Critical updates in neuroendocrine tumors: Version 9 American Joint Committee on Cancer staging system for gastroenteropancreatic neuroendocrine tumors.

The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP-NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP-NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP-NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP-NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP-NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.

DNA Methylation Profiling Enables Accurate Classification of Nonductal Primary Pancreatic Neoplasms.

BACKGROUND & AIMS: Cytologic and histopathologic diagnosis of non-ductal pancreatic neoplasms can be challenging in daily clinical practice, whereas it is crucial for therapy and prognosis. The cancer methylome is successfully used as a diagnostic tool in other cancer entities. Here, we investigate if methylation profiling can improve the diagnostic work-up of pancreatic neoplasms. METHODS: DNA methylation data were obtained for 301 primary tumors spanning 6 primary pancreatic neoplasms and 20 normal pancreas controls. Neural Network, Random Forest, and extreme gradient boosting machine learning models were trained to distinguish between tumor types. Methylation data of 29 nonpancreatic neoplasms (n = 3708) were used to develop an algorithm capable of detecting neoplasms of non-pancreatic origin. RESULTS: After benchmarking 3 state-of-the-art machine learning models, the random forest model emerged as the best classifier with 96.9% accuracy. All classifications received a probability score reflecting the confidence of the prediction. Increasing the score threshold improved the random forest classifier performance up to 100% with 87% of samples with scores surpassing the cutoff. Using a logistic regression model, detection of nonpancreatic neoplasms achieved an area under the curve of >0.99. Analysis of biopsy specimens showed concordant classification with their paired resection sample. CONCLUSIONS: Pancreatic neoplasms can be classified with high accuracy based on DNA methylation signatures. Additionally, non-pancreatic neoplasms are identified with near perfect precision. In summary, methylation profiling can serve as a valuable adjunct in the diagnosis of pancreatic neoplasms with minimal risk for misdiagnosis, even in the pre-operative setting.

Subgrading of G2 Pancreatic Neuroendocrine Tumors as 2A (Ki67 3% to < 10%) Versus 2B (10% to ≤ 20%) Identifies Behaviorally Distinct Subsets in Keeping with the Evolving Management Protocols.

BACKGROUND: Grade 1/2 PanNETs are mostly managed similarly, typically without any adjunct treatment with the belief that their overall metastasis rate is low. In oncology literature, Ki67-index of 10% is increasingly being used as the cutoff in stratifying patients to different protocols, although there are no systematic pathology-based studies supporting this approach. METHODS: Ki67-index was correlated with clinicopathologic parameters in 190 resected PanNETs. A validation cohort (n = 145) was separately analyzed. RESULTS: In initial cohort, maximally selected rank statistics method revealed 12% to be the discriminatory cutoff (close to 10% rule of thumb). G2b cases had liver/distant metastasis rate of almost threefold higher than that of G2a and showed significantly higher frequency of all histopathologic signs of aggressiveness (tumor size, perineural/vascular invasion, infiltrative growth pattern, lymph node metastasis). In validation cohort, these figures were as striking. When all cases were analyzed together, compared with G1, the G2b category had nine times higher liver/distant metastasis rate (6.1 vs. 58.5%; p < 0.001) and three times higher lymph node metastasis rate (20.5 vs. 65.1%; p < 0.001). CONCLUSIONS: G2b PanNETs act very similar to G3, supporting management protocols that regard them as potential therapy candidates. Concerning local management, metastatic behavior in G2b cases indicate they may not be as amenable for conservative approaches, such as watchful waiting or enucleation. This substaging should be considered into diagnostic guidelines, and clinical trials need to be devised to determine the more appropriate management protocols for G2b (10% to ≤ 20%) group, which shows liver/distant metastasis in more than half of the cases, which at minimum warrants closer follow-up.

Accuracy and Prognostic Impact of Nodal Status on Preoperative Imaging for Management of Pancreatic Neuroendocrine Tumors: A Multi-Institutional Study.

