1. Key Messages
Tumor size, tumor grade, invasion depth, and lymphovascular invasion have been reported as risk factors for rectal neuroendocrine tumors metastasizing to the lymph nodes. However, there are discrepancies among guidelines regarding the treatment, and the decision should be in consideration of risk factors and quality of life. Large prospective studies are needed.
2. Introduction
The incidence of neuroendocrine neoplasms (NENs) arising from gastro-entero-pancreatic tract (GEP-NENs), across all sites, stages, grades, is steadily increasing, with a 6.4-fold increase from 1.09 per 100,000 in 1973 to 6.98 per 100,000 in 2012.[1,2] The incidence of NEN by site differs according to the country and region of the world. In the United States, the rectum is the third most common site after the lung and small intestine.[1] Meanwhile, in Japan, South Korea, China, and Taiwan, the rectum is the most common site of occurrence.[3–6]
The increase in the number of colonoscopies for colorectal cancer screening and the improvement of endoscopic equipment and technology have contributed to the increase in rectal NENs, especially G1/G2 well-differentiated neuroendocrine tumors (NETs).[7,8] However, it has been reported that NETs and positive resection margins are often found on histopathological examination after the tumors are misidentified as colorectal polyps and managed with normal polypectomy.[9]
Localized, well-differentiated rectal NETs are mainly treated with local excision and radical rectal resection with lymphadenectomy. Compared with rectal cancer, rectal NET G1/G2 has different characteristics such as easy lymph node metastasis despite its small size and slow progression, and thus, there are many controversial aspects in its treatment strategy. In addition, most NETs occur in the lower rectum, and surgery has a significant adverse impact on quality of life (QOL), including on bowel function, urinary function, and sexual function, making treatment difficult. In this review, we focus on the treatment of localized well-differentiated rectal NET G1/G2, introduce the latest evidence, and organize current knowledge.
3. Methods
We conducted an electronic literature search using the PubMed database to identify studies conducted on rectal NETs that were published between January 1990 and October 2022. The following key words were used: “rectal,” “colorectal,” “gastrointestinal,” “neuroendocrine,” “neoplasm,” “tumor,” “carcinoma,” and “carcinoid” (title/abstract). Case reports, editorials, letters, and commentaries were excluded. The initial search identified 571 publications. After title and abstract screening, full-text screening was conducted on 478 studies, after which 95 studies that remained were included in the present study. Only full articles published in peer-reviewed journals and in English were included (Fig. 1).
;)
Figure 1: Flow diagram of the selection of articles.
3.1. Classification of neuroendocrine neoplasms according to the World Health Organization 2019
The most recent World Health Organization (WHO) classification separates GEP-NENs into prognostic groups[10,11] based on both the mitotic count and Ki-67 index. Cell proliferation should be evaluated in whole lesions, but Ki-67 immunostaining of biopsy specimens has limited utility because the staining varies even within a single tumor.[12] Well-differentiated G1/G2 NETs generally have better prognosis than well-differentiated G3 and neuroendocrine carcinomas. A study based on the Surveillance, Epidemiology, and End Results database reported that the median overall survival (OS) for all rectal NEN was 24.6 years, while the OS for localized well-differentiated rectal NETs was 26.4 years.[1] In an analysis of the Dutch database, the 5- and 10-year OS rates for rectal NETs without distant metastases were 91% and 81% for G1, 60% and 60% for G2, and 21% and 18% for G3, respectively.[13]
3.2. Treatment strategy for localized rectal NET G1/G2
Tumor diameter and invasion depth have long been reported as risk factors for lymph node metastasis in rectal NETs.[14,15] Recently, lymphovascular invasion, high mitotic rate, and high Ki-67 index (i.e., G2 or higher) have been reported as additional risk factors for lymph node metastasis.[12,16–25] Shields et al.[15] reported that the lymph node metastasis rate was 8% in tumors measuring 1–10 mm in diameter, 31%, for those measuring 11–20 mm, and 59% for those measuring ≥21 mm. Localized tumors with a diameter of less than 1 cm and a depth of invasion confined to the submucosal layer are considered to have a low frequency of lymph node metastasis and a favorable prognosis.[22] Endoscopic resection is indicated for these tumors according to the National Comprehensive Cancer Network (NCCN) guidelines,[26,27] European Neuroendocrine Tumor Society (ENETS) guidelines,[28] and Japanese guidelines[29] (Table 1, Figs. 2–4).
