INTRODUCTION

Although pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms, the incidence and prevalence of PanNET are steadily rising according tothe Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2012.1 PanNET represents heterogeneous biological behavior, most ofwhich the clinical behavior shows indolent feature, however, some PanNETs show rapid progression with poor prognosis. 2 Therefore, the 10- yearsurvival rate of patients with PanNETs is only 40%. According to the World Health Organization (WHO) 2010 grading classification, PanNETs aredivided into three groups by the proliferative fraction of neoplastic cells, such as low grade (G1), intermediate grade (G2), and high grade (G3). Thereare other prognostic factors of PanNETs including tumor size, the presence and the site of metastasis, the degree of tumor differentiation, andspontaneous tumor gr owth rapidity.3 However, the prognostic factors of PanNET are still debatable because their rarity and heterogeneity of biologicand clinical features. Recently, whole genome sequencing revealed some mutational signatures in PanNETs, and these genetic alterations maypredict the prognosis of PanNETs.

GENETIC ALTERATIONS IN PANNETS AND ITS CLINICAL APPLICATION AS A BIOMARKER

PanNET usually appears sporadically , but it can appear as part of three hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN-1),von Hippel-Lindau syndrome (VHL), and tuberous sclerosis complex (TSC).2 Therefore, genetic mutations may have roles in the development ofPanNETs. Recent large-scale expression profiling and whole exome sequencing discovered several frequently mutated genes, including DAXX(death-domain associated protein, the apoptotic regulator), ATRX (α thalassemia/mental retardation syndrome X-link ed, the chromatin modifier),MEN1 (tumor suppressor gene), mTOR (mammalian target of rapamycin) pathway genes, and some germline mutations (MUTYH, CHEK2 andBRCA2).2

Jiao et al. reported that 43% of PanNETs harbored inactivating DAXX (25%) or ATRX (18%) mutation.4 This whole-ex ome sequence data was acornerstone in understanding the molecular pathogenesis of well-diff erentiated PanNETs. These are tightly associated with alternative lengtheningof telomeres (ALT, a telomerase-indep endent mechanism) and chromosomal instability (CIN). CIN also significantly correlated with DAXX or ATRXloss and ALT activation. The presence of DAXX and ATRX mutations is mutually exclusive.4 Recent studies have suggested that ATRX loss and/orALT positivity confer in vitro sensitivity to inhibition of the DNA damage mediator, ATR, as well as topoisomerase inhibitors and radiation.5 Accordingto previous studies involving the majority of Caucasians, ALT was identified in a substantial fraction of PanNETs (48%–61%), unlike this a lowerprevalence (15%) was obser ved in a small K orean cohort, and ALT prevalence may vary by ethnics. 5

At first, DAXX/ATRX mutations were reported to be associated with better prognosis. 4 Dogeas et al. also reported that ALT activation which isassociated with DAXX/ATRX mutation is correlated with improved prognosis in patients with liver metastases of PanNETs.6 Conversely, Marinoni etal. reported that the loss of DAXX/ATRX are related with CIN and poor survival of patients with PanNETs.7 Singhi et al. also reported that ALT/andDAXX/ATRX loss in PanNETs was associated with shorter disease-fr ee survival and disease-specific survival and likely plays a significant role indriving metastatic disease. 8 The discrepancy between these studies can be explained by different study populations. Patients of the first two studieswere metastatic and mostly higher primary tumor stage of PanNETs.4, 6 In contrast, most of the patients in latter studies were lower primary tumorstage and nonmetastatic PanNETs.7, 8 Then, in a large Korean cohort study, ALT activation and loss of ATRX or DAXX expression developed at arelatively late stage of tumor progression, and ALT-positiv e primary PanNETs displayed aggressive clinicopathologic behavior with poor recurrence-free survival, whereas, ALT activation in patients with metastases was associated with better survival.5 Recently, another Korean cohort study ofPanNETs revealed that negative ATRX/DAXX protein expression was the independent prognostic factor for longer OS and showed significantly longersurvival after the recurrence.3 Therefore, these biomark ers may be used as pr ognostic mark ers depending on the context of the disease.