BACKGROUND: We sought to define the accuracy of preoperative imaging to detect lymph node metastasis (LNM) among patients with pancreatic neuroendocrine tumors (pNETs), as well as characterize the impact of preoperative imaging nodal status on survival. METHODS: Patients who underwent curative-intent resection for pNETs between 2000 and 2020 were identified from eight centers. Sensitivity and specificity of computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET)-CT, and OctreoScan for LNM were evaluated. The impact of preoperative lymph node status on lymphadenectomy (LND), as well as overall and recurrence-free survival was defined. RESULTS: Among 852 patients, 235 (27.6%) individuals had LNM on final histologic examination (hN1). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 12.4%, 98.1%, 71.8%, and 74.4% for CT, 6.3%, 100%, 100%, and 80.1% for MRI, 9.5%, 100%, 100%, and 58.7% for PET, 11.3%, 97.5%, 66.7%, and 70.8% for OctreoScan, respectively. Among patients with any combination of these imaging modalities, overall sensitivity, specificity, PPV, and NPV was 14.9%, 97.9%, 72.9%, and 75.1%, respectively. Preoperative N1 on imaging (iN1) was associated with a higher number of LND (iN1 13 vs. iN0 9, p = 0.003) and a higher frequency of final hN1 versus preoperative iN0 (iN1 72.9% vs. iN0 24.9%, p < 0.001). Preoperative iN1 was associated with a higher risk of recurrence versus preoperative iN0 (median recurrence-free survival, iN1→hN1 47.5 vs. iN0→hN1 92.7 months, p = 0.05). CONCLUSIONS: Only 4% of patients with LNM on final pathologic examine had preoperative imaging that was suspicious for LNM. Traditional imaging modalities had low sensitivity to determine nodal status among patients with pNETs.

Heterogeneity of Multiple Pancreatic Neuroendocrine Tumors Identified by 68Ga-DOTANOC and 68Ga-Exendin-4 PET/CT in a Patient with Endogenous Hyperinsulinemic Hypoglycemia and Multiple Endocrine Neoplasia 1.

INTRODUCTION: Insulinomas are the most frequent functional pancreatic neuroendocrine tumors. In about 10% of cases, insulinomas are associated with hereditary syndromes, including multiple endocrine neoplasia 1 (MEN1). CASE PRESENTATION: Herein, we present a 44-year-old female with recurrent hypoglycemia. In December 1998, this patient underwent resection of two pancreatic lesions due to hypoglycemia and was diagnosed with insulinoma. After the operation, the symptoms of hypoglycemia disappeared. However, from 2021, hypoglycemic symptoms reappeared frequently, as did coma. In June 2023, enhanced CT showed multiple pancreatic lesions abundant with blood supply. Fasting serum blood glucose and insulin were 1.73 mmol/L and 15.2 U/L (2.6-11.8 U/L). Germline genes suggested MEN1 pathogenic mutations. 68Ga-DOTANOC PET/CT indicated there were multiple lesions located in the pancreas and duodenum with high expression of the somatostatin receptor (SSTR). 68Ga-exendin-4 PET/CT was added to localize the insulinoma. Most lesions with high expression of SSTR in the body and tail of the pancreas manifested parts of them with high uptake of 68Ga-exendin-4, and an additional lesion with high expression of glucagon-like peptide-1 receptor (GLP-1R) was only detected by 68Ga-exendin-4 PET/CT. It showed inter-tumor heterogeneity in the expression of SSTR and GLP-1R. From the distal pancreatectomy, a total of 5 tumors were found in the body and tail of the pancreas, which were diagnosed as neuroendocrine tumors (NETs). After the operation, all the symptoms related to hypoglycemia disappeared. Immunohistochemical results of SSTR2 and insulin were consistent with the imaging findings of dual-tracer PET/CT. CONCLUSION: From this case, a combination of 68Ga-DOTANOC and 68Ga-exendin-4 PET/CT was recommended in the patients with MEN1 and insulinoma to estimate the heterogeneity of multiple neuroendocrine tumors that contribute to detect all the NET lesions and locate the tumors with secretion of insulin.

