Risk factors for lymph node metastasis in T2 colorectal cancer: a systematic review and meta-analysis.

BACKGROUND: Lymph node metastasis (LNM) occurs in 20-25% of patients with T2 colorectal cancer (CRC). Identification of risk factors for LNM in T2 CRC may help identify patients who are at low risk and thereby potential candidates for endoscopic full-thickness resection. We examined risk factors for LNM in T2 CRC with the goal of establishing further criteria of the indications for endoscopic resection. METHODS: MEDLINE, CENTRAL, and EMBASE were systematically searched from inception to November 2023. Studies that investigated the association between the presence of LNM and the clinical and pathological factors of T2 CRC were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Certainty of evidence (CoE) was assessed using the GRADE approach. RESULTS: Fourteen studies (8349 patients) were included. Overall, the proportion of LNM was 22%. The meta-analysis revealed that the presence of lymphovascular invasion (OR, 5.5; 95% CI 3.7-8.3; high CoE), high-grade tumor budding (OR, 2.4; 95% CI 1.5-3.7; moderate CoE), poor differentiation (OR, 2.2; 95% CI 1.8-2.7; moderate CoE), and female sex (OR, 1.3; 95% CI 1.1-1.7; high CoE) were associated with LNM in T2 CRC. Lymphatic invasion (OR, 5.0; 95% CI 3.3-7.6) was a stronger predictor of LNM than vascular invasion (OR, 2.4; 95% CI 2.1-2.8). CONCLUSIONS: Lymphovascular invasion, high-grade tumor budding, poor differentiation, and female sex were risk factors for LNM in T2 CRC. Endoscopic resection of T2 CRC in patients with very low risk for LNM may become an alternative to conventional surgical resection. TRIAL REGISTRATION: PROSPERO, CRD42022316545.

Impact of computer-aided characterization for diagnosis of colorectal lesions, including sessile serrated lesions: Multireader, multicase study.

OBJECTIVES: Computer-aided characterization (CADx) may be used to implement optical biopsy strategies into colonoscopy practice; however, its impact on endoscopic diagnosis remains unknown. We aimed to evaluate the additional diagnostic value of CADx when used by endoscopists for assessing colorectal polyps. METHODS: This was a single-center, multicase, multireader, image-reading study using randomly extracted images of pathologically confirmed polyps resected between July 2021 and January 2022. Approved CADx that could predict two-tier classification (neoplastic or nonneoplastic) by analyzing narrow-band images of the polyps was used to obtain a CADx diagnosis. Participating endoscopists determined if the polyps were neoplastic or not and noted their confidence level using a computer-based, image-reading test. The test was conducted twice with a 4-week interval: the first test was conducted without CADx prediction and the second test with CADx prediction. Diagnostic performances for neoplasms were calculated using the pathological diagnosis as reference and performances with and without CADx prediction were compared. RESULTS: Five hundred polyps were randomly extracted from 385 patients and diagnosed by 14 endoscopists (including seven experts). The sensitivity for neoplasia was significantly improved by referring to CADx (89.4% vs. 95.6%). CADx also had incremental effects on the negative predictive value (69.3% vs. 84.3%), overall accuracy (87.2% vs. 91.8%), and high-confidence diagnosis rate (77.4% vs. 85.8%). However, there was no significant difference in specificity (80.1% vs. 78.9%). CONCLUSIONS: Computer-aided characterization has added diagnostic value for differentiating colorectal neoplasms and may improve the high-confidence diagnosis rate.

Differentiation grade as a risk factor for lymph node metastasis in T1 colorectal cancer.

