Risk Factors for Rectal Neuroendocrine Tumors: A Population-Based Cohort Study of Sex-Specific Associations

Targeted next-generation sequencing of well-differentiated rectal, gastric, and appendiceal neuroendocrine tumors to identify potential targets

T1 rectal NET resection: Does size really matter?

Neuroendocrine tumors (NETs) are heterogeneous, and the incidence of NETs is rapidly increasing. We observed different survival in patients with rectal NETs and rectosigmoid junction NETs, which are treated similarly. We included patients with rectal and rectosigmoid junction NETs from the SEER database. The 5‐year survival was set as the end‐point. 6675 patients with rectal NETs and 329 patients with rectosigmoid junction NETs, were eligible for the analysis. Initially, the survival analyses suggested that the 5‐year survival significantly differed between the patients with rectal and rectosigmoid junction NETs (HR = 0.82, 95% CI 0.70‐0.95; P = .01). Tumor differentiation, an invasion deeper than T2, and lymph node and distant metastases were still important risk factors affecting survival for both location. While, the males showed better survival (HR = 0.69, 95% CI 0.55‐0.88; P < .01) and primary tumor surgery had no benefits (P = .56) for patients with rectosigmoid junction NETs. The factors that predict regional lymph node metastases varied by location. In rectal NETs, invasion deeper than T1 and a tumor larger than 1 cm could significantly increase the risk of regional lymph node metastases (all OR > 5, P < .01). In rectosigmoid junction NETs, the risk of regional lymph node metastases was considered significantly higher with invasion deeper than T1 (all OR > 5, P < .01) and a tumor larger than 2 cm (OR = 31.32, 95% CI 2.53‐387.57; P < .01). We advocate a clear and consistent definition of the rectosigmoid junction for future studies, and more studies are needed to determine the reason underlying differences between rectum and rectosigmoid junction.

Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway

Neuroendocrine tumors (NETs) are rare, representing 0.5% of all newly diagnosed malignancies. Rectal and anal canal (AC) NETs account for less than 1% of all rectal and AC cancers. Review our institutional experience on NET of the rectum and AC, with emphasis on demographic, histological and treatment features and oncologic outcomes. The study group was identified from the Portuguese Regional South Oncological Registry. From 2000 to 2014, 22 patients with rectal or AC NETs were treated at our institution. Medical records were retrospectively reviewed. There were 12 males (54.5%) and 10 females (45.5%) and the median age at diagnosis was 59.5 years. The majority had rectal NET (81.8%). All 4 patients with AC NETs had neuroendocrine carcinoid (NEC) tumors. Of the patients with rectal NETs, 3 had NEC and 15 had NET, mainly G1. Different approaches to treatment were made according to histological and staging features. After an average follow-up of 39.1 months, 16 patients were alive and only one with evidence of disease. The median time to progression was 12.4 months and the liver was the most frequent site of metastasis. The European and North American Neuroendocrine Societies offer guidelines for the treatment of rectal NETs. However, for AC NETs there are only small series and not prospective studies due to their rarity, hence the importance to report institutional experience. Our practice demonstrated that primary excisional treatment, regardless the histology, provides a favorable prognosis and long survival.

