Update on surgical treatment of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PNENs) are rare and account for only 2%-4% of all pancreatic neoplasms. All PNENs are potential(neurendocrine tumors PNETs) or overt(neuroendocrine carcinomas PNECs) malignant,but a subset of PNETs is low-risk. Even in case of low-risk PNETs surgical resection is frequently required to treat hormone-related symptoms and to obtain an appropriate pathological diagnosis. Low-risk PNETs in the body and the tail are ideal for minimallyinvasive approaches which should be tailored to the individual patient. Generally,surgeons must aim for parenchyma sparing in these cases. In high-risk and malignant PNENs,indications for tumor resection are much wider than for pancreatic adenocarcinoma,in many cases due to the relatively benign tumor biology. Thus,patients with locally advanced and metastatic PNETs may benefit from extensive resection. In experienced hands,even multi-organ resections are accomplished with acceptable perioperative morbidity and mortality rates and are associated with excellent long term survival. However,poorly differentiated neoplasms with high proliferation rates are associated with a dismal prognosis and may frequently only be treated with chemotherapy. The evidence on surgical treatment of PNENs stems from reviews of mostly singlecenter series and some analyses of nation-wide tumor registries. No randomized trial has been performed to compare surgical and non-surgical therapies in potentially resectable PNEN. Though such a trial would principally be desirable,ethical considerations and the heterogeneity of PNENs preclude realization of such a study. In the current review,we summarize recent advances in the surgical treatment of PNENs.

Advances in medical treatment for pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(PanNENs)are rare neoplasms with strong heterogeneity that have experienced an increasing incidence rate in recent years.For patients with locally advanced or distant metastatic PanNENs,systemic treatment options vary due to the different differentiations,grades and stages.The available options for systemic therapy include somatostatin analogs,molecularly targeted agents,cytotoxic chemotherapeutic agents,immune checkpoint inhibitors,and peptide receptor radionuclide therapy.In addition,the development of novel molecularly targeted agents is currently in progress.The sequence of selection between different chemotherapy regimens has been of great interest,and resistance to chemotherapeutic agents is the major limitation in their clinical application.Novel agents and high-level clinical evidence continue to emerge in the field of antiangiogenic agents.Peptide receptor radionuclide therapy is increasingly employed for the treatment of advanced neuroendocrine tumors,and greater therapeutic efficacy may be achieved by emerging radiolabeled peptides.Since immune checkpoint inhibitor monotherapies for PanNENs appear to have limited antitumor activity,dual immune checkpoint inhibitor therapies or combinations of antiangiogenic therapies and immune checkpoint inhibitors have been applied in the clinic to improve clinical efficacy.Combining the use of a variety of agents with different mechanisms of action provides new possibilities for clinical treatments.In the future,the study of systemic therapies will continue to focus on the screening of the optimal benefit population and the selection of the best treatment sequence strategy with the aim of truly achieving individualized precise treatment of PanNENs.

Risk factors for lymph node metastasis in patients with pancreatic neuroendocrine neoplasms

BACKGROUND Although PNENs generally have a better prognosis than pancreatic cancers,some PNENs display malignant behavior including lymph node(LN)metastasis.Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs.However,the indications for LN dissection are still controversial.Over the last decade,minimally invasive surgery such as laparoscopic pancreatic surgery(LPS)has been increasingly performed for pancreatic tumors including PNENs.AIM To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS.METHODS From April 2001 to December 2019,92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital.Finally,82 patients were enrolled in this study.Using perioperative factors,we examined the predictive factors for LN metastasis in PNENs.RESULTS Among the 82 patients,the percentage of LN metastasis according to the pathological findings was 12%(10/82 cases).The median tumor size was 12 mm(range:5-90 mm).The median tumor size in the LN-positive group(37 mm)was significantly larger than that in the LN-negative group(12 mm)(P=0.0001).Multivariate analyses revealed that larger tumor size(≥20 mm)was an independent risk factor for LN metastasis(odds ratio 16.8,P=0.0062).In patients with small tumors(≤10 mm),LN metastasis was not found.CONCLUSION Larger tumor size(≥20 mm)is an independent risk factor for LN metastasis in PNENs.In smaller PNENs(≤10 mm),we may be able to choose limited surgery without LN dissection.