Table 1 -
Comparison of Conditions Among the Three Guidelines Under Which Local Excision or Endoscopic Resection Is Acceptable
[26–30]
| Guidelines |
Conditions Under Which Local Resection or Endoscopic Resection is Acceptable if the Margin is Negative |
| NCCN |
T1–4, G1–2, ≦ 2 cm |
| ENETS |
T1–2, G1–2, <1 cm or T1, <2 cm |
| JNETS |
T1, G1, <1 cm, Ly(−), V(−) |
ENETS, European Neuroendocrine Tumor Society; JNETS, Japanese Neuroendocrine Tumor Society; NCCN, National Comprehensive Cancer Network.
Figure 2: Treatment strategies for well-differentiated rectal NETs in the (NCCN) guidelines.
[ 26,27 ] CT, computed tomography; EUS, endoscopic ultrasonography; MRI, magnetic resonance imaging; NCCN, National Comprehensive Cancer Network; PET, positron emission tomography; SRS, somatostatin receptor scintigraphy; TME,
total mesorectal excision.
Treatment strategies for well-differentiated rectal NETs in the ENETS guidelines.
[ 28,30 ] CT, computed tomography; ENETS, European Neuroendocrine Tumor Society; EUS, endoscopic ultrasonography; MRI, magnetic resonance imaging; PET, positron emission tomography; SRS, somatostatin receptor scintigraphy; TME,
total mesorectal excision.
Treatment strategies for well-differentiated rectal NETs in the JNETS guidelines.
[ 29 ] JNETS, Japanese Neuroendocrine Tumor Society; TME,
total mesorectal excision.
This indicates that among the risk factors of lymph node metastasis, tumor diameter and invasion depth, which can be diagnosed before treatment, are the initial factors considered in treatment decision making. In addition, depressions and ulcers (“Delle”) on the lesion surface are sometimes considered metastasis-related factors, particularly in Japan.[4,29] For these tumors, histopathological examination of the resected specimen determines the need for additional treatment. According to the NCCN and ENETS guidelines, invasion of the muscularis propria layer and the degree of tumor differentiation are important factor in determining treatment strategies.[26–28] Meanwhile, the Japanese guidelines recommend additional treatment when lymphovascular invasion is observed in addition to these factors.[29]
For well-differentiated rectal NETs with a tumor diameter of 1–2 cm, Japanese guidelines recommend radical surgery with lymphadenectomy (i.e., total mesorectal excision) for all NETs with a diameter of ≥10 mm.[8,29] This recommendation is reasonable from the perspective of minimizing the risk of future metastasis and recurrence. However, most previous reports on the risk of lymph node metastasis in rectal NETs are retrospective studies based on surgical cases. As such, there may be a problem of selection bias because the rate of lymph node metastasis and prognosis of patients who have not undergone surgery are unknown. Considering that surgery has a profound impact on invasiveness and QOL in NETs of the rectum,[31] it is debatable whether surgical excision is necessary for all rectal NETs even those with a tumor diameter of ≥1 cm.
The NCCN guidelines recommend local excision (preferably endoscopic) for tumors measuring 11–20 mm despite reports that the rate of lymph node metastasis is as high as 66% for tumors of this size.[27,32] The ENETS guidelines,[28] as well as the guidelines in Poland[33] and North America,[34] follow the same concept. In a recent analysis of data from 370 rectal NETs measuring ≤20 mm, the lymph node metastasis rate was 40.3% for rectal NETs measuring 11–20 mm and 30.8% for T1 alone.[35] An analysis of 199 cases from Italy showed that a tumor diameter ≥11.5 mm (odds ratio [OR]: 54.9) and vascular invasion (OR: 51.3) were independent risks for lymph node metastasis.[36] Accordingly, tumors measuring >10 mm in diameter have a reasonably high rate of lymph node metastasis. In contrast, Wang et al.[37] reported that depth of invasion and WHO grade were more important factors than tumor diameter.