To investigate the clinicopathological characteristics and their relationship with prognosis of colorectal neuroendocrine neoplasms (NEN). Medical records of 329 patients with colorectal NEN between June 2001 and July 2016 from 6 large scale centers in China were reviewed to investigate the clinicopathological characteristics and their relationship with prognosis of colorectal NEN. (1) Colonic NEN: A total of 41 patients with colonic NEN were enrolled from The First Affiliated Hospital of Sun Yat-sen University(n=11), Sun Yat-sen University Cancer Center (n=15), Guangdong General Hospital (n=10), Sun Yet-san Memorial Hospital of Sun Yat-sen University (n=3) and Fudan University Shanghai Cancer Center (n=2). 41 cases, including 20 males and 21 females with a mean age of (58.7±4.7) years. Twenty-three colonic NEN originated in hindgut (23/41, 56.1%), and 20 patients were stage IIII( (20/41, 48.8%). Nine cases (22.0%) were neuroendocrine tumor(NET), 25(61.0%) were neuroendocrine carcinoma (NEC) and 7(17.1%) were mixed adenoendocrine carcinoma (MANEC). Six cases (14.6%) were G1 grade, 3(7.3%) were G2 grade and 32(78.1%) were G3 grade. Ulcerative or cauliflower-like tumors were the most common appearance under endoscopy (both 9/41, 22.0%). Thirty-three patients (80.5%) underwent surgery. During follow-up, 19 cases died and the 3-year survival rate was 46.1%. Multivariate analysis revealed that stage IIII( was an independent risk factor of poor prognosis (HR=3.871, 95%CI:1.342 to 11.167, P=0.012) in colonic NEN patients. (2) Rectal NEN: A total of 288 patients with rectal NEN were enrolled from The First Affiliated Hospital of Sun Yat-sen University(n=130), Nanfang Hospital of Southern Medical University (n=115) and Fudan University Shanghai Cancer Center (n=43). Two hundred and eighty-eight cases, including 181 males and 107 females with a mean age of (47.7±1.5) years. One hundred and ninety-seven patients were stage I((197/288, 68.4%). Of 288 rectal NEN cases, 267(92.7%) were NET, 20(7.0%) were NEC and 1(0.3%) was MANEC; 214(74.3%) were G1 grade, 53(18.4%) were G2 grade and 21(7.3%) were G3 grade. Submucosal tumor was the most common appearance under endoscopy(164/288, 56.9%). Most of the rectal NET G1/G2 tumors were submucosal(146/214, 68.2%;18/53,34.0% respectively) while most of G3 tumors were cauliflower-like (14/21,66.7%). A total of 175 patients (60.8%) underwent endoscopic therapy, while 96 patients(33.3%) underwent surgery. During follow-up, 12 cases died and 3-year survival rate was 94.0%. Multivariate analysis revealed that poor differentiation as NEC or MANEC(HR=8.919, 95% CI:1.911 to 41.637, P=0.005) and stage III( to IIII((HR=10.304, 95%CI:1.772 to 59.916, P=0.009) were independent risk factors of poor prognosis in rectal NEN patients. The clinicopathological manifestations of rectal NEN and colonic NEN are quite different. Rectal NEN are more common with better differentiation and has better prognosis than colonic NEN.

The incidence of rectal neuroendocrine tumors (NET) has been increasing since the implementation of the screening colonoscopy. However, very little is known about risk factors associated with rectal NETs. We examined the prevalence of and the risk factors for rectal NETs in a Korean population. A cross-sectional study was performed on 62,171 Koreans who underwent screening colonoscopy. The clinical characteristics and serum biochemical parameters of subjects with rectal NET were compared with those of subjects without rectal NET using multivariate logistic regression. Of a total of 57,819 participants, 101 [OR, 0.17%; 95% confidence interval (CI), 0.14-0.20] had a rectal NET. Young age (<50 years; OR, 2.09; 95% CI, 1.06-4.15), male gender (OR, 1.92; 95% CI, 1.15-3.20), alcohol drinking [adjusted OR (AOR), 1.56; 95% CI, 1.01-2.42], and a low high-density lipoprotein-cholesterol (HDL-C) level (AOR, 1.85; 95% CI, 1.10-3.11) were independent risk factors for rectal NETs. Cigarette smoking, fatty liver, metabolic syndrome, higher triglyceride level (≥150 mg/dL), and higher homeostasis model assessment of insulin resistance (≥2.5) were not independently associated with rectal NETs, although these factors were more common in individuals with rectal NETs in the univariate analysis. Young age (<50 years), male gender, alcohol drinking, and a low HDL-C level were risk factors for rectal NETs. Our results suggest that gender, behavioral factors, and dyslipidemia may affect the risk for developing rectal NETs. The findings of this study contribute to a better understanding of the influence of gender, behavioral factors, and dyslipidemia in developing rectal NETs.

