Post-colonoscopy colorectal cancer (PCCRC), defined as colorectal cancer (CRC) detected after a cancer-negative colonoscopy, represents a key quality indicator for CRC detection and prevention. While most PCCRC is attributed to missed lesions, few studies examine pathologic and molecular characteristics of PCCRC to assess for possible de novo cancer formation causing PCCRC.

The aim of this study was to identify cases of PCCRC where prior colonoscopy was adequate (A-PCCRC) versus inadequate (I-PCCRC) and compare both subtypes with spontaneous CRC (sCRC) in terms of patient factors, histopathology and molecular characteristics.

This was a 12-year retrospective population-based study using a data set from the Western Australian Cancer Registry between 2000 and 2011. A-PCCRCs were identified by excluding lesions likely missed due to procedural factors or incomplete prior resection at index colonoscopy performed within 3-36 months of cancer diagnosis. Histopathological review and next-generation sequencing were conducted on subsets of patients with A-PCCRC and sCRC. Statistical analysis included univariable and multivariable regression models and chi-squared and Wilcoxon rank sum tests.

A total of 524 (3.81%) cases of PCCRC were identified out of 13 757 cases of CRC; 272 were A-PCCRC (1.98%) and 252 I-PCCRC (1.83%). Female sex, older age and proximal location were associated with A-PCCRC. Mutations in the PIK3CA gene were less common in A-PCCRC compared to sCRC.

A significant percentage of PCCRC occurred despite adequate prior colonoscopy. Missed sessile serrated lesions may contribute to many of these cases; however, further studies are required to examine possible de novo cancer as a cause of PCCRC that may involve unique biological pathways.

Chronic gut inflammation and dysbiosis contribute significantly to colorectal cancer (CRC) development. Shaoyao decoction (SYD) is a well-established Chinese medicine prescription. Besides ameliorating CRC via anti-inflammatory effects, SYD modulates gut microbiota (GM) to improve inflammatory responses in ulcerative colitis (UC). However, whether and how SYD suppresses CRC by regulating GM remains largely unknown.

SD rats were orally administered SYD for 7 days to obtain medicated serum. We utilized liquid chromatography-mass spectrometry (LC-MS) analysis, GeneCards, DisGeNET, and SwissTargetPrediction databases to analyze blank and SYD-medicated rat serum, comparing the findings with those of SYD aqueous extract in previous studies to identify SYD circulating compounds/components with predictable target genes. Using network pharmacology, the potential active compounds and corresponding hub genes associated with modulating GM to suppress CRC were selected for molecular docking. In vivo experiments, a CRC transplantation tumor model was established in BALB/c mice using CT26 cells, with SYD gavage for 14 days. To investigate the mechanism of SYD-regulated GM against CRC, HE and IHC staining, Western blotting, and 16S rRNA sequencing were employed.

LC-MS identified 26 SYD compounds with computationally predicted target genes. Network pharmacology prioritized 13 compounds targeting 8 inflammation/immunity-related genes (IL-17/TNF pathways), validated by molecular docking. In vivo experiments, SYD dose-dependently suppressed tumor growth (p < 0.05, medium/high doses), as confirmed by HE staining and IHC analysis of Ki-67. Notably, SYD potentially delayed CRC liver metastasis and alleviated hepatic injury in tumor-bearing mice. Western blotting demonstrated SYD's inhibition of the IL-17/TNF/NF-κB axis, aligning with computational predictions. 16S rRNA sequencing revealed SYD-enriched Akkermansia and GM structural shifts, mechanistically linking microbiota remodeling to anti-tumor efficacy.

SYD combats CRC via dual modulation of IL-17/TNF/NF-κB signaling and GM ecosystems (e.g., Akkermansia enrichment). This microbiota-immune crosstalk positions SYD as a potential adjunct to conventional therapies, particularly for CRC patients with dysbiosis.

