Risk and Time Pattern of Recurrences After Local Endoscopic Resection of T1 Colorectal Cancer: A Meta-analysis.

BACKGROUND & AIMS: Growing numbers of patients with T1 CRC are being treated with local endoscopic resection only and as a result, the need for optimization of surveillance strategies for these patients also increases. We aimed to estimate the cumulative incidence and time pattern of CRC recurrences for endoscopically treated patients with T1 CRC. METHODS: Using a systematic literature search in PubMed, EMBASE, Web of Science and Cochrane Library (from inception till 15 May 2020), we identified and extracted data from studies describing the cumulative incidence of local or distant CRC recurrence for patients with T1 CRC treated with local endoscopic resection only. Pooled estimates were calculated using mixed-effect logistic regression models. RESULTS: Seventy-one studies with 5167 unique, endoscopically treated patients with T1 CRC were included. The pooled cumulative incidence of any CRC recurrence was 3.3% (209 events; 95% CI, 2.6%-4.3%; I2 = 54.9%), with local and distant recurrences being found at comparable rates (pooled incidences 1.9% and 1.6%, respectively). CRC-related mortality was observed in 42 out of 2519 patients (35 studies; pooled incidence 1.7%, 95% CI, 1.2%-2.2%; I2 = 0%), and the CRC-related mortality rate among patients with recurrence was 40.8% (42/103 patients). The vast majority of recurrences (95.6%) occurred within 72 months of follow-up. Pooled incidences of any CRC recurrence were 7.0% for high-risk T1 CRCs (28 studies; 95% CI, 4.9%-9.9%; I2 = 48.1%) and 0.7% (36 studies; 95% CI, 0.4%-1.2%; I2 = 0%) for low-risk T1 CRCs. CONCLUSIONS: Our meta-analysis provides quantitative outcome measures which are relevant to guidelines on surveillance after local endoscopic resection of T1 CRC.

Local excision of T1 colorectal cancer: good differentiation, absence of lymphovascular invasion, and limited tumor radial infiltration (≤4.25 mm) may allow avoiding radical surgery.

BACKGROUND: Early colorectal cancer (ECC) is defined as T1NXM0 colorectal cancer (CRC). Although a non-negligible number of T1-CRCs presents metastatic lymph-nodes, local excision is increasingly proposed as alternative to radical resection. Several criteria have been suggested to identify low-risk T1-CRC, but recommendations on this topic are still heterogeneous. This study aims to identify criteria associated with N+ T1-CRC, to select patients to undergo (or not) local excision. METHODS: A retrospective analysis of demographic, clinical, and histology criteria of 122 consecutive T1-CRC patients undergoing radical resection at Parma University Hospital between 2000 and 2018 has been performed. RESULTS: Lymph-node metastasis (LNM) was observed in 15/122 patients (12.3%). No LNM was observed among well-differentiated (G1) tumors (0/37), while 10/65 (15.4%) G2 cases as well as 5/20 (25%) G3 patients presented LNM. G1 was associated with absence of LNM (p = 0.013). After excluding G1 patients, the rate of N + T1-CRC was 17.6% (15/85). LNM was observed in 4/8 (50%) patients with lymphovascular invasion (LVI) and in 11/77 (14.2%) without LVI. LVI resulted being associated with LNM (p < 0.042). LNM was reported in 28.3% of cases with a tumor infiltration >4.25 mm (13/46), compared to 5.1% in cases with an infiltration ≤4.25 mm (2/39) (p = 0.012). In Cox regression analysis, the higher hazard ratio (HR) was reported for the LVI + and infiltration >4.25 mm (HR 24.849). CONCLUSIONS: In patients with ECC (pT1NXM0), good differentiation (G1), absence of lymphovascular invasion (LVI-), and tumor radial infiltration ≤4.25 mm may allow performing local resection and avoiding radical surgery.

Vertical tumor margin of endoscopic resection for T1 colorectal carcinoma affects the prognosis of patients undergoing additional surgery.

