Cabozantinib for advanced grade 3 neuroendocrine tumors: subgroup analysis of the phase 3 CABINET trial (Alliance A021602).

The diagnosis and subsequent therapy of neuroendocrine neoplasms (NENs) have long relied on somatostatin receptor (SSTR) expression. The field of theranostics now uses newer SSTR-based PET imaging with 68Ga-DOTATATE or 68Ga-DOTATOC as a prerequisite for the administration of peptide receptor radionuclide therapy (PRRT). In the United States, Food and Drug Administration approval of 177Lu-DOTATATE, a form of PRRT, in 2018 for use in gastroenteropancreatic NENs was obtained on the basis of prolonged progression-free survival versus high-dose octreotide long-acting release in a phase III clinical trial of well-differentiated midgut NENs. Well-differentiated grade 1 and grade 2 NENs have a low proliferation index (Ki-67 < 20%) and longer overall survival (>10 y), whereas higher-grade (grade 3 [G3]) NENs have a high Ki-67 (>20%) and shorter overall survival (<1 y). Here, we present a review on the role of SSTR-based imaging and PRRT in G3 NENs, including a discussion of well-differentiated G3 NENs, the newest histologic classification. Some studies suggest that G3 NENs are less likely to be positive on SSTR-based imaging (but more likely on 18F-FDG PET) than are well-differentiated NENs, but these data are limited. We found only 13 studies mentioning the use of PRRT in G3 NENs and a total of only 151 patients across these studies in whom radiologic response was measured. Of these 151 patients, 99 (66%) demonstrated at least stable disease or a partial response, indicating that some G3 NENs can be responsive to PRRT. We suggest that patients with G3 NENs should receive both 18F-FDG PET and SSTR-based imaging to aid in both diagnosis and treatment selection, as positivity on SSTR-based imaging helps with patient identification for PRRT and discordance may suggest important clues to tumor biology and prognosis. However, prospective studies are needed to fully understand the role of PRRT in G3 NENs, especially in well- versus poorly differentiated G3 disease.

660 Background: The 2017 edition of the WHO classification categorized neuroendocrine neoplasms (NEN) as neuroendocrine tumors (NET) G1, G2, G3, and neuroendocrine carcinoma (NEC). Prior to 2017, NET G3 was categorized as NEC in the WHO 2010 classification. Platinum-based chemotherapy, commonly used as first-line treatment for these tumors, shows suboptimal efficacy for NET G3. Additionally, large-scale studies and robust evidence on chemotherapy outcomes for NET G3 are lacking. We investigated chemotherapy regimens for NET G3 and evaluated their outcomes. Methods: We included 73 patients (pts) who were clinically and pathologically diagnosed with unresectable NET G3 of gastroenteropancreatic or unknown primary origin and who started chemotherapy between Jan 2011 and Dec 2019. Clinical data were collected retrospectively and analyzed for regimen selected, treatment efficacy, and prognostic factors. A central pathological review was conducted if tissue samples were available. Results: The median age of pts was 65 years (range 27-85 years), with 45 being male. Among the pts, 49 had pancreatic NETs, 10 had gastrointestinal NETs, and 14 had NETs of unknown primary origin. The median Ki-67 index was 30% (range 20-70%). Twenty-seven patients (37%) had received prior treatment, such as surgery or local therapy. A central pathological diagnosis was confirmed NET G3 in 42 out of 44 patients (95%). Primary treatment regimens were NET-based (somatostatin analogues, everolimus, sunitinib, streptozocin-based chemotherapy, and capecitabine and temozolomide [CAPTEM]) and NEC-based (platinum-based chemotherapy) in 54% and 44% of patients, respectively. NET-based regimens were selected in 36% and 78% of pts, respectively, before and after publication of the WHO 2017 classification. The overall response rate (ORR) was 16% for NEC-based regimens and 19% for NET-based regimens. However, when focusing on NET-based chemotherapy (streptozocin-based and CAPTEM), the ORR was 54%. Median progression-free survival (PFS) was 118 days (95% confidence interval [CI]: 60-337 days) for NET-based regimens and 229 days (95%CI: 133-426 days) for NEC-based regimens. Median overall survival (OS) was 841 days for NET-based regimens (95%CI: 480-989 days) and 658 days (95%CI: 455-1144 days) for NEC-based regimens. There were no significant differences in PFS or OS between the regimens. In multivariable analysis, hepatic tumor volume &gt;25% was a negative predictor of PFS, and NSE ≥16.3 ng/mL was a negative predictor of OS. Conclusions: Since the introduction of NET G3 in the WHO classification, NET-based regimens have become the preferred treatment choice. Although there were no significant differences in PFS or OS between the regimens, the NEC-based regimens was limited. Pts with high hepatic tumor volume or elevated NSE levels had a worse prognosis.

