Neuroendocrine Tumor Metastases Research Articles

Clinical outcomes after endoscopic resection and the risk of lymph node metastasis in rectal neuroendocrine tumors: a single-center retrospective study.

The incidence of rectal neuroendocrine tumors (R-NETs) has increased in recent years. However, the predictors of lymph node (LN) metastasis and clinical outcomes, particularly following endoscopic treatment, remain unclear. Our study aims to elucidate the potential risk factors for LN metastasis and the clinical outcomes of patients undergoing endoscopic resection in R-NETs. A total of 128 patients with R-NETs were retrospectively identified from a single center between June 2012 and December 2021. Risk factors for LN metastasis in R-NETs were analyzed using multivariate analysis. Additionally, the clinical outcomes of endoscopic resections in patients with R-NETs were assessed. In our study, 128 patients with R-NETs were retrospectively analyzed. The risk factors for LN metastasis determined by multivariate analysis were tumor size and patient age at diagnosis. Among the 111 patients treated with endoscopic resection and with tumor margin records available, 92 underwent endoscopic submucosal dissection (ESD) and 19 underwent conventional endoscopic mucosal resection (EMR). There was no significant difference between the two groups regarding the positive rates of basal tumor margin and lateral tumor margin. Furthermore, 64 patients who underwent endoscopic resection for R-NETs were successfully followed up (range, 1.64-76.71months), during which only one patient developed local recurrence. Tumor size and age at diagnosis were predictors for LN metastasis of R-NETs. Both ESD and EMR are alternative techniques with a favorable prognosis for R-NETs, even in cases with positive resection margins. However, due to the relatively small number of patients undergoing EMR and missing data in follow-up protocols, definitive conclusions require further large-scale studies.

177Lu-DOTATATE Uptake in the Lungs of a Patient With COVID-19 Pneumonia.

A 76-year-old woman with liver and bone metastasis of a duodenal neuroendocrine tumor received peptide receptor radionuclide therapy with 177Lu-DOTATATE. Scintigraphy with SPECT/CT performed 4 days after the treatment demonstrated 177Lu-DOTATATE uptake as multifocal ground glass opacities in the bilateral lungs. This uptake was considered to be due to COVID-19 pneumonia because the patient was infected with the virus 7 days prior to the treatment. The lung opacities became smaller, showing a decreased uptake, 2 months later, after the second treatment. 177Lu-DOTATATE may be taken up during the active phase of COVID-19 pneumonia.

Hypoxia exosome derived CEACAM5 promotes tumor-associated macrophages M2 polarization to accelerate pancreatic neuroendocrine tumors metastasis via MMP9.

Exosomes play significant roles in the communications between tumor cells and tumor microenvironment. However, the specific mechanisms by which exosomes modulate tumor development under hypoxia in pancreatic neuroendocrine tumors (pNETs) are not well understood. This study aims to investigate these mechanisms and made several important discoveries. We found that hypoxic exosomes derived from pNETs cells can activate tumor-associated macrophages (TAM) to the M2 phenotype, in turn, the M2-polarized TAM, facilitate the migration and invasion of pNETs cells. Further investigation revealed that CEACAM5, a protein highly expressed in hypoxic pNETs cells, is enriched in hypoxic pNETs cell-derived exosomes. Hypoxic exosomal CEACAM5 was observed to induce M2 polarization of TAM through activation of the MAPK signaling pathway. Coculturing pNETs cells with TAM or treated with hypoxic exosomes enhanced the metastatic capacity of pNETs cells. In conclusion, these findings suggest that pNETs cells generate CEACAM5-rich exosomes in a hypoxic microenvironment, which in turn polarize TAM promote malignant invasion of pNETs cells. Targeting exosomal CEACAM5 could potentially serve as a diagnostic and therapeutic strategy for pNETs.

SLC7A11 promotes EMT and metastasis in invasive pituitary neuroendocrine tumors by activating the PI3K/AKT signaling pathway.

