Pathologic sm2 carries a moderate risk of metastases even without other unfavorable factors, but positive horizontal margins have low local recurrence risk after en bloc resection

I have read with great interest the articles by Santos-Antunes et al. [1] and Haasnoot et al. [2]

The multicenter study of colorectal endoscopic submucosal dissection (ESD) in the West, reported by Santos-Antunes et al. [1], showed that the risk factors for the presence of residual lesions in the wall were piecemeal resection, poor differentiation, and positive or indeterminate vertical margin. pT1b cancers (invasion deeper than 1000 μm from the muscularis mucosae) without any other risk factors did not present with residual lesions during the follow-up period. The authors developed predictive scores to better stratify the risk of residual neoplasia in patients after noncurative ESD.

“... in a large cohort of patients with long-term follow-up data, pT1b (sm2) results in an elevated risk of LNM even without other poor prognostic factors, and complementary surgical resection should be recommended in patients who are good candidates for surgery.”

The worldwide spread of colorectal ESD will likely reduce the number of unnecessary surgical procedures performed for benign tumors. En bloc ESD reduces local recurrence, and accurate pathological evaluation reduces unnecessary surgery and allows the selection of appropriate additional treatment. Furthermore, the interval between surveillance endoscopies can be extended, reducing patient burden and healthcare costs. We are pleased that colorectal ESD is becoming more widespread outside Asia. Our multicenter prospective study of colorectal ESD (CREAT-J) reported a favorable long-term outcome [3] [4], which should further promote the use of ESD in the West.

For patients with large colorectal lesions, appropriate selection of patients for endoscopic resection is critical for optimal outcomes. Careful endoscopic assessment is typically performed to select patients with noninvasive lesions or superficially invasive cancer for ESD, with the avoidance of endoscopic resection in patients with endoscopic features of deeply invasive cancer. However, despite using pit pattern, covert submucosal (sm) invasion is diagnosed histologically in about 15 % of all ESD cases [3] [5], and a decision needs to be made as to whether additional surgery is necessary.

There have been many studies on the risk of lymph node metastasis (LNM) in pT1 colorectal cancer. As found in the current study, the risk of metastasis is very low or nil in pathological sm1, based on the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines [6]. In addition, many studies, including this paper, have shown that the presence of lymphovascular invasion, budding grade, and a poorly differentiated component are risk factors, and surgery is recommended when one of these factors is positive in sm1 [6].

However, when depth of tumor invasion of sm2 or deeper (pT1b) is the only factor present, interpretations are conflicting. Some reports have shown that the risk of LNM is extremely low in pT1b cancers without any other risk factors, but our group has reported a 5 %–10 % risk of metastasis or recurrence [7]; therefore, surgery is recommended because the risk of metastases is not small, and any delay in cancer treatment can have adverse consequences on a patient’s outcome [7]. Additionally, given the fact that laparoscopic colectomy has become a standardized and simple-to-perform intervention, and postoperative quality of life is often restored after several months, the surgical option is more appealing than the surveillance strategy to these high risk patients [8]. For the lower rectum, a clinical trial of chemoradiotherapy after ESD has been started from the viewpoint of patients’ quality of life [9] [10].

In addition, it is essential to consider not only concurrent LNM, but also long-term outcomes and recurrence risk, especially if no surgery is to be performed after ESD, because additional surgery may theoretically reduce the risk of recurrence by cleaning up micrometastases, even if the lymph nodes are negative.

For noncurative pT1b cancers in the colon, it is not a good option to recommend follow-up colonoscopy instead of surgical resection, given the nontrivial risk of cancer recurrence and lower morbidity of surgery for colonic lesions. Of note, the rate of serious postoperative complications in the present paper (18 %) was higher than that reported in the published literature.

There are several points to keep in mind when evaluating the resected ESD specimens and the risk of LNM or other metastases. The resected specimen should be fully extended and affixed to a cork board. It is important to cut the resected specimen every 2–3 mm to obtain a detailed histopathological diagnosis. Moreover, the measurement of sm invasion has not been standardized, even in Japan. Although Desmin staining is required to assess the status of the muscularis mucosae, the diagnosis remains inconsistent depending on whether the muscularis mucosae is preserved or not. There is also an issue with the diagnostic accuracy of lymphovascular invasion. Immunochemical staining, such as D2–40, is mandatory for the evaluation of lymphovascular invasion, but this paper does not state how often it was done. Even with immunochemical staining, there are also interinstitutional differences in the diagnostic accuracy of lymphovascular invasion evaluation. More cases of positive lymphovascular invasion might have been diagnosed in this patient cohort if immunochemical staining had been performed on all ESD specimens.

In this paper, the residual lesion rate for sm1 cancers was 0 %, and it was also 0 % for > sm1 cancers if no other risk factors were present. The authors concluded that “Lymphatic permeation or poor differentiation warrant surgery owing to the high risk of LNM, mainly in > sm1 cancers. In the remaining cases, en bloc and R0 resections resulted in a low risk of a residual lesion in the wall.” However, there were only 32 patients in the analysis and the median endoscopic follow-up period was 12 months, which is inadequate to determine the actual risk of recurrence.