Incidence and Prognostic Implications of Lymphovascular Invasion in Node-Negative Pancreatic Neuroendocrine Tumors: Results From the US Neuroendocrine Study Group.

BACKGROUND: Despite the well-known prognostic role of lymph node metastasis (LNM) in pNETs, less is known about the importance of lymphovascular invasion (LVI) among patients with these tumors. METHODS: Patients undergoing pancreatectomy for pNET between 2002 and 2020 were identified in the US Neuroendocrine Tumor Study Group database. Cox regression analysis was utilized to identify the impact of LVI on recurrence-free survival (RFS) among patients with node-negative pNET. RESULTS: Among 853 patients who underwent resection for pNET, 214 patients (25.1%) had LNM, while 116 (13.6%) and 523 individuals (61.3%) were LVI + N0 and LVI - N0, respectively. The overall incidence of LVI among patients with N0 pNET was 18.1%; the incidence of LVI increased with increasing tumor size and Ki-67 levels (size < 2 cm and Ki-67 < 3%: 5.5%; size < 2 cm and Ki-67 ≥ 3%: 17.2%; size ≥ 2 cm and Ki-67 < 3%: 22.2%; size ≥ 2 cm and Ki-67 ≥ 3%: 43.1%, p < 0.001). Five-year RFS was highest among patients with LVI - N0 disease followed by individuals with LVI + N0 and N+ pNETs (92.8% vs. 61.6% vs. 58.3%, p < 0.001). On multivariable analysis, the presence of LVI on pathology remained independently associated with almost 2.5 times higher hazards of recurrence (HR 2.47, 05% CI 1.44-4.24) among individuals with N0 pNETs. CONCLUSION: The incidence of LVI varied according to tumor size and Ki-67. LVI was associated with a higher likelihood of recurrence among individuals who underwent formal pancreatic resection for N0 pNETs. LVI is an important prognostic indicator among patients with node-negative pNETs.

Oncogenic pathway signatures predict the risk of progression and recurrence in well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are genomically diverse tumors. The management of newly diagnosed well-differentiated pNETs is limited by a lack of sensitivity of existing biomarkers for prognostication. Our goal was to investigate the potential utility of genetic markers as a predictor of progression-free survival (PFS) and recurrence-free survival (RFS). METHODS: Whole-exome sequencing of resected well-differentiated, low and intermediate-grade (G1 and G2) pNETs and normal adjacent tissue from patients who underwent resection from 2005 to 2015 was performed. Genetic alterations were classified using pan-genomic and oncogenic pathway classifications. Additional samples with genetic and clinicopathologic data available were obtained from the publicly available International Cancer Genome Consortium (ICGC) database and included in the analysis. The prognostic relevance of these genomic signatures on PFS and RFS was analyzed. RESULTS: Thirty-one patients who underwent resection for pNET were identified. Genomic analysis of mutational, copy number, cytogenetic, and complex phenomena revealed similar patterns to prior studies of pNETs with relatively few somatic gene mutations but numerous instances of copy number changes. Analysis of genomic and clinicopathologic outcomes using the combined data from our study as well as the ICGC pNET cohort (n = 124 patients) revealed that the recurrent pattern of whole chromosome loss (RPCL) and metastatic disease were independently associated with disease progression. When evaluating patients with local disease at the time of resection, RPCL and alterations in the TGFß oncogenic pathway were independently associated with the risk of recurrence. CONCLUSIONS: Well-differentiated pNETs are genomically diverse tumors. Pathway signatures may be prognostic for predicting disease progression and recurrence.

Multicenter validation study of a treatment selection MAP for pancreatic neuroendocrine tumors.

