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The role of biomarker in pancreatic neuroendocrine tumor:a narrative review

Journal of Pancreatology 2021年第3期4卷 122-129页

作者： Xiaofan Guo Song Gao Zekun Li Jihui Hao Department of pancreatic Cancer Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinChina

pancreatic neuroendocrine tumors(pNET)are heterogenous tumors originated from the diffuse neuroendocrine cells of pancreas,which show the function of synthesis,storage and secretion of peptide hormones and biomimetic amines.Biomarkers play a crucial role in the diagnosing,evaluating prognosis and predicting treatment response for pNET patients.Traditional NET markers such as chromogranin A and Neuron Specific Enolase,as a diagnostic biomarker,have relatively low sensitivity and specificity in pNET patients.The emergence of new types of biomarkers provides more reliable indicators for diagnosis and prognosis evaluation.Among them,NETest score is a promising biomarker with the highest diagnostic sensitivity(80%)and specificity(94%).In addition,this molecule can be also used as a prognostic biomarker,which can predict disease progression and shorter overall survival.Biomarkers related to therapeutic targets,such as vascular endothelial growth factor,vascular endothelial growth factor receptor,and key molecules of mTOR signaling pathway,have capability to predict response of treatment.With the development of nextgeneration sequencing,chip array,and digital droplet PCR,novel biomarkers such as circulating tumor cells,tumor-derived exosomes,and circulating tumor DNA and mRNA are expected to provide more accurate diagnosis,prognostic information,and prospective therapeutic targets.In this paper,biomarkers of pancreatic neuroendocrine tumor and their role in diagnosis,prognosis,diagnosis,treatment and monitoring are systematically introduced.Our conclusions can provide new basis for clinicians in the diagnosis and treatment process.

关键词： Biomarker Diagnosis pancreatic neuroendocrine tumor Prognosis

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pancreatic neuroendocrine tumor with hypoglycemia and elevated insulin-like growth factor II:a case report

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Journal of Cancer Metastasis and Treatment 2016年第1期2卷 345-347页

作者： Roberta Modica Antonella Di Sarno Annamaria Colao Antongiulio Faggiano Department of Clinical Medicine and Surgery Federico II University80131 NaplesItaly UOC of Oncology A.O.Dei ColliMonaldi Unit80131 NaplesItaly Thyroid and Parathyroid Surgery Unit Istituto Nazionale per lo studio e la cura dei tumori“Fondazione G.Pascale”-IRCCS80131 NaplesItaly

pancreatic neuroendocrine tumors(pNETs)can be associated with different clinical syndromes.Insulinoma is the most common functioning pNET characterized by hypoglycemia and hyperinsulinemia.The authors report a case of a man presenting with hypoglycemia and biochemical features of insulinoma.A pancreatic lesion was found and growth hormone(GH)deficiency was also diagnosed associated with an empty sella present on the pituitary magnetic resonance imaging.The disappearance of hypoglycemia and normalization of GH secretion after surgical resection of the pancreatic lesion,revealed a rare pNET secreting insulin-like growth factor II.

关键词： pancreatic neuroendocrine tumor insulinoma hypoglycemia insulin-like growth factor II

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Advancements in medical treatment for pancreatic neuroendocrine tumors:A beacon of hope

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World Journal of Gastroenterology 2024年第12期30卷 1670-1675页

作者： Somdatta Giri Jayaprakash Sahoo Department of Endocrinology and Metabolism Jawaharlal Institute of Postgraduate Medical Education and ResearchPuducherry605006India

This editorial highlights the remarkable advancements in medical treatment strategies for pancreatic neuroendocrine tumors(pan-NETs),emphasizing tailored approaches for specific subtypes.Cytoreductive surgery and somatostatin analogs(SSAs)play pivotal roles in managing tumors,while palliative options such as molecular targeted therapy,peptide receptor radionuclide therapy,and chemotherapy are reserved for SSA-refractory patients.Gastrinomas,insul-inomas,glucagonomas,carcinoid tumors and VIPomas necessitate distinct thera-peutic strategies.Understanding the genetic basis of pan-NETs and exploring immunotherapies could lead to promising avenues for future research.This review underscores the evolving landscape of pan-NET treatment,offering renewed hope and improved outcomes for patients facing this complex disease.