572 Background: Limited research is available regarding colorectal neuroendocrine neoplasms (NENs), especially in China. The prognostic factors of colorectal NENs remain controversial. Methods: A total of 68 patients with colorectal NENs were studied retrospectively. Clinical characteristics and prognosis between colonic and rectal NENs were compared. The Kaplan-Meier method and Cox regression models were used to evaluate the capacity of various factors to predict the outcome. Results: Of the 68 colorectal NENs patients, 43 (63.2%) had rectal NENs, and 25 (36.8%) had colonic NENs. Compared with rectal NENs, colonic NENs more frequently exhibited larger tumor size ( P &lt; 0.0001) and distant metastasis ( P &lt; 0.0001). Colonic NENs had a worse prognosis ( P= 0.027), with 5-year overall survival rates of 66.7% vs. 88.1% compared with rectal NENs. Neuroendocrine tumors, neuroendocrine carcinomas and mixed adenoendocrine carcinomaswere noted in 61.8%, 23.5% and 14.7% of patients, respectively. According to the available data (n = 49), Ki-67 index values were ≤ 2% in 27 (39.7%) patients, ranged from 3 to 20% in 6 patients (8.8%) and were &gt; 20% in 16 patients (23.5%). Multivariate analyses revealed that tumor location was not an independent prognostic factor ( P= 0.081), but tumor size ( P= 0.037) and pathological classification ( P= 0.012) were independent prognostic factors. Conclusions: Significant differences in clinicopathological feature and outcome exist between colonic and rectal NENs. Multivariate analysis indicated that tumor size and pathological classification were associated with the prognosis. However, tumor location was not an independent factor. The worse outcome of colonic NENs observed in clinical practice might be due not only to the biological differences, but also to larger tumor size in colonic NENs caused by the delayed diagnosis.

Colorectal neuroendocrine tumors (NETs) are the most common NETs of the gastrointestinal tract. Due to the rarity, colorectal NETs are understudied and are not clearly understood. Our study sought to identify the factors associated with worse outcomes for colorectal NETs following resection. We identified patients diagnosed with colorectal NETs [2004-2014] who underwent resection from the National Cancer Data Base. Non-NETs were excluded. Overall survival (OS) was evaluated using the Kaplan Meier method. Cox proportional hazards and logistic regression models were used to assess factors associated with radical versus local resection, OS and LOS. A total of 7,967 colon and 11,929 rectal NETs were analyzed. The majority of colon (93.4%) and rectal (89.1%) NETs underwent radical and local resection respectively. The 5-year OS was 69% and 92% for colon and rectal NETs respectively. Older age (OR 1.45, CI 1.37-1.53) and clinical stage 4 (OR 9.91, CI 4.56-21.52) were associated with higher odds for colonic radical resection. Lowest median income quartile (OR 1.41, CI 1.21-1.64) and African Americans (OR 1.26, CI 1.07-1.49) experienced higher mortality for colon and rectal NETs respectively. Racial minority and low-income patients experience worse outcomes for colorectal NETs following resection.

Rectal neuroendocrine tumors (NET) are often asymptomatic and frequently discovered during health examinations. However, data on the risk factors of asymptomatic rectal NETs are lacking. We investigated the risk factors, clinical characteristics and outcomes of asymptomatic rectal NETs discovered during health screening. Asymptomatic subjects who underwent colonoscopy during routine health screening at a tertiary hospital from March 2009 to July 2014 were reviewed. Subjects with histologically confirmed rectal NETs were compared with healthy controls from the same population. Risk factors for rectal NETs were analyzed by multivariable analysis. Clinical outcomes of the resected NETs were also analyzed. A total of 21,706 Subjects underwent screening colonoscopy during the study period. 3417 were excluded from the study, and 180 rectal NET subjects were compared with 18,109 controls. Multivariable analysis showed that a previous history of malignancy (OR 2.960, 95% CI 1.673-5.237, p<0.001), hypertriglyceridemia (OR 1.482, 95% CI 1.046-2.100, p=0.027), higher fasting plasma glucose levels (OR 1.008, 95% CI 1.003-1.014, p=0.001) and higher carcinoembryonic antigen levels (OR 1.019, 95% CI 1.003-1.035, p=0.021) were significant risk factors while older age (OR 0.964, 95% CI 0.951-0.977, p<0.001) was a preventive factor. One hundred and sixty nine subjects had endoscopic resection, five were treated by local surgery and six by radical surgery. Complete resection was achieved in 152 subjects. There were three cases of positive lymph nodes and one metastasis. Histology revealed four lymphatic, five vascular and two cases of perineural invasion. One hundred and fifty seven subjects were followed up for at least 1year (median 38.6months, 12-84months). There were no recurrences during the follow-up period. Younger age, previous history of malignancy, higher fasting plasma glucose levels and hypertriglyceridemia are significantly associated with rectal NET risk.