BACKGROUND: Somatostatin analogs, molecular-targeted agents and cytotoxic anticancer agents are available as therapeutic agents for the systemic treatment of pancreatic neuroendocrine tumors, and we have developed a first-line treatment selection MAP to enable selection of the optimal treatment strategy for pancreatic neuroendocrine tumors. The purpose of this study was to validate the usefulness of the treatment selection MAP. METHODS: Patients who had received systemic therapy for a pancreatic neuroendocrine tumor between January 2017 and December 2020 were compared according to whether they had been treated as recommended by the MAP (matched patients) or not (unmatched patients) to determine whether better outcomes were achieved by the matched patients. The primary endpoint was progression-free survival of the matched group and unmatched groups in the somatostatin analog, molecular-targeted agent and cytotoxic anticancer agents areas of the MAP. RESULTS: There were 41 (55%) MAP-matched patients in all areas among the 74 patients registered at seven hospitals. The MAP-matched rates were 100, 77 and 38% in the somatostatin analog area, molecular-targeted agent area and cytotoxic anticancer agents area, respectively. All of the unmatched patients had been selected for less intensive treatment. The median progression-free survival in the matched group and unmatched group in the molecular-targeted agent area of the MAP were 46.6 and 15.4 months, respectively, and a multivariate analysis identified MAP-matched (hazard ratio 0.18 [95% confidence interval: 0.04-0.87], P = 0.032) as the only significant independent favorable predictive factor. CONCLUSION: The usefulness of the MAP for treatment selection was validated in the molecular-targeted agent area of the MAP.

Special issue "The advance of solid tumor research in China": Prediction of Sunitinib efficacy using computed tomography in patients with pancreatic neuroendocrine tumors.

Clinically effective methods to predict the efficacy of sunitinib, for patients with metastatic or locally advanced pancreatic neuroendocrine tumors (panNET) are scarce, making precision treatment difficult. This study aimed to develop and validate a computed tomography (CT)-based method to predict the efficacy of sunitinib in patients with panNET. Pretreatment CT images of 171 lesions from 38 patients with panNET were included. CT value ratio (CT value of tumor/CT value of abdominal aorta from the same patient) and radiomics features were extracted for model development. Receiver operating curve (ROC) with area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the proposed model. Tumor shrinkage of >10% at first follow-up after sunitinib treatment was significantly associated with longer progression-free survival (PFS; P < .001) and was used as the major treatment outcome. The CT value ratio could predict tumor shrinkage with AUC of 0.759 (95% confidence interval [CI], 0.685-0.833). We then developed a radiomics signature, which showed significantly higher AUC in training (0.915; 95% CI, 0.866-0.964) and validation (0.770; 95% CI, 0.584-0.956) sets than CT value ratio. DCA also confirmed the clinical utility of the model. Subgroup analysis showed that this radiomics signature had a high accuracy in predicting tumor shrinkage both for primary and metastatic tumors, and for treatment-naive and pretreated tumors. Survival analysis showed that radiomics signature correlated with PFS (P = .020). The proposed radiomics-based model accurately predicted tumor shrinkage and PFS in patients with panNET receiving sunitinib and may help select patients suitable for sunitinib treatment.

Long-Term Outcomes of Tuberous Sclerosis Complex-Associated Non-functional Pancreatic Neuroendocrine Tumors: Should We Be More Conservative?

BACKGROUND: Hereditary syndromes such as tuberous sclerosis complex (TSC) account for 10% of pancreatic neuroendocrine tumors (PNETs). Surgical intervention is the current standard of care for sporadic PNETs (spPNETs) that are >2 cm in size. We compared the long-term outcomes of resected TSC-PNETs with patients with spPNETs. METHODS: We conducted a retrospective review of perioperative data and outcomes of TSC-PNETs compared with spPNETs. Inclusion criteria involved selecting patients whose tumors were no larger than 5.1 cm, the maximum size observed in the TSC-PNET group. RESULTS: Of the 347 patients resected for PNETs, 14 were TSC-PNETs and 241 were non-functional spPNETs. The median age for the whole cohort was 56 years (interquartile range [IQR] 21.0) and 47% were female. The median follow-up was 103.8 months (95% confidence interval [CI] 89.2-118.6). Specifically, 14 patients with TSC-PNETs and 194 patients with spPNETs were included. Compared with spPNETs, patients with TSC-PNETs were operated on at a younger age (24.0 vs. 57.5 years; p < 0.001), were more frequently multifocal (28.5% vs. 0.0%; p < 0.001), were more likely to undergo minimally invasive operations (78.6% vs. 24.3%; p < 0.001), and had more R1 resections (28.6% vs. 5.7%; p = 0.006). Local and distant tumor recurrence was only observed in the spPNET group. The 5-year mortality rates for the spPNET and TSC-PNET groups were 6.2% and 0.0%, respectively. No PNET-related deaths were observed among TSC-PNETs. CONCLUSION: None of the TSC-PNET patients recurred after a median follow-up of 78.0 months. The risk-benefit of aggressive pancreatic operations in TSC-PNET patients is still unclear and our findings suggest a conservative approach should be considered.