Pancreatic Neuroendocrine Neoplasms: Correlation between MR Features and Pathological Tumor Grades

This study investigated the accuracy of MRI features in differentiating the pathological grades of pancreatic neuroendocrine neoplasms（PNENs）. A total of 31 PNENs patients were retrospectively evaluated, including 19 cases in grade 1, 5 in grade 2, and 7 in grade 3. Plain and contrastenhanced MRI was performed on all patients. MRI features including tumor size, margin, signal intensity, enhancement patterns, degenerative changes, duct dilatation and metastasis were analyzed. Chi square tests, Fisher＇s exact tests, one-way ANOVA and ROC analysis were conducted to assess the associations between MRI features and different tumor grades. It was found that patients with older age, tumors with higher TNM stage and without hormonal syndrome had higher grade of PNETs（all P〈0.05）. Tumor size, shape, margin and growth pattern, tumor pattern, pancreatic and bile duct dilatation and presence of lymphatic and distant metastasis as well as MR enhancement pattern and tumor-topancreas contrast during arterial phase were the key features differentiating tumors of all grades（all P〈0.05）. ROC analysis revealed that the tumor size with threshold of 2.8 cm, irregular shape, pancreatic duct dilatation and lymphadenopathy showed satisfactory sensitivity and specificity in distinguishing grade 3 from grade 1 and grade 2 tumors. Features of peripancreatic tissue or vascular invasion, and distant metastasis showed high specificity but relatively low sensitivity. In conclusion, larger size, poorlydefined margin, heterogeneous enhanced pattern during arterial phase, duct dilatation and the presence of metastases are common features of higher grade PNENs. Plain and contrast-enhanced MRI provides the ability to differentiate tumors with different pathological grades.

Surgical management of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms are a rare and complex group of neoplastic lesions that develop from pancreatic islet cells.Their incidence has dramatically increased during the last two decades.Due to its complex nature and pathophysiological behaviour,surgical management continues to evolve.Surgery remains the cornerstone of treatment for most non-functional and functional pancreatic neuroendocrine tumours,while lymphadenectomy remains a controversial subject.Different techniques,such as pancreas-preserving and minimally invasive approaches,continue to evolve and offer the same overall outcomes as open surgery.This comprehensive review describes in detail the current and most up-todate classification and staging of pancreatic neuroendocrine tumours,explores the rationale for nonsurgical and surgical management,and focuses on surgical treatment and more specifically,on minimally invasive approaches.

Current update on imaging for pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms(panNEN)are a heterogeneous group of tumors with differing pathological,genetic,and clinical features.Based on clinical findings,they may be categorized into functioning and nonfunctioning tumors.Adoption of the 2017 World Health Organization classification system,particularly its differentiation between grade 3,well-differentiated pancreatic neuroendocrine tumors(panNET)and grade 3,poorly-differentiated pancreatic neuroendocrine carcinomas(panNEC)has emphasized the role imaging plays in characterizing these lesions.Endoscopic ultrasound can help obtain biopsy specimen and assess tumor margins and local spread.Enhancement patterns on computed tomography(CT)and magnetic resonance imaging(MRI)may be used to classify panNEN.Contrast enhanced MRI and diffusion-weighted imaging have been reported to be useful for characterization of panNEN and quantifying metastatic burden.Current and emerging radiotracers have broadened the utility of functional imaging in evaluating panNEN.Fluorine-18 fluorodeoxyglucose positron emission tomography(PET)/CT and somatostatin receptor imaging such as Gallium-681,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid–octreotate PET/CT may be useful for improved identification of panNEN in comparison to anatomic modalities.These new techniques can also play a direct role in optimizing the selection of treatment for individuals and predicting tumor response based on somatostatin receptor expression.In addition,emerging methods of radiomics such as texture analysis may be a potential tool for staging and outcome prediction in panNEN,however further investigation is required before clinical implementation.