关键词： pancreatic neuroendocrine tumor Medical management Somatostatin analog Immunotherapy Everolimus

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Values of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumors:a comparative study

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Gastroenterology Report 2023年第1期11卷 247-253页

作者： Xi-Tai Huang Jin-Zhao Xie Liu-Hua Chen Jian-Peng Cai Wei Chen Li-Jian Liang Ning Zhang Xiao-Yu Yin Department of Pancreato-Biliary Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongP.R.China Department of Gastroenterology The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongP.R.China

Background and objective:The value of debulking surgery for unresectable well-differentiated metastatic pancreatic neuroendocrine tumor(m-PNET)remains poorly defined.This study aimed to evaluate the outcomes of m-PNET following debulking surgery in our institute.Methods:Patients with well-differentiated m-PNET in our hospital between February 2014 and March 2022 were collected.Clinicopathological and long-term outcomes of patients treated with radical resection,debulking surgery,and conservative therapy were compared retrospectively.Results:Fifty-three patients with well-differentiated m-PNET were reviewed,including 47 patients with unresectable m-PNET(debulking surgery,25;conservative therapy,22)and 6 patients with resectable m-PNET(radical resection).Patients undergoing debulking surgery had a post-operative Clavien–DindoIII complication rate of 16.0%without mortality.The 5-year overall survival(OS)rate of patients treated with debulking surgery was significantly higher than that of those treated with conservative therapy alone(87.5%vs 37.8%,log-rank P=0.022).Besides,the 5-year OS rate of patients treated with debulking surgery was comparable to that of patients with resectable m-PNET undergoing radical resection(87.5%vs 100%,log-rank P=0.724).Conclusions:Patients with unresectable well-differentiated m-PNET who underwent resection had better long-term outcomes than those who received conservative therapy alone.The 5-year OS of patients undergoing debulking surgery and radical resection were comparable.Debulking surgery could be considered for patients with unresectable well-differentiated m-PNET if no contraindication exists.

关键词： pancreatic neuroendocrine tumor metastasis debulking surgery prognosis

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Misdiagnosis of pancreatic metastasis from renal cell carcinoma:A case report

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World Journal of Clinical Cases 2022年第25期10卷 9012-9019页

作者： Xuan-Kun Liang Lu-Jing Li Ye-Mei He Zuo-Feng Xu Department of Medical Ultrasonics The Seventh Affiliated Hospital of Sun Yat-sen UniversityShenzhen 518107Guangdong ProvinceChina

BACKGROUND pancreatic metastases account for only a small proportion of all pancreatic malignancies.Isolated pancreatic metastasis from renal cell cancer(isPM-RCC)is extremely rare and may be difficult to differentiate from more common primary neoplasms.A history of nephrectomy is crucial for the diagnosis.CASE SUMMARY We report the case of a 64-year-old Asian man who was diagnosed with a mass in the pancreatic head using computed tomography.He had no related symptoms,and his medical history was unremarkable,except for unilateral nephrectomy performed to remove a“benign”tumor 19 years ago.All preoperative imaging findings suggested a diagnosis of pancreatic neuroendocrine tumor.However,ultrasound-guided biopsy revealed features of clear cell renal cell carcinoma(ccRCC).Re-examination of the specimen resected 19 years ago confirmed that he had a ccRCC.The pancreatic mass was resected and pathological examination confirmed isPM-RCC.CONCLUSION Misdiagnosis of isPM-RCC is common because of its rarity and the long interval from resection of the primary tumor and manifestation of the metastasis.The history of the previous surgery may be the only clue.

关键词： Renal cell carcinoma pancreatic neuroendocrine tumor pancreatic metastases Case report

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Peripancreatic paraganglioma:Lesson from a round table

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World Journal of Gastroenterology 2022年第21期28卷 2396-2402页

作者： Federica Petrelli Geri Fratini Andrea Sbrozzi-Vanni Andrea Giusti Raffele Manta Claudio Vignali Gabriella Nesi Andrea Amorosi Andrea Cavazzana Marco Arganini Maria Raffaella Ambrosio Pathology Unit Azienda Sanitaria Toscana Nord OvestPisa 56121Italy Surgery Unit Azienda Sanitaria Toscana Nord OvestPisa 56121Italy Endoscopic Unit Azienda Sanitaria Toscana Nord OvestPisa 56121Italy Endoscopic Unit Santa Maria Misericordia HospitalPerugia 06122Italy Interventional Radiology Unit Azienda Sanitaria Toscana Nord OvestPisa 56121Italy Department of Health Sciences University of FlorenceFlorence 50139Italy Pathology Unit UniversitàMagna GraeciaCatanzaro 88100Italy