A 50-year-old woman underwent distal pancreatectomy for pancreatic neuroendocrine neoplasm(NEN). Pathological analysis showed that the pancreatic tumor was composed of neuroendocrine tumors(NETs)G2 and G3, along with neuroendocrine cancer (NEC), and was accompanied by NET G2 and G3 lymph node metastasis around the pancreas. The primary tumor exhibited neural invasion with NET G3, vascular invasion with NET G2, splenic vein invasion with NET G3, lymphatic duct invasion with NEC, anterior surrounding tissue invasion with NET G2, and posterior surrounding tissue invasion with NET G2, G3, and NEC. The patient was not given adjuvant chemotherapy. Fifteen months postoperatively, computed tomography( CT)and positron emission tomography(PET)detected para-aortic lymph node metastasis, which was treated with 50 Gy radiation therapy. PET-CT imaging showed reduced viability of the metastatic lymph nodes 3 months after radiation, with complete remission observed on CT 6 months after radiation. Fifty-two months postoperatively, a solitary liver metastasis was identified and resected laparoscopically, revealing NET G2. The patient has remained recurrence-free for 27 months after the liver resection. This case emphasizes the efficacy of radiation therapy in achieving remission and long-term survival of patients with lymph node metastasis from NEN, despite the lack of histological differentiation between NET and NEC.

179 Background: Pancreatic neuroendocrine tumors (NETs) are rare neoplasms that exhibit a variety of diverse morphological, functional and behavioral characteristics. However, only a few reports have evaluated large case series of pancreatic endocrine tumors. Methods: We conducted a retrospective review of 100 consecutive patients with pancreatic NETs diagnosed pathologically and treated at the National Cancer Center Hospital between 1991 and 2010. Results: The characteristics of the 100 patients were as follows: male, 49; female, 51; median age, 55 years. Fourteen patients gave a history of endocrine symptoms at the time of diagnosis. The primary tumors arose in the head, body and tail of the pancreas in 54, 25 and 21 patients, respectively. According to the 2010 grading classification of the World Health Organization, 11 patients were classified as having NET G1, 44 as having NET G2 and 29 as having NEC. The five-year survival rates of the patients with NET G1, NET G2 and NEC were 91%, 78% and 12%, respectively. The five-year survival rates of the patients with stage I, II and III, and IV disease classified according to the American Joint Committee on Cancer (AJCC) were 100%, 68% and 9%, respectively. Distant metastases occurred in 18% percent of the NET G1 patients, 39% of the NET G2 patients and 83% of the NEC patients. Treatment was undertaken by surgical resection in 82%, 59% and 24% of patients with NET G1, NET G2 and NEC, respectively. The five-year survival rates of the patients with NET G1, NET G2 and NEC after radical surgery were 100%, 91% and 36%, respectively. Among the 33 patients treated by systemic chemotherapy, the median survival period was 22.9 months in the patients with NET G1/G2 and 6.6 months in those with NEC. A multivariate analysis identified lower age, good performance status (PS) and lower histopathologic grade as independent favorable prognostic factors. Conclusions: Patients with NET G1, G2 treated by surgical resection had a good prognosis. Most patients with NEC exhibited distant metastases and had a poor prognosis. Histopathologic grade is an important factor for selecting the appropriate treatment strategy and predicting the prognosis in patients with pancreatic NETs.

BackgroundGangliocytic paraganglioma (GP) is an extremely rare benign tumor that commonly arises from the second part of the duodenum. Since GP exhibit neither prominent mitotic activity nor Ki-67 immunoreactivity, this tumor is often misdiagnosed as neuroendocrine tumor (NET) G1 (carcinoid tumor). However, patients with GP may have a better prognosis than patients with NET G1. This fact emphasizes the importance of differentiating GP from NET G1, but few studies have reported the epidemiology and histopathology of GP because of its rarity. To differentiate GP from NET G1 with ease, we conducted a multi-institutional retrospective study analyzing the morphometric and immunohistochemical features of this tumor.MethodsSince only a limited number of patients with GP could be identified in our institute, we conducted a multi-institutional retrospective study of GP in Japan, which was approved by the Ethics Committee of our medical institute. The obtained tissue sections underwent detailed morphometric and immunohistochemical analyses. Additionally, to differentiate GP from NET G1 with ease, immunohistochemical findings were compared.ResultsIn our examination of 12 cases of duodenal GP, we found that epithelioid cells of GP exhibited positive reactivity for progesterone receptor and pancreatic polypeptide, whereas tumor cells of NET G1 were completely negative reactivity for both. Additionally, although GP is considered to be an extremely rare NET, we found that four (40.0%) of the ten patients at our institute with duodenal NET G1 actually had GP.ConclusionsAlthough GP is regarded as a rare NET, our results suggest that it accounts for a substantial percentage of duodenal NETs. Additionally, confirmation of immunoreactivity for progesterone receptor and pancreatic polypeptide can assist in differentiating GP from NET G1.