Correlation between radiologic features on contrastenhanced CT and pathological tumor grades in pancreatic neuroendocrine neoplasms

Contrast-enhanced computed tomography(CT)contributes to the increasing detection of pancreatic neuroendocrine neoplasms(PNENs).Nevertheless,its value for differentiating pathological tumor grades is not well recognized.In this report,we have conducted a retrospective study on the relationship between the 2017 World Health Organization(WHO)classification and CT imaging features in 94 patients.Most of the investigated features eventually provided statistically significant indicators for discerning PNENs G3 from PNENs G1/G2,including tumor size,shape,margin,heterogeneity,intratumoral blood vessels,vascular invasion,enhancement pattern in both contrast phases,enhancement degree in both phases,tumor-to-pancreas contrast ratio in both phases,common bile duct dilatation,lymph node metastases,and liver metastases.Ill-defined tumor margin was an independent predictor for PNENs G3 with the highest area under the curve(AUC)of 0.906 in the multivariable logistic regression and receiver operating characteristic curve analysis.The portal enhancement ratio(PER)was shown the highest AUC of 0.855 in terms of quantitative features.Our data suggest that the traditional contrastenhanced CT still plays a vital role in differentiation of tumor grades and heterogeneity analysis prior to treatment.

Analysis of 100 consecutive cases of resectable pancreatic neuroendocrine neoplasms： clinicopathological characteristics and long-term outcomes

The incidence rate of pancreatic neuroendocrine neoplasms （pNENs） has increased rapidly in recent years. However, the clinicopathological characteristics of pNENs are poorly understood. Medical records of patients who underwent surgery and were confirmed as pNENs by pathological examination from January 2003 to February 2015 in Qilu Hospital were reviewed retrospectively. A total of 100 patients, 36 males and 64 females, were included with a mean operation age of 46.26 ± 13.41 years. Among the 100 cases, 76 had insulinomas and 24 had non-functional pNENs. Tumor size ranged from 0.5 cm to 9 cm, and the mean size was 2.20 ± 1.40 cm. The percentages of TNM stages I, II, III, and IV tumors were 89.0%, 8.0%, 0.0%, and 3.0%, respectively. Based on the WHO classification, pNENs were classified into three grades： G1, G2, and G3. G1, G2, and G3 tumors were confirmed in 72.9%, 23.7%, and 3.4% patients, respectively. The positive rates of CgA and Syn immunohisto- chemical staining were 94.5% （69/73） and 100% （74/74）, respectively. Compared with insulinoma, non-functional pNENs have larger tumor sizes, more advanced TNM staging, a higher Ki-67 index, and a higher rate of liver metastasis （P 〈 0.05）. In conclusion, pNENs are heterogeneous tumors with varying clinical manifestations, diverse tumor biological characteristics, and different prognoses. Non-functional pNENs present a more aggressive behavioral model and have poorer prognosis than functional pNENs.

The current surgical treatment of pancreatic neuroendocrine neoplasms in China: a national wide cross-sectional study

Objective:The aim of this study is to investigate the current status of the diagnosis and treatment of patients with pancreatic neuroendocrine neoplasms(pNENs)undergoing surgery in China.Methods:This is a multicenter cross-sectional study performed in China.Data from patients with pNENs undergoing surgery at 33 high-volume medical centers,where the number of pancreatectomies exceeds 20 cases per year,were collected and analyzed between March 1,2016 and February 28,2017.Results:In total,392 patients with pNENs were enrolled.The male to female ratio was 1.4.The majority of patients were aged between 40 and 70 years.65.6%of the patients had non-functional tumors.Among those with functional tumors,the percentages of insulinomas,gastrinomas,glucagonomas,and vasoactive intestinal peptide-secreting tumors were 94.8%,1.5%,2.2%,and 1.5%,respectively.Multidisciplinary team(MDT)discussion was conducted for 39.0%of the patients.Minimally invasive surgery was performed on 31.1%of the 392 patients.The incidence of grade B/C pancreatic fistula formation was 4.4%.A total of 89.0%of the surgeries achieved R0 resection,and 41.6%of the tumors were well differentiated.Lymph node metastasis was present in 8.9%of the patients.The percentages of patients with grades G1,G2,and G3 disease were 49.2%,45.7%,and 5.1%,respectively.Conclusion:This multicenter cross-sectional study systematically presents the current status of the diagnosis and treatment of patients with pNENs undergoing surgery in China.MDT consultation for pNENs has not been widely implemented in China.Although the incidence of surgical complications is relatively low,minimally invasive procedures should be further promoted.This study shows us how to improve the outcomes of these patients.