Invasive pituitary neuroendocrine tumors (PitNETs) are the most prevalent types of intracranial and neuroendocrine tumors. Their aggressive growth and difficulty in complete resection result in a high recurrence rate. Cystine transporter solute carrier family 7 member 11 (SLC7A11) is overexpressed in various cancers, which contributes to tumor growth, progression, and metastasis by promoting cystine uptake and glutathione biosynthesis. We identified SLC7A11 as an invasive biomarker based on three Gene Expression Omnibus cohorts. This study aimed to investigate the role of SLC7A11 in invasive PitNETs. Cell proliferation was assessed using CCK-8 and colony formation assays, while cell apoptosis was estimated with flow cytometry. Wound healing assays and transwell assays were utilized to evaluate migration and invasion ability. Our findings demonstrated that SLC7A11 was markedly upregulated in invasive PitNETs, and was associated with the invasiveness of PitNETs. Knockdown of SLC7A11 could largely suppress tumor cell proliferation, migration, and invasion, while inducing apoptosis. Furthermore, SLC7A11 depletion was implicated in regulating epithelial-mesenchymal transition and inactivating the PI3K/AKT signaling pathway. These insights suggest SLC7A11 as a potential therapeutic target for invasive PitNETs.

Abstract A047: ARID1A mutations drive metastasis of pancreatic neuroendocrine tumors and pancreatic adenocarcinomas by activation of NTN1/UNC5B signaling

Abstract ARID1A, a component of the SWI/SNF DNA chromatin remodeling complex, is recurrently mutated in many types of cancer. In pancreatic ductal adenocarcinomas (PDACs), mutations in ARID1A are found in 6-15% of cases, and ARID1A expression has previously been shown to associate with poor patient outcome. But the effect of ARID1A mutations on pancreatic neuroendocrine tumors (PNETs) has not been previously studied, and we observed that ARID1A mutations were 15-fold more common in patients with metastatic PNETs than in patients with localized disease, indicating the importance of ARID1A mutations in driving the progression of what is normally an indolent disease. We have studied ARID1A mutations in models of both PDACs and PNETs and observe that in both diseases ARID1A mutations associated with several properties common to metastatic cells including epithelial-mesenchymal transition, in vitro invasiveness, and insensitivity to anoikis. Mutation of ARID1A activated expression of the axonal guidance protein NTN1 in both PDACs and PNETs, and interaction between the NTN1 ligand and its dependence receptor UNC5b were required for the metastatic properties of ARID1A mutant cells. Treatment with a NTN1 inhibitor, NP137, overcame insensitivity to anoikis, while deletion or knockdown of UNC5b caused ARID1A mutant cells to undergo a mesenchymal-epithelial transition. In vivo, metastasis of PDACs was blocked by NP137 treatment, or by deletion of UNC5b. NP137 is currently in clinical trials for many tumor types including PDACs, and our data strongly indicate that NP137 should also be tested in patients with metastatic PNETs. Citation Format: Chris Harris, Muhammad Sadeqi Nezhad, Asra Asad, Wade Narrow, Orjola Prela, Darren Carpizo. ARID1A mutations drive metastasis of pancreatic neuroendocrine tumors and pancreatic adenocarcinomas by activation of NTN1/UNC5B signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A047.

Resection for liver metastasis of neuroendocrine tumor of unknown primary (NET-UP): a retrospective, single center, comparative study

Resection for liver metastasis of neuroendocrine tumor of unknown primary (NET-UP): a retrospective, single center, comparative study

Development and validation of CT-based radiomics deep learning signatures to predict lymph node metastasis in non-functional pancreatic neuroendocrine tumors: a multicohort study

Lymph node status is an important factor for the patients with non-functional pancreatic neuroendocrine tumors (NF-PanNETs) with respect to the surgical methods, prognosis, recurrence. Our aim is to develop and validate a combination model based on contrast-enhanced CT images to predict the lymph node metastasis (LNM) in NF-PanNETs. Retrospective data were gathered for 320 patients with NF-PanNETs who underwent curative pancreatic resection and CT imaging at two institutions (Center 1, n=236 and Center 2, n=84) between January 2010 and March 2022. RDPs (Radiomics deep learning signature) were developed based on ten machine-learning techniques. These signatures were integrated with the clinicopathological factors into a nomogram for clinical applications. The evaluation of the model's performance was conducted through the metrics of the area under the curve (AUC). The RDPs showed excellent performance in both centers with a high AUC for predicting LNM and disease-free survival (DFS) in Center 1 (AUC, 0.88; 95% CI: 0.84-0.92; DFS, p<0.05) and Center 2 (AUC, 0.91; 95% CI: 0.85-0.97; DFS, p<0.05). The clinical factors of vascular invasion, perineural invasion, and tumor grade were associated with LNM (p<0.05). The combination nomogram showed better prediction capability for LNM (AUC, 0.93; 95% CI: 0.89-0.96). Notably, our model maintained a satisfactory predictive ability for tumors at the 2-cm threshold, demonstrating its effectiveness across different tumor sizes in Center 1 (≤2cm: AUC, 0.90 and>2cm: AUC, 0.86) and Center 2 (≤2cm: AUC, 0.93 and>2cm: AUC, 0.91). Our RDPs may have the potential to preoperatively predict LNM in NF-PanNETs, address the insufficiency of clinical guidelines concerning the 2-cm threshold for tumor lymph node dissection, and provide precise therapeutic strategies. This work was supported by JSPS KAKENHI Grant Number JP22K20814; the Rare Tumor Research Special Project of the National Natural Science Foundation of China (82141104) and Clinical Research Special Project of Shanghai Municipal Health Commission (202340123).