Pancreatic neuroendocrine tumors: A single-center 20-year experience with 100 patients.

To explore the primary site and pathological feature of neuroendocrine neoplasm (NEN), especially the NEN of digestive system. Clinicopathological data of NEN patients at China-Japan Friendship Hospital from January 2012 to December 2016 were retrospectively analyzed. Tumor primary sites were summarized. Association between tumor site and pathological grading in gastroenteropancreatic neuroendocrine neoplasm(GEP-NEN) was examined. There were a total of 903 cases of NEN. Sites of primary tumor included the digestive system in 699 cases(77.4%), the thorax(including lung, thymus and mediastinum) in 87 cases(9.6%), other sites in 60 cases (6.6%), unknown in 57 cases(6.3%). Among 699 GEP-NEN cases, the primary sites included the stomachin in 207 cases (29.6%), pancreas in 201 (28.8%), rectumin in 185 (26.5%), duodenum in 43(6.2%), jejunum and ileum in 18(2.6%), appendix in 15 (2.1%), gallbladder in 11(1.6%), esophagus in 10(1.4%), and the colon in 9 cases (1.3%). Pathologically, the tumor grading was neuroendocrine tumor (NET) G1 in 336 cases(48.1%), NET G2 in 203 cases (29.0%), neuroendocrine carcinoma (NEC) G3 in 139 cases (19.9%). All the esophagus NEN(10/10), most gallbladder NEN(9/11) and colon NEN(6/9) were poorly-differentiated NEC (G3), while all appendix NEN(15/15), most stomach NEN(147/207, 71.0%), pancreas NEN (156/201, 77.6%), rectum NEN (169/185, 91.4%), duodenum NEN (31/43, 72.1%), jejunum and ileum NEN(16/18, 88.9%) were well-differentiated NET G1 or G2. The most common primary site of NEN is the digestive system. The stomach, pancreas and rectum are most common primary sitesof GEP-NEN. Difference in pathological grading is quite greatin different primary sites of GEP-NEN. Most NENs fromesophagus, colon and gallbladder are poorly-differentiated NEC.

Background: In gastroenteropancreatic (GEP) high-grade neuroendocrine neoplasms (H-NENs), Ki-67 threshold of 55% defines three prognosis subclasses: neuroendocrine tumor (NET) G3, neuroendocrine carcinoma (NEC) <55%, and NEC ≥55%. We investigated whether the molecular profiling of H-NENs differs among these subcategories and evaluated potential therapeutic targets, including PD-L1. Methods: In GEP-NEN patients, we evaluated: (i) 55% threshold for Ki-67 labeling index for further stratifying NEC and (ii) immunoreactivity and gene mutations by immunohistochemistry and targeted next-generation sequencing (T-NGS). Results: Fifteen NETs G3 and 39 NECs were identified. Ki-67 labeling index was <55% in 9 NECs and ≥55% in 30 NECs. Gene mutations by NGS (TP53, 32.9%; KRAS, 5.5%; BRAF, 4.1%) were detected in 46.6% NENs, significantly enriched in NEC ≥55% (76.7%) compared to NEC <55% (55.6%) or NET (20.0%). PD-L1 staining in tumor-infiltrating lymphocytes was observed in NEC ≥55% (36.7%; p = 0.03). Median OS was 4.3 years in NET G3, 1.8 years in NEC <55%, and 0.7 years in NEC ≥55% (p <0.0001); it was 2.3 years with NGS wild-type, 0.7 years with ≥1 mutation (p <0.0001), 0.8 years in PD-L1-positive patients, and 1.7 years in PD-L1-negative subjects (p = 0.0004). In multivariate analysis, only the proposed subclassification approach yielded statistically significant differences between groups (NEC <55% vs. NET G3, HR 14.1, 95% CI 2.2–89.8, p = 0.005; NEC ≥55% vs. NET G3, HR 25.8, 95% CI 3.9–169, p = 0.0007). Conclusions: These findings identify NEC ≥55% as a biologically and prognostically distinct subtype and pave the way for more personalized treatment.

