Critical appraisal of the adequacy of surgical indications for non-functioning pancreatic neuroendocrine tumours.

BACKGROUND: The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness. METHODS: A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002-2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse). RESULTS: A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001). CONCLUSIONS: Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment.

Preoperative assessment of lymph nodal metastases with [68Ga]Ga-DOTATOC PET radiomics for improved surgical planning in well-differentiated pancreatic neuroendocrine tumours.

PURPOSE: Accurate identification of lymph node (LN) metastases is pivotal for surgical planning of pancreatic neuroendocrine tumours (PanNETs); however, current imaging techniques have sub-optimal diagnostic sensitivity. Aim of this study is to investigate whether [68Ga]Ga-DOTATOC PET radiomics might improve the identification of LN metastases in patients with non-functioning PanNET (NF-PanNET) referred to surgical intervention. METHODS: Seventy-two patients who performed preoperative [68Ga]Ga-DOTATOC PET between December 2017 and March 2022 for NF-PanNET. [68Ga]Ga-DOTATOC PET qualitative assessment of LN metastases was measured using diagnostic balanced accuracy (bACC), sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV). SUVmax, SUVmean, Somatostatin receptor density (SRD), total lesion SRD (TLSRD) and IBSI-compliant radiomic features (RFs) were obtained from the primary tumours. To predict LN involvement, these parameters were engineered, selected and used to train different machine learning models. Models were validated using tenfold repeated cross-validation and control models were developed. Models' bACC, SN, SP, PPV and NPV were collected and compared (Kruskal-Wallis, Mann-Whitney). RESULTS: LN metastases were detected in 29/72 patients at histology. [68Ga]Ga-DOTATOC PET qualitative examination of LN involvement provided bACC = 60%, SN = 24%, SP = 95%, PPV = 78% and NPV = 65%. The best-performing radiomic model provided a bACC = 70%, SN = 77%, SP = 61%, PPV = 60% and NPV = 83% (outperforming the control model, p < 0.05*). CONCLUSION: In this study, [68Ga]Ga-DOTATOC PET radiomics allowed to increase diagnostic sensitivity in detecting LN metastases from 24 to 77% in NF-PanNET patients candidate to surgery. Especially in case of micrometastatic involvement, this approach might assist clinicians in a better patients' stratification.

Recent developments in the diagnosis of pancreatic neuroendocrine neoplasms.

INTRODUCTION: Pancreatic Neuroendocrine Neoplasms (PanNENs) are characterized by a highly heterogeneous clinical and biological behavior, making their diagnosis challenging. PanNENs diagnostic work-up mainly relies on biochemical markers, pathological examination, and imaging evaluation. The latter includes radiological imaging (i.e. computed tomography [CT] and magnetic resonance imaging [MRI]), functional imaging (i.e. 68Gallium [68 Ga]Ga-DOTA-peptide PET/CT and Fluorine-18 fluorodeoxyglucose [18F]FDG PET/CT), and endoscopic ultrasound (EUS) with its associated procedures. AREAS COVERED: This review provides a comprehensive assessment of the recent advancements in the PanNENs diagnostic field. PubMed and Embase databases were used for the research, performed from inception to October 2023. EXPERT OPINION: A deeper understanding of PanNENs biology, recent technological improvements in imaging modalities, as well as progresses achieved in molecular and cytological assays, are fundamental players for the achievement of early diagnosis and enhanced preoperative characterization of PanNENs. A multimodal diagnostic approach is required for a thorough disease assessment.

Diagnostic work-up and surgical management of insulinoma: A retrospective analysis from a tertiary referral center.