We described the case of a peripancreatic paraganglioma(PGL)misdiagnosed as pancreatic lesion.Surgical exploration revealed an unremarkable pancreas and a large well-defined cystic mass originating at the mesocolon root.Radical enucleation of the mass was performed,preserving the pancreatic tail.Histologically,a diagnosis of PGL was rendered.Interestingly,two previously unreported mutations,one affecting the KDR gene in exon 7 and another on the JAK3 gene in exon 4 were detected.Both mutations are known to be pathogenetic.Imaging and cytologic findings were blindly reviewed by an expert panel of clinicians,radiologists,and pathologists to identify possible causes of the misdiagnosis.The major issue was lack of evidence of a cleavage plane from the pancreas at imaging,which prompted radiologists to establish an intraparenchymal origin.The blinded revision shifted the diagnosis towards an extrapancreatic lesion,as the pancreatic parenchyma showed no structural alterations and no dislocation of the Wirsung duct.Ex post,the identified biases were the emergency setting of the radiologic examination and the very thin mesocolon sheet,which hindered clear definition of the lesion borders.Original endoscopic ultrasonography diagnosis was confirmed,emphasizing the intrinsic limit of this technique in detecting large masses.Finally,pathologic review favored a diagnosis of PGL due to the morphological features and immonohistochemical profile.Eighteen months after tumor excision,the patient is asymptomatic with no disease relapse evident by either radiology or laboratory tests.Our report strongly highlights the difficulties in rendering an accurate preoperative diagnosis of PGL.

关键词： Peripancreatic paraganglioma pancreatic neuroendocrine tumor Solid pseudopapillary neoplasm S100 Succinate dehydrogenase subunit B gene and expression Fine needle biopsy

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Values of spleen-preserving distal pancreatectomy in well-differentiated non-functioning pancreatic neuroendocrine tumors:a comparative study

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Gastroenterology Report 2022年第1期10卷 513-518页

作者： Xi-Tai Huang Jin-Zhao Xie Jian-Peng Cai Peng Fang Chen-Song Huang Wei Chen Li-Jian Liang Xiao-Yu Yin Department of Pancreato-Biliary Surgery The First Affiliated HospitalSun Yat-sen UniversityGuangzhouGuangdongP.R.China

Background The feasibility of spleen-preserving distal pancreatectomy(SPDP)to treat well-differentiated non-functioning pancreatic neuroendocrine tumors(NF-pNETs)located at the body and/or tail of the pancreas remains controversial.Distal pancreatectomy with splenectomy(DPS)has been widely applied in the treatment of NF-pNETs;however,it may increase the post-operative morbidities.This study aimed to evaluate whether SPDP is inferior to DPS in post-operative outcomes and survivals when being used to treat patients with NF-pNETs in our institute.Methods Clinicopathological features of patients with NF-pNETs who underwent curative SPDP or DPS at the First Affiliated Hospital of Sun Yat-sen University(Guangzhou,China)between January 2010 and January 2022 were collected.Short-term outcomes and 5-year survivals were compared between patients undergoing SPDP and those undergoing DPS.Results Sixty-three patients(SPDP,27;DPS,36)with well-differentiated NF-pNETs were enrolled.All patients had grade 1/2 tumors.After identifying patients with T1–T2 NF-pNETs(SPDP,27;DPS,15),there was no disparity between the SPDP and DPS groups except for tumor size(median,1.4 vs 2.6 cm,P=0.001).There were no differences in operation time(median,250 vs 295 min,P=0.478),intraoperative blood loss(median,50 vs 100 mL,P=0.145),post-operative major complications(3.7%vs 13.3%,P=0.287),clinically relevant post-operative pancreatic fistula(22.2%vs 6.7%,P=0.390),or post-operative hospital stays(median,9 vs 9 days,P=0.750)between the SPDP and DPS groups.Kaplan–Meier curve showed no significant differences in the 5-year overall survival rate(100%vs 100%,log-rank P>0.999)or recurrence-free survival(100%vs 100%,log-rank P>0.999)between patients with T1–T2 NF-pNETs undergoing SPDP and those undergoing DPS.Conclusions In patients with T1–T2 well-differentiated NF-pNETs,SPDP could achieve comparable post-operative outcomes and prognosis compared with DPS.

关键词： pancreatic neuroendocrine tumor distal pancreatectomy spleen preservation prognosis

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pancreatic neuroendocrine tumors:A review of serum biomarkers,staging,and management

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World Journal of Gastroenterology 2020年第19期26卷 2305-2322页

作者： Zu-Yi Ma Yuan-Feng Gong Hong-Kai Zhuang Zi-Xuan Zhou Shan-Zhou Huang Yi-Ping Zou Bo-Wen Huang Zhong-Hai Sun Chuan-Zhao Zhang Yun-Qiang Tang Bao-Hua Hou Department of General Surgery Guangdong Provincial People’s HospitalGuangdong Academy of Medical SciencesGuangzhou 510080Guangdong ProvinceChina Shantou University of Medical College Shantou 515000Guangdong ProvinceChina Department of Hepatobiliary Surgery the Affiliated Cancer Hospital and Institute of Guangzhou Medical UniversityGuangzhou 510080Guangdong ProvinceChina

pancreatic neuroendocrine tumors(pNETs)are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading,clinical staging,and presence of symptoms related to hormonal secretion.With regard to diagnosis,remarkable advances have been made:Chromogranin A is recommended as a general marker for pNETs.But other new biomarker modalities,like circulating tumor cells,multiple transcript analysis,microRNA profile,and cytokines,should be clarified in future investigations before clinical application.Therefore,the currently available serum biomarkers are insufficient for diagnosis,but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs.Surgical resection is still the only curative therapeutic option for localized pNETs.However,a debulking operation has also been proven to be effective for controlling the disease.As for drug therapy,steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor,while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs.Great progress has been achieved in the combination of systematic therapy with local control treatments.The optimal timing of local control intervention,planning of sequential therapies,and implementation of multidisciplinary care remain pending.