In 2010, World Health Organization classified gastric neuroendocrine tumor (NET) as follows: NET grade (G) 1, NET G2, neuroendocrine carcinoma (NEC). We reviewed 22 gastric NETs that were encountered in our institutions. Nine, 6, and 4 were NET G1, G2, and NEC, respectively. We also encountered 3 NET G3. NET G1 was treated with observation in 2 patients, endoscopic mucosal resection (EMR) in 3, and gastrectomy in 4 patients. No recurrence was experienced during a median of 53 months of follow-up. All NET G2 was treated with gastrectomy. No patient experienced recurrence during a median of 25 months of follow-up. NET G3 was treated with gastrectomy. One patient died of liver metastasis 52 months after gastrectomy. For NEC, gastrectomy was performed in 3 cases and no patients died of tumor-related death. We conclude that the prognoses of NET G1 and G2 were good. We also experienced long-term survivors of NEC. An accumulation of more patients is needed for further investigation.

In the 2019 WHO guidelines, the classification of gastro-entero-pancreatic neuroendocrine neoplasms (GEP NEN) has changed from one being based on Ki-67 proliferation index alone to one that also includes tumor differentiation. Consequently, GEP NENs are now classified as well-differentiated neuroendocrine tumor (NET), NET G1 (Ki-67 <3%), NET G2 (Ki-67 3-20%) and NET G3 (Ki-67 >20%), and poorly differentiated neuroendocrine carcinoma (NEC) (Ki-67 >20%). It has been suggested that NET G3 should be treated as NET G2 with respect to surgery, while surgical management of NEC should be expanded from local disease to also include patients with advanced disease where curative surgery is possible. High grade mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) have a neuroendocrine and a non-neuroendocrine component mostly with a poor prognosis. All studies evaluating the effect of surgery in NEC and MiNEN are observational and hold a risk of selection bias, which may overestimate the beneficial effect of surgery. Further, only a few studies on the effect of surgery in MiNEN exist. This review aims to summarize the data on the outcome of surgery in patients with GEP NET G3, GEP NEC and high grade MiNEN. The current evidence suggests that patients with NEN G3 and localized disease and NEN G3 patients with metastatic disease where curative surgery can be achieved may benefit from surgery. In patients with MiNEN, it is currently not possible to evaluate on the potential beneficial effect of surgery due to the low number of studies.

177-LuDOTATE is an effective but expensive treatment for neuroendocrine tumors (NETs). Reducing treatment-related costs, such as the number of images, could improve access to 177-LuDOTATE. We evaluated early radiological tumor progression and prognostic factors in patients with NETs treated with 177-LuDOTATE. We retrospectively included all patients with NETs who received at least one cycle of 177-LuDOTATE. The primary endpoint was the rate of early radiological progression between cycles 2 and 3 (in 10-16 weeks). Secondary endpoints were progression-free survival (PFS) and overall survival (OS) according to prognostic factors (tumor grade, primary site, functioning syndrome, 177-LuDOTATE treatment line) in Cox proportional hazards models. The median number of 177-LuDOTATE cycles was 3 (range 1-6) among 59 patients included. Ten (17%) patients had early progression. Among 14 patients who received ≤2 cycles of 177-LuDOTATE, ten (72%) stopped treatment due to disease progression, with five patients having a G2 (ki67: 5-25%) and 4, a G3 (ki67: 25-90%) NET. In the Cox multivariable analysis, higher grade (G2 or G3 vs G1) were significantly associated with inferior PFS and OS. The median PFS of G1, G2 and G3 NET patients were: 34.1, 11.7 and 6.1 months (P = 0.015), respectively. It is feasible to perform imaging tests after 177-LuDOTATE completion for patients with indolent NETs with the intent to avoid futile assessments. For patients with more aggressive diseases, such as G3 NETs and G2 tumors with high tumor burden, we advise to perform more frequent images during 177-LuDOTATE therapy.