A 69-year-old female was presented with a history of sigmoid colon cancer, uterine cancer, and intrahepatic carcinomas. After computed tomography revealed a disseminated nodule located in the peritoneum, colonoscopy demonstrated a rather flat-to-slightly elevated lesion with a depressed area located in the ascending colon. The flat component showed color similar to its surrounding area, and the depressed area showed redness and an expanded appearance. We obtained a biopsy specimen from the depressed area, and microscopic examination revealed well-differentiated adenocarcinoma, which was immunohistochemically positive for BRAF V600E-mutated and PMS2 proteins, and showed loss of MSH2 and MSH6 protein expressions. These findings suggested the lesion to have transformed from a sessile serrated lesion (SSL) to mismatch repair (MMR) deficient colon cancer. The patient underwent surgical removal of the nodule, which interpreted as metastasis of intrahepatic cholangiocarcinoma histopathologically. After postoperative chemotherapy, the follow-up colonoscopy revealed only the flat portion of the lesion without depressed area. Consequently, we performed an endoscopic resection, and microscopic examination confirmed the existence of BRAF V600E-mutated protein-positive and MMR protein-retained SSL without residual carcinoma. This is the first report of BRAF-mutant and MMR-deficient colon cancer, in association with SSL, showing regression.

Sessile serrated lesions (SSLs) are precursors of sporadic colorectal cancer (CRC) and have distinct characteristics compared with conventional adenomas (CAs). Several lifestyle and environmental factors may play critical roles in the development of advanced lesions. Our aim is to describe the features of SSLs and CAs and further explore risk factors for advanced lesions.

This is an observational study that collected demographic, endoscopic, and histological data from the China-Japan Friendship Hospital among the inpatient population with pathologically reported as SSL or CA between 2015 and 2022. We analyzed the clinicopathology and endoscopic differences between SSL alone, CA alone, and synchronous SSL+CA groups, and identified risk factors using multiple regression analysis.

A total of 9236 polyps from 6598 patients were included in the cohort. Patients with SSL+CA were more likely to be older (p=0.008), while individuals with SSL alone had a higher proportion of early-onset polyps (p<0.001), and SSLs were more common in advanced polyps than CAs (p<0.001). A greater proportion of advanced polyps in the SSL and CA groups were diagnosed as Yamada III, Yamada IV, and laterally spreading tumor (p=0.002, p<0.001, respectively), and multiple SSLs and CAs were more represented in nonadvanced polyps than in advanced polyps. In multiple regression analysis, older patients were more likely to develop advanced SSLs (aOR 1.05, 95% CI 1.02-1.09, p=0.005).

SSLs and CAs have diverse demographic, endoscopic, and histological characteristics, and their advanced lesions share different risk factors, which advances the understanding of the etiology and progression of SSLs.

As the serrated pathway has gained prominence as an alternative colorectal carcinogenesis pathway, sessile serrated adenomas or polyps (SSA/P) have been highlighted as lesions to rule out during colonoscopy. These lesions are however morphologically difficult to detect on endoscopy and can be mistaken for hyperplastic polyps due to similar endoscopic features. With the underlying nature of rapid progression and malignant transformation, interval cancer is a likely consequence of undetected or overlooked SSA/P. Real-time artificial intelligence (AI)-assisted colonoscopy via the computer-assisted detection system (CADe) is an increasingly useful tool in improving adenoma detection rate by providing a second eye during the procedure. In this article, we describe a guide through a video to illustrate the detection of SSA/P during AI-assisted colonoscopy.

Consultant-grade endoscopists utilized real-time AI-assisted colonoscopy device, as part of a larger prospective study, to detect suspicious lesions which were later histopathologically confirmed to be SSA/P.

All lesions were picked up by the CADe where a real-time green box highlighted suspicious polyps to the clinician. Three SSA/P of varying morphology are described with reference to classical SSA/P features and with comparison to the features of the hyperplastic polyp found in our study. All three SSA/P observed are in keeping with the JNET Classification (Type 1).

In conclusion, CADe is a most useful aid to clinicians during endoscopy in the detection of SSA/P but must be complemented with factors such as good endoscopy skill and bowel prep for effective detection, and biopsy coupled with subsequent accurate histological diagnosis.

Sessile serrated lesions (SSLs) are often missed on colonoscopy, and studies have shown this to be an essential cause of interstitial colorectal cancer. The SSLs with dysplasia (SSL-D+), in particular, have a faster rate of carcinogenesis than conventional tubular adenomas. Therefore, there is a clinical need for some endoscopic features with independent diagnostic value for SSL-D+s to assist endoscopists in making immediate diagnoses, thus improving the quality of endoscopic examination and treatment.

To compare the characteristics of SSLs, including those with and without dysplasia (SSL-D+ and SSL-D-), based on white light and image-enhanced endoscopy, to achieve an immediate differential diagnosis for endoscopists.