Pancreatic steatosis and its correlation with clinicopathological features in patients with pancreatic neuroendocrine neoplasms

Background and objective:The incidence of pancreatic neuroendocrine neoplasms(pNENs)has been increasing year by year,and pancreatic steatosis has been paid more and more attention to by clinicians.Our study aims to reveal the correlation between pancreatic steatosis,clinicopathological parameters,and the prognosis of patients with pNENs.Methods:The clinicopathological data of patients with pNENs who underwent surgical resections in our institution from January 2013 to May 2022 were retrospectively analyzed.The mean computed tomography(CT)values of the pancreas and spleen were used to assess the severity of the pancreatic steatosis.Pearson Chi-square test,T test,Mann Whitney U test,Univariate Cox re-gression,and Multivariate Cox regression were used to explore the relationship between pancreatic steatosis and age,sex,body mass index,tumor type,tumor location,tumor stage,blood lipid,prognosis,and other factors.Results:A total of 122 patients were included in our study,and 19.67%have pancreatic steatosis.The incidence of pancreatic steatosis was significantly higher in patients with fatty liver than in patients without fatty liver(36.8%vs 16.5%,P=.04).In insu-linoma,the incidence of pancreatic steatosis in elderly patients was significantly higher than in young and middle-aged patients(41.7%vs 9.3%,P=.025).There was no significant difference in lipid levels between the pancreatic steatosis group and the non-pancreatic steatosis group(P>.05).Kaplan-Meier curves show that the prognosis of stage III/IV patients was significantly worse than that of stage I/II patients(P<.001).However,there was no significant difference in prognosis between patients with and without pancreatic steatosis(P=.404).Conclusion:The incidence of pancreatic steatosis was significantly higher in those with fatty liver than those without fatty liver.There is a high incidence of pancreatic steatosis in elderly patients with insulinoma.American Joint Committee on Cancer(AJCC)stage,but not pancreatic steatosis,significantly affected the prognosis of patients with pNENs.

Consensus of clinical diagnosis and treatment for non-functional pancreatic neuroendocrine neoplasms with diameter<2 cm

In clinical practice,pancreatic neuroendocrine neoplasms(pNENs)with a diameter smaller than 2 cm are commonly referred to as small pNENs.Due to their generally favorable biological characteristics,the diagnosis and treatment of small pNENs differ from other pNENs and are somewhat controversial.In response to this,the Chinese Pancreatic Surgery Association,Chinese Society of Surgery,Chinese Medical Association have developed a consensus on the diagnosis and treatment of small pNENs,which is based on evidence-based medicine and expert opinions.This consensus covers various topics,including concepts,disease assessment,treatment selection,follow-up,and other relevant aspects.

Pancreatic neuroendocrine tumors:Are tumors smaller than 2 cm truly indolent?