Rectal neuroendocrine tumors (NETs) are currently divided into L-cell and non-L-cell types. In the World Health Organization 2010 classification, L-cell tumors are defined as borderline, whereas non-L-cell tumors are considered to represent malignancies. To establish differential diagnostic criteria and therapeutic strategy, we investigated the pathologic features of rectal NETs associated with lymph node metastasis and the clinicopathologic significance of the L-cell phenotype. We analyzed 284 patients with rectal NETs. Factors, including T stage, mitosis, histologic pattern, lymphatic invasion, tumor border, and lymph node metastasis, were retrospectively evaluated. We also evaluated tumor immunoreactivity for L-cell markers, including glucagon-like peptide 1, pancreatic peptide, and peptide YY, in 240 cases. L-cell immunoreactivity was detected in 189 of 240 NETs (79%). Of the factors evaluated, only age and the frequency of lymphatic invasion were significantly different between patients with L-cell and non-L-cell tumors. Of the 284 patients, 18 (6.3%) had lymph node metastases. Lymphatic invasion and T stage were independent risk factors for lymph node metastasis. Subgroup analysis based on tumor size showed lymph node metastasis in 0%, 4%, 24%, and 100% of patients with NETs with a size of <5, 5 to 9, 10 to 14, and ≥ 15 mm, respectively. Depth of tumor invasion, lymphatic invasion, and mitosis were correlated with tumor size (P<0.0001). In conclusion, L-cell phenotype alone does not guarantee favorable biological characteristics. The clinical management of rectal NETs should depend on tumor size. Careful pathologic examination of lymphatic invasion is necessary.

Rectal neuroendocrine tumours (NETs) are increasingly identified at endoscopy possibly as a result of bowel cancer screening programmes. To present a review of the literature to aid clinicians in the diagnosis and management of rectal neuroendocrine tumours. A literature search was conducted through MEDLINE using search terms: rectal, rectum, carcinoid, NET, therapy, endoscopy, mucosal resection, submucosal dissection. Relevant articles were identified through manual review with reference lists reviewed for additional articles. The incidence of rectal neuroendocrine tumours is approximately 1 per 100 000 population per year with the majority (80-90%) being <1 cm and localised to the submucosa. Metastatic disease is infrequent (<20%) with risk factors including size, atypical appearance, grade and depth of invasion. The primary resection modality influences complete resection rates and the need for secondary therapy. A thorough pre-resection diagnostic work up is required for lesions that are at higher risk of invasion and metastasis. Device-assisted endoscopic mucosal resection and endoscopic submucosal dissection are used to resect localised rectal neuroendocrine tumours <2 cm. Transanal surgery is also used to resect localised 1-2 cm rectal neuroendocrine tumours. Oncological surgical resection is used for rectal neuroendocrine tumours that are >2 cm or with invasion and regional disease. The treatment of advanced disease is multimodal. The long-term tumour biology of small rectal neuroendocrine tumours remains unclear. There is uncertain impact from bowel cancer screening programmes on rectal neuroendocrine tumour incidence, morbidity and mortality. Referral to neuroendocrine tumour centres for patients with locally advanced disease or metastatic disease is recommended.

