Consensus molecular subtype transition during progression of colorectal cancer.

The consensus molecular subtype (CMS) classification divides colorectal cancer (CRC) into four distinct subtypes based on RNA expression profiles. The biological differences between CMSs are already present in CRC precursor lesions, but not all CMSs pose the same risk of malignant transformation. To fully understand the path to malignant transformation and to determine whether CMS is a fixed entity during progression, genomic and transcriptomic data from two regions of the same CRC lesion were compared: the precursor region and the carcinoma region. In total, 24 patients who underwent endoscopic removal of T1-2 CRC were included. Regions were subtyped for CMS and DNA mutation analysis was performed. Additionally, a set of 85 benign adenomas was CMS-subtyped. This analysis revealed that almost all benign adenomas were classified as CMS3 (91.8%). In contrast, CMS2 was the most prevalent subtype in precursor regions (66.7%), followed by CMS3 (29.2%). CMS4 was absent in precursor lesions and originated at the carcinoma stage. Importantly, CMS switching occurred in a substantial number of cases and almost all (six out of seven) CMS3 precursor regions showed a shift to a different subtype in the carcinoma part of the lesion, which in four cases was classified as CMS4. In conclusion, our data indicate that CMS3 is related to a more indolent type of precursor lesion that less likely progresses to CRC and when this occurs, it is often associated with a subtype change that includes the more aggressive mesenchymal CMS4. In contrast, an acquired CMS2 signature appeared to be rather fixed during early CRC development. Combined, our data show that subtype changes occur during progression and that CMS3 switching is related to changes in the genomic background through acquisition of a novel driver mutation (TP53) or selective expansion of a clone, but also occurred independently of such genetic changes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Extracolonic cancer risk in Dutch patients with APC (adenomatous polyposis coli)-associated polyposis.

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.

Optical diagnosis of malignant colorectal polyps: is it feasible?

BACKGROUND AND STUDY AIMS: As colorectal cancer screening programs are being implemented worldwide, an increasing number of early (T1) cancers are being diagnosed. These cancers should be recognized during colonoscopy because they require a specific therapeutic approach. Several studies have shown that Asian experts can reliably recognize T1 cancers during colonoscopy. In daily practice, however, accurate endoscopic diagnosis of T1 cancers still seems challenging. We evaluated the performance of optical diagnosis of T1 cancers by European colonoscopy experts, general gastroenterologists and gastrointestinal fellows. PATIENTS AND METHODS: We collected endoscopic images of 43 colonic lesions: 19 T1 cancers (excluding intramucosal carcinoma) and 24 benign polyps ranging from 7 mm to 30 mm in size. Seven colonoscopy experts, 7 general gastroenterologists, and 14 gastrointestinal fellows assessed these images. We calculated sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) and their 95 % confidence intervals for optical diagnosis of T1 cancers. RESULTS: Overall sensitivity for correct diagnosis of T1 cancers was 60 % (95 % CI;45 - 72). Sensitivity was highest for experts (67 %: 95 %CI; 48 - 81), when compared to general gastroenterologists (53 %: 95 %CI; 37 - 69) and gastrointestinal fellows (59 %: 95 %CI;45 - 72). The overall NPV was 75 % (95 %CI;60 - 86); NPV was lowest for general gastroenterologists 72 % (95 %CI;57 - 83) vs 78 % (95 %CI;63 - 89) for experts and 75 % (95 %CI;60 - 85) for gastrointestinal fellows. CONCLUSIONS: In this image-based study, both sensitivity for the optical diagnosis of a T1 cancer and NPV for excluding a T1 cancer were insufficient. Experts performed best with a sensitivity of 67 % and a NPV of 78 %, while the performance of fellows in the last year of training was comparable to that of experts. Our study indicates that training for endoscopic diagnosis for T1 cancers is urgently needed to ensure optimal clinical practice for treatment of these lesions.