Authors Minseok Albert Kim, Woo Hyun Paik1

E- mail whpaik@snuh.org

Institute Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 101,

Daehak- ro, Jongno- gu, Seoul 03080, Korea

City/Nationality Seoul, Republic of Korea

Title of Ar ticle

Prognostic biomarkers in pancreatic neuroendocrine tumor

Comprehensive molecular analysis of 102 clinically sporadic PanNETs was conducted recently to define molecular pathology and to identify severalnovel candidate mechanisms that activate mTOR signaling, including novel gene fusion events.2 They found five mutational signatures, of whichgermline MUTYH inactivation was not previously reported and found other unreported germline mutations including CHEK2 and BRCA2. A total of3,097 somatic mutations were detected in 2,567 genes and MEN1, DAXX, and ATRX were found frequently. Inactivating mutations in negativeregulators of mTOR signaling (PTEN and DEPDC5, mTOR pathway genes; TSC1 and TSC2, negative regulators of mTOR signaling) were also presentin 12% of their patients. They presented four core pathways of somatic mutations in PanNETs: DNA damage repair, chromatin modification,activation of mTOR signaling, and alter ed lengthening of telomer e. The mutations of mT OR signaling wer e associated with a poor pr ognosis in the G2PanNETs. Previously undescribed three mTOR pathway activation mechanisms including DEPDC5 (encoding a subunit of the GATOR1 complex, asuppressor of mTOR signaling), EWSR fusion genes (previously undescribed EWSR1-BEND2 fusion and EWSR1 exon 7-FLI1 exon 6 fusion genes),and amplification of the PSPN (RET receptor ligand) wer e also disco vered by whole genome sequencing of PanNETs.2

Pancreatic neuroendocrine carcinomas (PanNECs) are usually more aggressive, however, their clinicopathologic and genetic features are largelyunknown. Yachida et al. reported that 57% of the cases had inactivating mutations of the TP53 gene and 71% had inactivating mutations of the RB1gene in 19 cases of PanNECs.9 The targeted sequencing data for 593 cases of small cell lung cancer (SCLC) and 274 GEP-NECs reported byBergsland et al. included 123 cases of PanNECs.10 Mutations in TP53 (18%) and RB1 (10%) are less common in PanNECs than in SCLC, colon NECand other types of gastrointestinal NECs, whereas mutations in MEN1 (33%) and DAXX (20%) are more common in PanNECs.10 These results areconsistent with a previous study that presented higher inactivating mutation rate of DAXX/ATRX and MEN1 in advanced PanNETs.5 In addition, theproportion of K-ras mutation was lower in PanNEC (7%) than PDAC, which means genetically different entities each other .

CCOONNCCLLUUSSIIOONNSS

Based on the recently published genome analysis, we improved our understanding for PanNETs. DAXX/ATRX and MEN1 mutations may be promisingbiomarkers predicting the prognosis of PanNETs. Understanding of the molecular mechanisms leading to the development of PanNETs can beinvaluable for a more personaliz ed treatment approach. The mutations in PanNETs may provide a way to prioritiz e patients for molecular targetedtherapy including mTOR inhibitors. Future studies in genetic alterations of PanNETs may give us insights to discover strong prognostic markers forsurvival and therapeutic r esponse and will pr ovide a breakthrough in conquering diseases with high mor tality such as P anNECs.

RREEFFEERREENNCCEESS

01 Dasari A, Shen C, Halperin D, et al. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With NeuroendocrineTumors in the United States. J AMA Oncol. 2017;3:1335-1342.

02 Scarpa A, Chang DK, Nones K, et al. Whole-genome landscape of pancr eatic neuroendocrine tumours. Natur e. 2017;543:65-71.

