T1 rectal NET resection: Does size really matter?

Abstract

Over the past 2 decades, the detection of rectal neuroendocrine tumors (NETs) has been increasing worldwide. This can be attributed to incidental diagnosis at screening and surveillance colonoscopy, heightened endoscopist’s and histopathologist’s awareness, and advances in endoscopic imaging. Consequently, questions have arisen regarding the optimal therapeutic approach. Accurate staging and subsequent treatment are of the utmost importance in ensuring long-term progression-free survival.1Basuroy R. Haji A. Ramage J.K. et al.Review article: the investigation and management of rectal neuroendocrine tumours.Aliment Pharmacol Ther. 2016; 44: 332-345Crossref PubMed Scopus (43) Google Scholar, 2Kulke M.H. Shah M.H. Benson 3rd, A.B. et al.Neuroendocrine tumors, version 1.2015.J Natl Compr Canc Netw. 2015; 13: 78-108Crossref PubMed Scopus (234) Google Scholar, 3Ramage J.K. De Herder W.W. Delle Fave G. et al.ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.Neuroendocrinology. 2016; 103: 139-143Crossref PubMed Scopus (132) Google Scholar, 4Shah M.H. Goldner W.S. Halfdanarson T.R. et al.NCCN guidelines insights: neuroendocrine and adrenal tumors, version 2.2018.J Natl Compr Canc Netw. 2018; 16: 693-702Crossref PubMed Scopus (159) Google Scholar, 5Anthony L.B. Strosberg J.R. Klimstra D.S. et al.The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum.Pancreas. 2010; 39: 767-774Crossref PubMed Scopus (170) Google Scholar NETs constitute a heterogenous group of tumors arising from the diffuse neuroendocrine cell system and can be identified at various organs (eg, digestive system and lung). The hallmarks of histologic diagnosis include the characteristic morphology and differentiation at hematoxylin and eosin staining along with positive immunostaining for neuroendocrine and proliferation markers.6Perren A. Couvelard A. Scoazec J.-Y. et al.ENETS consensus guidelines for the standards of care in neuroendocrine tumors: pathology: diagnosis and prognostic stratification.Neuroendocrinology. 2017; 105: 196-200Crossref PubMed Scopus (98) Google Scholar Rectal NETs are usually well-differentiated neoplasms confined to the submucosal layer. Histologically these lesions can be classified in 3 grades depending on their tumor cell proliferation: (1) G1 with <2 mitotic count per 10 high-power fields and/or Ki-67 ≤2%, (2) G2 with mitotic count 2 to 20 per 10 high-power fields and/or Ki-67 3% to 20%, and (3) G3 with mitotic count and Ki-67 both >20. G1 tumors are generally considered slow growing and less aggressive than G2 tumors , which are more heterogenous and well differentiated. G3 tumors are poorly differentiated, aggressive, and linked with poor outcomes. Recently G3 tumors have been further subclassified as G3a Ki-67 >20% with well-differentiated morphology and G3b with poorly differentiated morphology. Size >20 mm and G3 lesions are among the less favorable characteristics and are associated with a higher risk of metastatic disease.4Shah M.H. Goldner W.S. Halfdanarson T.R. et al.NCCN guidelines insights: neuroendocrine and adrenal tumors, version 2.2018.J Natl Compr Canc Netw. 2018; 16: 693-702Crossref PubMed Scopus (159) Google Scholar,6Perren A. Couvelard A. Scoazec J.-Y. et al.ENETS consensus guidelines for the standards of care in neuroendocrine tumors: pathology: diagnosis and prognostic stratification.Neuroendocrinology. 2017; 105: 196-200Crossref PubMed Scopus (98) Google Scholar,7Caplin M. Sundin A. Nillson O. et al.ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms.Neuroendocrinology. 2012; 95: 88-97Crossref PubMed Scopus (182) Google Scholar At initial diagnosis, rectal NETs are more often small, localized lesions, with a low risk of distal metastasis; thus, the prognosis is good, with an overall 5-year survival rate >75%. In particular, survival rate is 98% to 100% when there is evidence of localized disease confined to the mucosa or submucosa without regional lymph nodes (T1), whereas when local (N1) or distant (M1) metastases are found, the survival rates decrease to 54% to 74% and 15% to 37%, respectively.1Basuroy R. Haji A. Ramage J.K. et al.Review article: the investigation and management of rectal neuroendocrine tumours.Aliment Pharmacol Ther. 2016; 44: 332-345Crossref PubMed Scopus (43) Google Scholar In addition, the risk of regional lymph node involvement and metastatic disease for rectal NET <10 mm is 1% to 10%; this risk increases significantly to 60% when the primary lesion is >20 mm, and it is approximately 30% for NETs 10 to 20 mm.2Kulke M.H. Shah M.H. Benson 3rd, A.B. et al.Neuroendocrine tumors, version 1.2015.J Natl Compr Canc Netw. 2015; 13: 78-108Crossref PubMed Scopus (234) Google Scholar,3Ramage J.K. De Herder W.W. Delle Fave G. et al.ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.Neuroendocrinology. 2016; 103: 139-143Crossref PubMed Scopus (132) Google Scholar,5Anthony L.B. Strosberg J.R. Klimstra D.S. et al.The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum.Pancreas. 2010; 39: 767-774Crossref PubMed Scopus (170) Google Scholar,7Caplin M. Sundin A. Nillson O. et al.ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms.Neuroendocrinology. 2012; 95: 88-97Crossref PubMed Scopus (182) Google Scholar Although the guidelines of the European Neuroendocrine Tumor Society (ENETS) and the North American Neuroendocrine Tumor Society provide a comprehensive tool for advice on the management of rectal NETs, the evidence on which these recommendations are based is largely from retrospective studies and expert opinion. Estimated size at diagnosis and careful staging play a crucial role in the choice of the adequate therapeutic approach in order to ensure optimal oncologic resection and avoid recurrence. Lesions ≤20 mm should be treated with endoscopic or transanal resection, and anorectal endoscopic ultrasound (EUS) is recommended before resection; endoscopic treatment modalities are preferred for lesions <10 mm, and surgical options are advised for tumors >20 mm or those associated with lymph node metastasis. However, the optimal management of rectal NETs 10 to 20 mm is still unclear.2Kulke M.H. Shah M.H. Benson 3rd, A.B. et al.Neuroendocrine tumors, version 1.2015.J Natl Compr Canc Netw. 2015; 13: 78-108Crossref PubMed Scopus (234) Google Scholar,3Ramage J.K. De Herder W.W. Delle Fave G. et al.ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.Neuroendocrinology. 2016; 103: 139-143Crossref PubMed Scopus (132) Google Scholar,5Anthony L.B. Strosberg J.R. Klimstra D.S. et al.The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum.Pancreas. 2010; 39: 767-774Crossref PubMed Scopus (170) Google Scholar In this issue of Gastrointestinal Endoscopy, Park et al8Park S.S. Kim B.C. Lee D.-e. et al.Comparison of endoscopic submucosal dissection and transanal endoscopic microsurgery for T1 rectal neuroendocrine tumors: a propensity score-matched study.Gastrointest Endosc. 2021; 94: 408-415Abstract Full Text Full Text PDF Scopus (1) Google Scholar retrospectively compared the efficacy and safety of endoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEM) for the resection of rectal NETs ≤20 mm. They initially evaluated 226 ESD and 59 TEM procedures, which were then compared in a matched cohort (52 ESD and 52 TEM), using the propensity score matching method, with NET size and previous history of endoscopic mucosal resection (EMR) balanced among the 2 groups. The results showed that TEM achieved an R0 resection more often than did ESD (92.3% vs 71.2%, respectively, P = .005) and the rate of deep positive margins was higher in the ESD group (25% vs 0%, P < .001), whereas there was no difference in terms of lateral margins (ESD 9.6% vs TEM 7.7%, P = 1.000). Interestingly, when further subgroup analysis was performed, dividing all resections in 2 groups (ESD, n = 218; TEM, n = 49) based on tumor size, no significant differences were found in terms of R0 resection in the <10 mm group (83.5% vs 93.9%, P = .063). This finding is in keeping with those of previously published retrospective studies,1Basuroy R. Haji A. Ramage J.K. et al.Review article: the investigation and management of rectal neuroendocrine tumours.Aliment Pharmacol Ther. 2016; 44: 332-345Crossref PubMed Scopus (43) Google Scholar,3Ramage J.K. De Herder W.W. Delle Fave G. et al.ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.Neuroendocrinology. 2016; 103: 139-143Crossref PubMed Scopus (132) Google Scholar suggesting that NETs <10 mm should be resected with ESD because of the low risk of muscularis propria invasion, 2% risk of lymph node metastases, and 0.2% risk of distant metastases.3Ramage J.K. De Herder W.W. Delle Fave G. et al.ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.Neuroendocrinology. 2016; 103: 139-143Crossref PubMed Scopus (132) Google Scholar,9McConnell Y.J. Surgical management of rectal carcinoids: trends and outcomes from the Surveillance, Epidemiology, and End Results database (1988 to 2012).Am J Surg. 2016; 211: 877-885Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar,10Gleeson F.C. Levy M.J. Dozois E.J. et al.Endoscopically identified well-differentiated rectal carcinoid tumors: impact of tumor size on the natural history and outcomes.Gastrointest Endosc. 2014; 80: 144-151Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Surprisingly, the authors found that for NETs between 10 and 20 mm, the R0 resection rate was only 37.5% in the ESD group and 80% in the TEM group. Although statistical significance was not reached (P = .145) because of the small number of patients included in this subgroup, it appears evident that TEM should be preferred for resection of 10- to 20-mm NETs as being more effective in achieving a R0 resection. Unfortunately, it appears that anorectal EUS was not routinely performed in this subgroup; this could potentially explain such a high R1 resection in the ESD group. When ESD is the preferred option for rectal NET resection, we recommend performing anorectal EUS to reduce the risk of muscularis propria involvement. Additionally, an open discussion with the patient should take place, highlighting the significant risk of incomplete resection that might eventually require further surgical management. This isn’t just a matter of a mere technical superiority of one procedure over another for achieving a R0 resection but should be contextualized with the fact that 10- to 20-mm NETs are more often found to be T2, carrying a substantial risk of lymph node metastases (8.2%) and distant metastases (2.4%), with a 10-year survival rate of 71.5%10Gleeson F.C. Levy M.J. Dozois E.J. et al.Endoscopically identified well-differentiated rectal carcinoid tumors: impact of tumor size on the natural history and outcomes.Gastrointest Endosc. 