Insulinoma is a multifaceted disease that poses several challenges in terms of clinical presentation, diagnostic work-up, and surgical management. The aim of this study was to describe diagnostic work-up, surgical management, and postoperative outcomes of patients with insulinoma. All consecutive patients who underwent surgery for insulinoma at San Raffaele Hospital (Milan, Italy) between January 2008 and January 2022 were included. Overall, 98 patients were considered. The median delay between presenting symptoms and insulinoma diagnosis was 10 months (IQR, 4-21). Insulinoma diagnosis was made at our Institution in 45 patients, 20 of whom referred within 6 months from symptoms onset. In this subgroup, the median interval between symptoms presentation and insulinoma diagnosis was 4 months (IQR, 2-6), as compared to 14 months (IQR, 10-26) in patients (n = 25) who referred to our institution after 6 months from symptoms onset (p < .001). The insulinoma was localized preoperatively in all the cases. All patients underwent ≥1 high-quality imaging: computed tomography (CT: n = 87, sensitivity 84%), magnetic resonance imaging (MRI: n = 55, sensitivity 85%) and endoscopic ultrasound (EUS: n = 79, sensitivity 100%). MRI identified the tumor in eight patients with negative CT. EUS localized the insulinoma in three patients with negative CT and negative MRI. Parenchyma-sparing resections were performed in 41 patients. Contact with major vessels, lesion close to Wirsung duct and suspect of malignancy were the main reasons to perform a formal resection. An early referral to high-volume centers is important for reducing diagnostic delay in patients with insulinoma. The diagnostic work-up of insulinoma frequently requires several imaging modalities to be performed, with EUS being the most sensitive one. Parenchyma-sparing surgery for insulinoma should be performed whenever technically and oncologically feasible.

Role of Preoperative High-Resolution Manometry in the Identification of Patients at High Risk of Postoperative GERD Symptoms 1 Year After Sleeve Gastrectomy.

PURPOSE: Sleeve gastrectomy (SG) has become the most common bariatric procedure, but it is often characterized by the onset of postoperative gastroesophageal reflux disease (GERD). High-resolution manometry (HRM) is a useful tool to detect risk factors for GERD. The aim of this study was to evaluate preoperative manometric parameters as possible predictors of postoperative GERD. MATERIALS AND METHODS: This was a monocentric retrospective study. We analyzed 164 patients, with preoperative esophagitis/GERD symptoms who underwent preoperative HRM and were submitted to SG (July 2020-February 2022). RESULTS: Postoperative GERD was observed in 60 patients (36.6%): 41 of them (68%) already had preoperative GERD symptoms, whereas the remaining 19 patients (32%) developed postoperative symptoms. Female patients developed postoperative GERD in a significantly higher fraction of cases as compared to male patients (82% versus 18%; p < 0.001). DCI (distal contractile integral) was identified as the only HRM parameter correlating with the presence of GERD. Patients with DCI ≤ 1623 mmHg*cm*s developed postoperative GERD in 46% of cases (n = 43/94), as compared to 24% of cases (n = 17/70) among patients with DCI > 1623 mmHg*cm*s (p = 0.005). At multivariable analysis, female sex (OR 3.402, p = 0.002), preoperative GERD symptoms (OR 2.489, p = 0.013), and DCI ≤ 1623 mmHg*s*cm (OR 0.335, p = 0.003) were identified as independent determinants of postoperative GERD. CONCLUSION: All the patients with preoperative risk factors for reflux, such as GERD symptoms or esophagitis on EGDS (esophagogastroduodenoscopy), should be considered for an HRM. Moreover, when a DCI ≤ 1623 mmHg*s*cm is found, a bariatric procedure different from SG might be considered.

Could Glycated Hemoglobin be Leakage Predictor in Sleeve Gastrectomy? A Retrospective Observational Study on 4233 Patients.

PURPOSE: Diabetes increases the risks related to surgery. At the same time, bariatric surgery improves diabetes. Glycated hemoglobin (A1C) is an index of diabetes severity. The purpose of this study is to evaluate A1C as a possible predictor of postoperative complications after Sleeve Gastrectomy (SG), focusing on leakage. MATERIALS AND METHODS: Monocentric retrospective study considering all consecutive patients with obesity, with or without diabetes, who underwent bariatric surgical procedures, from January 2018 to December 2021. All patients had preoperative A1C values. RESULTS: 4233 patients were considered. 522 patients (12.33%) were diabetics (A1C ≥ 6.5%). Of these, 260 patients (6.14%) had A1C ≥ 7% and 59 (1.39%) A1C ≥ 8%. 1718 patients (40.58%) were in a pre-diabetic range (A1C 5.7%-6.5%). Higher A1C values were associated with older age, male gender, higher BMI and increased rate of comorbidities. A longer operative time was observed for patients with A1C ≥ 7%, p = 0.027 (53 ± 20 vs 51 ± 18 min). The frequency of leakage was significantly higher when A1C ≥ 7% (3.8% vs 2.0%, p = 0.026). The frequency of leakage further increased when A1C ≥ 8% (5.1%), although this difference did not reach statistical significance. CONCLUSION: Patients with obesity and A1C ≥ 7% need to be referred to a diabetologist to treat diabetes before surgery and consequently decrease the risk of leakage.