03 Park JK, Paik WH, Lee K, et al. DAXX/ATRX and MEN1 genes are strong prognostic markers in pancreatic neuroendocrine tumors.Oncotarget. 2017;8:49796-49806.

04 Jiao Y, Shi C, Edil BH, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.Science. 2011;331:1199-1203

05 Kim JY, Brosnan-Cashman JA, An S, et al. Alternative Lengthening of Telomeres in Primary Pancreatic Neuroendocrine Tumors IsAssociated with Aggr essive Clinical Beha vior and Poor Survival. Clin Cancer Res. 2017;23:1598-1606.

06 Dogeas E, Karagkounis G, Heaphy CM, et al. Alternative lengthening of telomeres predicts site of origin in neuroendocrine tumor livermetastases. J Am Coll Sur g. 2014;218:628-635.

07 Marinoni I, Kurrer AS, Vassella E, et al. Loss of DAXX and ATRX are associated with chromosome instability and reduced survival ofpatients with pancr eatic neuroendocrine tumors. Gastr oenterology. 2014;146:453-60.e5

08 Singhi AD, Liu TC, Roncaioli JL, et al. Alternative Lengthening of Telomeres and Loss of DAXX/ATRX Expression Predicts MetastaticDisease and P oor Survival in Patients with P ancreatic Neuroendocrine Tumors. Clin Cancer Res. 2017;23:600-609

09 Yachida S, Vakiani E, White CM, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar anddistinct from well-diff erentiated pancr eatic neuroendocrine tumors. Am J Sur g. Pathol. 2012;36:173–184.

10 Bergsland EK, Roy, R, Stephens P, et al. Genomic profiling to distinguish poorly differentiated neuroendocrine carcinomas arising indifferent sites. J Clin Oncol. 2016;34(Suppl 15) Abstract 4020.

CASE DESCRIPTION

A 35- year-old man was admitted to a local hospital for intermittent right upper quadrant pain. He had no history of underlying disease. Abdominalcomputed tomography (CT) revealed three arterial enhancing and delayed wash-out lesions in hepatic S5 (2.8 cm) and hepatic S6 (6.0 cm, 3.0 cm)(Figure 1). Hepatic adenoma was suspected and the S5 lesion was removed. The frozen section was diagnosed as neuroendocrine carcinoma. Thepatient was referred to our hospital without fur ther surgery.

At admission, his vital signs were stable and routine laboratory tests were normal. However, NSE (neuron specific enolase) was elevated (32.76ng/mL, normal range 0–16.3 ng/mL). Upper endoscopy was performed and 2 cm sized, dumbbell shaped subepithelial tumor was found in thegreater curvature of the proximal antrum (Figure 2). Endoscopic biopsy revealed a large cell neuroendocrine carcinoma. PET-C T showed nometastases other than the liv er metastasis (Figure 3). The final diagnosis was gastric neur oendocrine car cinoma with multiple hepatic metastases

For the purpose of neoadjuvant chemotherapy, octreotide (30 mg, intramuscularly) was started at monthly intervals on an outpatient basis. Afterthree cycles of octreotide treatment, the size of the largest tumor decreased slightly from 6.0 cm to 5.5 cm by follow-up CT. An additional threecycles of octreotide were administered. However, no change in tumor size was observed by follow-up abdominal CT (Figure 4). Surgery was decidedand the gastric lesion was removed by wedge resection, and the S5 and S6 lesions by segmentectomy. Follow-up CT findings at one month aftersurgery revealed a new focal attenuated lesion in the hepatic S4 surface (1.5 cm) (Figure 5), which was subsequently treated by radiofrequencyablation (RFA).

Thereafter, the patient was administered octreotide 4 weekly at our outpatient clinic, and underwent abdominal and chest CT every three months.Fortunately, at one year after RFA treatment and on-going tr eatment at the outpatient clinic, no r ecurrence was encounter ed.