Objectives: Japanese guidelines include high-grade (poorly differentiated) tumors as a risk factor for lymph node metastasis (LNM) in T1 colorectal cancer (CRC). However, whether the grading is based on the least or most predominant component when the lesion consists of two or more levels of differentiation varies among institutions. This study aimed to investigate which method is optimal for assessing the risk of LNM in T1 CRC. Methods: We retrospectively evaluated 971 consecutive patients with T1 CRC who underwent initial or additional surgical resection from 2001 to 2021 at our institution. Tumor grading was divided into low-grade (well- to moderately differentiated) and high-grade based on the least or predominant differentiation analyses. We investigated the correlations between LNM and these two grading analyses. Results: LNM was present in 9.8% of patients. High-grade tumors, as determined by least differentiation analysis, accounted for 17.0%, compared to 0.8% identified by predominant differentiation analysis. A significant association with LNM was noted for the least differentiation method (p < 0.05), while no such association was found for predominant differentiation (p = 0.18). In multivariate logistic regression, grading based on least differentiation was an independent predictor of LNM (p = 0.04, odds ratio 1.68, 95% confidence interval 1.00-2.83). Sensitivity and specificity for detecting LNM were 27.4% and 84.1% for least differentiation, and 2.1% and 99.3% for predominant differentiation, respectively. Conclusions: Tumor grading via least differentiation analysis proved to be a more reliable measure for assessing LNM risk in T1 CRC compared to grading by predominant differentiation.

Molecular and clinicopathological differences between depressed and protruded T2 colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) can be classified into four consensus molecular subtypes (CMS) according to genomic aberrations and gene expression profiles. CMS is expected to be useful in predicting prognosis and selecting chemotherapy regimens. However, there are still no reports on the relationship between the morphology and CMS. METHODS: This retrospective study included 55 subjects with T2 CRC undergoing surgical resection, of whom 30 had the depressed type and 25 the protruded type. In the classification of the CMS, we first defined cases with deficient mismatch repair as CMS1. And then, CMS2/3 and CMS4 were classified using an online classifier developed by Trinh et al. The staining intensity of CDX2, HTR2B, FRMD6, ZEB1, and KER and the percentage contents of CDX2, FRMD6, and KER are input into the classifier to obtain automatic output classifying the specimen as CMS2/3 or CMS4. RESULTS: According to the results yielded by the online classifier, of the 30 depressed-type cases, 15 (50%) were classified as CMS2/3 and 15 (50%) as CMS4. Of the 25 protruded-type cases, 3 (12%) were classified as CMS1 and 22 (88%) as CMS2/3. All of the T2 CRCs classified as CMS4 were depressed CRCs. More malignant pathological findings such as lymphatic invasion were associated with the depressed rather than protruded T2 CRC cases. CONCLUSIONS: Depressed-type T2 CRC had a significant association with CMS4, showing more malignant pathological findings such as lymphatic invasion than the protruded-type, which could explain the reported association between CMS4 CRC and poor prognosis.

Tumor Location as a Prognostic Factor in T1 Colorectal Cancer.

The incidence of T1 colorectal cancer is expected to increase because of the prevalence of colorectal cancer screening and the progress of endoscopic treatment such as endoscopic submucosal dissection or endoscopic full-thickness resection. Currently, the requirement for additional surgery after endoscopic resection of T1 colorectal cancer is determined according to several treatment guidelines (in USA, Europe, and Japan) referring to the following pathological findings: lymphovascular invasion, tumor differentiation, depth of invasion, and tumor budding, all of which are reported to be risk factors for lymph node metastasis. In addition to these factors, in this review, we investigate whether tumor location, which is an objective factor, has an impact on the presence of lymph node metastasis and recurrence. From recent studies, left-sided location, especially the sigmoid colon in addition to rectum, could be a risk factor for lymph node metastasis and cancer recurrence. The treatment of T1 colorectal cancer should be managed considering these findings.

Combined endocytoscopy with pit pattern diagnosis in ulcerative colitis-associated neoplasia: Pilot study.