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.

Two machine learning-based nomogram to predict risk and prognostic factors for liver metastasis from pancreatic neuroendocrine tumors: a multicenter study.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are one of the most common endocrine tumors, and liver metastasis (LMs) are the most common location of metastasis from PNETS; However, there is no valid nomogram to predict the diagnosis and prognosis of liver metastasis (LMs) from PNETs. Therefore, we aimed to develop a valid predictive model to aid physicians in making better clinical decisions. METHODS: We screened patients in the Surveillance, Epidemiology, and End Results (SEER) database from 2010-2016. Feature selection was performed by machine learning algorithms and then models were constructed. Two nomograms were constructed based on the feature selection algorithm to predict the prognosis and risk of LMs from PNETs. We then used the area under the curve (AUC), receiver operating characteristic (ROC) curve, calibration plot and consistency index (C-index) to evaluate the discrimination and accuracy of the nomograms. Kaplan-Meier (K-M) survival curves and decision curve analysis (DCA) were also used further to validate the clinical efficacy of the nomograms. In the external validation set, the same validation is performed. RESULTS: Of the 1998 patients screened from the SEER database with a pathological diagnosis of PNET, 343 (17.2%) had LMs at the time of diagnosis. The independent risk factors for the occurrence of LMs in PNET patients included histological grade, N stage, surgery, chemotherapy, tumor size and bone metastasis. According to Cox regression analysis, we found that histological subtype, histological grade, surgery, age, and brain metastasis were independent prognostic factors for PNET patients with LMs. Based on these factors, the two nomograms demonstrated good performance in model evaluation. CONCLUSION: We developed two clinically significant predictive models to aid physicians in personalized clinical decision-makings.

The Ki67 index evaluation of pancreatic neuroendocrine tumors using 3D immunohistochemistry in small tissue specimens.

BACKGROUND: /Objectives: This study aimed to evaluate the usefulness of three-dimensional (3D) immunohistochemistry for the Ki67 index of small tissue specimens of pancreatic neuroendocrine tumor (PanNET). METHODS: Clinicopathological materials from 17 patients with PanNET who underwent surgical resection at Jichi Medical University Hospital were analyzed. We compared the Ki67 index of endoscopic ultrasonography-fine-needle aspiration biopsy (EUS-FNAB) specimens, surgical specimens, and small tissue specimens hollowed from paraffin blocks of surgical specimens that were substituted for EUS-FNAB specimens ("sub-FNAB"). The sub-FNAB specimens were optically cleared using LUCID (IlLUmination of Cleared organs to IDentify target molecules) and analyzed using 3D immunohistochemistry. RESULTS: The median Ki67 index in FNAB, sub-FNAB, and surgical specimens with conventional immunohistochemistry were 1.2% (0.7-5.0), 2.0% (0.5-14.6), and 5.4% (1.0-19.4), respectively. The median Ki67 index in sub-FNAB specimens with tissue clearing was calculated separately using the total number of cells on multiple images ("multiple slice"), with the image of the fewest positive cells ("coldspot"), and with the image of most positive cells ("hotspot"), which were 2.7% (0.2-8.2), 0.8% (0-4.8), and 5.5% (2.3-12.4), respectively. PanNET grade evaluated for the hotspot of the surgical specimens was significantly more consistent with those of the hotspot than multiple images of sub-FNAB specimens (16/17 vs. 10/17, p = 0.015). Hotspot evaluation using 3D immunohistochemistry of the sub-FNAB specimens showed agreement with the assessment of the surgical specimens (Kappa coefficient: 0.82). CONCLUSIONS: Tissue clearing and 3D immunohistochemistry for the Ki67 index can potentially improve the preoperative evaluation of EUS-FNAB specimens of PanNET in routine clinical practice.

