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.

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).

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 ).

Clinicopathological features of T1 colorectal carcinomas with skip lymphovascular invasion.

With recent advances in endoscopic treatment, many T1 colorectal carcinomas (CRCs) are resected endoscopically with a negative margin. However, some lesions exhibit skip lymphovascular invasion (SLVI), which is defined as the discontinuous foci of the tumor cells within the colon wall. The aim of the present study was to reveal the clinicopathological features of T1 CRCs with SLVI and validate the Japanese guidelines regarding SLVI. A total of 741 patients with T1 CRCs that were resected surgically between April 2001 and October 2016 in our hospital were divided into two groups: With SLVI and without SLVI. Clinicopathological features compared between the two groups were patient's gender, age, tumor size, location, morphology, lymphovascular invasion, tumor differentiation, tumor budding and lymph node metastasis. The incidence of T1 CRCs with SLVI was 0.9% (7/741). All cases with SLVI were found in the sigmoid colon or rectum. T1 CRCs with SLVI showed significantly higher rates of lymphovascular invasion than those without SLVI (P<0.01). In conclusion, lymphovascular invasion was a significant risk factor for SLVI in T1 CRCs, and for which surgical colectomy was necessary. The Japanese guidelines are appropriate regarding SLVI. Registered in the University Hospital Medical Network Clinical Trials Registry (UMIN000027097).

Risk factors of recurrence in T1 colorectal cancers treated by endoscopic resection alone or surgical resection with lymph node dissection.

PURPOSE: The recurrence of T1 colorectal cancers is relatively rare, and the prognostic factors still remain obscure. This study aimed to clarify the risk factors for recurrence in patients with T1 colorectal cancers treated by endoscopic resection (ER) alone or surgical resection (SR) with lymph node dissection, respectively. METHODS: We reviewed 930 patients with resected T1 colorectal cancers (mean follow-up, 52.3 months). Patients were divided into two groups: those who underwent ER alone (298 cases), and those who underwent initial or additional SR with lymph node dissection (632 cases). Group differences in recurrence-free survival were evaluated using the Kaplan-Meier method and log-rank test. Associations between recurrence and clinicopathological features were evaluated in Cox regression analyses; hazard ratios (HRs) were calculated for the total population and each group. RESULTS: Recurrence occurred in four cases (1.34%) in the ER group and six cases (0.95%) in the SR group (p = 0.32). Endoscopic resection, rectal location, and poor or mucinous (Por/Muc) differentiation were prognostic factors for recurrence in the total population. Por/Muc differentiation was prognostic factor in both groups. Female sex, depressed-type morphology, and lymphatic invasion were also prognostic factors in the ER group, but not in the SR group. CONCLUSIONS: Endoscopic resection, rectal location, and Por/Muc differentiation are prognostic factors in the total population. For patients who undergo ER alone, female sex, depressed-type morphology, and lymphatic invasion are also risk factors for recurrence. For such patients, regional en-bloc surgery with lymph node dissection could reduce the risk of recurrence.

Artificial intelligence may help in predicting the need for additional surgery after endoscopic resection of T1 colorectal cancer.

BACKGROUND AND STUDY AIMS: Decisions concerning additional surgery after endoscopic resection of T1 colorectal cancer (CRC) are difficult because preoperative prediction of lymph node metastasis (LNM) is problematic. We investigated whether artificial intelligence can predict LNM presence, thus minimizing the need for additional surgery. PATIENTS AND METHODS: Data on 690 consecutive patients with T1 CRCs that were surgically resected in 2001 - 2016 were retrospectively analyzed. We divided patients into two groups according to date: data from 590 patients were used for machine learning for the artificial intelligence model, and the remaining 100 patients were included for model validation. The artificial intelligence model analyzed 45 clinicopathological factors and then predicted positivity or negativity for LNM. Operative specimens were used as the gold standard for the presence of LNM. The artificial intelligence model was validated by calculating the sensitivity, specificity, and accuracy for predicting LNM, and comparing these data with those of the American, European, and Japanese guidelines. RESULTS: Sensitivity was 100 % (95 % confidence interval [CI] 72 % to 100 %) in all models. Specificity of the artificial intelligence model and the American, European, and Japanese guidelines was 66 % (95 %CI 56 % to 76 %), 44 % (95 %CI 34 % to 55 %), 0 % (95 %CI 0 % to 3 %), and 0 % (95 %CI 0 % to 3 %), respectively; and accuracy was 69 % (95 %CI 59 % to 78 %), 49 % (95 %CI 39 % to 59 %), 9 % (95 %CI 4 % to 16 %), and 9 % (95 %CI 4 % - 16 %), respectively. The rates of unnecessary additional surgery attributable to misdiagnosing LNM-negative patients as having LNM were: 77 % (95 %CI 62 % to 89 %) for the artificial intelligence model, and 85 % (95 %CI 73 % to 93 %; P < 0.001), 91 % (95 %CI 84 % to 96 %; P < 0.001), and 91 % (95 %CI 84 % to 96 %; P < 0.001) for the American, European, and Japanese guidelines, respectively. CONCLUSIONS: Compared with current guidelines, artificial intelligence significantly reduced unnecessary additional surgery after endoscopic resection of T1 CRC without missing LNM positivity.

