Deficient mismatch repair screening of advanced adenomas in the population screening program for colorectal cancer is not effective.

AIM: Currently, screening of colorectal cancers (CRC) by assessing mismatch repair deficiency (dMMR) or microsatellite instability (MSI) is used to identify Lynch syndrome (LS) patients. Advanced adenomas are considered immediate precursor lesions of CRC. In this study we investigate the relevance of screening of advanced adenomas for LS in population screening. METHODS AND RESULTS: Advanced adenomas (n = 1572) were selected from the Dutch colorectal cancer population screening programme, based on one or more of the criteria: tubulovillous (n = 848, 54%) or villous adenoma (n = 118, 7.5%), diameter ≥ 1 cm (n = 1286, 82%) and/or high-grade dysplasia (n = 176, 11%). In 86 cases (5%), all three criteria were fulfilled at the same time. MMR-IHC and/or MSI analyses were performed on all cases. Only five advanced adenomas (0.3%) showed dMMR and MSI, including two cases with hypermethylation. In at least two patients a germline event was suspected based on allelic frequencies. No pathogenic explanation was found in the last case. CONCLUSION: Timely testing of precursor lesions would be preferable to detect new LS patients before CRC development. However, standard assessment of dMMR of advanced adenomas from the population screening is not effective.

Risk factors for advanced colorectal neoplasia and colorectal cancer detected at surveillance: a nationwide study in the modern era.

AIM: Recommendations for surveillance after colonoscopy are based on risk factors for metachronous advanced colorectal neoplasia (AN) and colorectal cancer (CRC). The value of these risk factors remains unclear in populations enriched by individuals with a positive faecal immunochemical test and were investigated in a modern setting. METHODS AND RESULTS: This population-based cohort study included all individuals in the Netherlands of ≥55 years old with a first adenoma diagnosis in 2015. A total of 22,471 patients were included. Data were retrieved from the Dutch Nationwide Pathology Databank (Palga). Primary outcomes were metachronous AN and CRC. Patient and polyp characteristics were evaluated by multivariable Cox regression analyses. During follow-up, 2416 (10.8%) patients were diagnosed with AN, of which 557 (2.5% from the total population) were CRC. Adenomas with high-grade dysplasia (hazard ratio [HR] 1.60, 95% confidence interval [CI] 1.40-1.83), villous histology (HR 1.91, 95% CI 1.59-2.28), size ≥10 mm (HR 1.12, 95% CI 1.02-1.23), proximal location (HR 1.12, 95% CI 1.02-1.23), two or more adenomas (HR 1.28, 95% CI 1.16-1.41), and serrated polyps ≥10 mm (HR 1.67, 95% CI 1.42-1.97) were independent risk factors for metachronous AN. In contrast, only adenomas with high-grade dysplasia (HR 2.49, 95% CI 1.92-3.24) were an independent risk factor for metachronous CRC. CONCLUSIONS: Risk factors for metachronous AN and CRC were identified for populations with access to a faecal immunochemical test (FIT)-based screening programme. If only risk factors for metachronous CRC are considered, a reduction in criteria for surveillance seems reasonable.

Colorectal Cancer Risk in Patients With Lynch Syndrome and Inflammatory Bowel Disease.

Lynch syndrome and inflammatory bowel diseases (IBD) are associated with an increased risk of colorectal cancer (CRC). However, it is not clear whether the risk of CRC is even higher for patients with a combination of Lynch syndrome and IBD. We investigated the risk for CRC in this subgroup by establishing a Lynch syndrome cohort from the Radboud University Medical Center (Nijmegen, The Netherlands) and the Academic Medical Center (Amsterdam, The Netherlands). Patients with heterozygous germline mutations in MLH1, MSH2 (and EPCAM deletion-mediated MSH2 methylation), MSH6, or PMS2 who were tested and/or treated from 1998 through 2014 were included. Patients who developed IBD were identified by linkage of this cohort to the Dutch nationwide Pathology Registry (PALGA). Subsequently, we compared the risk of CRC between Lynch syndrome patients with IBD and without IBD. Of 1046 patients with Lynch syndrome, 15 developed IBD (1.4%). Patients with Lynch syndrome and IBD were significantly younger (median age, 38.0 y) than patients with Lynch syndrome without IBD (median age, 52.0 y; P = .001). Nevertheless, a similar proportion of patients in each group developed CRC: 4 of the 15 patients (26.7%) with Lynch syndrome and IBD compared with 311 of the 1031 patients (30.2%) with Lynch syndrome without IBD. Patients with Lynch syndrome and IBD developed CRC at a younger age (median age, 36.0 y) than patients with Lynch syndrome without IBD (median age, 46.0 y; P = .045). However, the cumulative incidence of CRC was similar between groups (P = .121). All patients with Lynch syndrome and IBD who developed CRC had ulcerative colitis, producing a higher cumulative incidence of CRC for this IBD subgroup (P < .001). In conclusion, patients with Lynch syndrome and IBD develop CRC risk at a younger age than patients without IBD; patients with ulcerative colitis are at especially high risk.