From January 2017 to February 2023, cases of colorectal SSLs confirmed by colonoscopy and histopathology at the Gastrointestinal Endoscopy Center of Beijing Tsinghua Changgung Hospital were collected. The general, endoscopic, and histopathological data were reviewed and analyzed to determine the diagnostic utility. Univariate analysis was used to find potential diagnostic factors, and then multivariate regression analysis was performed to derive endoscopic features with independent diagnostic values for the SSL-D+.

A total of 228 patients with 253 lesions were collected as a result. There were 225 cases of colorectal SSL-D-s and 28 cases of SSL-D+s. Compared to the colorectal SSL-D-, the SSL-D+ was more common in the right colon (P = 0.027) with complex patterns of depression, nodule, and elevation based on cloud-like surfaces (P = 0.003), reddish (P < 0.001), microvascular varicose (P < 0.001), and mixed type (Pit II, II-O, IIIL, IV) of crypt opening based on Pit II-O (P < 0.001). Multifactorial logistic regression analysis indicated that lesions had a reddish color [odds ratio (OR) = 18.705, 95% confidence interval (CI): 3.684-94.974], microvascular varicose (OR = 6.768, 95%CI: 1.717-26.677), and mixed pattern of crypt opening (OR = 20.704, 95%CI: 2.955-145.086) as the independent predictors for SSL-D+s.

The endoscopic feature that has independent diagnostic value for SSL-D+ is a reddish color, microvascular varicose, and mixed pattern of crypt openings.

Annexin A10 (ANXA10) belongs to a family of membrane-bound calcium-dependent phospholipid-binding proteins, but its precise function remains unclear. Further research is required to understand its role in sessile serrated lesions (SSL) and colorectal cancer (CRC). We conducted transcriptome sequencing on pairs of SSL and corresponding normal control (NC) samples. Bioinformatic methods were utilized to assess ANXA10 expression in CRC. We knocked down and overexpressed ANXA10 in CRC cells to examine its effects on cell malignant ability. The effect of ANXA10 on lung metastasis of xenograft tumor cells in nude mice was also assessed. Furthermore, we used quantitative polymerase chain reaction, western blotting, and flow cytometry for reactive oxygen species (ROS), lipid ROS, and intracellular Fe2+ to measure ferroptosis. Immunoblotting and Immunofluorescence staining were used to detect autophagy. We found that ANXA10 was significantly overexpressed in SSL compared to NC. ANXA10 was also highly expressed in BRAF mutant CRCs and was associated with poor prognosis. ANXA10 knockdown reduced the survival, proliferation, and migration ability of CRC cells. Knockdown of ANXA10 inhibited lung metastasis of CRC cells in mice. ANXA10 knockdown increased transferrin receptor (TFRC) protein levels and led to downregulation of GSH/GSSG, increased Fe2+, MDA concentration, and ROS and lipid ROS in cells. Knockdown of ANXA10 inhibited TFRC degradation and was accompanied by an accumulation of autophagic flux and an increase in SQSTM1. Finally, Fer-1 rescued the migration and viability of ANXA10 knockdown cell lines. In brief, the knockdown of ANXA10 induces cellular ferroptosis by inhibiting autophagy-mediated TFRC degradation, thereby inhibiting CRC progression. This study reveals the mechanism of ANXA10 in ferroptosis, suggesting that it may serve as a potential therapeutic target for CRC of the serrated pathway.

The serrated neoplasia pathway constitutes an "alternative route" to colorectal cancer (CRC), and sessile serrated lesions with dysplasia (SSLDs) are an intermediate step between sessile serrated lesions (SSLs) and invasive CRC in this pathway. While SSLs show indolent growth before becoming dysplastic (> 10-15 years), SSLDs are considered to rapidly progress to either immunogenic microsatellite instable-high (MSI-H) CRC (presumably 75% of cases) or mesenchymal microsatellite stable (MSS) CRC. Their flat shapes and the relatively short window of this intermediate state make it difficult to detect and diagnose SSLDs; thus, these lesions are potent precursors of post-colonoscopy/interval cancers. Confusing terminology and the lack of longitudinal observation data of serrated polyps have hampered the accumulation of knowledge about SSLDs; however, a growing body of evidence has started to clarify their characteristics and biology. Together with recent efforts to incorporate terminology, histological studies of SSLDs have identified distinct dysplastic patterns and revealed alterations in the tumor microenvironment (TME). Molecular studies at the single-cell level have identified distinct gene alterations in both the epithelium and the TME. Mouse serrated tumor models have demonstrated the importance of TME in disease progression. Advances in colonoscopy provide clues to distinguish pre-malignant from non-malignant-SSLs. Recent progress in all aspects of the field has enhanced our understanding of the biology of SSLDs. The aim of this review article was to assess the current knowledge of SSLDs and highlight their clinical implications.