An analysis of 531 cases of rectal NETs measuring 11–20 mm extracted from the Surveillance, Epidemiology, and End Results database found no difference in cancer-specific survival and OS between local excision and radical surgery.[38] In another study of 284 cases of NETs measuring ≤2 cm, evaluated only by size, all cases had no recurrence after local excision alone.[39] Neuroendocrine tumors are often divided by size into ≤10 mm and 11–20 mm, but there have been several reports that the risk of metastasis is low in tumors measuring up to 15 mm, and there are no other risk factors for metastasis.[22,40–43] The risk of metastasis in these tumors remains controversial, and prospective high-evidence-level research that considers various risk factors is warranted.
Lymphovascular invasion have been intensively evaluated. Neuroendocrine tumors do not show strong cell atypia, and thus, it is difficult to evaluate vascular invasion by hematoxylin-eosin (HE) staining alone. D2–40 staining is used to evaluate lymphatic invasion, while Elastica van Gieson staining and Victoria Blue staining are used to evaluate venous invasion. These methods have enabled a more accurate evaluation of vascular invasion. However, vascular invasion can now be identified even in very small NET lesions, increasing the number of cases in which it is difficult to determine the need for radical surgery.[44] Previous studies that considered vascular invasion as a risk factor for metastasis were mainly retrospective studies that targeted only surgical cases and were from a period when immunostaining and special staining were not used.[15,16]
Evidence regarding the significance of lymphovascular invasion in smaller lesions that have recently been discovered by immunostaining and special staining is still lacking. Sekiguchi et al.[44] re-evaluated lymphovascular invasion using D2–40 and Elastica van Gieson staining in 90 rectal NET lesions that had previously been evaluated using only HE staining. While only one case of venous invasion was observed in the HE evaluation, additional staining revealed that 46.7% of cases were positive for lymphovascular invasion (25.6% were positive for lymphatic invasion and 38.9% were positive for venous invasion). All these cases were followed up without any treatment, but no recurrence or metastasis was observed within a median follow-up period of 88 months.
This study revealed a very high rate of lymphovascular invasion, even in small rectal NET G1. Vascular invasion alone, as detected by immunostaining or special staining, might not be an absolute indication for recommending additional radical surgery.[44] Similar findings have been reported in recent years, and further investigation is required to establish the appropriate treatment modality for small G1 NETs with vascular invasion.[45–49] There are currently no follow-up studies for patients with G2 NET lesions positive for lymphovascular invasion, and surgery remains the primary treatment modality.
A multicenter study in Japan identified the following five risk factors for lymph node metastasis: (1) tumor diameter ≥10 mm, (2) surface depression, (3) G2NET, (4) pT2 or deeper, and (5) positive lymphovascular invasion. The lymph node metastasis rates according to the number of risk factors were as follows: none, 0.7%; 1, 19.1%; 2, 20.7%; 3:, 61.7%; 4, 75%; and 5, 75%. Patients with 3 or more risk factors showed a significantly higher rate of lymph node metastasis.[4] Meanwhile, one study showed that even if there are risk factors such as lymphovascular invasion, the prognostic benefit of local excision alone is equivalent to that of radical resection.[50] There are few studies on tumor budding [51] or perineural invasion,[52] and there is no conclusive evidence yet. Thus, future studies are needed.