BACKGROUND: Vertical tumor margin-negative T1 colorectal carcinoma (CRC) is an absolute curative condition following complete endoscopic resection (ER). However, the influence on prognosis in relation to vertical tumor margin is unclear. Therefore, we evaluated the influence of the distance from vertical tumor margin to resected specimen edge (vertical margin distance) of ER for T1b (submucosal invasion depth > 1000 µm) CRC on the prognosis of patients undergoing additional surgery after ER. METHODS: In total, 215 consecutive patients with T1b CRC who underwent additional surgery after ER at Hiroshima University Hospital between February 1992 and June 2019 were enrolled. We assessed 191 patients without lymph node metastases at the additional surgery. The specimens resected by ER were classified into three groups based on the vertical margin distance: patients with a vertical margin distance of ≥ 500 µm (Group A); patients with a vertical margin distance of < 500 µm (Group B); and patients with a positive vertical tumor margin (Group C). Subsequently, we evaluated the prognosis of the patients in relation to the clinicopathological characteristics among the three groups. RESULTS: There were no significant differences in clinicopathological characteristics among the three groups. Group A had a significantly higher recurrence-free 5-year survival rate than Groups B and C (100%, 84.5%, and 81.8%, respectively). Similarly, Group A had a significantly higher disease-specific 5-year survival rate than Group C (100% vs. 95.5%). CONCLUSIONS: Complete en bloc resection with sufficient submucosal layer from the invasive front (vertical margin distance > 500 µm) by ER for T1 CRC reduces the risk of metastatic recurrence after additional surgery.

Clinical significance of immunohistochemical lymphovascular evaluation to determine additional surgery after endoscopic submucosal dissection for colorectal T1 carcinoma.

PURPOSE: The Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines indicate lymphovascular invasion-evaluated by hematoxylin and eosin (HE) staining-as a surgical requirement after endoscopic submucosal dissection (ESD) in T1 colorectal carcinoma (CRC) patients; however, immunohistochemical evaluation may be superior. This study aimed to clarify the significance of immunohistochemical lymphovascular evaluation as an indicator for additional surgery of T1 CRC after ESD, and assessed the guidelines' adequacy, even when evaluating through immunostaining. METHODS: Patients with T1 CRC who underwent ESD were enrolled across three institutions between January 2012 and December 2017. Immunohistochemical lymphovascular evaluation was performed. Clinicopathological features, pathological evaluations, and surgery indications were recorded. Univariate and multivariate logistic regression identified risk factors for lymph node (LN) metastasis of T1 CRC after ESD. RESULTS: Among 370 patients with T1 CRC, recurrence, 5-year overall survival, and 5-year disease specific survival rates were 1.6%, 94.6%, and 99.5%, respectively. Six patients (1.6%) experienced recurrence, five of whom underwent additional surgery. Those with no risk factors did not exhibit recurrence. A total of 215 (58.1%) patients underwent additional surgery after ESD, 21 (9.7%) of whom exhibited LN metastasis. Among 16 patients who underwent additional surgery due to lymphovascular invasion, three (18.8%) had LN metastasis. Multivariate logistic regression analysis identified lymphatic invasion as a significant risk factor for LN metastasis (odds ratio 3.9, 95% confidence interval 1.0-14.6, P = 0.0421). CONCLUSIONS: The JSCCR guidelines have clinical validity, and immunohistochemical lymphatic evaluation findings potentially predict LN metastasis for T1 CRC after ESD.

The effect of non-curative endoscopic resection on cT1N0M0 colorectal carcinoma patients who underwent additional surgery.