2014; 80: 144-151Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar; therefore, selecting the correct procedure is crucial. As acknowledged by the authors, the 10-year sampling period may represent a limitation of the study because it may have had an impact on the endoscopists’ and surgeons’ procedural skills. Furthermore, during this time, the related guidelines have changed repeatedly (for example, the ENETS guidelines were updated 3 times in 2008, 2012, and 2016) on the basis of new scientific evidence.3Ramage J.K. De Herder W.W. Delle Fave G. et al.ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.Neuroendocrinology. 2016; 103: 139-143Crossref PubMed Scopus (132) Google Scholar,7Caplin M. Sundin A. Nillson O. et al.ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms.Neuroendocrinology. 2012; 95: 88-97Crossref PubMed Scopus (182) Google Scholar This could have led to a different management of the NETs during the study period, weakening its homogeneity. Unfortunately, the authors failed to report the grade of the lesions included in their study. As reported in the ENETS guidelines,3Ramage J.K. De Herder W.W. Delle Fave G. et al.ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.Neuroendocrinology. 2016; 103: 139-143Crossref PubMed Scopus (132) Google Scholar,7Caplin M. Sundin A. Nillson O. et al.ENETS consensus guidelines for the management of patients with digestive neuroendocrine neoplasms: colorectal neuroendocrine neoplasms.Neuroendocrinology. 2012; 95: 88-97Crossref PubMed Scopus (182) Google Scholar over the past decade, the histologic classification has become a key factor for the management of rectal NETs and can completely change the treatment algorithm, independently of the NET’s size. Data regarding grades may have explained the liver recurrence 4 months after ESD, reported by the authors in a patient who initially presented with 2 rectal NETs. Apart from multicentricity, evidence of G2 or G3 lesions could elucidate the cause of this recurrence. Another interesting outcome in the matched ESD and TEM groups was the difference in procedural time (ESD 22 minutes [range, 11-65] vs TEM 35 minutes [range, 17-160], P < .001) and length of hospital stay (ESD 2.5 days [range, 1-5] vs TEM 4 days [range, 3-8], P < .001); both were significantly shorter in the ESD group. Although the procedural time was statistically shorter for ESD, the difference was so small that, in our opinion, it should not influence the treatment selection. On the other hand, ESD had a significantly shorter hospitalization, and this is indeed noteworthy. If we also consider that nowadays ESD of rectal NET is usually performed in an outpatient setting, and most patients are no longer admitted for postprocedural observation, the difference with post-TEM hospital admission is likely to be even more significant, with further impact on the direct medical cost. Finally, the authors decided to include only T1 lesions <20 mm. It would have been extremely interesting to include all of the NETs <20 mm, including the T2 NETs. This would probably have provided a more complete overview of the technical and clinical efficacy of these procedures. The authors should be praised for sharing these exciting results, which should be taken into consideration for the management of 1- to 20-mm rectal NETs. In addition, further studies evaluating the role of endoscopic full-thickness resection techniques for 10- to 20-mm NETs with no lymphovascular involvement are needed, since it might allow a quick, safe, and effective resection for both T1 and T2 NETs, filling the existing gap between ESD and TEM and potentially resolving the dilemma of the appropriate resection of this particular NET subgroup. It is clear that more prospective multicenter studies are indeed needed to stratify and identify the optimal resection method. Therefore, size does matter and has been a focal point of decision making so far. Nevertheless, other important factors, such as grade and TNM classification, should always be part of the NET management equation and should be routinely evaluated to ensure the most appropriate treatment. Dr Murino is the recipient of lecture honoraria from Olympus. The other author disclosed no financial relationships. Comparison of endoscopic submucosal dissection and transanal endoscopic microsurgery for T1 rectal neuroendocrine tumors: a propensity score-matched studyGastrointestinal EndoscopyVol. 94Issue 2PreviewEndoscopic submucosal dissection (ESD) and transanal endoscopic microsurgery (TEM) are the most effective endoscopic resection methods for T1 rectal neuroendocrine tumors (NETs). We aimed to compare the efficacy and safety of ESD and TEM for rectal NETs ≤20 mm. Full-Text PDF