Both vertical and horizontal margins are evaluated for postendoscopic resection margins. It is important to aim for negative margins after resection, and this is usually achieved via modified endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). However, in routine clinical practice, we often encounter cases in which a normal EMR or polypectomy is performed, resulting in a positive margin.[9] There are three possible treatment options for positive margins: additional surgical resection, additional local (endoscopic) resection, and observation.[53] A multicenter retrospective study in Korea focused on positive margins and indeterminate cases and found that the long-term prognosis is good even if no treatment is administered to patients with positive or indeterminate margins.[54,55] In another study of 77 G1 NET patients with positive surgical margins, 31 patients did not receive additional treatment and did not develop recurrence.[56]
Japanese guidelines recommend additional local excision for positive margins after endoscopic resection, even for NET G1 < 1 cm.[8] In Europe and the United States, additional treatment is recommended when invasion of the muscular propria layer is observed or when G2 NET is observed.[26–28]
3.3. Local excision
Endoscopic treatment and transanal surgery are options for local resection of rectal NETs; however, in recent years, endoscopic treatment has become mainstream because of the development of endoscopic treatment techniques. As rectal NETs are mainly located in the submucosal layer, there is a high risk of a positive vertical margin in treatment with conventional polypectomy or EMR. Modified EMR and ESD have been found to be useful since 2000 and 2010, respectively. Representative examples of modified EMR include EMR using a cap[57] and endoscopic submucosal resection with a ligation device (ESMR-L).[58–60] Both are methods of resection after aspiration of the lesion and are aimed for reliable deep margin-negative resection. Although ESMR-L is an established treatment modality that has been reported to be usefulness,[61–65] ligation devices are not covered by insurance in Japan.
More recently proposed treatment modalities include the two-channel method,[66] EMR with circumferential incision EMR,[67,68] underwater EMR,[69–71] traction-assisted hybrid ESD,[72] and EMR with double-band ligation.[73] Endoscopic submucosal dissection has also been approved for insurance coverage for colorectal NETs of up to 5–10 mm in Japan. Given that it is possible to dissect the deeper submucosa while visualizing the lesion, more reliable en bloc resection with negative margins can be expected. Initial results have been promising.[42,74–76] Modified EMR and ESD have similar benefits.[77–79] For endoscopic full-thickness resection, the German registry reported favorable outcomes in 40 cases (median procedure time, 18.5 minutes; negative margins in all cases).[80] Reliable endoscopic resection should be performed using appropriate methods based on an accurate preoperative diagnosis.[81]
A multicenter prospective case accumulation is ongoing in Japan. Over 3 years from 2017 to 2019, 500 patients with colorectal NETs were enrolled, and 95.4% underwent endoscopic treatment. A 10-year follow-up is planned, and the results are worthy of attention.[6] For local excision, good results have been reported in transanal surgery. The advantage is that full-thickness resection is possible, and safe surgical outcomes have been reported, including in those with large tumor diameters.[82,83] Although there are few studies comparing between transanal surgery and endoscopic treatment, retrospective studies have shown that ESD and endoscopic full-thickness resection are associated with fewer adverse events and shorter operating time and hospital stay than is transanal surgery for tumors measuring ≤10 mm.[84,85]
3.4. Surgical treatment with lymphadenectomy
Japanese guidelines recommend rectal resection with lymph node dissection for rectal NETs with a tumor diameter of ≥1 cm, invasion of the muscularis propria, or with risk factors such as lymphovascular invasion.[29] Surgical treatment for rectal NETs is similar to that for rectal cancer; however, there is no clear evidence regarding the extent of intestinal resection or lymph node dissection. Western guidelines also recommend total mesorectal excision as the initial treatment for tumors ≥2 cm.[26–28] The safety of laparoscopic surgery for rectal NETs has been reported.[86]
There are limited data on the frequency of lateral lymph node involvement, with only a few case reports or series.[87] Takatsu et al.[86] evaluated 77 patients with rectal NET; among them, 6 patients with lymph nodes with a short diameter of ≥8 mm on computed tomography (CT) underwent lateral pelvic lymph node dissection, and metastasis was found in 5 patients. It is necessary to accumulate data regarding the indications for lateral pelvic lymph node dissection. In a retrospective study of 22 surgical patients, Tanaka et al.[88] investigated the criteria for diagnosing lymph node metastasis on preoperative CT by using the largest lymph node diameter on imaging. When the cutoff was set at 3 mm, the sensitivity was 66.7% and 100%, the specificity was 87.5% and 82.4%, and the area under the curve (AUC) was 0.844 and 0.897, in perirectal and intermediate nodes, respectively.[88] There are similar studies with cutoff values of 5[89] and 3 mm,[90] and it may be appropriate to use a more stringent cutoff value than that in cancer. Therefore, further studies are warranted. Furthermore, there is no evidence on adjuvant therapy for well-differentiated rectal NETs.