Patient gender as a factor associated with lymph node metastasis in T1 colorectal cancer: A systematic review and meta-analysis.

Approximately 10% of patients with T1 colorectal cancer have lymph node metastases (LNM), requiring node dissection along with surgical resection. Patient gender was recently reported to affect the occurrence of LNM. The aim of the present study was to assess whether patient gender was predictive of LNM in T1 colorectal cancer. Public databases, including PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched, using key terms related to 'T1 colorectal cancer' and 'lymph node'. All relevant studies reporting the adjusted odds ratio or risk ratio of LNM in relation to patient gender were included. The quality of the studies was classified according to the Quality in Prognostic Studies tool. A random-effects model was used and the quality of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. The initial database search identified 2,492 publications; of those, 36 studies reported unadjusted results. Of the 36 studies, 4 reported adjusted results and fulfilled the inclusion criteria for this meta-analysis: 3 studies were graded as having a moderate risk of bias, and 1 had a low risk of bias. The present meta-analysis demonstrated that female gender was associated with increased risk of LNM (risk ratio=2.45, 95% confidence interval: 1.03-3.88). The I2 statistic was 0.901, classified as very low (+OOO) and was downgraded by the risk of bias, inconsistency and publication bias. In conclusion, female gender was found to be correlated with LNM in patients with T1 colorectal cancer.

Comparative clinicopathological characteristics of colon and rectal T1 carcinoma.

Lymph node metastasis significantly influences the management of patients with colorectal carcinoma. It has been observed that the biology of colorectal carcinoma differs by location. The aim of the current study was to retrospectively compare the clinicopathological characteristics of patients with colon and rectal T1 carcinomas, particularly their rates of lymph node metastasis. Of the 19,864 patients who underwent endoscopic or surgical resection of colorectal neoplasms at Showa University Northern Yokohama Hospital, 557 had T1 surgically resected carcinomas, including 457 patients with colon T1 carcinomas and 100 patients with rectal T1 carcinomas. Analysed clinicopathological features included patient age, gender, tumor size, morphology, tumor budding, invasion depth, vascular invasion, histological grade, lymphatic invasion and lymph node metastasis. Rectal T1 carcinomas were significantly larger than colon T1 carcinomas (mean ± standard deviation: 23.7±13.1 mm vs. 19.9±11.0 mm, P<0.01) and were accompanied by significantly higher rates of vascular invasion (48.0% vs. 30.2%, P<0.01). Significant differences were not observed among any other clinicopathological factors. In conclusion, tumor location itself was not a risk factor for lymph node metastasis in colorectal T1 carcinomas, even though on average, rectal T1 carcinomas were larger and accompanied by a significantly higher rate of vascular invasion than colon T1 carcinomas.

'Head Invasion' Is Not a Metastasis-Free Condition in Pedunculated T1 Colorectal Carcinomas Based on the Precise Histopathological Assessment.