Application of Machine Learning in Predicting Hepatic Metastasis or Primary Site in Gastroenteropancreatic Neuroendocrine Tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) account for 80% of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). GEP-NETs are well-differentiated tumors, highly heterogeneous in biology and origin, and are often diagnosed at the metastatic stage. Diagnosis is commonly through clinical symptoms, histopathology, and PET-CT imaging, while molecular markers for metastasis and the primary site are unknown. Here, we report the identification of multi-gene signatures for hepatic metastasis and primary sites through analyses on RNA-SEQ datasets of pancreatic and small intestinal NETs tissue samples. Relevant gene features, identified from the normalized RNA-SEQ data using the mRMRe algorithm, were used to develop seven Machine Learning models (LDA, RF, CART, k-NN, SVM, XGBOOST, GBM). Two multi-gene random forest (RF) models classified primary and metastatic samples with 100% accuracy in training and test cohorts and >90% accuracy in an independent validation cohort. Similarly, three multi-gene RF models identified the pancreas or small intestine as the primary site with 100% accuracy in training and test cohorts, and >95% accuracy in an independent cohort. Multi-label models for concurrent prediction of hepatic metastasis and primary site returned >98.42% and >87.42% accuracies on training and test cohorts, respectively. A robust molecular signature to predict liver metastasis or the primary site for GEP-NETs is reported for the first time and could complement the clinical management of GEP-NETs.

Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment.

Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.

Hepatic Arteriography and C-Arm CT-Guided Ablation (HepACAGA) to Improve Tumor Visualization, Navigation and Margin Confirmation in Percutaneous Liver Tumor Ablation

PurposeWe present a technique that combines Hepatic Arteriography with C-arm CT-Guided Ablation (HepACAGA) to improve tumor visualization, navigation and margin confirmation for percutaneous ablation of liver tumors.Materials and MethodsAll consecutive patients scheduled for HepACAGA between April 20th, 2021, and November 2nd, 2021, were included in this retrospective, cohort study. HepACAGA was performed in an angiography-suite under general anesthesia. The hepatic artery was catheterized for selective contrast injection. C-arm CT and guidance software were then used to visualize the tumor and the microwave antenna was inserted during apnea. Pre- and post-ablation C-arm CTs were performed and ablation margins assessed. Technical success, antenna placement deviation, number of repositions, tumor recurrence, and safety were evaluated. Technical success was defined as a tumor that was ablated according to the HepACAGA technique.ResultsA total of 21 patients (28 tumors) were included. The main tumor type was colorectal cancer liver metastases (11/21, 52%), followed by hepatocellular carcinoma (7/21, 33%), neuroendocrine tumor metastases (1/21, 5%), and other tumor types (2/21, 10%). The technical success rate was 93% (26/28 tumors) with two small hypovascular lesions unable to be identified. A single microwave antenna was used in all patients. The median antenna placement deviation was 1 mm (range 0–6 mm). At a median follow-up time of 16 months (range 5–22 months), there was no tumor recurrence in any patient. Safety analysis showed a complication rate of 5% grade 2 and 5% grade 3.ConclusionHepACAGA was demonstrated to be a safe and effective percutaneous ablation technique, without any local tumor recurrence in this study.Graphic

Risk of metastasis and survival in patients undergoing different treatment strategies with T1 colonic neuroendocrine tumors.