DISCUSSION

Gastric neuroendocrine tumor (GNET) is classified into three types.1 Type 1 GNET is related to chronic atrophic gastritis and type 2 GNET toZollinger-Ellison syndrome or multiple endocrine neoplasia. Both type 1 and type 2 GNET have multiple gastric lesions and are associated withhypergastrinemia. Metastasis from type 1 GNET is rare and from type 2 GNET has been reported to be 10-30%. On the other hand, type 3 GNET is notrelated to any associated disease, has a normal gastrin level, and presents a solitary lesion. Notably, type 3 GNET has a poor prognosis because ofits high metastatic potential (>50%). The described case was classified as type 3 GNET because this was only one primary lesion, no associateddisease, and multiple hepatic metastasis. Little evidence-based data is available regarding the optimal management of patients with hepaticmetastasis from a neuroendocrine tumor. In one study of 172 patients, hepatic resection of metastatic neuroendocrine tumors achieved long-termsurvival in some patients (a 10-y ear overall sur vival rate of 50.4%), 2 and a recent meta-analysis r eported a 5-y ear overall sur vival rate of 41% to 100%in patients with neuroendocrine tumors that underwent hepatic resection. 3 However, most patients with resected metastatic disease will eventuallyexperience recurrence.4,5 If metastatic lesions are resected, future treatment with octreotide or lanreotide may be anticipated. Residual disease maybe effectively controlled postoperativ ely with long-acting somatostatin analogues, which inhibit tumor growth and tumor progression. 6 In addition,the somatostatin analogue octreotide is an important adjunct for regulating carcinoid syndrome and preventing perioperativ e carcinoid crisis. 7 Forpatients with clearly unresectable disease, transarterial chemo (radio) embolization may be considered with the primary palliativ e goal of reducing

Author Byoung Wook Bang

E- mail bangbyoung@naver.com

Institute Division of Gastroenterology, Department of Internal Medicine, Inha University College of Medicine, Incheon, Korea

City/Nationality Incheon, Republic of Korea

Category Case

Upper GI Lower GI Pancreatobiliary tract Others

Title of Case

A case of gastric neuroendocrine tumor with multiple hepatic metastases

hormonal symptoms or delaying liver failure.8 In summary, in the described case of type III GNET with multiple hepatic metastases, successfulcurative treatment was achie ved by aggressive surgery and RFA. Long-term octr eotide treatment is needed to pr event recurrence for this patient.

FIGURE

 

FIGURE 1 Abdominal CT

FIGURE 2 Upper endoscopy FIGURE 3 PET

 

FIGURE 4 Follow-up abdominal C T

FIGURE 5 Follow-up C T (at one month after sur

REFERENCES

01 Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E. Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrinecarcinoma: A clinicopathologic study . Gastroenterology. 1993;104(4):994-1006..

02 Glazer ES, Tseng JF, Al�Refaie W, et al. Long�term survival after surgical management of neuroendocrine hepatic metastases. HPB(Oxford). 2010;12(6):427-433.

03 Lesurtel M, Nagorney DM, Mazzaferro V, Jensen RT, Poston GJ. When should a liver resection be performed in patients with livermetastases from neuroendocrine tumours? A systematic r eview with practice r ecommendations. HPB (Oxfor d). 2015;17(1):17-22.

04 Mayo SC, De Jong MC, Pulitano C, et al. Surgical management of hepatic neuroendocrine tumor metastasis: Results from aninternational multi-institutional analysis. Ann Sur g Oncol. 2010;17(12):3129-3136.

05 Saxena A, Chua TC, Perera M, Chu F, Morris DL. Surgical resection of hepatic metastases from neuroendocrine neoplasms: asystematic review. Surg Oncol. 2012;21(3):e131-e141.

06Rinke A, Müller H, Schade-Brittinger C, et al. Placebo-contr olled, double-blind, prospective, randomized study on the effect ofoctreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMIDstudy group. J Clin Oncol. 2009;27(28):4656-4663.