Background: Neuroendocrine tumors (NETs) are clinical heterogeneous. To date, no studies have focused on the genetic characteristics of NETs at different anatomical sites in the Chinese cohort. We aim to explore the genetic similarities or differences between NETs at different sites, and evaluate the predictive indicators of chemotherapy based on Temozolomide. Methods: The patients were from a prospective clinical study STEM (from a single institute, NCT03204032, NCT03204019). This cohort included 47 patients with NETs, including 14 Pancreatic NETs (PanNETs), 11 Rectal NETs, 14 Thoracic NETs, and 8 Others. Whole exome sequencing (WES) was performed. Results: A total of 76,057 somatic mutations were detected in 16,510 genes. The median tumor mutation burden (TMB) was 13.4, 10.5, 11.0 and 11.9 in PanNETs, Rectal NETs, Thoracic NETs and Others, respectively. After sequencing depth filtering, they were 3.5, 3.9, 3.3 and 3.6, respectively. Low intra-tumoral heterogeneity (ITH) was observed in NETs. The median ITH index was 2, 2.5, 2.5 and 2 in PanNETs, Rectal NETs, Thoracic NETs and Others, respectively; the median Shannon diversity index (SDI) was 0.23, 0.13, 0.23 and 0.24, respectively. The driver gene mutations varied in NETs at different sites. The recurrently mutated driver genes were MEN1, ATM, TSC2, PLXNB2, MUC6, AMER1 and USP9X for PanNETs; APC, APOB and FAT1 for Rectal NETs; KMT2B and CACNA1A for Thoracic NETs. Copy number analysis showed that copy number loss frequently occurred in all NETs. The median copy number variation burden (CNV burden) was 34.0, 10.9, 16.1 and 11.6 in PanNETs, Rectal NETs, Thoracic NETs and Others, respectively. The CNV burden of PanNETs was higher than others. Based on the results of CNVs, NETs at different sites could be distinguished by linear discriminant analysis (LDA). We analyzed the correlation between genetic characteristics and progression-free survival (PFS). As a result, NETs with higher TMB (&amp;gt;10 /Mb, P=0.043) or higher CNV burden (&amp;gt;20, P=0.047) showed statistically longer PFS. More patients should be included to find a correlation between genetic characteristics and PFS. Conclusions: NETs at different sites harbored different somatic driver mutations, and copy number loss was widespread in NETs. NETs with higher TMB or higher CNV burden showed statistically longer PFS. Citation Format: Yihebali Chi, Weili Liu, Lijie Zuo, Yuehua Wang, Weijing Cai, Susheng Shi, Yanying Ge, Rui Li, Lijie Song, Yiqi Yang, Zheng Liu, Xiaowu Dou, Hong Zhao. Genetic characteristics of PanNETs, Rectal NETs, Thoracic NETs and its correlation with efficacy of chemotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4743.

Incidental, small rectal neuroendocrine tumors during colonoscopy screening are sometimes removed using biopsy forceps. Few studies have examined the clinical course of rectal neuroendocrine tumors removed by simple excisional biopsy. We investigated the long-term outcome of rectal neuroendocrine tumors removed by simple excisional biopsy compared with standard endoscopic resection. This was a cohort study. This study was performed at a healthcare center in Korea. We enrolled patients with rectal neuroendocrine tumors detected during a screening colonoscopy between 2003 and 2015. The clinical characteristics and long-term outcomes (overall survival and disease-free survival) of small neuroendocrine tumors <10 mm were compared between the simple excisional biopsy group and advanced endoscopic resection group. In total, 166 patients were diagnosed with rectal neuroendocrine tumors (≤5 mm, n = 100; 6-9 mm, n = 50; 10-19 mm, n = 15; ≥20 mm, n = 1). Among the 150 patients with neuroendocrine tumors <10 mm, follow-up endoscopy was performed on 99 (59.6%). All of the tumors were confined to the mucosa or submucosa. Thirty-one and 68 patients were included in the simple excisional biopsy and advanced endoscopic resection groups. The overall follow-up duration was 6.5 years (range, 1.0-12.8 y). Neither overall nor disease-related death occurred. Two patients exhibited local recurrence (6.5%, at 8 and 11 y) in the simple excisional biopsy group and 1 patient (1.5%, at 7 y) in the advanced endoscopic resection group, resulting in no significant difference (p = 0.37). All of the recurrences were diagnosed >5 years from initial diagnosis and successfully treated endoscopically. More long-term data should be warranted. The long-term outcome of small rectal neuroendocrine tumors <10 mm removed by simple excisional biopsy was excellent. Neither overall survival nor disease-free survival significantly differed between the simple excisional biopsy group and the advanced endoscopic resection group. Thus, simple excisional biopsy and long-term follow-up can be cautiously applied for small rectal neuroendocrine tumors in clinical practice. See Video Abstract at http://links.lww.com/DCR/A406.

