Rectal neuroendocrine tumors: Update

Table 1 International guidelines for management of rectal neuroendocrine tumors

Guidelines	Treatment recommendations
European Neuroendocrine Tumor Society, 2023[76]	For lesions ≤ 10 mm: Endoscopic resection such as mEMR, ESD, and eFTR is recommended and recurrence rates are low
	For lesions ≥ 20 mm: Initial assessment is performed using EUS and pelvic MRI for local staging. Distant metastases staging is done using chest and abdominal CT/MRI and 68Gallium-SSA-PET-CT. For positive lesions Surgical resection using LAR or APR is recommended (after exclusion of unresectable distant metastases)
	For lesions 10-20 mm: Initial assessment is performed using EUS and pelvic MRI for local staging. Distant metastases staging is done using chest and abdominal CT/MRI and 68Gallium SSA-PET-CT. For positive lesions, either endoscopic or definitive surgical therapy is decided through multidisciplinary team discussions
National Cancer Comprehensive Cancer Network, 2025[77]	Very small (< 1 cm)
	Negative margin: No further follow-up
	Indeterminate margin: Classification into low grade (G1) that requires endoscopy follow up (6-12 months) and referral to the pathway below (all other tumor sizes) if positive or intermediate grade (G2)
	All other tumor sizes
	T1 stage: Resection (endoscopic or transanal)
	Lesions less than 1 cm with no follow up
	Lesions follow up every 6-12 months
	Management depends on the size for T2-T4 stages: Comprehensive assessment by colonoscopy, multiphasic imaging CT scan/MRI, Chest CT scan, SSTR PET-CT or SSTR PET-MRI and biochemical evaluation as clinically indicated
	Size ≤ 2 cm: Resection by endoscopy or transanal surgery; if size < 1 cm, no further follow up is needed; if 1-2 cm, frequent (6-12 months) follow up by endoscopy or MRI
	Size > 2 cm or presence of positive lymph nodes: Low anterior resection, abdominoperineal resection, or Neoadjuvant or definitive chemoradiation. Aim for cytoreduction
	Metastatic lesions: Management with aim of cytoreduction
Polish Network of Neuroendocrine Tumors, 2022[78]	Size < 1 cm with no risk factors: Endoscopic resection
	Size 1-2 cm with no risk factors: Endoscopic resection
	Size 1-2 cm with risk factors: Surgical treatment using: (1) Transanal approach with either Transanal endoscopic microsurgery or through the open rectum access; (2) Laparoscopic approach with either abdominoperineal amputation of the rectum or anterior resection of the rectum; and (3) Through open access with either abdominoperineal amputation of the rectum or anterior resection of the rectum
	Risk factors to consider include: Infiltration of the muscular membrane proper, involvement of regional lymph nodes, infiltration of lymphatic and/or blood vessels, and a proliferation index above 2%

T1 means tumor invades the lamina propria or submucosa; T2 means tumor invades the muscular layer or is 2 cm in size; T3 means tumor invades into subserosal tissue; T4 means tumor invades serosa and/or adjacent organs (American Joint Committee on Cancer (AJCC) 8^th edition)[79]. mEMR: Modified endoscopic mucosal resection; ESD: Endoscopic submucosal dissection; eFTR: Endoscopic full-thickness resection; MRI: Magnetic resonance imaging; CT: Computed tomography; SSA: Somatostatin analogues; EUS: Endoscopic ultrasound; PET: Positron emission tomography; LAR: Low anterior resection; APR: Abdominoperineal resection; SSRT: Somatostatin receptor.