Management of sporadic duodenal adenomas and the association with colorectal neoplasms: a retrospective cohort study.

GOALS: To evaluate management, outcome, and follow-up of patients with sporadic duodenal adenomas and assess the presence of colorectal neoplasms. BACKGROUND: With the widespread use of esophagogastroduodenoscopy, an increasing number of sporadic duodenal adenomas are diagnosed. An optimal algorithm for management has not been fully defined. Accumulating data suggest an association with colorectal neoplasms. STUDY: Patients diagnosed with sporadic duodenal adenomas at our institute from 1986 until 2008 were retrospectively reviewed. Data were collected from medical records. RESULTS: Fifty-four patients (28 men, 52%) were diagnosed with a sporadic duodenal adenoma at a median age of 59 years (range, 27 to 84 y); 33 patients (61%) underwent endoscopic or surgical intervention, 5 (9%) were only followed endoscopically, and 16 (30%) underwent no intervention or follow-up. Complete endoscopic removal was accomplished in at least 81% of cases, and no complications were reported; surgical intervention was complicated in 4 patients, with 1 resulting in death. Adenoma recurrence was 20% at a median follow-up of 18 months (range, 4 to 54 mo), but no carcinoma developed. Colorectal neoplasms were found in 16 of 29 patients (55%) who underwent colonoscopy, including 2 cancers (7%), 7 advanced adenomas (24%), and 7 nonadvanced adenomas (24%). CONCLUSIONS: Although no consistent approach to management of sporadic duodenal adenomas was followed, no duodenal carcinoma developed during the follow-up. Endoscopic intervention is preferred over surgical intervention, whenever possible. Once complete removal is ascertained, there is no strict indication for regular follow-up esophagogastroduodenoscopy, especially in elderly patients or patients with relevant comorbidity. Colonoscopic assessment is warranted in all patients diagnosed with sporadic duodenal adenomas.

Detection and Yield of Colorectal Cancer Surveillance in Adults with PTEN Hamartoma Tumour Syndrome.

Colorectal cancer surveillance (CCS) with colonoscopy every five years is advised for PTEN Hamartoma Tumour Syndrome (PHTS) patients aged ≥40 due to an increased colorectal cancer (CRC) risk. However, data to support CCS guidelines are scarce and available CRC risks are low (0-5% at age 50) and likely overestimated. We aimed to assess the detection and yield of CCS for PHTS patients without a CRC history. A retrospective cohort study including PHTS patients aged ≥40 with CCS at a PHTS expertise centre between 2011 and 2022. Adenomas with a ≥10 mm size, (tubulo)villous histology, or high-grade dysplasia were considered advanced. During 67 follow-up years, 37 patients (median age 47 years) underwent 61 colonoscopies. CCS yielded no CRCs. Adenomas were diagnosed in 13/37 (35%) patients during 23/100 colonoscopies (95% CI: 14-36), including one advanced adenoma. Baseline adenoma detection rates were similar to follow-up and higher in patients aged above 50 (50/100, 95% CI: 24-76) vs. age 50 or below (11/100, 95% CI: 3-30; p = 0.021). The low CRC and advanced adenoma yield allow for a more personalised surveillance program. Following our findings combined with literature on CRC risk and progression, we suggest starting CCS at age 40 with variable follow-up intervals between 1 and 10 years depending on previous colonoscopy findings.