Efficacy and predictive factors of endoscopic ultrasound-guided ethanol ablation in benign solid pancreatic tumors.

BACKGROUNDS AND OBJECTIVES: Endoscopic ultrasound-guided ethanol ablation (EUS-EA) has recently been introduced for the management of solid pancreatic tumors, including pancreatic neuroendocrine tumors (PNETs) and solid pseudopapillary tumors (SPTs). The study aims to evaluate the efficacy and predictive factors for response of EUS-EA in solid pancreatic tumors. METHODS: Between October 2015 and July 2021, 72 patients who underwent EUS-EA for solid pancreatic tumors were included. The study outcomes were to evaluate the efficacy of EUS-EA with complete remission (CR) and objective response, and their predictive factors. RESULTS: During follow-up, 47 patients were diagnosed with PNETs and 25 with SPTs. Eight cases reached CR and 48 reached objective response. When compared with SPTs, PNETs showed similar duration to reach CR (median not reached; p = 0.319), but shorter duration to reach objective response (PNETs: median 20.6 months, 95%CI 10.26-30.88; SPTs: median 47.7 months, 95%CI 18.14-77.20; p = 0.018). Ethanol dosage > 0.35 ml/cm3 shortened the duration to reach CR (median not reached; p = 0.026) and objective response (median 42.5 months, 95%CI 25.34-59.66 vs. 19.6 months, 95%CI 10.17-29.09; p = 0.006). CR had no significant predictive factors, but PNETs showed significant predictive factors for objective response (HR 3.34, 95%CI 1.07-10.43; p = 0.038). Twenty-seven patients experienced adverse events, and there were two severe cases. CONCLUSION: EUS-EA for pancreatic solid lesions seems feasible as a local treatment for patients who refuse or are unfit for surgery. Additionally, PNETs seem to be the better candidate for EUS-EA.

FAM83A promotes the progression and metastasis of human pancreatic neuroendocrine tumors by inducing the epithelial-mesenchymal transition via the PI3K/AKT and ERK pathways.

PURPOSE: Family with sequence similarity 83, member A (FAM83A) has been reported to play an important role in cancer progression and metastasis. The purpose of this study was to clarify the role and mechanism of FAM83A in pancreatic neuroendocrine tumors (PanNETs). METHODS: PanNET specimens and adjacent nontumor pancreatic tissues obtained from 68 patients who underwent curative surgery for PanNETs were assessed for FAM83A expression using immunochemical staining. The relationships between FAM83A expression, clinicopathological parameters and prognosis were statistically analyzed. PanNET cell lines were used to study the role of FAM83A in the progression and metastasis of PanNETs in vitro and in vivo. RESULTS: FAM83A was overexpressed in PanNET specimens compared with adjacent nontumor tissues. Furthermore, FAM83A expression was closely associated with lymph node metastasis (P = 0.02), perineural invasion (P = 0.001), WHO classification (P = 0.039), AJCC stage (P = 0.01) and shorter disease-free survival in patients with PanNETs (P < 0.001). FAM83A overexpression effectively promoted PanNET cell proliferation, migration, invasion and growth both in vitro and in vivo, whereas FAM83A inhibition exerted the opposite effects. Subsequent mechanistic investigations revealed that FAM83A promotes the progression and metastasis of PanNETs by inducing epithelial-mesenchymal transition (EMT) via the PI3K/AKT and ERK pathways. CONCLUSIONS: FAM83A plays an important role in the progression and metastasis of PanNET by inducing the EMT via the activation of the ERK and PI3K/AKT pathways and may serve as a valuable molecular target in PanNET treatment.

Pancreatoblastoma in an elderly woman: A case report simulating a pancreatic neuroendocrine tumour with emphasis on cytomorphological features.

