. The best known ones are familial adenomatous polyposis (FAP), Peutz-Jeghers (PJS), juvenile polyposis and Cowden syndromes, as well as conditions predisposing to cancer, such as Lynch syndrome. Some of them are characterized by an increased risk of small bowel polyps occurrence. AREAS COVERED: Literature search in PubMed was performed in November 2022 and a narrative review was carried out. Since performing small bowel polypectomy is important in such patients, device assisted enteroscopy (DAE) is the key for this procedure. A screening strategy for small bowel polyps is recommended only for PJS. Guidelines endorse either magnetic resonance imaging (MRI) or videocapsule endoscopy (VCE) every 1-3 years, according to the phenotype of the disease. Enteroscopy should be considered for therapeutic purpose in patients with a positive VCE or MRI. DAE has a central role in the resection of polyps larger than mm or causing symptoms of subocclusion or intussusception. Both single (SBE) and double balloon enteroscopy (DBE) are indicated and able to resect polyps up to 6-10 cm. American guidelines have restricted the indications to small bowel enteroscopy only to FAP patients with grade IV Spiegelman. EXPERT OPINION: Only some groups of patients (PJS, FAP with demonstrated small bowel polyp burden) may benefit from DAE.

Through-the-scope suture closure of nonampullary duodenal endoscopic mucosal resection defects: a retrospective multicenter cohort study.

BACKGROUND: Delayed bleeding is among the most common adverse events associated with endoscopic mucosal resection (EMR) of nonampullary duodenal polyps. We evaluated the rate of delayed bleeding and complete defect closure using a novel through-the-scope (TTS) suturing system for the closure of duodenal EMR defects. METHODS: We reviewed the electronic medical records of patients who underwent EMR for nonampullary duodenal polyps of ≥ 10 mm and prophylactic defect closure with TTS suturing between March 2021 and May 2022 at centers in the USA. We evaluated the rates of delayed bleeding and complete defect closure. RESULTS: 36 nonconsecutive patients (61 % women; mean [SD] age, 65 [12] years) underwent EMR of ≥ 10-mm duodenal polyps followed by attempted defect closure with TTS suturing. The mean (SD) lesion size was 29 (19) mm, defect size was 37 (25) mm; eight polyps (22 %) involved > 50 % of the lumen circumference. Complete closure was achieved in all cases (78 % with TTS suturing alone), using a median of one TTS suturing kit. There were no cases of delayed bleeding and no adverse events attributed to application of the TTS suturing device. CONCLUSION: Prophylactic closure of nonampullary duodenal EMR defects using TTS suturing resulted in a high rate of complete closure and no delayed bleeding events.

Solitary juvenile polyp of the rectum with intramucosal adenocarcinoma.

We describe a case of solitary juvenile polyp of the rectum with intramucosal adenocarcinoma. A 55-year-old man presented to our hospital for evaluation after a positive fecal occult blood test. Colonoscopy revealed a pedunculated polyp of 25 mm in size which has an irregular shape and pale red color on the rectum. The polyp had a proliferation of blood vessels and an invisible surface pattern. Endoscopic mucosal resection was performed. Pathologically, it was diagnosed as a solitary juvenile polyp with intramucosal well-differentiated adenocarcinoma. When we encounter juvenile polyps, the possibility of malignancy should be taken into consideration for treatment.

Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. SUMMARY: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. KEY MESSAGES: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.