BACKGROUND AND AIM: Radical surgery is recommended for T1 colorectal cancer with non-curative endoscopic resection. However, there is still insufficient evidence about whether the non-curative endoscopic resection prior to surgical resection affects the short-term and long-term outcomes of patients. The purpose of this study was to investigate the effect of non-curative endoscopic resection before surgical resection on short-term and long-term outcomes in patients with T1 colorectal cancer. PATIENTS AND METHODS: Patients with clinical T1N0M0 (cT1N0M0) colorectal cancer who underwent direct surgery or additional radical surgery after non-curative endoscopic resection were collected. We evaluated postoperative complications and long-term prognosis between the two groups. RESULTS: From 2011 to 2017, 779 patients were clinically diagnosed with T1N0M0 colorectal cancer at Zhongshan Hospital. We assessed patients who underwent additional surgery following the prior non-curative endoscopic resection (n = 145) and patients who underwent radical surgery directly (n = 336). There was no significant difference in 5-year OS (99.3% vs. 99.4%, P = 0.866) and 5-year DFS (97.2% vs. 97.3%, P = 0.909) between the two groups. The total complication rate was slightly higher in prior endoscopic resection group (15.2% vs. 9.5%, P = 0.111). The 5-year OS and 5-year DFS of patients who refused additional surgery (n = 95) were significantly lower than ER prior to surgery group (For OS, 92.6% vs. 99.3%, P = 0.017; for DFS, 91.2% vs. 97.2%, P = 0.021). CONCLUSION: In patients who underwent additional surgery, non-curative endoscopic resection of cT1 colorectal carcinoma did not have adverse effect on short-term and long-term outcomes. Additional surgery should be recommended in patients who received non-curative ER.

Long-term prognosis after treatment for T1 carcinoma of laterally spreading tumors: a multicenter retrospective study.

PURPOSE: Long-term prognosis of T1 laterally spreading tumors (LSTs) after treatment have not been clarified. This study compared clinicopathological characteristics and long-term prognosis of T1 LSTs. METHODS: We retrospectively assessed 169 patients with 169 T1 LSTs between January 1992 and December 2008 by ten hospitals. Patients who did not meet the Japanese Society for Cancer of the Colon and Rectum (JSCCR) 2016 guidelines for the treatment of colorectal carcinoma (CRC) criteria were defined as non-endoscopically curable. The number of non-endoscopically curable patients with LST-granular/ nodular mixed (LST-G-M) was 61, that with LST-non-granular/ flat elevated (LST-NG-FE) was 23, and that with LST-non-granular/ pseudo depressed (LST-NG-PD) was 23. Clinicopathological variables and long-term prognosis were analyzed. RESULTS: For overall patients, tumor size, number of non-endoscopically curable cases, and rate of submucosal invasion depth ≥ 1000 µm for the LST-G-M group were significantly higher than those in the other groups. For non-endoscopically curable patients, the tumor size for those with LST-G-M was significantly larger than those in the other groups. The rate of submucosal invasion width ≥ 4000 µm and type B/C muscularis mucosae with LST-G-M was higher than that with LST-NG-FE. All recurrences occurred in non-endoscopically curable patients with LST-G-M. Five-year overall and disease-free survivals for non-endoscopically curable patients with LST-G-M were significantly shorter than those for patients with non-endoscopically curable LST-NG-FE and PD. CONCLUSIONS: Our data supported adequacy of the JSCCR guidelines for the treatment of CRC criteria for endoscopically curable patients after T1 LSTs treatment. Patients with T1 LST-G-M should be followed up more carefully.

The prognostic value of lymph node yield in the earliest stage of colorectal cancer: a multicenter cohort study.

BACKGROUND: 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. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.

Long-term outcomes after treatment for T1 colorectal carcinoma.

PURPOSE: Long-term outcomes of patients with T1 colorectal carcinoma (CRC) treated by endoscopic resection (ER) or surgical resection are unclear in relation to the curative criteria in the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines. The aim of this study was to retrospectively compare the long-term outcomes among patients with T1 CRC in relation to the treatment methods. METHODS: We examined 322 T1 CRC cases treated between January 1992 and August 2008 at Hiroshima University Hospital. Patients who did not meet the curative criteria in the JSCCR guidelines were defined as "non-endoscopically curable" and classified into three groups: underwent ER alone (group A: 45 patients), underwent additional surgery after ER (group B: 106 patients), and underwent surgical resection alone (group C: 92 patients). RESULTS: Of the 322 T1 CRC patients, 79 were categorized as endoscopically curable and 243 as non-endoscopically curable. Among the endoscopically curable T1 CRC patients, recurrence and 5-year OS rates were 0 and 94.2%, respectively. In groups A, B, and C, recurrence rates were 4.4, 6.6, and 4.3%, and OS rates were 85.6, 95.1, and 96.3%, respectively (p < 0.05). Local recurrence or distant/lymph node metastasis was observed in 13 patients (group A: 2; group B: 7; group C: 4). Death due to primary CRC occurred in six patients (group B: 4; group C: 2). CONCLUSION: Long-term outcomes support the curative criteria according to the JSCCR guidelines. ER for T1 CRC did not worsen clinical outcomes in cases that required additional surgical resection.