The efficacy and safety of local excision (LE) for small (< 1‒2cm) colonic neuroendocrine tumors (NETs) is controversial due to the higher metastasis risk when compared with rectal NETs. The study aimed to evaluate the metastasis risk of T1 colonic NETs and compare patients' long-term prognosis after LE or radical surgery (RS). The Surveillance Epidemiology and End Results database was used to identify patients with T1 colonic NETs (2004‒2015). Multivariable logistic regression was performed to assess factors associated with metastasis risk. Propensity score matching was used to balance the variables. Cancer-specific survival (CSS) and overall survival (OS) were calculated to estimate the prognosis of patients with T1N0M0 colonic NETs who underwent LE or RS. Of the 610 patients with colonic NETs, 46 (7.54%) had metastasis at diagnosis. Tumor size (11-20mm) (OR = 9.51; 95% confidence interval (CI): 4.32‒21.45; P < 0.001), right colon (OR = 15.79; 95% CI 7.20‒38.56; P < 0.001), submucosal infiltration (OR = 2.08; 95% CI 0.84‒5.57; P = 0.125) were independent risk factors associated with metastasis. Of the 515 patients with T1N0M0 colonic NETs, the overall long-term prognosis of LE was as good as that of RS groups (after matching, 5-year CSS: 97.9% vs. 94.6%, P = 0.450; 5-year OS: 92.7% vs. 85.6%, P = 0.009). Tumor size (11‒20mm) and site (right colon) are associated with metastasis in T1 colonic NETs. In the absence of metastasis, LE could be a viable option for 0‒10mm T1 colonic NETs with well/moderate differentiation in the left colon in terms of long-term survival.

Evaluation of MRI in the diagnostic accuracy of extrahepatic metastases in neuroendocrine tumors in comparison with the reference standard somatostatin-receptor-PET/CT.

The aim of this study was to compare the diagnostic performance of different sets of MR sequences in detecting extrahepatic disease of NETs on routine liver magnetic resonance imaging (MRI). One hundred twenty-seven patients with NETs with and without hepatic and extrahepatic metastases who underwent liver MRI and SSTR-PET/CT were retrospectively analyzed. Two radiologists evaluated in consensus in four sessions: (1) non-contrast T1w+T2w (NC), (2) NC+DWI, (3) NC+ contrast-enhanced T1w (CE), and (4) NC+DWI+CE the presence and number of metastases (lymph nodes, bone, peritoneal surface, lung base, and abdominal organ). Sensitivity, specificity, positive, and negative predictive value for detection of metastases were calculated for each session in a patient-based manner; detection and error rates were calculated for lesion-based analysis. Comparison between the MR-sessions and positron emission tomography-computed tomography (PET/CT) was performed with the McNemar test. Regarding all 1,094 lesions detected in PET/CT, NC+DWI, and NC, CE+DWI identified most true-positive lesions 779 (71%) and 775 (71%), respectively. Patient-based analysis revealed significantly higher sensitivity by NC+DWI (85%) than NC and NC+CE (p = 0.011 and 0.004, respectively); the highest specificity was reached by NC+CE+DWI (100%). Site-based analysis revealed highest detection rates for lymph node metastases for NC+DWI and NC, CE+DWI (73 and 76%, respectively); error rates were lower for NC, CE+DWI with 5% compared with 17% (NC+DWI). Detection rates for bone metastases were similarly high in NC+DWI and NC, CE+DWI (75 and 74%, respectively), while CE showed no benefit. For peritoneal metastases highest sensitivity was reached by NC+DWI (67%). The combination of NC+DWI showed better sensitivities than the combination of NC+CE. NC+DWI showed similar, sometimes even better sensitivities than NC+CE+DWI, but with lower specificities.

Testicular Metastasis of Jejunal Neuroendocrine Tumor on 68Ga-DOTATATE PET/CT.

Neuroendocrine tumors are slow-growing tumors originating from neuroendocrine cells and capable of metastasis. Most of them are found in the gastrointestinal tract; however, they can also be rarely seen in other organs. Testicular neuroendocrine tumors account for less than 1% of all testicular neoplasms. They may present as primary testicular or secondary tumors from extratesticular sources. Jejunal neuroendocrine tumor metastasis to the testis is extremely rare. We present the case of a 61-year-old man with a jejunal neuroendocrine tumor and metastases to bilateral testicles revealed on Gallium-68-DOTATATE positron emission tomography/computed tomography.

ASO Visual Abstract: Risk Factors for Lymph Node Metastasis of Rectal Neuroendocrine Tumor and its Prognostic Impact-A Single-Center Retrospective Analysis of 195 Cases with Radical Resection.