The Workgroup Serrated Polyps and Polyposis (WASP) classification for optical diagnosis of colorectal diminutive polyps with iScan and the impact of the revised World Health Organization (WHO) criteria.

BACKGROUND AND AIMS: The Workgroup Serrated Polyps and Polyposis (WASP) developed criteria for optical diagnosis of colorectal polyps. The aims of this study were: (1) to improve optical diagnosis of diminutive colorectal polyps, especially SSLs, after training endoscopists in applying WASP criteria on videos of polyps obtained with iScan and (2) to evaluate if the WASP criteria are still useful when polyps are pathologically revised according to the World Health Organization (WHO) 2019 criteria. METHODS: Twenty-one endoscopists participated in a training session and predicted polyp histology on 30 videos of diminutive polyps, before and after training (T0 and T1 ). After three months, they scored another 30 videos (T2 ). Primary outcome was overall diagnostic accuracy (DA) at T0 , T1 and T2 . Polyps were histopathologically classified according to the WHO 2010 and 2019 criteria. RESULTS: Overall DA (both diminutive adenomas and SSLs) significantly improved from 0.58 (95% CI 0.55-0.62) at T0 to 0.63 (95% CI 0.60-0.66, p = 0.004) at T1 . For SSLs, DA did not change with 0.51 (95% CI 0.46-0.56) at T0 and 0.55 (95% CI 0.49-0.60, p = 0.119) at T1 . After three months, overall DA was 0.58 (95% CI 0.54-0.62, p = 0.787, relative to T0 ) while DA for SSLs was 0.48 (95% CI 0.42-0.55, p = 0.520) at T2 . After pathological revision according to the WHO 2019 criteria, DA of all polyps significantly changed at all time points. CONCLUSION: A training session in applying WASP criteria on endoscopic videos made with iScan did not improve endoscopists' long-term ability to optically diagnose diminutive polyps. The change of DA following polyp revision according to the revised WHO 2019 criteria suggests that the WASP classification may need revision.

2-(18F)-fluoro-2-deoxy-D-glucose positron emission tomography detects clinical relevant adenomas of the colon: a prospective study.

PURPOSE: 2-(18F)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is a noninvasive imaging technique used clinically to detect malignant tumors. FDG-PET has been established as a tool for diagnosis of recurrent or metastatic colorectal carcinoma. Several case series suggest that FDG-PET also detects larger adenomas. The goal of this study was to investigate whether FDG-PET is able to detect colonic adenomas. PATIENTS AND METHODS: FDG-PET was performed in 100 consecutive patients in whom colonic adenomas were suspected on barium enema (n = 47) or sigmoidoscopy (n = 53). A positive scan was defined as focal large bowel FDG accumulation. FDG-PET was followed in all cases by colonoscopy, and removed adenomas were examined histopathologically. RESULTS: Colonoscopy confirmed the presence of adenomas in 68 of 100 patients. In 35 patients, there was focal FDG accumulation at site of the adenoma. The sensitivity of FDG-PET increased with adenoma size (21%, adenomas 1 to 5 mm; 47%, 6 to 10 mm; and 72%, > 11 mm). The sensitivity of FDG-PET also increased with the grade of dysplasia (33%, low grade; 76%, high grade; and 89%, carcinomas). The overall specificity was 84%. CONCLUSION: FDG-PET detects colonic adenomas and the diagnostic test characteristics improve with size and grade of dysplasia of the adenoma.

Noninvasive monitoring of colonic carcinogenesis: feasibility of [(18)F]FDG-PET in the azoxymethane model.