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.

Are the width, length, depth, and area of submucosal invasion predictive of lymph node metastasis in pT1 colorectal cancer?

PURPOSE: Submucosa-limited (pathological T1, pT1) colorectal cancers (CRCs) pose a continuing challenge in the choice of treatment options, which range from local excision to radical surgery. The aim of this study was to evaluate the morphometric and morphologic risk factors associated with regional lymph node metastasis (LNM) in pT1 CRC. METHODS: We performed a histological review of patients who underwent oncological resection between 2016 and 2022. Tumor grade, budding, poorly differentiated clusters (PDCs), cancer gland rupture, lymphovascular invasion (LVI), and presence of deep submucosal invasion (DSI), as well as width, length, total area, and area of DSI, were evaluated as potential risk factors for LNM. RESULTS: A total of 264 cases of colon and rectal carcinomas with invasion into the submucosal layer (pT1) were identified. LNM was found in 46 of the 264 cases (17.4%). All morphometric parameters, as well as DSI (P=0.330), showed no significant association with LNM. High grade adenocarcinoma (P=0.050), budding (P=0.056), and PDCs (P<0.001) were associated with LNM. In the multivariate analysis, LVI presence remained the only significant independent risk factor (odds ratio, 15.7; 95% confidence interval, 8.5-94.9; P<0.001). CONCLUSION: The DSI of T1 CRC, as well as other morphometric parameters of submucosal tumor spread, held no predictive value in terms of LNM. LVI was the only independent risk factor of LNM.

Preceding endoscopic submucosal dissection for T1 colorectal carcinoma does not affect the prognosis of patients who underwent additional surgery: a large multicenter propensity score-matched analysis.

BACKGROUND: We analyzed the influence of preceding endoscopic submucosal dissection (ESD) on the prognosis of patients with T1 colorectal carcinoma (CRC) after additional surgery using propensity-score matching. METHODS: 1638 consecutive patients with T1 CRC were retrospectively identified between January 1998 and December 2016 at the Hiroshima GI Endoscopy Research Group. We assessed 602 patients with 602 T1 CRC who underwent additional surgery after ESD (n = 216) or surgery alone (n = 386). The enrolled patients were treated according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016, and were defined as non-endoscopically curable (non-e-curable) when they did not satisfy its curative criteria. We analyzed the pathological characteristics and the prognosis of non-e-curable patients using propensity-score matching between the additional surgery after ESD and surgery alone groups. RESULTS: There were no cases of recurrence and lymph node metastasis among the e-curable patients. The rate of lymph node metastasis and recurrences in the non-e-curable patients were 10.8% and 2.6%, respectively. After propensity-score matching, there were no significant differences in the 5-year overall survival rates (96.9% vs. 92.0%), 5-year disease-free survival rates (96.7% vs. 96.7%) and 5-year disease-specific survival rates (100% vs. 98.6%) after treatment of T1 CRCs between the 2 groups in non-e-curable patients. CONCLUSIONS: Preceding ESD with histological en bloc resection for patients with T1 CRC did not affect their oncologic behavior adversely after additional surgery.

Long-term outcomes after treatment for T1 colorectal carcinoma: a multicenter retrospective cohort study of Hiroshima GI Endoscopy Research Group.