OBJECTIVES: Ulcerative colitis-associated neoplasias (UCAN) are often flat with an indistinct boundary from surrounding tissues, which makes differentiating UCAN from non-neoplasias difficult. Pit pattern (PIT) has been reported as one of the most effective indicators to identify UCAN. However, regenerated mucosa is also often diagnosed as a neoplastic PIT. Endocytoscopy (EC) allows visualization of cell nuclei. The aim of this retrospective study was to demonstrate the diagnostic ability of combined EC irregularly-formed nuclei with PIT (EC-IN-PIT) diagnosis to identify UCAN. METHODS: This study involved patients with ulcerative colitis whose lesions were observed by EC. Each lesion was diagnosed by two independent expert endoscopists, using two types of diagnostic strategies: PIT alone and EC-IN-PIT. We evaluated and compared the diagnostic abilities of PIT alone and EC-IN-PIT. We also examined the difference in the diagnostic abilities of an EC-IN-PIT diagnosis according to endoscopic inflammation severity. RESULTS: We analyzed 103 lesions from 62 patients; 23 lesions were UCAN and 80 were non-neoplastic. EC-IN-PIT diagnosis had a significantly higher specificity and accuracy compared with PIT alone: 84% versus 58% (P < 0.001), and 88% versus 67% (P < 0.01), respectively. The specificity and accuracy were significantly higher for Mayo endoscopic score (MES) 0-1 than MES 2-3: 93% versus 68% (P < 0.001) and 95% versus 74% (P < 0.001), respectively. CONCLUSIONS: Our novel EC-IN-PIT strategy had a better diagnostic ability than PIT alone to predict UCAN from suspected and initially detected lesions using conventional colonoscopy. UMIN clinical trial (UMIN000040698).

Current problems and perspectives of pathological risk factors for lymph node metastasis in T1 colorectal cancer: Systematic review.

With the prevalence of endoscopic submucosal dissection and endoscopic full thickness resection, which enable complete resection of T1 colorectal cancer with a negative margin, the treatment strategy following endoscopic resection has become more important. The necessity of secondary surgical resection is determined on the basis of the risk of lymph node metastasis according to the histopathological findings of resected specimens because ~10% of T1 colorectal cancer cases have lymph node metastasis. The current Japanese treatment guidelines state four risk factors for lymph node metastasis: lymphovascular invasion, histological differentiation, depth of submucosal invasion, and tumor budding. These guidelines have succeeded in stratifying the low-risk group for lymph node metastasis, in which endoscopic resection alone is acceptable for cure. On the other hand, there are some problems: there is variation in diagnosis methods and low interobserver agreement for each pathological factor and 90% of surgical resections are unnecessary, with lymph node metastasis negativity. To ensure patients with T1 colorectal cancer receive more appropriate treatment, these problems should be addressed. In this systematic review, we gave some suggestions to these practical issues of four pathological factors as predictors.

Real-Time Artificial Intelligence-Based Optical Diagnosis of Neoplastic Polyps during Colonoscopy.

BACKGROUND: Artificial intelligence using computer-aided diagnosis (CADx) in real time with images acquired during colonoscopy may help colonoscopists distinguish between neoplastic polyps requiring removal and nonneoplastic polyps not requiring removal. In this study, we tested whether CADx analyzed images helped in this decision-making process. METHODS: We performed a multicenter clinical study comparing a novel CADx-system that uses real-time ultra-magnifying polyp visualization during colonoscopy with standard visual inspection of small (≤5 mm in diameter) polyps in the sigmoid colon and the rectum for optical diagnosis of neoplastic histology. After committing to a diagnosis (i.e., neoplastic, uncertain, or nonneoplastic), all imaged polyps were removed. The primary end point was sensitivity for neoplastic polyps by CADx and visual inspection, compared with histopathology. Secondary end points were specificity and colonoscopist confidence level in unaided optical diagnosis. RESULTS: We assessed 1289 individuals for eligibility at colonoscopy centers in Norway, the United Kingdom, and Japan. We detected 892 eligible polyps in 518 patients and included them in analyses: 359 were neoplastic and 533 were nonneoplastic. Sensitivity for the diagnosis of neoplastic polyps with standard visual inspection was 88.4% (95% confidence interval [CI], 84.3 to 91.5) compared with 90.4% (95% CI, 86.8 to 93.1) with CADx (P=0.33). Specificity was 83.1% (95% CI, 79.2 to 86.4) with standard visual inspection and 85.9% (95% CI, 82.3 to 88.8) with CADx. The proportion of polyp assessment with high confidence was 74.2% (95% CI, 70.9 to 77.3) with standard visual inspection versus 92.6% (95% CI, 90.6 to 94.3) with CADx. CONCLUSIONS: Real-time polyp assessment with CADx did not significantly increase the diagnostic sensitivity of neoplastic polyps during a colonoscopy compared with optical evaluation without CADx. (Funded by the Research Council of Norway [Norges Forskningsråd], the Norwegian Cancer Society [Kreftforeningen], and the Japan Society for the Promotion of Science; UMIN number, UMIN000035213.)