In the study by Kadota et al. [10], time to recurrence varied from 8 to 69 months after ESD for pT1 cancers. In our CREAT-J study [3], recurrence was also found 13–25 months after ESD. Furthermore, metastasis was diagnosed in 9.7 % (3/31) of noncurative pT1b cancers without any other risk factors, who underwent additional surgery (CREAT-J study group, unpublished data). Therefore, long-term surveillance is needed for accurate recurrence risk assessment. Additionally, the small sample size of this study resulted in a large margin of error, and the authors did not provide a 95 %CI for the point estimate of the frequency of LNM and recurrences.

The data from the multicenter European study from Haasnoot et al. [2] is clinically important as it provides the largest number of horizontal margin-positive/indeterminate (HM1) cases after complete colorectal ESD published to date. The authors concluded that a positive horizontal margin after an en bloc ESD for noninvasive lesions is associated with a marginal nonsignificant increase in the local recurrence rate, equal to an ESD with clear horizontal margins. We have reported similar results from our institution [11]. The authors did not report specifically whether there was any difference between en bloc resection and piecemeal resection in cases with an indeterminate horizontal margin (HMX). In our study [11], the local recurrence rate of the en bloc HMX group (2.2 %) was significantly lower than that of the piecemeal HMX group (15.2 %), so knowing this difference would be clinically important.

In addition, Haasnoot et al. reported that two of the six cases of recurrence were successfully treated with an additional endoscopic resection [2]. Therefore, HM1/HMX, even if it does carry a risk of local recurrence, is of less clinical importance because it can be cured by further endoscopic resection. Conversely, a positive vertical margin may also result in LNM and/or distant metastasis.

The authors have not reported the depth of invasion for patients in the high risk category. A mean follow-up of 22 months for HM1 is in any case too short to assess the risk of metastatic recurrence, as discussed earlier in this editorial. It should be noted that metastatic recurrence may occur even in those patients in whom the depth of invasion is the only risk factor if the patient is followed up for a longer period of time.

In summary, the results of the study by Santos-Antunes et al. [1] on the risk of lymph node metastasis should be interpreted with great caution. In our experience, in a large cohort of patients with long-term follow-up data, pT1b (sm2) still results in an elevated risk of LNM even without other poor prognostic factors, and complementary surgical resection should be recommended in patients who are good candidates for surgery. In contrast, we agree that positive horizontal resection margins are associated with a low risk of local recurrences, as reported by Haasnoot et al. [2]. Should local recurrence occur, it can usually be managed endoscopically with no serious consequence. Therefore, positive horizontal resection margins should be considered separately from positive vertical resection margins.

Publication History

Article published online:
11 January 2023

• References

• 1 Santos-Antunes J, Pioche M, Ramos-Zabala F. et al. Risk of residual neoplasia after a noncurative colorectal endoscopic submucosal dissection for malignant lesions: a multinational study. Endoscopy 2023; 55: 235-244
• 2 Haasnoot K, Baldaque-Silva F, Koch A. et al. Low risk of local recurrence after a successful en bloc endoscopic submucosal dissection for noninvasive colorectal lesions with positive horizontal resection margins (R-ESD study). Endoscopy 2023; 55: 244-251
• 3 Ohata K, Kobayashi N, Sakai E. et al. Long-term outcomes after endoscopic submucosal dissection for large colorectal epithelial neoplasms: a prospective, multicenter, cohort trial from Japan. Gastroenterology 2022; 163: 1423-1434.e2
• 4 Kobayashi N, Takeuchi Y, Ohata K. et al. Outcomes of endoscopic submucosal dissection for colorectal neoplasms: Prospective, multicenter, cohort trial. Dig Endosc 2022; 34: 1042-1051
• 5 Yamada M, Saito Y, Sakamoto T. et al. Endoscopic predictors of deep submucosal invasion in colorectal laterally spreading tumors. Endoscopy 2016; 48: 456-464
• 6 Hashiguchi Y, Muro K, Saito Y. et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 2020; 25: 1-42
• 7 Takamaru H, Saito Y, Sekiguchi M. et al. Endoscopic resection before surgery does not affect the recurrence rate in patients with high-risk T1 colorectal cancer. Clin Transl Gastroenterol 2021; 12: e00336
• 8 Nakamura F, Saito Y, Haruyama S. et al. Short-term prospective questionnaire study of early postoperative quality of life after colorectal endoscopic submucosal dissection. Dig Dis Sci 2017; 62: 3325-3335
• 9 Kiriyama S, Saito Y, Matsuda T. et al. Comparing endoscopic submucosal dissection with transanal resection for non-invasive rectal tumor: a retrospective study. J Gastroenterol Hepatol 2011; 26: 1028-1033
• 10 Kadota T, Ikematsu H, Sasaki T. et al. Protocol for a single-arm confirmatory trial of adjuvant chemoradiation for patients with high-risk rectal submucosal invasive cancer after local resection: Japan Clinical Oncology Group Study JCOG1612 (RESCUE study). BMJ Open 2020; 10: e034947
• 11 Makazu M, Sakamoto T, So E. et al. Relationship between indeterminate or positive lateral margin and local recurrence after endoscopic resection of colorectal polyps. Endosc Int Open 2015; 3: E252-E257