BACKGROUND: We aimed to clarify the long-term outcomes of patients with T1 colorectal carcinoma (CRC) after endoscopic resection (ER) and surgical resection. METHODS: We examined T1 CRC patients treated during 1992-2008 and who had ≥5 years of follow-up. Patients who did not meet the curative criteria after ER according to the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines were defined as "non-endoscopically curable" and classified into three groups: ER alone (Group A: 121 patients), additional surgery after ER (Group B: 238 patients), and surgical resection alone (Group C: 342 patients). Long-term outcomes and predictors of recurrence were analyzed. RESULTS: Of the 882 patients with T1 CRC, 701 were non-endoscopically curable. Among these patients, recurrence and 5-year overall survival (OS) rates were 0.6 and 91.1%, respectively. In Groups A, B, and C, recurrence rates were 5.0, 5.5, and 3.8%, OS rates were 79.3, 92.4, and 91.5% (p < 0.01), and 5-year disease-free survival (DFS) rates were 98.1, 97.9, and 98.5%, respectively. Thirty-two patients experienced local recurrence or distant/lymph node metastasis (Group A: 6; Group B: 13; Group C: 13) and 14 patients died of primary CRC (Group A: 3; Group B: 7; Group C: 4). Age ≥65 years, protruded gross type, positive lymphatic invasion, and high budding grade were significant predictors of recurrence in non-endoscopically curable patients. CONCLUSIONS: Our findings supported the JSCCR criteria for endoscopically curable T1 CRC. ER for T1 CRC did not worsen the clinical outcomes of patients who required additional surgical resection.

Pedunculated-type T1 colorectal carcinoma with lung carcinoma metastasis at the deepest invasive portion.

We present a rare case of colorectal T1 carcinoma with metastasis of previous lung carcinoma found at the deepest invasive portion. A 61-year-old man presented with cervical lymphadenopathy 18 years after undergoing surgery for right lung carcinoma [poorly differentiated adenocarcinoma stage IIb (T3N0M0)]. Contrast-enhanced computed tomography showed enlarged lymph nodes (LNs) in the neck and mediastinal regions. Combined hybrid-F-fluorodeoxyglucose positron emission-computerized tomography showed increased radionuclide uptake in multiple cervical LNs and mediastinal LNs. LN biopsy revealed a poorly differentiated adenocarcinoma, suspected to be a metastatic tumor of the lung. Subsequent colonoscopy revealed a pedunculated-type lesion with a depressed area in the ascending colon. We performed polypectomy as total excisional biopsy; this tumor was composed mainly of moderately differentiated adenocarcinoma, partially mixed with mucinous adenocarcinoma. The pathological findings of the invasive front of the colorectal carcinoma showed poorly differentiated adenocarcinoma with a morphological pattern similar to that of the previous lung carcinoma. Furthermore, immunohistochemical results for the histological type of the deepest invasive portion of the tissue specimen were positive for thyroid transcription factor-1 but negative for Caudal-type homeobox 2. From these morphological and immunohistochemical findings, the final diagnosis was moderately differentiated lung carcinoma, pTX N3 M1b (LN, colon) Stage IV.

Long-term outcomes after treatment for pedunculated-type T1 colorectal carcinoma: a multicenter retrospective cohort study.

BACKGROUND: The risk for lymph node metastasis and the prognostic significance of pedunculated-type T1 colorectal carcinomas (CRCs) require further study. We aimed to assess the validity of the 2014 Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines based on long-term outcomes of pedunculated-type T1 CRCs. METHODS: In this multicenter retrospective cohort study, we examined 176 patients who underwent resection endoscopically or surgically at 14 institutions between January 1990 and December 2010. Patients meeting the JSCCR curative criteria were defined as "endoscopically curable (e-curable)" and those who did not were "non-e-curable". We evaluated the prognosis of 116 patients (58 e-curable, 58 non-e-curable) who were observed for >5 years after treatment. RESULTS: Overall incidence of lymph node metastasis was 5 % (4/81; 95 % confidence interval 1.4-12 %: three cases of submucosal invasion depth ≥1000 µm [stalk invasion] and lymphatic invasion, one case of head invasion and budding grade 2/3). There was no local or metastatic recurrence in the e-curable patients, but six of them died of another cause (observation period, 80 months). There was no local recurrence in the non-e-curable patients; however, distant metastasis was observed in one patient. Death due to the primary disease was not observed in non-e-curable patients, but six of them died of another cause (observation period, 72 months). CONCLUSIONS: Our data support the validity of the JSCCR curative criteria for pedunculated-type T1 CRCs. Endoscopic resection cannot be considered curative for pedunculated-type T1 CRC with head invasion alone.