BACKGROUND/AIM: Previous reports stated that pedunculated T1 colorectal carcinomas with 'head invasion' showed almost no nodal metastasis, requiring endoscopic treatment alone. However, clinically, some lesions develop nodal metastasis. We aimed to validate the necessity of distinguishing between 'pedunculated' and 'non-pedunculated' lesions, and also between 'head' and 'stalk' invasions. METHODS: Initial or additional surgery with lymph node dissection was performed in 76 pedunculated and 594 non-pedunculated cases. Among pedunculated lesions, the baseline was defined as the junction line between normal and neoplastic epithelium (Haggitt's level 2). The degree of invasion was classified as 'head invasion' (above the baseline) or 'stalk invasion' (beyond the baseline). Clinicopathological factors were analyzed with respect to nodal metastasis. RESULTS: Nine of 76 (11.8%) pedunculated cases and 52/594 (8.8%) non-pedunculated cases developed nodal metastasis (p = 0.40). No significant differences were found in the rate of nodal metastasis between 'head invasion' (4/30, 13.3%) and 'stalk invasion' (5/46, 10.9%). All the 4 cases with 'head invasion' had at least one pathological factor. CONCLUSIONS: 'Head invasion' was not a metastasis-free condition. Even for pedunculated T1 cancers with 'head invasion', additional surgery with lymph node dissection should be considered if these have pathological risk factors.

Management of T1 colorectal cancers after endoscopic treatment based on the risk stratification of lymph node metastasis.

BACKGROUND AND AIM: Recent advances in endoscopic technology have allowed many T1 colorectal carcinomas to be resected endoscopically with negative margins. However, the criteria for curative endoscopic resection remain unclear. We aimed to identify risk factors for nodal metastasis in T1 carcinoma patients and hence establish the indication for additional surgery with lymph node dissection. METHODS: Initial or additional surgery with nodal dissection was performed in 653 T1 carcinoma cases. Clinicopathological factors were retrospectively analyzed with respect to nodal metastasis. The status of the muscularis mucosae (MM grade) was defined as grade 1 (maintenance) or grade 2 (fragmentation or disappearance). The lesions were then stratified based on the risk of nodal metastasis. RESULTS: Muscularis mucosae grade was associated with nodal metastasis (P = 0.026), and no patients with MM grade 1 lesions had nodal metastasis. Significant risk factors for nodal metastasis in patients with MM grade 2 lesions were attribution of women (P = 0.006), lymphovascular infiltration (P < 0.001), tumor budding (P = 0.045), and poorly differentiated adenocarcinoma or mucinous carcinoma (P = 0.007). Nodal metastasis occurred in 1.06% of lesions without any of these pathological factors, but in 10.3% and 20.1% of lesions with at least one factor in male and female patients, respectively. There was good inter-observer agreement for MM grade evaluation, with a kappa value of 0.67. CONCLUSIONS: Stratification using MM grade, pathological factors, and patient sex provided more appropriate indication for additional surgery with lymph node dissection after endoscopic treatment for T1 colorectal carcinomas.

Practical problems of measuring depth of submucosal invasion in T1 colorectal carcinomas.

PURPOSE: Submucosal invasion depth (SID) in colorectal carcinoma (CRC) is an important factor in estimating risk of lymph node metastasis, but can be difficult to measure, leading to inadequate or over-extensive treatment. Here, we aimed to clarify the practical aspects of measuring SID in T1 CRC. METHODS: We investigated 568 T1 CRCs that were resected surgically at our hospital from April 2001 to December 2013, and relationships between SID and clinicopathological factors, including the means of measurement, lesion morphology, and lymph node metastasis. RESULTS: Of these 568 lesions, the SID was ≥1000 µm in 508 lesions. SIDs for lesions measured from the surface layer were all ≥1000 µm. Although lesions with SIDs ≥1000 µm were associated with significantly higher levels of unfavorable histologic types and lymphovascular infiltration than shallower lesions, a depth of ≥1000 µm was not a significant risk factor for lymph node metastasis (LNM) (6.7 vs. 9.8 %; P = 0.64), and no lesions for which the sole pathological factor was SID ≥1000 µm had lymph node metastasis. Protruded lesions showed deeper SIDs than other types. CONCLUSIONS: Although we found several problems of measuring SID in this study, we also found, surprisingly, that SID is not a risk factor for lymph node metastasis, and its measurement is not needed to estimate the risk of lymph node metastasis.