BACKGROUND Pancreatic neuroendocrine tumors(PNETs)are relatively rare but rank as the second most common pancreatic neoplasm.They can be functional,causing early metabolic disturbances due to hormone secretion,or non-functional and diagnosed later based on tumor size-related symptoms.Recent diagnoses of PNETs under 2 cm in size have sparked debates about their management;some practitioners advocate for surgical removal and others suggest observation due to the tumors’lower potential for malignancy.However,it is unclear whether managing these small tumors expectantly is truly safe.AIM To evaluate poor prognostic factors in PNETs based on tumor size(>2 cm or<2 cm)in surgically treated patients.METHODS This cohort study included 64 patients with PNETs who underwent surgical resection between 2006 and 2019 at a high-complexity reference hospital in Medellín,Colombia.To assess patient survival,quarterly follow-ups were conducted during the first year after surgery,followed by semi-annual con-sultations at the hospital's hepatobiliary surgery department.Qualitative variables were described using absolute and relative frequencies,and quantitative variables were expressed using measures of central tendency and their corresponding measures of dispersion.RESULTS The presence of lymph node involvement,neural involvement,and lymphovascular invasion were all associated with an increased risk of mortality,with hazard ratios of 5.68(95%CI:1.26–25.61,P=0.024),6.44(95%CI:1.43–28.93,P=0.015),and 24.87(95%CI:2.98–207.19,P=0.003),respectively.Neural involvement and lymphovascular invasion were present in tumors smaller than 2 cm in diameter and those larger than 2 cm in diameter.The recurrence rates between the two tumor groups were furthermore similar:18.2%for tumors smaller than 2 cm and 21.4%for tumors larger than 2 cm.Patient survival was additionally comparable between the two tumor groups.CONCLUSION Tumor size does not dictate prognosis;lymph node and lymphovascular involvement affect mortality,which high-lights that histopathological factors-rather than tumor size-may play a role in management.

The Chinese guidelines for the diagnosis and treatment of pancreatic neuroendocrine neoplasms(2020)

Pancreatic neuroendocrine neoplasms(pNENs)are highly heterogeneous,and the management of pNENs patients can be intractable.To address this challenge,an expert committee was established on behalf of the Chinese Pancreatic Surgery Association,which consisted of surgical oncologists,gastroenterologists,medical oncologists,endocrinologists,radiologists,pathologists,and nuclear medicine specialists.By reviewing the important issues regarding the diagnosis and treatment of pNENs,the committee concluded evidence-based statements and recommendations in this article,in order to further improve the management of pNENs patients in China.

Percutaneous transhepatic intraportal biopsy using gastroscope biopsy forceps for diagnosis of a pancreatic neuroendocrine neoplasm:A case report

BACKGROUND Pancreatic neuroendocrine neoplasms(PNENs)are a rare group of neoplasms originating from the islets of the Langerhans.Portal vein tumor thrombosis has been reported in 33%of patients with PNENs.While the histopathological diagnosis of PNENs is usually based on percutaneous biopsy or endoscopic ultrasound-guided fine-needle aspiration(EUS-FNA),these approaches may be impeded by gastric varices,poor access windows,or anatomically contiguous critical structures.Obtaining a pathological diagnosis using a gastroscope biopsy forceps via percutaneous transhepatic intravascular pathway is an innovative method that has rarely been reported.CASE SUMMARY A 72-year-old man was referred to our hospital for abdominal pain and melena.Abdominal contrast-enhanced magnetic resonance imaging revealed a wellenhanced tumor(size:2.4 cm×1.2 cm×1.2 cm)in the pancreatic tail with portal vein invasion.Traditional pathological diagnosis via EUS-FNA was not possible because of diffuse gastric varices.We performed a percutaneous transportal biopsy of the portal vein tumor thrombus using a gastroscope biopsy forceps.Histopathologic examination revealed a pancreatic neuroendocrine neoplasm(G2)with somatostatin receptors 2(+),allowing systemic treatment.CONCLUSION Intravascular biopsy using gastroscope biopsy forceps appears to be a safe and effective method for obtaining a histopathological diagnosis.Although welldesigned clinic trials are required to obtain more definitive evidence,this procedure may help improve the diagnosis of portal vein thrombosis and related diseases.

