Objective This study evaluated the preresection accuracy of optical diagnosis of T1 colorectal cancer (CRC) in large non-pedunculated colorectal polyps (LNPCPs). Design In this multicentre prospective study, endoscopists predicted the histology during colonoscopy in consecutive patients with LNPCPs using a standardised procedure for optical assessment. The presence of morphological features assessed with white light, and vascular and surface pattern with narrow-band imaging (NBI) were recorded, together with the optical diagnosis, the confidence level of prediction and the recommended treatment. A risk score chart was developed and validated using a multivariable mixed effects binary logistic least absolute shrinkage and selection (LASSO) model. Results Among 343 LNPCPs, 47 cancers were found (36 T1 CRCs and 11 ≥T2 CRCs), of which 11 T1 CRCs were superficial invasive T1 CRCs (23.4% of all malignant polyps). Sensitivity and specificity for optical diagnosis of T1 CRC were 78.7% (95% CI 64.3 to 89.3) and 94.2% (95% CI 90.9 to 96.6), and 63.3% (95% CI 43.9 to 80.1) and 99.0% (95% CI 97.1 to 100.0) for optical diagnosis of endoscopically unresectable lesions (ie, ≥T1 CRC with deep invasion), respectively. A LASSO-derived model using white light and NBI features discriminated T1 CRCs from non-invasive polyps with a cross-validation area under the curve (AUC) of 0.85 (95% CI 0.80 to 0.90). This model was validated in a temporal validation set of 100 LNPCPs (AUC of 0.81; 95% CI 0.66 to 0.96). Conclusion Our study provides insights in the preresection accuracy of optical diagnosis of T1 CRC. Sensitivity is still limited, so further studies will show how the risk score chart could be improved and finally used for clinical decision making with regard to the type of endoresection to be used and whether to proceed to surgery instead of endoscopy. Trial registration number NTR5561.

Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5–2.5, 2.5–3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III–IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.

Background Screening of patients with familial adenomatous polyposis (FAP) have led to a substantial reduction in mortality due to colorectal cancer (CRC). Recent guidelines suggest that surveillance of non-intestinal malignancies should also be considered in those patients. However, the value of these surveillance programmes is unknown. The aims of this study were (1) to assess the occurrence of extracolonic malignancies in a large series of adenomatous polyposis coli (APC) mutation carriers and (2) to evaluate the causes of death. Methods All APC mutation carriers were selected from the Dutch polyposis registry. Data on causes of death were collected. Pathology reports were retrieved from the Dutch Pathology Registry. Results A total of 85 extracolonic malignancies were diagnosed in 74 of 582 APC mutation carriers. Duodenal and skin cancers were the most prevalent cancers. Thyroid cancer was observed in only 1.5% of the cases. The main cause of death was cancer (59% of all deaths), with 42% due to CRC and 21% due to duodenal cancer. One patient died from thyroid cancer. The second and third most common causes of death were cardiovascular disease (13% of all deaths) and desmoid tumours (11% of all deaths), respectively. Conclusion Extending surveillance programmes to other cancers will not contribute significantly to the survival of patients with FAP.

In patients with stage II colorectal cancer (CRC) the number of surgically retrieved lymph nodes (LNs) is associated with prognosis, resulting in a minimum of 10–12 retrieved LNs being recommended for this stage. Current guidelines do not provide a recommendation regarding LN yield in T1 CRC. Studies evaluating LN yield in T1 CRC suggest that such high LN yields are not feasible in this early stage, and a lower LN yield might be appropriate. We aimed to validate the cut-off of 10 retrieved LNs on risk for recurrent cancer and detection of LN metastasis (LNM) in T1 CRC, and explored whether this number is feasible in clinical practice. Patients diagnosed with T1 CRC and treated with surgical resection between 2000 and 2014 in thirteen participating hospitals were selected from the Netherlands Cancer Registry. Medical records were reviewed to collect additional information. The association between LN yield and recurrence and LNM respectively were analyzed using 10 LNs as cut-off. Propensity score analysis using inverse probability weighting (IPW) was performed to adjust for clinical and histological confounding factors (i.e., age, sex, tumor location, size and morphology, presence of LNM, lymphovascular invasion, depth of submucosal invasion, and grade of differentiation). In total, 1017 patients with a median follow-up time of 49.0 months (IQR 19.6–81.5) were included. Four-hundred five patients (39.8%) had a LN yield ≥ 10. Forty-one patients (4.0%) developed recurrence. LN yield ≥ 10 was independently associated with a decreased risk for recurrence (IPW-adjusted HR 0.20; 95% CI 0.06–0.67; P = 0.009). LNM were detected in 84 patients (8.3%). LN yield ≥ 10 was independently associated with increased detection of LNM (IPW-adjusted OR 2.27; 95% CI 1.39–3.69; P = 0.001). In this retrospective observational study, retrieving < 10 LNs was associated with an increased risk of CRC recurrence, advocating the importance to perform an appropriate oncologic resection of the draining LNs and diligent LN search when patients with T1 CRC at high-risk for LNM are referred for surgical resection. Given that both gastroenterologists, surgeons and pathologists will encounter T1 CRCs with increasing frequency due to the introduction of national screening programs, awareness on the consequences of an inadequate LN retrieval is of utmost importance.