Either High or Low Risk: The Acinar Score at the Resection Margin Dichotomizes the Risk Spectrum of Pancreas-specific Complications After Pancreatoduodenectomy.

BACKGROUND: Pancreatic acinar content (Ac) has been associated with pancreas-specific complications after pancreatoduodenectomy. The aim of this study was to improve the prediction ability of intraoperative risk stratification by integrating the pancreatic acinar score. METHODS: A training and validation cohort underwent pancreatoduodenectomy with a subsequent histologic assessment of pancreatic section margins for Ac, fibrosis (Fc), and fat. Intraoperative risk stratification (pancreatic texture, duct diameter) and pancreas-specific complications (postoperative hyperamylasemia [POH], postpancreatectomy acute pancreatitis [PPAP], pancreatic fistula [POPF]) were classified according to ISGPS definitions. RESULTS: In the validation cohort (n= 373), the association of pancreas-specific complications with higher Ac and lower Fc was replicated (all P <0.001). In the entire cohort (n= 761), the ISGPS classification allocated 275 (36%) patients into intermediate-risk classes B (POH 32%/PPAP 3%/POPF 17%) and C (POH 36%/PPAP 9%/POPF 33%). Using the acinar score (Ac ≥60% and/or Fc ≤10%), intermediate-risk patients could be dichotomized into a low-risk (POH 5%/PPAP 1%/POPF 6%) and a high-risk (POH 51%/PPAP 9%/POPF 38%) group (all P <0.001). The acinar score AUC for POPF prediction was 0.70 in the ISGPS intermediate-risk classes. Overall, 239 (31%) patients were relocated into the high-risk group from lower ISGPS risk classes using the acinar score. CONCLUSIONS: The risk of pancreas-specific complications appears to be dichotomous-either high or low-according to the acinar score, a tool to better target the application of mitigation strategies in cases of intermediate macroscopic features.

Somatostatin receptor activity assessed by 68Ga-DOTATOC PET can preoperatively predict DAXX/ATRX loss of expression in well-differentiated pancreatic neuroendocrine tumors.

PURPOSE: To evaluate the role of 68Ga-DOTATOC PET parameters in predicting DAXX/ATRX loss of expression in patients with Pancreatic neuroendocrine tumors (PanNET) candidate to surgery. METHODS: This retrospective study included 72 consecutive patients with PanNET (January 2018-March 2022) who underwent to 68Ga-DOTATOC PET for preoperative staging. Image analysis: qualitative assessment and extraction of SUVmax, SUV mean, somatostatin receptor density (SRD), and total lesion somatostatin receptor density (TLSRD) from primary PanNET. Radiological diameter and biopsy information (grade, Ki67) were collected. Loss of expression (LoE) of DAXX/ATRX was assessed by immunohistochemistry on surgical specimen. Student t-test, univariate and multivariate logistic regression and ROC curves have been used to investigate the predictive value of PET parameters on DAXX/ATRX LoE. RESULTS: Forty-two/72 patients had a G1, 28/72 a G2, and 2/72 a G3 PanNET. Seven/72 patients had DAXX LoE, 10/72 ATRX LoE, and 2/72 DAXX/ATRX LoE. SRD and TLSRD could predict DAXX LoE (p = 0.002, p = 0.018, respectively). By evaluating SRD in combination with radiological diameter, only SRD maintained statistical significance (multivariate logistic regression: p = 0.020, OR = 1.05), providing the best prediction (AUC-ROC = 79.01%; cut-off = 46.96; sensitivity = 77.78%; specificity = 88.89%). In the sub-analysis performed on 55 patients with biopsy availability, SRD demonstrated its role in providing useful and additional information (multivariate logistic regression: SRD p = 0.007; grade p = 0.040). CONCLUSION: SRD has a predictive role on DAXX LoE in PanNETs, with higher probability of LoE at increasing SRD values. SRD provides complementary/additional information to grade assessed on biopsy material, and the combined use of these approaches might support patients' management by preoperatively identifying subjects with more aggressive diseases.