Pancreatic Neuroendocrine Tumors Are Characterized by Loss of Noxa Expression that Can be Recovered by the Proteasome Inhibitor Bortezomib

Prognosis in well-differentiated neuroendocrine carcinomas varies considerably and therapeutic targets for metastatic disease are urgently needed. cDNA microarray studies in our laboratory revealed a significantly lower expression level of the Noxa-gene in human pancreatic neuroendocrine neoplasms (PNENs) as compared to normal islet cells. To determine the validity of the downregulation of Noxa in PNENs, benign and malignant tumors from both sporadic and MEN1 patients were selected for expression analysis. To further verify the findings, neuroendocrine BON1 and QGP cell lines were tested for Noxa expression and its recovery by treatment with the proteasome inhibitor bortezomib. The expression of Noxa was significantly downregulated in 20 PNENs (p = 0.0036). There was no significant difference between MEN1 and sporadic tumors. However, the malignant tumors showed a more significant decrease as compared to benign tumors?(p = 0.0385) and the decrease in expression in tumors greater than 20 mm was very highly significant (p Noxa protein in the absence of the proteasome inhibitor, Bortezomib. After stimulation with the drug for 16 h, the expression was induced in both cell lines that are correlated with an increase in the level of c-MYC expression, cleaved caspase 3 and cell death. The low expression level of Noxa in PNENs contributes to the inability of these tumor entities to undergo apoptosis. The recovery of Noxa expression following treatment with the proteasome inhibitor, bortezomib, leading to caspase activation and cell death supports the use of such drugs for the treatment of these tumor entities.

Chinese expert consensus on multidisciplinary diagnosis and treatment of pancreatic neuroendocrine liver metastases

Many management strategies are available for pancreatic neuroendocrine neoplasms with liver metastases.However,a lack of biological,molecular,and genomic information and an absence of data from rigorous trials limit the validity of these strategies.This review presents the viewpoints from an international conference consisting of several expert working groups.The working groups reviewed a series of questions of particular interest to clinicians taking care of patients with pancreatic neuroendocrine neoplasms with liver metastases by reviewing the existing management strategies and literature,evaluating the evidence on which management decisions were based,developing internationally acceptable recommendations for clinical practice,and making recommendations for clinical and research endeavors.The review for each question will be followed by recommendations from the panel.

Gastrinoma and Zollinger Ellison syndrome:A roadmap for the management between new and old therapies

Zollinger-Ellison syndrome(ZES)associated with pancreatic or duodenal gastrinoma is characterized by gastric acid hypersecretion,which typically leads to gastroesophageal reflux disease,recurrent peptic ulcers,and chronic diarrhea.As symptoms of ZES are nonspecific and overlap with other gastrointestinal disorders,the diagnosis is often delayed with an average time between the onset of symptoms and final diagnosis longer than 5 years.The critical step for the diagnosis of ZES is represented by the initial clinical suspicion.Hypergastrinemia is the hallmark of ZES;however,hypergastrinemia might recognize several causes,which should be ruled out in order to make a final diagnosis.Gastrin levels>1000 pg/mL and a gastric pH below 2 are considered to be diagnostic for gastrinoma;some specific tests,including esophageal pH-recording and secretin test,might be useful in selected cases,although they are not widely available.Endoscopic ultrasound is very useful for the diagnosis and the local staging of the primary tumor in patients with ZES,particularly in the setting of multiple endocrine neoplasia type 1.Some controversies about the management of these tumors also exist.For the localized stage,the combination of proton pump inhibitory therapy,which usually resolves symptoms,and surgery,whenever feasible,with curative intent represents the hallmark of gastrinoma treatment.The high expression of somatostatin receptors in gastrinomas makes them highly responsive to somatostatin analogs,supporting their use as anti-proliferative agents in patients not amenable to surgical cure.Other medical options for advanced disease are super-imposable to other neuroendocrine neoplasms,and studies specifically focused on gastrinomas only are scant and often limited to case reports or small retrospective series.The multidisciplinary approach remains the cornerstone for the proper management of this composite disease.Herein,we reviewed available literature about gastrinoma-associated ZES with a specific focus on differential diagnosis,providing potential diagnostic and therapeutic algorithms.