ASO Visual Abstract: Risk Factors for Lymph Node Metastasis of Rectal Neuroendocrine Tumor and its Prognostic Impact-A Single-Center Retrospective Analysis of 195 Cases with Radical Resection.

Stratification of rate of lymph node metastasis according to risk factors and oncologic outcomes in patients who underwent radical resection for rectal neuroendocrine tumors.

Most predictive factors for lymph node metastasis in rectal neuroendocrine tumors (NETs) have been based on local and endoscopic resection. We aimed to evaluate the risk factors for lymph node metastasis in patients who underwent radical resection for rectal NETs and stratify the risk of lymph node metastasis. Sixty-four patients who underwent radical resection for rectal NETs between January 2001 and January 2018 were included. We investigated the risk factors of lymph node metastasis using clinicopathologic data. We also performed a risk stratification for lymph node metastases using the number of previously known risk factors. For oncologic outcomes, the 5-year overall survival and recurrence-free survival were evaluated in both groups. Among the patients who underwent radical surgery, 32 (50.0%) had lymph node metastasis and 32 (50.0%) had non-lymph node metastasis. In the multivariable analysis, only the male sex was identified as a risk factor for lymph node metastasis (odds ratio, 3.695; 95% confidence interval, 1.128-12.105; P=0.031). When there were 2 or more known risk factors, the lymph node metastasis rate was significantly higher than when there were one or no risk factors (odds ratio, 3.667; 95% confidence interval, 1.023-13.143; P=0.046). There was also no statistical difference between the 2 groups in 5-year overall survival (P=0.431) and 5-year recurrence-free survival (P=0.144). We found that the rate of lymph node metastasis increased significantly when the number of known risk factors is 2 or more.

Comparison of Whole-Body Ga-68 DOTA TATE Positron Emission Tomography and Magnetic Resonance Imaging in the Detection of Bone Metastasis of Neuroendocrine Tumor in Simultaneous 3T Positron Emission Tomography/Computed Tomography

Comparison of Whole-Body Ga-68 DOTA TATE Positron Emission Tomography and Magnetic Resonance Imaging in the Detection of Bone Metastasis of Neuroendocrine Tumor in Simultaneous 3T Positron Emission Tomography/Computed Tomography

Risk Factors for Lymph Node Metastasis of Rectal Neuroendocrine Tumor and Its Prognostic Impact: A Single-Center Retrospective Analysis of 195 Cases with Radical Resection.

The incidence of rectal neuroendocrine tumors (NETs) has been steadily increasing. The risk factors for and prognostic impact of lymph node (LN) metastasis were analyzed in 195 patients with stage I-III rectal NET who underwent radical surgery. This retrospective, single-center study analyzed risk factors for LN metastasis focusing on previously identified factors and a novel risk factor: multiple rectal NETs. The association between LN metastasis and the prognosis was also analyzed. Pathologically, the LN metastasis rate (also the rate of stage III disease) was 39%, which was higher than the clinical LN metastasis rate of 14%. Tumor size > 10 mm, presence of central depression, tumor grade G2, depth of invasion, LN swelling on preoperative imaging (cN1), venous invasion and multiple NETs were identified as risk factors for LN metastasis. As the tumor size and risk factors increased, the rate of LN metastasis increased. Among these 7 factors, venous invasion, cN1, and multiple NETs were identified as independent predictors of LN metastasis. LN metastasis of rectal NETs was associated with significantly poor disease-free and disease-specific survival. As risk factors increase, the potential for rectal NETs to metastasize to the LNs increases and LN metastasis is associated with a poor prognosis. This is the first study to report multiple NETs as a risk factor for LN metastasis. A future study examining the survival benefit of radical surgery accompanying LN dissection compared with local resection is warranted.