Pancreatectomy with venous vascular resection for pancreatic cancer: Impact of types of vein resection on timing and pattern of recurrence.

INTRODUCTION: Few studies analysed the impact of different venous resection techniques on recurrence in patients with pancreatic ductal adenocarcinoma (PDAC). Primary aim was to compare local recurrence rate and disease-free survival (DFS) between patients who underwent pancreatectomy with tangential versus segmental resection of portal vein/superior mesenteric vein. MATERIALS AND METHODS: All consecutive patients who underwent pancreatectomy with venous resection for PDAC between 2009 and 2019 were included. A propensity score matching (PSM) was used to reduce the effect of treatment selection bias. RESULTS: Overall, 120 patients (68%) underwent pancreatectomy with tangential venous resection and 57 patients (32%) were submitted to pancreatectomy with segmental venous resection. After a median follow-up of 24 months, local recurrence was comparable between the two groups (tangential: n = 32/120, 26.7% versus segmental: n = 10/57, 17.5%; p = 0.58). The median DFS was 17 months (IQR 9-31) in patients who underwent tangential resection, as compared to 12 months (IQR 5-21) in those who underwent segmental resection (p = 0.049). After PSM (n = 106), the median DFS was 18 months (IQR 9-26) in the tangential resection group, and 12 months (IQR 5-21) in the segmental resection group (p = 0.17). In the PSM population, lymph node ratio (HR 4.83; p = 0.028) and tumor size >25 mm (HR 3.26; p = 0.007) were identified as determinants of local recurrence. CONCLUSION: Tangential venous resections are not associated with a higher rate of local recurrence. Long-term outcomes are more related to tumors characteristics than to venous resection techniques. A step-up approach to vein resection, with tangential resection being performed whenever technically feasible, should be strongly encouraged.

Prognostic Significance and Predictors of Nodal Recurrence After Surgery for Non-Functioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: The prognosis of nodal recurrence after surgery for non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) and its predictors have been poorly investigated. This study aimed to compare clinicopathologic features and survival between patients with nodal relapse and those with distant relapse and to identify predictors of nodal relapse after surgery for NF-PanNETs. METHODS: All patients (n = 321) submitted to surgery for NF-PanNETs were included. Nodal recurrence was defined as the presence of one or more enlarged LNs at high-quality radiologic examinations and always confirmed by 68Ga-DOTA-PET or biopsy. RESULTS: Altogether, 21 patients (6 %) experienced nodal (± distant) relapse, and 35 patients (11 %) had distant recurrence alone. Isolated nodal recurrence occurred for 23 % of patients with recurrence. Overall, 11 patients died of disease, one of whom (pT3N1G3) had an isolated nodal relapse. The rate of LN metastases (81 % vs 54 %; p = 0.044) and median number of positive LNs (PLN) (3 vs 0; p = 0.019) both were significantly higher for the patients with nodal (± distant) relapse than for those with distant relapse alone. Microvascular invasion (p = 0.046), T stage (p = 0.004), N stage (N1 [p = 0.049]; N2 [p = 0.001]), M stage (p < 0.001), and necrosis (p = 0.011) independently predicted nodal relapse. After distal pancreatectomy (n = 182), 13 patients experienced nodal recurrence, 9 of whom had left paraortic LNs involvement. DISCUSSION: Lymph nodes are not rare sites of recurrence after surgery for NF-PanNETs. Lymph node involvement is a powerful determinant of nodal relapse. Nodal relapse frequently involves LNs that are not removed during standard lymphadenectomy.

Prediction of the characteristics of aggressiveness of pancreatic neuroendocrine neoplasms (PanNENs) based on CT radiomic features.