Neuroendocrine tumors (NETs) are slow-growing tumors with different biological and clinical characteristics. The incidence of NETs varies depending on the organ; however, the rectum is the most prevalent tumor site in the gastrointestinal system, accounting for 60-89% of all gastrointestinal NETs.1 These tumors are often found incidentally during colonoscopy without any symptoms. They are usually detected on endoscopy as small, protruding subepithelial lesions located between 4-20 cm above the dentate line on the anterior or lateral rectal wall. According to the European Neuroendocrine Tumor Society (ENETS) 2012 Consensus Guidelines,2 well-differentiated rectal NETs <10 mm without muscle invasion or lymph node involvement could be treated by performing local resection. For local resection, various treatment modalities have evolved, including endoscopic polypectomy, endoscopic mucosal resection (EMR), endoscopic submucosal dissection, transanal excision, and transanal endoscopic microsurgery.3 To evaluate the risk of metastasis, pathological examination of lymph nodes should be implemented. However, small rectal NETs are known to have little risk of metastasis, making local resection desirable. Radical surgery is reserved for selected cases with risk factors associated with lymph node metastasis. In rectal NETs 20 per 10 HPF and/or Ki-67 >20%. In the current case,7 it may be reasonable to omit surgical resection for the perirectal lymph nodes after EMR, as histological analysis of the tumor revealed no lymphovascular invasion, no mitosis per 50 HPF, and a Ki-67 labeling index of 0.8%. In the current case, the authors followed the patient using annual endoscopy and abdominopelvic CT for 7 years after resection. Fortunately, the perirectal lymph node metastasis was completely removed via laparoscopic surgical resection and lymph node dissection, vigorous surveillance in this case. A population-based study4 in Japan also reported a prevalence of 3.7% for lymph node metastasis in rectal NETs 20 mm within the first year, and every 4-6 months in the first year and at least annually thereafter for G3 tumors. In the current case, the authors followed the patient using annual endoscopy and abdominopelvic CT. Although ENETS guidelines3 do not recommend routine follow-up with CT or MRI for rectal NETs <10 mm, follow-up modalities may include endoscopy, EUS or MRI. Considering the possibility of lymph node metastasis in the first presentation of the current case, additional investigation with rectal MRI or EUS that can more accurately assess perirectal lymph nodes than conventional CT may be helpful in assessing the nature of perirectal lymph node enlargement.11 Furthermore, EUS-guided fine needle aspiration or laparoscopic lymph node sampling may be considered if MRI or EUS suggests the possibility of lymph node metastasis. As the natural course of rectal NETs is not fully understood and the risk of lymph node metastasis has varied in previous studies, the metastatic potential of rectal NETs, even in tumors <10 mm, should not be ignored. The current case report is very informative for clinicians, because the natural course of untreated perirectal lymph node metastasis of G1 rectal NETs <10 mm has never been described previously. Generally, the risk of lymph node metastasis for rectal NETs <10 mm is low; however, NETs are classified as a malignant disease in the recently revised American Joint Committee on Cancer (AJCC) cancer staging guidelines. Therefore, clinicians should remember that the clinical behavior of rectal NETs might sometimes resemble that of malignant tumors, even when tumors are small.