Table 2 Studies of factors related to lymph nodes metastasis in rectal neuroendocrine tumors

Level of assessment	Ref.	Country	Study type	Cohort	Stage	Risk factors
Studies that assess lymph nodes metastasis at baseline, prior to tumor intervention	Hyun et al[80], 2015	South Korea	Retrospective	247 patients; at baseline prior to excisional intervention	Not mentioned	Univariate analysis: Tumor size (P < 0.001), shape (P < 0.001), color (P < 0.001) and surface changes (P < 0.001) were significantly associated with LNM
						Multivariate analysis: Tumor size (OR = 11.53, 95%CI: 2.51-52.93, P = 0.002) and atypical surface (OR = 27.44, 95%CI: 5.96-126.34, P < 0.001) changes were independent risk factors for LNM
						Atypical endoscopic features were associated with LNM in RNETs < 10 mm (P = 0.005) and 10-19 mm (P = 0.041) in diameter
	Wang et al[81], 2021	China	Retrospective	223 patients; the incidence of LNM was 10.8%		Univariate and multivariate regression analyses: Tumor size, grade A, and depth of tumor invasion were independent risk factors for LNM (P < 0.05); AUC = 0.948 (95%CI: 0.890-1.000)
	O’Neill et al[82], 2021	United Kingdom	Retrospective	32 patients had small lymph nodes (≤ 10 mm)		Radiological staging confirmed nodal involvement in 25% (8/32)
				81% (n = 26) are grade 1 with Ki67 < 3%		Two cases had distant metastatic disease
				At baseline with no management intervention		LVI in 3% (1/32) of patients but none demonstrated peri-neural invasion
	Wei et al[83], 2018	China	Retrospective	419 patients; at baseline, prior to interventions		Univariate and multivariate regression: Tumor size, G grade and the depth of tumor invasion were independent risk factors for LNM (P < 0.05)
	Kojima et al[84], 2019	Japan	Retrospective	79 patients; at baseline prior to interventions; LNM in 12.7%, recurrences in 3.8%, and multiple cancers in 30.4% of the subjects		LOH of PHLDA3 and MEN1 tumor suppressor genes at Lymph nodes of RNET
						LOH PHLDA3 (60%) and MEN1 (66.7%)
						Lymphatic invasion and WHO classification were found to be independent risks for LNM
	Concors et al[85], 2018	United States	Retrospective	3880 (79.3%) had well-differentiated tumors, 540 (11.0%) had moderately differentiated tumors, 473 (9.7%) had poorly differentiated tumors		The association between tumor size and distant metastatic disease was stronger for well-differentiated and moderately differentiated tumors (OR = 1.4, P < 0.001 for both) than for poorly differentiated tumors (OR = 1.1, P = 0.010). For well-differentiated tumors, the optimal cut point for distant metastatic disease was 1.15 cm (AUC = 0.88, 88% sensitive and 88% specific). Tumors ≥ 1.15 cm in diameter were associated with a substantially increased incidence of distant metastatic disease [72/449 (13.8%)]. For moderately differentiated tumors, the optimal cut point was also 1.15 cm (AUC = 0.87, 100% sensitive and 75% specific)
Study that assesses LNM after endoscopic resection	Tie et al[86], 2024	China	Retrospective	128 patients; 92 patients underwent ESD; 19 patients underwent EMR; no significant difference between the two groups regarding the positive rates of basal tumor margin and lateral tumor margin		Tumor size and age at diagnosis were predictors for LNM
Studies that assess LNM following endoscopic resection and curative surgery	Sohn et al[87], 2017	Korea	Retrospective	28 (43.8%) patients underwent transanal excision, EMR or ESD was performed in 15 (23.4%) patients, and radical resection in 21 (31.8%) patients		Multivariable analyses: Tumor size (≥ 2 cm, P = 0.003) and tumor grade (G2, P < 0.001; G3, P = 0.008). Tumor < 2 cm, the risk factors for LNM include: Tumor grade, mitosis count, and Ki-67 index
						Significant prognostic factors for survival include: Tumor size, T stage, LNM, and tumor grade