OBJECTIVES: To predict tumor grade (G1 vs. G2/3), presence of distant metastasis (M+), metastatic lymph nodes (N+), and microvascular invasion (VI) of pancreatic neuroendocrine neoplasms (PanNEN) based on preoperative CT radiomic features (RFs), by applying a machine learning approach aimed to limit overfit. METHODS: This retrospective study included 101 patients who underwent surgery for PanNEN; the entire population was split into training (n = 70) and validation cohort (n = 31). Based on a previously validated methodology, after tumor segmentation on contrast-enhanced CT, RFs were extracted from unenhanced CT images. In addition, conventional radiological and clinical features were combined with RFs into multivariate logistic regression models using minimum redundancy and a bootstrap-based machine learning approach. For each endpoint, models were trained and validated including only RFs (RF_model), and both (radiomic and clinicoradiological) features (COMB_model). RESULTS: Twenty-five patients had G2/G3 tumor, 37 N+, and 14 M+ and 38 were shown to have VI. From a total of 182 RFs initially extracted, few independent radiomic and clinicoradiological features were identified. For M+ and G, the resulting models showed moderate to high performances: areas under the curve (AUC) for training/validation cohorts were 0.85/0.77 (RF_model) and 0.81/0.81 (COMB_model) for M+ and 0.67/0.72 and 0.68/0.70 for G. Concerning N+ and VI, only the COMB_model could be built, with poorer performance for N+ (AUC = 0.72/0.61) compared to VI (0.82/0.75). For all endpoints, the negative predictive value was good (≥ 0.75). CONCLUSIONS: Combining few radiomic and clinicoradiological features resulted in presurgical prediction of histological characteristics of PanNENs. Despite the limited risk of overfit, external validations are warranted. KEY POINTS: • Histology is the only tool currently available allowing characterization of PanNEN biological characteristics important for prognostic assessment; significant limitations to this approach exist. • Based upon preoperative contrast-enhanced CT images, a machine learning approach optimized to favor models' generalizability was successfully applied to train predictive models for tumor grading (G1 vs. G2/3), microvascular invasion, metastatic lymph nodes, and distant metastatic spread. • Moderate to high discriminative models (AUC: 0.67-0.85) based on few parameters (≤ 3) showing high negative predictive value (0.75-0.98) were generated and then successfully validated.

Infiltrative Growth Predicts the Risk of Recurrence After Surgery in Well-Differentiated Non-Functioning Pancreatic Neuroendocrine Tumors.

The incidence of well-differentiated non-functioning pancreatic neuroendocrine tumors (NF-PanNET) increased during the last decades. The risk of relapse after curative surgery, albeit low, is not negligible; moreover, adjuvant treatment is currently not an option and a reliable predictive model based on prognostic characteristics is urgently needed for tailoring a follow-up strategy. The histological classification of PanNET now relies only on the proliferative activity (mitosis and Ki67) and staging. In contrast to other endocrine neoplasms, the role of infiltrative growth pattern in NF-PanNET is not taken into consideration at present. In the current study, 247 consecutive patients who underwent surgical resection for a NF-PanNET were examined for the histological growth pattern of the tumor. Two distinct patterns (non-infiltrative vs. infiltrative) were described with the latter being further subclassified according to the type of structures invaded by the tumor (non-infiltrative: pattern 1; infiltration of adjacent pancreatic parenchyma and/or peripancreatic soft tissue: pattern 2; invasion of nearby organs and/or major vessels: pattern 3). The infiltrative growth resulted to be strongly associated with a poorer survival compared to a non-infiltrative growth (p < 0.001). In particular, the distinction between pancreatic parenchyma and/or peripancreatic soft tissue invasion versus adjacent organs and/or major vessels invasion was the most powerful predictor of recurrence after surgery at multivariate analysis (pattern 2 vs. pattern 1: HR 10.136, p = 0.028; pattern 3 vs. pattern 1: HR 15.775, p = 0.015). The infiltrative growth pattern could therefore provide additional prognostic information implementing the current grading and staging system.

Multidisciplinary management of patients diagnosed with von Hippel-Lindau disease: A practical review of the literature for clinicians.