关键词： pancreatic neuroendocrine tumor Serum biomarkers Staging Grading Management Therapy

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Malignant insulinoma:Can we predict the long-term outcomes?

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World Journal of Clinical Cases 2022年第16期10卷 5124-5132页

作者： Maja Cigrovski Berkovic Monika Ulamec Sonja Marinovic Ivan Balen Anna Mrzljak Department of Endocrinology DiabetesMetabolism and Clinical PharmacologyClinical Hospital DubravaZagreb 10000Croatia Department of Kinesiological Anthropology and Methodology Faculty of KinesiologyUniversity of ZagrebZagreb 10000Croatia Department of Pathology and Cytology“Ljudevit Jurak” University Hospital Center“Sestre milosrdnice”Zagreb 10000Croatia Scientific Group for Research on Epigenetic Biomarkers and Department of Pathology School of MedicineUniversity of ZagrebZagreb 10000Croatia Laboratory for Personalized Medicine Division of Molecular MedicineRudjer Boskovic InstituteZagreb 10000Croatia Department of Gastroenterology and Endocrinology General Hospital“Dr.Josip Bencevic”Slavonski Brod 35000Croatia Department of Gastroenterology and Hepatology UHC ZagrebZagreb 10000Croatia School of Medicine University of ZagrebZagreb 10000Croatia

Insulinomas are the most frequent type of functional pancreatic neuroendocrine tumors with a variety of neuroglycopenic and autonomic symptoms and welldefined diagnostic criteria;however,prediction of their clinical behavior and early differentiation between benign and malignant lesions remain a challenge.The comparative studies between benign and malignant cases are limited,suggesting that short clinical history,early hypoglycemia during fasting,high proinsulin,insulin,and C-peptide concentrations raise suspicion of malignancy.Indeed,malignant tumors are larger with higher mitotic count and Ki-67 proliferative activity,but there are no accurate histological criteria to distinguish benign from malignant forms.Several signaling pathways have been suggested to affect the pathophysiology and behavior of insulinomas;however,our knowledge is limited,urging a further understanding of molecular genetics.Therefore,there is a need for the identification of reliable markers of metastatic disease that could also serve as therapeutic targets in patients with malignant insulinoma.This opinion review reflects on current gaps in diagnostic and clinical aspects related to the malignant behavior of insulinoma.

关键词： pancreatic neuroendocrine tumor Malignant insulinoma Resection Liver Transplantation

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Perspective of molecular imaging and peptide receptor radionuclide therapy in pancreatic neuroendocrine tumors:where do we stand?

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Journal of Pancreatology 2023年第4期6卷 210-224页

作者： Wenjia Zhu Meixi Liu Li Huo Department of Nuclear Medicine Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear MedicinePeking Union Medical College HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing100730China

The clinical use of nuclear medicine imaging and therapy in pancreatic neuroendocrine tumors has been greatly strengthened since the approval of ^(68)Ga-DOTATATE and ^(177)Lu-DOTATATE.However,many aspects are still under discussion.In this 2-part article,we aim to collect and discuss current evidence of molecular imaging and peptide receptor radionuclide therapy(PRRT)in pancreatic neuroendocrine tumor.In the first part,we will address some critical aspects of ^(68)Ga-SSAs imaging,including diagnostic efficacy,recurrence detection and follow-up,patient selection for PRRT,and pitfalls in image interpretation.Besides,we will also briefly discuss the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography,special imaging strategy in regard to insulinoma,and the status of radiolabeled somatostatin receptor antagonist.In the second part,we aim to review the current evidence of PRRT in pancreatic neuroendocrine tumor,focusing on efficacy and safety in particular.We will also introduce the recent development of PRRT,including PRRT in high-grade neuroendocrine neoplasms,retreatment PRRT,upfront PRRT,PRRT in the setting of neoadjuvant therapy and conversion therapy,combination therapies with PRRT,PRRT withαradionuclides,and PRRT with antagonists.

关键词： ^(68)Ga-SSA pancreatic neuroendocrine tumor Peptide receptor radionuclide therapy Somatostatin receptor

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