Objective Primary hepatobiliary neuroendocrine neoplasms (NENs) are rare tumors exhibiting several morphological and behavioral characteristics. Considering the lack of relevant data on this topic, we evaluated the clinicopathological features and treatment outcomes of patients with primary hepatobiliary NENs. Methods/Patients We examined 43 consecutive patients treated at the National Cancer Center Hospital with pathological diagnoses of primary hepatobiliary NEN between 1980 and 2016. Results Nine patients were diagnosed with neuroendocrine tumor (NET) G1, 9 with NET G2, and 25 with neuroendocrine carcinoma (NEC) based on the World Health Organization 2019 classification. Patients with NEC had primary sites across the hepatobiliary organs, although sites in patients with NET G1 and NET G2 only included the liver and ampulla of Vater. Patients with primary extrahepatic bile duct or ampulla of Vater NENs tended to be diagnosed earlier than patients with primary gallbladder NENs. The median survival times in the NET G1, NET G2, and NEC groups were 167.9, 97.4, and 11.1 months, respectively. A good performance status, absence of distant metastases, and low tumor grade were identified as independent predictors of a favorable prognosis. Conclusion The NET-to-NEC ratio and tumor stage distribution at the diagnosis differed depending on the primary site. Patients with G1 and G2 NETs who underwent surgical resection had good prognoses, whereas those with NEC exhibited more advanced disease and poorer prognoses. The performance status, staging classification, and tumor grade are important factors to consider when devising an appropriate treatment strategy and predicting the prognoses of patients with primary hepatobiliary NEN.

4129 Background: In contrast to the 2000 World Health Organization (WHO) classification of digestive neuroendocrine tumors (NET) in which morphologic differentiation was the first criterion, the 2010 WHO classification of NET is based mostly on histologic grade. NET are now classified into three main categories: NET G1 (mitotic count &lt;2/10 HPF and/or ≤2% Ki67 index), NET G2 (2-20/10 HPF and/or 3-20%), and neuroendocrine carcinoma (NEC) of small or large cell type. While NET G1 and G2 are well-differentiated tumors, NEC are considered poorly differentiated G3 tumors. We looked at the agreement between grade and differentiation to determine whether all NET can be readily classified according to the 2010 WHO classification. Methods: We designed a 1-year prospective, epidemiologic study to assess the characteristics of newly diagnosed NET, including diagnostic pathology. From August 2010 to July 2011, all pathology laboratories in France were invited to register all incident cases of gastroenteropancreatic (GEP) and thoracic NET, excluding small cell carcinoma. For GEP-NET, investigators were asked to indicate morphologic differentiation (according to WHO 2000) and elements of histologic grade (mitotic index, Ki67 index), according to ENETS. Results: Of 500 invited centers, 80 participated; 1417 incidental cases were included and 77 excluded (duplicates or exclusion criteria), totaling 1340 cases; 778 (58.1%) were GEP-NET; 660/778 (85%) were well differentiated, 72 (9%) poorly differentiated, and 46 (6%) adenocarcinoid, nonclassified, or not evaluable; 422 (54.2%) were G1, 220 (28%) G2, 104 (13.5%) G3, and 32 (4.1%) had missing grades. Of those deemed G3, 72 (69%) were described as poorly differentiated, 21 (20%) as well differentiated (mean Ki67 index 35%, range 25%-60%), and 11 (10.5%) as adenocarcinoid. Conclusions: In this prospective, epidemiologic study, overall agreement between grade and differentiation was good. However, a significant proportion of G3 NET were classified as well differentiated and thus unclassifiable by 2010 WHO classification. This group of tumor deserves to be included in future classifications to help the clinician decide whether they should be treated as NET G1/G2 or NEC G3.