07 Öberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumorsof the gastroenteropancreatic system. Ann Oncol. 2004;15(6):966-973.

08 Johnston FM, Mavros MN, Herman JM, Pawlik TM. Local therapies for hepatic metastases. J Natl Compr Canc Netw. 2013;11(2):153-160.

CASE DESCRIPTION

A 35-y ear-old female, who began to suffer repeated palpitation, tremor, and sweating 1 year ago, was sent to a local hospital because of aggravatedsymptoms and unconsciousness. Blood test showed glucose of 1.4 mmol/L and insulin greater than 300 μU/mL. The patient was transferred to ourhospital due to refractory hypoglycemia. The laboratory findings on admission were as follows: blood glucose was 2.4 mmol/L, serum CgA was45.38 ng/ml, and serum NSE was 35.11 ng/mL.18F-FDG PET/CT and 68Ga-DO TA-somatostatin analog-PET/C T showed a mass in the head ofpancreas, enlarged peripheral lymph nodes, and multiple lesions in liver, which showed high uptake of FDG and positive somatostatin receptorimaging findings (Figure 1). Biopsy on hepatic metastasis confirmed that they were grade II neuroendocrine tumors with a ki-67 proliferation index of15% and positive staining for Insulin, CgA, Syn, MGMT and SSTR2. The diagnosis was malignant insulinoma with metastasis in peripheral lymphnodes and liv er (G2, T1N1M1, stage IV ).

Diazoxide (100 mg q12h) was applied to control glycaemia. Then six cycles of chemotherapy with temozolomide/capecitabine (Captem) regimen(capecitabine 1 g bid, D1-D14; temozolomide 300 mg qd, D10-D14, q4w) was conducted, during which three cycles of trans-ar terial embolization(TAE) procedures were performed. Blood glucose level and serum insulin level were successfully controlled in the normal range during the first stageof treatment. CT scan was performed 1 month after every TAE procedure and showed constant shrinkage of tumor size and decrease in tumorquantity and density in the liv er (Figure 2).

In the second stage of treatment, octreotide LAR (30 mg IM, q4w) was applied for maintenance therapy, accompanied with Diazoxide (100 mg q12h).Blood glucose level and serum insulin level were under control all the time. However, new metastatic lesions were found in liver by CT scan after 2cycles of octreotide LAR treatment.

Taking tumor progression into account, chemotherapy with Captem regimen was reused, combined with Diazoxide and 1 cycle of TAE procedure inthe third stage of treatment. After 2 cycles of chemotherapy, primary tumor and hepatic metastases were found stable by CT scan, but the patientsuffered intermittent hypogly cemia again. Lowest blood glucose le vel reached 2.2 mmol/L.

Everolimus was used instead of Captem and Diazoxide in the fourth stage of treatment, with the dose of 5 mg/d in the beginning. The dosage wasadjusted to 7.5 mg/d 7 days later and increased to 10 mg/d after another 7 days. Meanwhile, 1 cycle of TAE procedure was performed. CT scanrevealed that the lesions both in liver and pancreas were stable after 3 months. Blood glucose level and serum insulin level were in the normal range.However, stomatitis and skin rash occurred 2 weeks after everolimus was administered (Figure 3). The patient’ s condition is still being followed upuntil present.

Authors Yiming Liu1, Luohai Chen2, Yu Wang1b, Jie Chen2a

E- mail aChen0jie@hotmail.com, bzsyyjr@163.com

Institute 1Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat- Sen University 2Department of Gastroenterology, the First Affiliated Hospital, Sun Yat- Sen University

City/Nationality Guangzhou, China

Category Case

Upper GI Lower GI Pancreatobiliary tract Others

Title of Case

A case of malignant insulinoma with metastasis in peripheral lymph nodes andliver (G2, T1N1M1, stage IV)

DISCUSSION

Insulinomas, which derive from insulin-secr eting pancreatic beta cells, are the most common functional neuroendocrine tumors (NETs) originating inpancreas, accounting for 93.1% of functional p-NETs in South China.1 About 90% cases of insulinomas are benign, while others present malignantcharacteristics, such as local invasion into the surrounding soft tissue, lymph nodes or liver metastasis. 2 Clinical manifestations resulting fromhypoglycemia caused by high secretion of insulin include palpitation, tremor, sweating, etc. and unconsciousness in some severe cases. The keytreatments for patients with insulinoma ar e controlling hypogly cemia and suppr essing tumor gr owth.