Objective: The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance, treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau (VHL) syndrome. Methods: A non-systematic narrative review of original articles, meta-analyses, and randomized trials was conducted, including articles in the pre-clinical setting to support relevant findings. Results: VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma. Affected individuals inherit a germline mutation in one VHL allele, and any somatic event that disrupt the other allele can trigger mutations, chromosomal rearrangements, or epigenetic regulations leading to oncogenesis. From a clinical perspective, patients continuously develop multiple primary tumors. Conclusion: Because VHL is considered a rare disease, very limited evidence is available for diagnosis, surveillance, active treatment with local or systemic therapy and follow-up.

A Single-center Prospective Observational Study Investigating the Accuracy of Preoperative Diagnostic Procedures in the Assessment of Lymph Node Metastases in Nonfunctioning Pancreatic Neuroendocrine Tumors.

OBJECTIVE: To determine the accuracy of preoperative imaging, including contrast-enhanced computed tomography (CE-CT), endoscopic ultrasound (EUS), and 68 Gallium-DOTATOC positron emission tomography ( 68 Ga-DOTATOC PET), in identifying nodal metastases (N+) in sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). BACKGROUND: An accurate preoperative identification of N+ in NF-PanNETs is critical for surgical planning. The accuracy of different imaging techniques in detecting lymph node (LN) metastases in NF-PanNETs has been poorly investigated. METHODS: All consecutive patients undergoing surgery for sporadic NF-PanNETs (2018-2021) were enrolled in a prospective study (DETECTYON; NCT03918759). The accuracy of preoperative imaging techniques in detecting N+ was assessed through sensitivity, specificity positive and negative predictive values. RESULTS: Overall, 100 patients with NF-PanNETs underwent CE-CT, EUS, and 68 Ga-DOTATOC PET before pancreatic resection. LN metastases were found in 42 cases (42%). Sensitivity, specificity, positive predictive value, and negative predictive value of different imaging techniques were 26%, 95%, 79%, 64% for CE-CT, 19%, 98%, 89%, 63% for EUS, and 12%, 95%, 63%, 60% for 68 Ga-DOTATOC PET, respectively. Radiologic tumor size >4 cm and the presence of radiologic N+ at ≥1 imaging were independent predictors of N+ at pathology. The identification of N+ at ≥1 imaging technique was associated with a higher number of positive LNs compared with negative imaging (4 vs 2) ( P =0.012). CONCLUSIONS: CE-CT, EUS, and 68 Ga-DOTATOC PET are poorly sensitive in predicting nodal status in NF-PanNETs despite a high specificity.

Preoperative assessment of microvessel density in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs).

BACKGROUND: Hypervascularization is a typical feature of pancreatic neuroendocrine tumors, and it frequently allows their recognition at imaging studies. However, the density of microvessels in pancreatic neuroendocrine tumors changes according to their biological behavior, and a low microvessel density is associated with higher disease aggressiveness. The primary aim was to investigate the relationship between microvessel density and aggressiveness of nonfunctioning pancreatic neuroendocrine tumors. The secondary aim was to evaluate the ability of contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound in predicting tumor microvessel density. METHODS: The patients who underwent surgery for nonfunctioning pancreatic neuroendocrine tumors (n = 66) with an available preoperative contrast-enhanced computed tomography (n = 39) and/or contrast-enhanced endoscopic ultrasound (n = 37) performed at San Raffaele Hospital (2016-2020) were included. The tumor vascularization was assessed by CD-34 staining, contrast-enhanced computed tomography, and contrast-enhanced endoscopic ultrasound. Median microvessel density (165 microvessels/mm2) was chosen as the cutoff to define low microvessel density and high microvessel density. RESULTS: The patients with a low microvessel density showed a significantly higher frequency of nodal metastases (P = .026), G2-G3 tumors (P = .022), and death domain-associated protein/α-thalassemia/mental retardation syndrome X-linked loss (P = .011) compared to patients with high microvessel density. The contrast-enhanced computed tomography tumor density in the arterial phase was significantly higher in patients with high microvessel density compared to those with low microvessel density (P = .016). The patients with a low microvessel density showed a significantly higher frequency of contrast-enhanced endoscopic ultrasound arterial hypoenhancement (P = .042) and late washout (P = .034). Contrast-enhanced computed tomography arterial hypoenhancement (P = .007) and contrast-enhanced endoscopic ultrasound late washout (P = .048) independently predicted a low microvessel density in the patients who underwent contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound, respectively. CONCLUSION: A low microvessel density represents a marker of aggressiveness in the patients with nonfunctioning pancreatic neuroendocrine tumors. Contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound are reliable and easily available tools for preoperative assessment of microvessel density.