BACKGROUND: Azoxymethane (AOM) is a potent carcinogen that induces colorectal cancer and adenomas in rats. [(18)F]FDG-PET is a molecular imaging technique that is based on the elevated uptake and retention of radiolabeled glucose. At present, it is unknown at which stage FDG accumulation occurs during the adenoma carcinoma sequence. To address this issue, we studied the FDG uptake in AOM-induced rat colorectal adenocarcinoma (CRC) and correlated this with histopathological findings. METHODS: Seventy Fischer 344 rats were injected with AOM. Terminal autopsy took place 20-38 weeks after the first AOM injection. After [(18)F]FDG PET scanning, the rats were sacrificed, tissue [(18)F]FDG uptake was measured, followed by histopathological examination. RESULTS: Macroscopic examination revealed 21 tumors (7 located in the small bowel and 14 in the colon) in 19 rats. On histological examination, we found 10 colonic adenocarcinomas (the first being observed at Week 22) and 7 adenocarcinoma in the small bowel. In total, seven colon adenomas were found in five rats, six of which expressed high-grade dysplasia. The [(18)F]FDG accumulation in small intestine carcinomas was well beyond background accumulation (P<.0001). On PET scanning, two rats showed focal accumulation of the abdominal area, corresponding to small intestine carcinomas. CONCLUSION: Adenocarcinomas had a significantly higher [(18)F]FDG uptake than background bowel uptake. [(18)F]FDG uptake was lower in adenomas than in carcinomas. These data suggest that the AOM model allows the evaluation of intervention strategies with [(18)F]FDG uptake as a valid outcome measure.

FDG-PET in the detection of early pancreatic cancer in a BOP hamster model.

BACKGROUND: The prognosis of pancreatic cancer (PC) is highly dependent on the stage of the disease, and early recognition improves survival. Positron emission tomography (PET) using (18)F-fluoro-2-deoxyglucose ([(18)F]FDG) has been established as an important clinical tool for PC diagnosis, but it is not known whether FDG-PET detects premalignant stages of PC. We speculate that [(18)F]FDG uptake precedes the onset of PC in a hamster model. We used the N-nitrosobis(2-oxopropyl)amine (BOP) model, as these animals consistently develop PC within 20 weeks after first injection. METHODS: Male Syrian hamsters were injected once a week with 10 mg BOP/kg body weight for 10 consecutive weeks. Terminal autopsy took place in groups of five hamsters from 4 weeks until 28 weeks after first BOP injection. After an 8-h fast, hamsters were injected with [(18)F]FDG and sacrificed 1 h after [(18)F]FDG injection. The pancreata were histopathologically examined, and the [(18)F]FDG uptake was determined and expressed as percentage of the injected dose per gram tissue (%ID/g). RESULTS: Seven of 55 hamsters developed macroscopic signs of tumor. Histopathological examination revealed PC in 13 hamsters. [(18)F]FDG uptake increased gradually with time and was significantly higher in the group with PC compared to the group without PC. CONCLUSION: [(18)F]FDG accumulates preferentially in PC, and pancreata exposed to BOP showed a gradual increase in [(18)F]FDG accumulation.

[18F]Fluoro-2-deoxy-D-glucose positron emission tomography detects gastric carcinoma in an early stage in an asymptomatic E-cadherin mutation carrier.

PURPOSE: Autosomal dominant hereditary diffuse gastric cancer (HDGC) is caused by germ-line E-cadherin (CDH1) gene mutations. Early detection of cancer in carriers is difficult because HDGC escapes endoscopic detection. We hypothesized that the glucose metabolism is enhanced in HDGC and that this can be detected with [18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET). EXPERIMENTAL DESIGN AND RESULTS: An asymptomatic twenty-eight year-old female was seen at our outpatient clinic because of a request for screening on HDGC. Her father and younger sister died of diffuse gastric cancer, at the ages of 52 and 27, respectively. Mutational analysis of the CDH1 gene in this patient demonstrated a novel heterozygous splice-site mutation in exon 8 (1135delACGGTAATinsTTAGA). Upper gastrointestinal endoscopies revealed no macroscopic abnormalities, but one of the 40 random biopsy specimens showed well-differentiated signet-cell carcinoma. A FDG-PET scan demonstrated two spots of FDG accumulation, one located in the proximal part of the stomach and the second in the region of the pylorus. A total gastrectomy was performed and microscopic examination showed focal localization of intramucosal adenocarcinoma of the signet-cell type in the cardiac and antrum area. Most notably, the localization of the FDG accumulation matched the localization of the carcinoma. CONCLUSIONS: We present an asymptomatic patient from a HDGC family carrying a novel CDH1 mutation in whom FDG-PET scanning facilitated early detection of HDGC. This calls for further investigation of the role of FDG-PET scan as a screening modality in HDGC.