Clinicopathological features of small T1 colorectal cancers.

BACKGROUND: Although small colorectal neoplasms (< 10 mm) are often easily resected endoscopically and are considered to have less malignant potential compared with large neoplasms (≥ 10 mm), some are invasive to the submucosa. AIM: To clarify the clinicopathological features of small T1 colorectal cancers. METHODS: Of 32025 colorectal lesions between April 2001 and March 2018, a total of 1152 T1 colorectal cancers resected endoscopically or surgically were included in this study and were divided into two groups by tumor size: a small group (< 10 mm) and a large group (≥ 10 mm). We compared clinicopathological factors including lymph node metastasis (LNM) between the two groups. RESULTS: The incidence of small T1 cancers was 10.1% (116/1152). The percentage of initial endoscopic treatment in small group was significantly higher than in large group (< 10 mm 74.1% vs ≥ 10 mm 60.2%, P < 0.01). In the surgical resection cohort (n = 798), the rate of LNM did not significantly differ between the two groups (small 12.3% vs large 10.9%, P = 0.70). In addition, there were also no significant differences between the two groups in pathological factors such as histological grade, vascular invasion, or lymphatic invasion. CONCLUSION: Because there was no significant difference in the rate of LNM between small and large T1 colorectal cancers, the requirement for additional surgical resection should be determined according to pathological findings, regardless of tumor size.

Left-sided location is a risk factor for lymph node metastasis of T1 colorectal cancer: a single-center retrospective study.

PURPOSE: Although some studies have reported differences in clinicopathological features between left- and right-sided advanced colorectal cancer (CRC), there are few reports regarding early-stage disease. In this study, we aimed to compare the clinicopathological features of left- and right-sided T1 CRC. METHODS: Subjects were 1142 cases with T1 CRC undergoing surgical or endoscopic resection between 2001 and 2018 at Showa University Northern Yokohama Hospital. Of these, 776 cases were left-sided (descending colon to rectum) and 366 cases were right-sided (cecum to transverse colon). We compared clinical (patients age, sex, tumor size, morphology, initial treatment) and pathological features (invasion depth, histological grade, lymphatic invasion, vascular invasion, tumor budding) including lymph node metastasis (LNM). RESULTS: Left-sided T1 CRC showed significantly higher rates of LNM (left-sided 12.0% vs. right-sided 5.4%, P < 0.05) and lymphatic invasion (left-sided 32.7% vs. right-sided 23.2%, P < 0.05). Especially, the sigmoid colon and rectum showed higher rates of LNM (12.4% and 12.1%, respectively) than other locations. Patients with left-sided T1 CRC were younger than those with right-sided T1 CRC (64.9 years ±11.5 years vs. 68.7 ± 11.6 years, P < 0.05), as well as significantly lower rates of poorly differentiated carcinoma/mucinous carcinoma than right-sided T1 CRC (11.6% vs. 16.1%, P < 0.05). CONCLUSION: Left-sided T1 CRC, especially in the sigmoid colon and rectum, exhibited higher rates of LNM than right-sided T1 CRC, followed by higher rates of lymphatic invasion. These results suggest that tumor location should be considered in decisions regarding additional surgery after endoscopic resection. TRIAL REGISTRATION: This study was registered with the University Hospital Medical Network Clinical Trials Registry ( UMIN 000032733 ).