Duodenal Gastric Metaplasia and Duodenal Neuroendocrine Neoplasms: More Than a Simple Coincidence?

BACKGROUND: Duodenal gastric metaplasia (DGM) is considered a precancerous lesion. No data are available regarding its possible role as a risk factor for duodenal neuroendocrine neoplasms (dNENs). AIMS: To assess the prevalence of DGM in a cohort of dNENs. METHODS: Subgroup analysis of a retrospective study including dNEN patients who underwent surgical resection between 2000 and 2019 and were observed at eight Italian tertiary referral centers. RESULTS: 109 dNEN patients were evaluated. Signs of DGM associated with the presence of dNEN were reported in 14 patients (12.8%). Among these patients, nine (64.4%) had a dNEN of the superior part of the duodenum, one (7.1%) a periampullary lesion, three (21.4%) a dNEN located in the second portion of the duodenum, with a different localization distribution compared to patients without DGM (p = 0.0332). Ten were G1, three G2, and in one patient the Ki67 was not available. In the group with DGM, six patients (35.7%) were classified at stage I, five (28.6%) at stage II, three (21.4%) at stage III, and no one at stage IV. In the group without DGM, 20 patients (31%) were at stage I, 15 (15%) at stage II, 42 (44%) at stage III, and 19 (20%) at stage IV (p = 0.0236). At the end of the study, three patients died because of disease progression. CONCLUSIONS: our findings might suggest that DGM could represent a feature associated with the occurrence of dNEN, especially for forms of the superior part of the duodenum, which should be kept in mind in the endoscopic follow up of patients with DGM. Interestingly, dNEN inside DGM showed a more favorable staging, with no patients in stage IV. The actual relationship and the clinical relevance of this possible association require further clarification.

Survival after active surveillance versus upfront surgery for incidental small pancreatic neuroendocrine tumours.

BACKGROUND: The safety of observing small non-functioning pancreatic neuroendocrine tumours (NF-Pan-NETs) remains under debate. METHODS: This was a multicentre retrospective study of patients with small incidental NF-Pan-NETs. Survival of patients who underwent upfront surgery versus active surveillance was compared. The risk of death was matched with that in the healthy population. The excess hazard rate and probability of a normal lifespan (NLP) were calculated. Propensity score matching (PSM) with a 1 : 1 ratio was used to minimize the risk of selection bias. RESULTS: Some 222 patients (43.7 per cent) underwent upfront surgery and 285 (56.3 per cent) were observed. The excess hazard rate for the entire cohort was quantifiable as 0.04 (95 per cent c.i. 0 to 0.08) deaths per 1000 persons per year, and the NLP was 99.7 per cent. Patients in the active surveillance group were older (median age 65 versus 58 years; P < 0.001), and more often had co-morbidity (45.3 versus 24.8 per cent; P = 0.001), and smaller tumours (median 12 versus 13 mm; P < 0.001), less frequently located in the pancreatic body-tail (59.5 versus 69.6 per cent; P = 0.008, 59.3 versus 73.9 per cent; P = 0.001). Median follow-up was longer for patients who underwent upfront surgery (5.6 versus 2.7 years; P < 0.001). After PSM, 118 patients per group were included. The excess hazard rates were 0.2 and 0.9 deaths per 1000 persons per year (P = 0.020) for patients in the active surveillance and upfront surgery groups respectively. Corresponding NLPs were 99.9 and 99.5 per cent respectively (P = 0.011). CONCLUSION: Active surveillance of small incidental NF-Pan-NETs is a reasonable alternative to resection.