[A man with multiple mucosal lesions and pancytopenia]. / Een man met pancytopenie en mucosale afwijkingen.

A 57-year-old man came to the Emergency Department because of painful oral ulcers and skin lesions. He used methotrexate because of psoriasis, but he stopped using folic acid. Laboratory tests showed signs of dehydration and pancytopenia. We made the diagnosis 'methotrexate-intoxication'.

Upper gastrointestinal endoscopy in patients aged 85 years or more. Results of a feasibility study in a district general hospital.

We performed a cross sectional analysis of the feasibility and yield of upper gastrointestinal endoscopy (UGE) in a cohort of patients aged 85 years or more. The study involved 218 patients who underwent diagnostic upper gastrointestinal endoscopy in a district general hospital between 1994 and 1998. Indication, use of sedation, endoscopic findings and treatment after endoscopy were evaluated. Indications for gastroscopy were suspicious of upper gastrointestinal bleeding (UGI) bleeding (41%), anemia (15%), and presence of dyspeptic- (31%), alarm- (9%) and/or reflux symptoms (3%). Serious UGI disease (cancer, peptic ulcer, reflux oesofagitis and/or erosive gastritis/duodenitis) was detected in 97 patients (44%). With respect to clinical presentation, serious UGI disease was present in 61% with bleeding, in 57% with reflux symptoms, in 42% with alarm symptoms, in 33% with anemia and in 28% with dyspepsia. Carcinoma was detected in eight patients (3.8%), all of them were treated with supportive care. In very old people gastroscopy is generally performed on sound indications reveals serious UGI disease in almost one out of two patients, markedly influences medical treatment, and reveals low malignancy rates (3.8%). In these patients, UGE is worthwhile and should not be omitted because of age considerations.

Patients' perception of colonoscopy: patients with inflammatory bowel disease and irritable bowel syndrome experience the largest burden.

BACKGROUND: Colonoscopy is a frequently performed procedure worldwide with a negative perception, leading to reluctance to undergo the procedure. Perceptions could differ depending on the specific indication for the colonoscopy. AIMS: To compare patient satisfaction with the colonoscopy procedure between five different patient groups: inflammatory bowel disease (IBD), familial predisposition for cancer, adenoma/carcinoma surveillance, symptoms suggestive of cancer, and irritable bowel syndrome (IBS). METHODS: A prospective questionnaire study was carried out in two regional hospitals and two tertiary teaching hospitals in the Netherlands. A total of 797 consecutive patients scheduled for colonoscopy between October 2009 and June 2010, 146 (18%) IBD, 153 (19%) adenoma or carcinoma surveillance, 104 (13%) familial predisposition, 280 (35%) symptoms suggestive of cancer, and 114 (14%) IBS-like symptoms, were included. Two questionnaires were administered: one on the day of the procedure and another 6 weeks after the procedure. The main outcome measurements were embarrassment, pain, burden, most burdensome aspect, and overall level of satisfaction. RESULTS: Patients with IBD and IBS reported significantly more embarrassment and burden from the bowel preparation phase (P=0.040 and 0.018, respectively) and more pain during the colonoscopy procedure (P=0.018). This difference in pain was also observed when adjusting for volume of sedation administered, familiarity with the endoscopist, duration of the colonoscopy, or whether or not an intervention was performed. All patient groups were less satisfied with the procedure at 6 weeks than directly after the colonoscopy; they recalled more embarrassment and burden, but less pain. CONCLUSION: Patient groups, defined by indication for colonoscopy, experience the colonoscopy procedure differently.

A prospective study of bowel preparation for colonoscopy with polyethylene glycol-electrolyte solution versus sodium phosphate in Lynch syndrome: a randomized trial.