Objective: To explore the clinicopathological features, treatment strategy and to analysis of prognosis-related risk factors of gastric neuroendocrine neoplasms(G-NEN). Methods: In this study, a retrospective observational study method was used to collect the clinicopathological data of patients diagnosed with G-NEN by pathological examination in the First Medical Center of PLA General Hospital from January 2000 to December 2021. The basic information of the patients, tumor pathological characteristics, and treatment methods were entered, and the treatment information and survival data after discharge were followed up and recorded. The Kaplan-Meier method was used to construct survival curves, and the log-rank test to analyze the differences in survival between groups. Cox Regression model analysis of risk factors affecting the prognosis of G-NEN patients. Results: Among the 501 cases confirmed as G-NEN, 355 were male and 146 were female, and their median age was 59 years. The cohort comprised 130 patients (25.9%) of neuroendocrine tumor (NET) G1, 54 (10.8%) of NET G2, 225 (42.9%) of neuroendocrine carcinoma (NEC), and 102 cases (20.4%) of mixed neuroendocrine-non-neuroendocrine(MiNEN). Patients NET G1 and NET G2 were mainly treated by endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR). The main treatment for patients with NEC/MiNEN was the same as that for gastric malignancies, namely radical gastrectomy+lymph node dissection supplemented with postoperative chemotherapy. There were significant differences in sex, age, maximum tumor diameter, tumor morphology, tumor numbers, tumor location, depth of invasion, lymph node metastasis, distant metastasis, TNM staging and expression of immunohistological markers Syn and CgA among NET, NEC, and MiNEN patients (all P<0.05). Further for NET subgroup analysis, there were significant differences between NET G1 and NET G2 in the maximum tumor diameter, tumor shape and depth of invasion(all P<0.05). 490 patients (490/501, 97.8%) were followed up with a median of 31.2 months. 163 patients had a death during follow-up (NET G1 2, NET G2 1, NEC 114, MiNEN 46). For NET G1, NET G2, NEC and MiNEN patients,the 1-year overall survival rates were 100%, 100%, 80.1% and 86.2%, respectively; the 3-year survival rates were 98.9%, 100%, 43.5% and 55.1%, respectively. The differences were statistically significant (P<0.001). Univariate analysis showed that gender, age, smoking history, alcohol history, tumor pathological grade, tumor morphology, tumor location, tumor size, lymph node metastasis, distant metastasis, and TNM stage were associated with the prognosis of G-NEN patients (all P<0.05). Multivariate analysis showed that age ≥60 years, pathological grade of NEC and MiNEN, distant metastasis, and TNM stage III-IV were independent factors influencing the survival of G-NEN patients (all P<0.05). 63 cases were stage IV at initial diagnosis. 32 of these were treated with surgery and 31 with palliative chemotherapy. Stage IV subgroup analysis showed that the 1-year survival rates were 68.1% and 46.2% in the surgical treatment and palliative chemotherapy groups, respectively, and the 3-year survival rates were 20.9% and 10.3%, respectively; the differences were statistically significant (P=0.016). Conclusions: G-NEN is a heterogeneous group of tumors. Different pathological grades of G-NEN have different clinicopathological features and prognosis. Factors such as age ≥ 60 years old, pathological grade of NEC/MiNEN, distant metastasis, stage III, IV mostly indicate poor prognosis of patients. Therefore, we should improve the ability of early diagnosis and treatment, and pay more attention to patients with advanced age and NEC/MiNEN. Although this study concluded that surgery improves the prognosis of advanced patients more than palliative chemotherapy, the value of surgical treatment for patients with stage IV G-NEN remains controversial.

Small studies suggest that a new entity of high-grade (HG) (G3, by Ki-67 or mitotic index) well-differentiated (histologically) gastrointestinal neuroendocrine tumors (NETs) exists, but prognosis and characteristics are unknown. We further characterized demographics and prognosis of patients with colorectal G3 NETs. We used the Surveillance Epidemiology and End Results (SEER) database to study colorectal NETs diagnosed from 2000 to 2015. We evaluated demographic, clinical, and tumor characteristics. We compared overall survival (OS) for G1-2 NET, G3 NET, and NEC (neuroendocrine carcinoma). We used logistic regression to detect grade associations and Cox proportional hazards models to examine predictors of survival. We identified 5894 cases with colorectal NET (5780 [98.1%] G1-2 and 114 [1.9%] G3); the cohort was 66% white, 47% male, and had a median age of 54. Patients with G3 NET were likely to be older (odds ratio [OR]: 2.23; 95% confidence interval [CI]: 1.19-4.19 for 60 to 69 vs. <50), unmarried (OR: 1.56; 95% CI: 1.02-2.38), and less likely to be diagnosed after 2010 (OR: 0.09; 95% CI: 0.06-0.15). OS for G3 NET (median, 36 mo; 95% CI: 13-92) fell between OS for NEC (median, 7 mo; 95% CI: 6-8), and G1-2 NET (median not reached, >120 mo). Among G1-3 NETs, black patients (hazard ratio [HR]: 1.30; 95% CI: 1.03-1.62), older patients (HR: 3.63; 95% CI: 2.63-5.01 for age 60 to 69 vs. <50), unmarried patients (HR: 1.40; 95% CI: 1.17-1.68), and those with HG features (HR: 3.97; 95% CI: 3.15-4.99) had worse survival. We defined a subset of G3 NETs that are HG and well differentiated, more common in older, unmarried patients, with a prognosis between that of NEC and G1-2 NETs. Our analysis adds the first national registry study in support of a new classification of nonpancreatic HG and well-differentiated NETs.