Approximately one-third of colorectal cancers develop from serrated lesions (SLs), including hyperplastic polyp (HP), sessile serrated lesion (SSL), traditional serrated adenoma (TSA), and SSL with dysplasia (SSLD) through the serrated neoplasia pathway, which progresses faster than the conventional adenoma-carcinoma pathway. We sought to depict the currently unclarified molecular and immune alterations by the single-cell landscape in SLs.

We performed single-cell RNA sequencing of 16 SLs (including 4 proximal HPs, 5 SSLs, 2 SSLDs, and 5 TSAs) vs 3 normal colonic tissues.

A total of 60,568 high-quality cells were obtained. Two distinct epithelial clusters with redox imbalance in SLs were observed, along with upregulation of tumor-promoting SerpinB6 that regulated ROS level. Epithelial clusters of SSL and TSA showed distinct molecular features: SSL-specific epithelium manifested overexpressed proliferative markers with Notch pathway activation, whereas TSA-specific epithelium showed Paneth cell metaplasia with aberrant lysozyme expression. As for immune contexture, enhanced cytotoxic activity of CD8⁺ T cells was observed in SLs; it was mainly attributable to increased proportion of CD103⁺CD8⁺ tissue-resident memory T cells, which might be regulated by retinoic acid metabolism. Microenvironment of SLs was generally immune-activated, whereas some immunosuppressive cells (regulatory T cells, anti-inflammatory macrophages, MDK⁺IgA⁺ plasma cells, MMP11-secreting PDGFRA⁺ fibroblasts) also emerged at early stage and further accumulated in SSLD.

Epithelial, immune, and stromal components in the serrated pathway undergo fundamental alterations. Future molecular subtypes of SLs and potential immune therapy might be developed.

Lynch syndrome (LS) is an inherited predisposition to colorectal cancer (CRC), responsible for 3-5% of all CRC. This syndrome is characterized by the early occurrence of colorectal neoplastic lesions, with variable incidences depending on the type of pathogenic variants in MMR genes (MLH1, MSH2, MSH6, PMS2 and EPCAM) and demographics factors such as gender, body mass index, tobacco use and physical activity. Similar to sporadic cancers, colorectal screening by colonoscopy is efficient because it is associated with a reduction >50% of both CRC incidence and CRC related mortality. To that end, most guidelines recommend high definition screening colonoscopies in dedicated centers, starting at the age of 20-25 years old, with a surveillance interval of 1-2 years. In this review, we discuss the importance of high definition colonoscopies, including the compliance to specific key performance indicators, as well as the expected benefits of specific imaging modalities including virtual chromoendoscopy and dye-spray chromoendoscopy.

Here, we provide an up-to-date review of the histopathology and molecular pathology of serrated colorectal lesions. First, we introduce the updated contents of the 2019 World Health Organization classification for serrated lesions. The sessile serrated lesion (SSL) is a new diagnostic terminology that replaces sessile serrated adenoma and sessile serrated polyp. The diagnostic criteria for SSL were revised to require only one unequivocal distorted serrated crypt, which is sufficient for diagnosis. Unclassified serrated adenomas have been included as a new category of serrated lesions. Second, we review ongoing issues concerning the morphology of serrated lesions. Minor morphologic variants with distinct molecular features were recently defined, including serrated tubulovillous adenoma, mucin-rich variant of traditional serrated adenoma (TSA), and superficially serrated adenoma. In addition to intestinal dysplasia and serrated dysplasia, minimal deviation dysplasia and not otherwise specified dysplasia were newly suggested as dysplasia subtypes of SSLs. Third, we summarize the molecular features of serrated lesions. The critical determinant of CpG island methylation development in SSLs is patient age. Interestingly, there may be ethnic differences in BRAF/KRAS mutation frequencies in SSLs. The molecular pathogenesis of TSAs is divided into KRAS and BRAF mutation pathways. SSLs with MLH1 methylation can progress into favorable prognostic microsatellite instability-positive (MSI+)/CpG island methylator phenotype-positive (CIMP+) carcinomas, whereas MLH1-unmethylated SSLs and BRAF-mutated TSAs can be precursors of poor-prognostic MSI-/CIMP+ carcinomas. Finally, based on our recent data, we propose an algorithm for stratifying risk subgroups of non-dysplastic SSLs.