Pancreatoblastoma (PB), a rare malignant epithelial neoplasm, is the most common pancreatic neoplasm of childhood. It is exceptionally rare in the adult population and its occurrence is limited to case reports. Although the neoplastic cells of PB can have a number of different directions of differentiation, PB is defined by the combination of neoplastic cells with acinar differentiation and squamoid morules. We report a case of a female patient in her 70s who presented with elevated creatinine level, concerning a kidney disorder, and was found to have an abdominal mass on CT scan. Fine needle aspiration (FNA) showed cellular smears with numerous 3-dimentional clusters of acinar cells and scattered squamoid morules. A cell block showed sheets of cells, some of which formed acini. Numerous squamoid morules were noted and were highlighted by nuclear labelling with antibodies to B-catenin in the cell block. The FNA diagnosis was rendered as "carcinoma with acinar differentiation, favour pancreatoblastoma." Subsequent histological findings confirmed the PB diagnosis. Next generation sequencing detected a CTNNB1 mutation. Given the wide usage of FNA in the preoperative diagnosis of pancreatic masses, the cytopathologist needs to be aware of the morphological features of PB and its cytological differential diagnosis, even in an elderly patient. The differential diagnosis includes acinar cell carcinoma, pancreatic neuroendocrine tumour, and solid pseudopapillary neoplasm. In conclusion, the cytological finding of neoplastic cells with acinar differentiation combined with squamous morules and/or mesenchymal elements in the smears and more commonly in the cell blocks appears to be the most specific finding for the diagnosis of PB.

Transarterial chemoembolization for liver metastases of a pancreatic neuroendocrine neoplasm: a single-center experience.

Transarterial chemoembolization (TACE) is performed for pancreatic neuroendocrine tumor (PanNEN) liver metastases; however, the safety and efficacy of TACE procedures, especially for patients who have undergone previous pancreatic surgery, have not been established. We reviewed 48 TACE procedures (1-6 procedures/patient) performed on 11 patients with PanNEN liver metastases, including 16 TACE procedures (4-6 procedures/patient) for 3 patients with a history of biliary-enteric anastomosis. The overall tumor objective response rate was 94%. The incidence of Clavien‒Dindo grade ≥ 2 complications was 1/16 (6%) and 1/32 (3%), and the median time to untreatable progression was 31 (14-41) and 27 (2-60) months among patients with and without a history of biliary-enteric anastomosis, respectively. Although validation is needed in future studies, our experiences have shown that TACE treatment is a viable treatment option for PanNEN liver metastases, even after biliary-enteric anastomosis with experienced teams and careful patient follow-up.

The Expression of Autophagy-Associated Genes Represents a Valid Footprint for Aggressive Pancreatic Neuroendocrine Neoplasms.

Pancreatic neuroendocrine neoplasms (pNEN) are rare and heterogeneous tumors. Previous investigations have shown that autophagy can be a target for cancer therapy. This study aimed to determine the association between the expression of autophagy-associated gene transcripts and clinical parameters in pNEN. In total, 54 pNEN specimens were obtained from our human biobank. The patient characteristics were retrieved from the medical record. RT-qPCR was performed to assess the expression of the autophagic transcripts BECN1, MAP1LC3B, SQSTM1, UVRAG, TFEB, PRKAA1, and PRKAA2 in the pNEN specimens. A Mann-Whitney U test was used to detect differences in the expression of autophagic gene transcripts between different tumor characteristics. This study showed that G1 sporadic pNEN have a higher expression of autophagic genes compared to G2. Lymphatic and distant metastasis occurred significantly more often in pNEN with a decreased expression of the autophagic genes. Within sporadic pNEN, the insulinomas express higher levels of autophagic transcripts than gastrinomas and non-functional pNEN. MEN1-associated pNEN show a higher expression of autophagic genes than sporadic pNEN. In summary, a decreased expression of autophagic transcripts distinguishes metastatic from non-metastatic sporadic pNEN. The significance of autophagy as a molecular marker for prognosis and therapy decisions needs to be further investigated.

A MODEL TO PREDICT DIAGNOSIS OF PANCREATIC NEUROENDOCRINE TUMORS BASED ON EUS IMAGING FEATURES.