3.5. Surveillance after treatment
There is no mention of surveillance in the latest Japanese guidelines.[29] The NCCN guidelines do not require surveillance of endoscopically resected NETs confined to the submucosa <1 cm without metastasis. Endoscopy and CT/magnetic resonance imaging (MRI) follow-up (period not stated) are recommended after local resection tumors of measuring ≤1–2 cm. Ten-year surveillance with CT or MRI is recommended for patients with tumors measuring >2 cm or those with lymph node metastasis.[26,27] The ENETS 2017 guidelines recommend only one endoscopic check at 12 months after the endoscopic resection for small (<10 mm) G1/2 r-NENs treated with curative resection, and no further investigations are recommended. For G1/2 lesions measuring 10–20 mm, annual endoscopic follow-up and radiological imaging using either CT or MRI are recommended.
Somatostatin receptor scintigraphy (SRS) is advisable every 12–24 months. For G1/2 lesions >20 mm, both curatively and noncuratively resected, closer follow-up (every 3–12 months), endoscopy every 6–12 months, CT or MRI every 3–12 months, and SRS every 12–24 months are recommended.[30] However, evidence is still lacking and regular surveillance is desirable. Neuroendocrine tumors have slower progression than cancer, and thus, long-term follow-up is reasonable. It is necessary to pay attention to long-term prognosis after endoscopic and surgical treatment.[91] Somatostatin receptor scintigraphy has been reported be more useful than positron emission tomography for imaging for recurrence,[92] and further investigation of its usefulness is required. No serum tumor markers have been recommended in any guidelines as being useful for surveillance. However, serum CgA is the most commonly used serum biomarker in clinical practice for surveillance of NETs, although its assay specificity and standardization are insufficient and the usefulness as a biomarker is still controversial.[93,94]
4. Conclusions
Rectal NET is one of the most common gastrointestinal NENs, and its incidence has significantly increased in recent years because of widespread endoscopic screening for colorectal cancer and improvements in endoscopic techniques. Tumor size, tumor grade, invasion depth, and lymphovascular invasion have been reported as risk factors for rectal NETs metastasizing to the lymph nodes. However, there are discrepancies among guidelines regarding the treatment of tumors measuring 10–20 mm, and the treatment decision should be in consideration of other risk factors and QOL. Large prospective studies are needed to establish standardized treatment strategies for rectal NET.
Author contributions
Concepts and the study design were created by Shigenobu Emoto and Soichiro Ishihara. Literature search, data acquisition and analyses were done by Shigenobu Emoto. Manuscript preparation was done by Shigenobu Emoto and Soichiro Ishihara. Manuscript was edited and approved by all authors. The manuscript has been read and approved by all the authors, that the requirements for authorship as stated earlier in this document have been met, and that each author believes that the manuscript represents honest work.
Data availability statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Financial support and sponsorship
This research was supported by Grants-in-Aid for Scientific Research (C: grant number 19K09114, C: grant number 19K09115, C: grant number 20K09051, Challenging Research [Exploratory]: grant number 20K21626, B: grant number 21H02778) from the Japan Society for the Promotion of Science. This research was also supported by the Project for Cancer Research and Therapeutic Evolution (grant number JP 19 cm0106502) from the Japan Agency for Medical Research and Development.
Conflict of interest statement
Prof. Soichiro Ishihara, a co-editor at Formosan Journal of Surgery, had no role in the peer review process of or decision to publish this article. The authors declare that they have no financial conflict of interest with regard to the content of this report.
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