Identification of the Immune Subtypes for the Prediction of Metastasis in Pancreatic Neuroendocrine Tumors

Introduction: Most patients with pancreatic neuroendocrine tumors (pNETs) present with unresectable or metastatic disease. Increasing evidence shows that the immune cell infiltration patterns play a pivotal role in tumor progression in pNETs. Nonetheless, there has been no comprehensive analysis of the effect of immune infiltration patterns on metastasis. Methods: The gene expression profiling dataset and clinical data were obtained from the Gene Expression Omnibus database. Estimation of Stromal and Immune Cells in Malignant Tumors using the Expression Data and single-sample Gene Set Enrichment Analysis were used to uncover the landscape of the tumor immune microenvironment. Subtypes based on the immune infiltration patterns were identified by the unsupervised clustering algorithm. Differentially expressed genes were identified using the limma packages of R. Functional enrichment analyses of these genes were carried out using STRING, Kyoto Encyclopedia of Genes and Genomes, and Reactome. Results: The landscape of immune cells in pNET samples was constructed, and three immune cell infiltration subtypes (Immunity-H, Immunity-M, and Immunity-L) were identified. Immune cell infiltration degrees and metastasis were positively correlated. A protein-protein interaction network containing 80 genes was constructed, and functional enrichment revealed that these genes were mainly enriched in immune-related pathways. Eleven metastasis-related genes were differentially expressed among three subtypes, including MMP14, MMP2, MMP12, MMP7, SPARC, MMP19, ITGAV, MMP23B, MMP1, MMP25, and MMP9. There is a certain consistency of immune infiltration pattern between the primary tumor and metastatic tumor samples. Conclusion: Our findings may deepen the understanding of the immune-mediated regulatory mechanisms underlying pNETs and may provide some promising targets for immunotherapy.

Development of novel prediction models for nodal and distant metastasis in G1 and G2 colorectal neuroendocrine tumors

We aimed to construct novel nomograms for nodal and distant metastasis for patients with G1 and G2 colorectal neuroendocrine tumors (NETs). A training set and validation set were obtained by including G1 and G2 colorectal NET patients from the Surveillance, Epidemiology, and End Results database and the Cancer Hospital Chinese Academy of Medical Science, respectively. The area under curve (AUC) values under receiver operating characteristic (ROC) curves, calibration plots, and the Hosmer‒Lemeshow tests were used to evaluate the discriminability and calibration of nomograms. In total, 3690 and 172 patients were included in the training set and validation set, respectively. Tumor size, location, and T stage were included in the nomogram predicting nodal metastasis. The AUC values of the nomogram were 0.972 (95% confidence interval (CI): 0.964-0.980) and 0.897 (95% CI: 0.846-0.948) in the training set and validation set, respectively. The calibration plots and Hosmer‒Lemeshow test for the training set (P = 0.999) and validation set (P = 0.537) showed good model calibration. Tumor size, T stage, and N stage were incorporated into the nomogram predicting distant metastasis. The ROC curves demonstrated desirable discrimination both in the training set (AUC = 0.938 (95% CI: 0.921-0.954)) and validation set (AUC = 0.938 (95% CI: 0.890-0.988)). The calibration curves and Hosmer‒Lemeshow test indicated acceptable model calibration both in the training set (P = 0.908) and validation set (P = 0.722). The proposed nomograms may be used as a reliable tool to predict the nodal and distant metastasis in G1 and G2 colorectal NETs.

Clinicopathological Characteristics of Low to Intermediate Grade Neuroendocrine Tumors with Oncocytic Features

Neuroendocrine tumors (NETs) with oncocytic features are rare. To date, few studies have described the metastatic characteristics of these tumors, most of which were limited by the low number of cases. One article characterized intermediate to high grade (G2 and G3) oncocytic NETs of the pancreas as having an ominous outcome; however, metastatic features of low-grade oncocytic NETs have, to our knowledge, been hitherto unexplored. Our study characterized the clinicopathological and metastatic features of 32 low to intermediate-grade oncocytic NETs of various organs. The most frequent metastatic site was the liver (63%). The metastatic rate of our cases was compared with Riihimaki’s study (metastatic rate of G1/G2 NETs was reported), as well as Heetfeld’s study and Lithgow’s study (metastatic rate of G3 NETs was reported). The overall metastatic rate of our cases is 84.4%, which is significantly higher than that of the G1/2 NETs from Riihimaki’s study (84.4% vs. 25%, p &lt; 0.0001), while similar to that of the G3 NETs from Heetfeld’s study (84.4% vs. 86.5%, p &gt; 0.05) and Lithgow’s study (84.4% vs. 80.8%, p &gt; 0.05). These data indicate that oncocytic features could potentially be characterized as high-risk features in addition to high Ki-67 index, mitotic count, and necrosis. Thus, imaging studies such as liver magnetic resonance imaging (MRI) may be warranted to detect liver metastases in NETs with distinctive oncocytic cytologic features even in the absence of other high-risk features.