	Storino et al[88], 2021	United States	Retrospective	Local excision in 93.4% of cases with polypectomy in 52 (42.6%), EMR in 48 (39.3%), and transanal excision in 14 (11.5%). The 3 patients (2.5%) underwent abdominoperineal resection or low anterior resection and 5 patients (4.1%) received adjuvant chemotherapy	LNM 4 (3.3%) and distant metastasis 4 (3.3%)	Overall, 5-year survival for patients with localized disease was 98.2% (95%CI: 93-99.5)
	Sugimoto et al[89], 2016	Japan	Retrospective	55 patients metastatic (11 lesions) and non-metastatic (46 lesions) endoscopic submucosal resection with a ligation device, transanal full-thickness surgical resection, or radical surgery		Univariate analysis: Ki-67 labeling index > 3.0% (OR = 120, P < 0.001); positive lymphatic or venous permeation (OR = 67.6, P < 0.001); WHO grading classification G2 (OR = 58.7, P < 0.001); tumor size > 10 mm (OR = 9.8, P = 0.0037); submucosal invasion > 4000 μm (OR = 6.8, P = 0.012); central depression (OR = 5.7, P = 0.018)
						Multivariate logistic regression analyses vascular permeation (OR = 111; P = 0.006) and Ki-67 labeling index > 3.0% (OR = 88; P = 0.012) were independent risk factors for metastasis
	Tsang et al[90], 2018	Canada; United States	Retrospective	91 RNET: Local ablation (n = 5); local excision (n = 79); surgical resection (n = 4); pelvic radiation (n = 1; T3N1 tumor)	G1 and G2 tumors with a Ki-67 ≤ 20% and/or mitotic count ≤ 20 per high-power field	Univariate analysis: Association between local relapses and; Ki-67, mitotic count, grade, and LVI (P < 0.01) was found. Larger tumor size was associated with decreased disease-free survival
Studies that assess LNM following curative surgery	Kim et al[91], 2016	Korea	Retrospective	40 patients had 1052 lymph nodes removed Following curative surgery	Not mentioned	Metastasis-positive lymph nodes had significantly greater long and short diameters (P < 0.001) than metastasis-negative lymph nodes
	Takaoka et al[92], 2025	Japan	Retrospective	28 patients had post rectal resection with total mesorectal excision. LNM was found in 20 patients (39.2%), with lateral LNM occurring in 4 (7.8%) patients		No significant association was found between LNM and 5-year relapse-free survival (90%) for metastasis-negative patients vs 58.1% for metastasis-positive patients (P = 0.094)
	Ushigome et al[93], 2019	Japan	Retrospective	From 102 patients 1169 lymph nodes in the mesorectum were retrieved from all specimens, with 78 (6.7%) lymph nodes showing metastasis. Post-rectal resection with total mesenteric excision or tumor-specific mesenteric excision with or without lateral pelvic lymph node dissection		Mean length (long-axis diameter) of metastatic lymph nodes in the mesorectum was significantly larger than that of non-metastatic lymph nodes (4.31 mm vs 2.39 mm, P < 0.01)
						The optimal cut-off of major axis length for predicting mesorectal LNM was 3 mm
						Prediction of the small size of lymph nodes preoperatively is limited with CT scan of the abdomen and requires more precise imaging or EUS
	Wang et al[94], 2021	China	Prospective	58 patients post radical surgical treatment		At 1 year and 3 years postoperative, disease-free survival rates were 64.5% and 48.8%, respectively; while OS rates were 90.5% and 75.4%, respectively
						Univariate analysis: Tumor differentiation (P = 0.002), gross morphology (P = 0.009), T stage (P = 0.024), and extramural vascular invasion (P = 0.009) were associated with OS
						Multivariate analysis: Tumor differentiation (HR = 6.002, 95%CI: 1.210-29.767, P = 0.028) and gross morphology (HR = 3.438, 95%CI: 1.038-11.382, P = 0.043) were independent prognostic factors affecting the clinical outcomes

Grade A: According to World Health Organization grading of neuroendocrine tumor. LNM: Lymph node metastasis; OR: Odds ratio; 95%CI: 95% confidence interval; RNET: Rectal neuroendocrine tumor; AUC: Area under the curve; LVI: Lymph vascular invasion; LOH: Loss of heterozygosity; WHO: World Health Organization; ESD: Endoscopic submucosal dissection; EMR: Endoscopic mucosal resection; CT: Computed tomography; EUS: Endoscopic ultrasound; OS: Overall survival; HR: Hazard ratio.