Diazoxide, a benzothiadiazine derivative, is regarded as first-line treatment for glycemic control in patients with insulinoma. By opening ATP-dependent potassium channels in pancreatic beta cells to inhibit insulin secretion and potentially increasing hepatic glucose production andinhibiting glucose uptake, Diazoxide is able to increase blood glucose level effectively.2 In this case, Diazoxide was applied to control the symptomsof hypoglycemia from beginning, until everolimus was used. An effective result of glycemic control was achieved. Blood glucose level of the patientwas controlled in normal range for 8 months.

Somatostatin analogs (octreotide, lanreotide) are known for their ability to exert both anti-pr oliferative and symptom-contr olling effect by activationof somatostatin receptors (SSTR), and are thus commonly used in treatments for neuroendocrine tumors. The hyperglycemic effect of somatostatinanalogs relies mainly on activation of the SSTR2. However, in the cases that SSTR2 is low expressed or not expressed at all in insulinoma, moresevere hypoglycemia could be paradoxically caused by somatostatin analogs due to inhibition of glucagon secretion.3 Therefore, somatostatinanalogs should be applied with caution in tr eating patients with insulinoma.

The role of chemotherapy in NETs has evolved in recent years. Systemic chemotherapy is one of different treatment options in pancreatic NETs,especially in progressive NET or in patients with high tumor burden. Temozolomide/capecitabine (Captem) regimen, as a replacement of STZ/5-FU,is gaining popularit y in the recent 10 years. Objective response rates ranging from 15% to 70% were achieved in several retrospective studies inpancreatic NET treatment with Captem regimen. Some studies indicated that MGMT deficiency in tumor tissues is correlated with tumor response totemozolomid-based chemotherapy. However, due to limited clinical evidence, MGMT deficiency is not yet established as predictor for the efficacy oftemozolomid-based chemotherapy in NETs.4 Thus, although positive staining for MGMT was shown in this case, effective result of tumor growthcontrol was still achie ved by the use of Captem r egimen.

Everolimus, a mTOR-tar geted drug, suppresses tumor proliferation by inhibiting mTOR, which is a component of signaling pathways regulating cellsurvival and growth, as well as angiogenesis. Two randomized clinical studies showed that everolimus was effective in the treatment of advancedpancreatic NET.5,6 Stomatitis, rash, diarrhea and fatigue were commonly observed as adverse effects of everolimus, but most adverse events weregrade 1 or 2. Another observed side effect in clinical studies of everolimus was hyperglycemia, which can be taken advantage of to increase bloodglucose level in treatment of insulinoma. 5

For malignant insulinomas with liver metastasis, metastatic lesions in liver comprise the main tumor burden in most cases, and most metastaticNETs are highly vascular, deriving their blood supply mainly from the hepatic arterial circulation. 7 It is necessary to reduce tumor burden in liverthrough interventional therapies so as to control refractory neuroendocrine symptoms. Interventional therapies, including liver-dir ectedembolotherapies and thermal ablation, have demonstrated efficacy for tumor burden reduction and symptom relief.8 Although thermal ablation candestroy hepatic lesions completely, the majority of patients with metastatic NETs, who have diffused liver metastasis, are not suitable for ablationtherapy which requires single or few lesions with diameters no more than 3 cm. Therefore, trans-ar terial chemoembolization (TACE) and trans-arterial embolization (TAE) are commonly chosen as regional therapy for liver metastasis of NETs. As no significant superiority of TACE over TAE wasobserved in treatment efficacy and chemotherapeutics might cause additional toxicities, TAE is regarded as an appropriate approach for tumorburden reduction. 9 In our experience, it is important to perform super-selectiv e embolization. The catheter should be super-selectiv ely guided tosecond arterial branches or further to inject embolization agents. Solid embolization agents such as microspheres, PVA and gelfoam particles,instead of lipiodol, should be used in TAE procedures for more complete embolization effect (Figure 4). Two to four cycles of TAE should beperformed to ensure ischemia inside tumors, leading to tumor necrosis to a maximal extent, thus achieving a relatively long-term control of tumorgrowth and neuroendocrine symptoms in the pr esence of combined systemic therapies.