Lynch gene carriers undergo regular surveillance colonoscopies. Polyethylene glycol-electrolyte solution (PEG) is routinely prescribed for bowel cleansing, but often poorly tolerated by patients. Sodium phosphate (NaP) may be an alternative. Prospective and random comparison of bowel preparation with PEG and NaP on colon cleansing and patients' acceptance. Patients, who previously underwent a colonoscopy, were invited to participate and randomly assigned to either PEG or NaP. They were asked to fill in a questionnaire about preparation tolerability and future preferences. The endoscopist filled out a report about the quality of colon cleansing. 125 Patients were included in the study. Nine (7%) were excluded because of missing data. The remaining 116 patients (53 PEG and 63 NaP) were included in the analysis. Baseline characteristics did not differ between groups. Before colonoscopy 20 (38%) patients using PEG experienced the preparation almost intolerable, in contrast to 7(11%) of those using NaP (P = 0.001). Eleven patients in the PEG group and 48 in the NaP group would prefer NaP in the future. The colonoscopy was poorly tolerated in 17% of the individuals in both groups (P = 0.963). The endoscopist observed a more than 75% clean colon in 83% of patients on PEG and in 71% of patients on NaP (P = 0.076), however the coecum (P = 0.025) and ascending colon was cleaner after PEG. Lynch patients tolerated NaP better and preferred this formula for future bowel preparation. Colon cleansing was suboptimal with both treatments with a tendency towards a cleaner proximal colon with PEG.

Ability of FDG-PET to detect all cancers in patients with familial adenomatous polyposis, and impact on clinical management.

PURPOSE: Familial adenomatous polyposis (FAP) is characterised by colonic and duodenal adenomatous polyps that carry a risk of malignant transformation. Malignant degeneration of duodenal adenomas is difficult to detect. We speculated that 2-((18)F)-fluoro-2-deoxy-D: -glucose positron emission tomography (FDG-PET) might be able to detect early duodenal cancer in FAP. Accordingly, we investigated the role of FDG-PET in the management of FAP patients. METHODS: FDG-PET was performed in 24 FAP patients. Eight had advanced duodenal adenomas (Spigelman IV), including two patients with duodenal cancer. Scans were defined as positive on the basis of focal FDG accumulation. RESULTS: Pathological FDG accumulation was absent in 19 of 24 patients. All six patients with Spigelman IV duodenal adenomas (without cancer) were negative; two of these underwent a duodenectomy and pathological examination did not reveal duodenal cancer. In five patients, FDG-PET revealed significant uptake, in the duodenum (2), lower abdomen (1), lung (1) and multiple sites in the abdomen (1). These hot spots correlated with duodenal cancer (2), abdominal metastasis (1) and sclerosing haemangioma of the lung (1). We failed to make a histopathological diagnosis in the single patient with multiple intra-abdominal sites of FDG uptake. None of the patients from the FDG-PET-negative group developed cancer during follow-up (mean 2.8 years). CONCLUSION: FDG-PET detected all the cancers present, and none of the patients with negative FDG-PET developed cancer. This suggests that positive FDG-PET in FAP patients should lead to further examinations to rule out cancer. In patients with negative FDG-PET a more conservative approach seems justified.

FDG-PET is able to detect pancreatic carcinoma in chronic pancreatitis.

PURPOSE: 2-(18F)-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is an imaging technique which enables detection of malignancies. FDG-PET has been established as a tool for the diagnosis of pancreatic carcinoma (CA). Early detection is mandatory as cure can only be achieved in non-advanced disease. This is, however, very difficult with conventional radiological techniques. Patients with chronic pancreatitis (CP) are at risk of developing CA. A simple, reliable screening method for malignant degeneration is highly desirable. We set out to investigate whether FDG-PET is able to detect CA in the setting of CP and can fulfil a potential role in the early detection of CA in CP. METHODS: FDG-PET was performed in 77 CP patients and in six patients with CP complicated by CA (CP + CA). We included 26 CA patients as a positive control. A positive scan was defined as focal FDG accumulation in the pancreas region. RESULTS: In 67 of the 77 CP (87%) patients, pancreatic FDG accumulation was absent. Six patients had significant accumulation. In CA, 24/26 patients had a positive PET. Five out of the six patients with CP + CA had focal uptake, while minor uptake was seen in one patient. FDG-PET was positive in almost all CA patients and CP + CA patients. FDG-PET was negative in the large majority (87%) of CP patients, which suggests that a positive PET scan in CP patients must lead to efforts to exclude a malignancy. CONCLUSION: These data suggest that FDG-PET has a potential role as a diagnostic tool for detecting CA in longstanding CP.