Background: This study aimed to determine predictive clinical and endoscopic ultrasound (EUS) features for pancreatic neuroendocrine tumor (PNET) diagnosis, utilizing EUS-guided tissue acquisition. Methods: A prospective study from 2018-2022 included patients with pancreatic masses undergoing EUS with elastography. Univariate binomial logistic regression followed by multiple logistic regression with significant predictors was employed. A forward selection algorithm identified optimal models based on predictor numbers. Variables encompassed EUS tumor characteristics (e.g., location, size, margins, echogenicity, vascularity on Doppler, main pancreatic duct dilation, elastography appearance, vascular invasion, and hypoechoic rim), alongside demographic and risk factors (smoking, alcohol, diabetes). Results: We evaluated 165 patients (24 PNETs). EUS features significantly linked with PNET diagnosis were well-defined margins (79% vs. 26%, p < 0.001), blue elastography appearance (46% vs. 9.9%, p < 0.001), vascularization (67% vs. 25%, p < 0.001), hypoechoic rim (46% vs. 10%, p < 0.001). The top-performing model, with 89.1% accuracy, included two predictors: a homogeneous lesion (OR, 95% CI) and a hypoechoic rim (OR, 95% CI). Conclusions: EUS appearance can differentiate PNETs from non-PNETs, with the hypoechoic rim being an independent predictor of PNET diagnosis. The most effective predictive model for PNETs combined the homogeneous lesion and presence of the hypoechoic rim.

Multimodal 3-D/2-D human islet and duct imaging in exocrine and endocrine lesion environment: associated pancreas tissue remodeling.

Pancreatic intraepithelial neoplasia (PanIN) and islet cell microadenoma are exocrine and endocrine neoplasms of human pancreas that have been linked to pancreatic ductal adenocarcinoma (PDAC) and neuroendocrine tumor, respectively. However, in health and at the surgical margin of pancreatic cancer, it remains unresolved how to simultaneously characterize duct and islet remodeling to investigate the exocrine-endocrine association in the lesion microenvironment. Here, we develop a new vibratome-based approach to detect, confirm, and analyze the two types of pancreas remodeling via stereo/three-dimensional (3-D) and classic/two-dimensional (2-D) histology. Surgical margins of PDAC (n = 10, distal) and cadaveric donor pancreases (n = 10, consecutive cases) were fixed, sectioned by vibratome (350 µm), and surveyed for PanIN and microadenoma via stereomicroscopy. After lesion detection, PanIN and microadenoma were analyzed with 3-D fluorescence imaging and clinical microtome-based histology for confirmation and assessment of microenvironment. Multimodal imaging of PDAC surgical margins and cadaveric donor pancreases detected the peri-PanIN islet aggregation with duct-islet cell clusters. Organ-wide survey of cadaveric donor pancreases shows a marked 2.3-fold increase in the lesion size with the PanIN-islet association vs. without the association. In the survey, we unexpectedly detected the islet cell microadenoma adjacent to (<2 mm) PanIN. Overall, among the 53 early lesions in the cadaveric donor pancreases (PanINs and microadenomas), 81% are featured with the associated exocrine-endocrine tissue remodeling. Multimodal 3-D/2-D tissue imaging reveals local and simultaneous duct and islet remodeling in the cancer surgical margin and cadaveric donor pancreas. In the cadaveric donor pancreas, the peri-PanIN islet aggregation and PanIN-microadenoma association are two major features of pancreas remodeling in the early lesion microenvironment.NEW & NOTEWORTHY We develop a new multimodal 3-D/2-D imaging approach (matched stereomicroscopic, fluorescence, and H&E signals) to examine human duct-islet association in the PDAC surgical margin and cadaveric donor pancreas. In both conditions, peri-PanIN islet aggregation with duct-islet cell clusters was identified. The PanIN-islet cell microadenoma association was unexpectedly detected in the donor pancreas. Our work provides the technical and morphological foundations to simultaneously characterize human islets and ducts to study their association in health and disease.