FIGURES

FIGURE 1

A. 68Ga-DO TA-somatostatin analog-PET/CT showed the primar y tumor in the head of pancr eas (red arrow) and metastases in liver (yellow arrow).

B. 18F-FDG PET/C T showed the primar y tumor in the head of pancr eas (red arrow) and metastases in liver (yellow arrow).

FIGURE 2

A. CT scan for hepatic metastases (arrow) on admission. B. CT scan for hepatic metastases after 3 cycles of TAE.

FIGURE 3 Skin rash after administration of everolimus

FIGURE 4

A. Digital subtraction angiography (DSA) showed metastatic lesions and arterial branches in liv er before embolization. B. Angiography after embolization by 40-120 μm micr ospheres and 100-300 μm PVA.

REFERENCES

01 Wang YH, Lin Y, Xue L, Wang JH, Chen MH, Chen J. Relationship between clinical characteristics and survival of gastroenteropancreaticneuroendocrine neoplasms: A single-institution analysis (1995-2012) in South China. BMC Endocr Disor d. 2012;12:30.

02 Matej A, Bujwid H, W roński J. Gly cemic control in patients with insulinoma. Hormones (A thens). 2016;15(4): 489–499.

03 Baudin E. Caron P, Lombard-Bohas C, et al. Malignant insulinoma: recommendations for characterisation and treatment. AnnEndocrinol (P aris). 2013;74:523–533.

04 Pavel M, O'Toole D, Costa F, et al. ENETS consensus guidelines update for the management of distant metastatic disease of intestinal,pancreatic, bronchial neur oendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology . 2016;103(2):172–185.

05 Yao JC, Shah MH, Ito T, et al. Everolimus for adv anced pancreatic neuroendocrine tumors. N Engl J Med. 2011;364(6):514–523.

06 Yao JC, Lombard-B ohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumorsafter failure of cytotoxic chemotherap y: a phase II trial. J Clin Oncol. 2010;28(1):69–76

07 Proye C. Natural history of liver metastasis of gastroenteropancreatic neuroendocrine tumors: place for chemoembolization. World JSurg. 2001;25(6):685–688.

08 Vogl TJ. Naquib NN, Zangos S, et al. Liver metastases of neuroendocrine carcinomas: Interventional treatment via transarterialembolization, chemoembolization and thermal ablation. E ur J Radiol. 2009:72(3):517–528.

09 Fiore F, Del Prete M, Franco R, et al. Transarterial embolization (TAE) is equally effective and slightly safer than transarterialchemoembolization (T ACE) to manage liver metastases in neur oendocrine tumors. Endocrine. 2014;47(1):177–182.

CASE DESCRIPTION

A 30-y ear-old man was admitted to this hospital in October 2016 because of a six-month history of diarrhea and fatigue. The patient had been in hisusual state of health until 6 months before admission to this hospital, when he developed watery diarrhea with frequency of more than 10 times perday, with no abdominal pain, blood or mucus, nausea or vomiting. He also noted fatigue and weight loss of 5 kg. He had no family history of cancer.Two months later, the patient was admitted to a local hospital. He was tr eated with Berberine and le vofloxacin, but symptoms were not relieved.

Six months later, the patient was admitted to our hospital. The laboratory test results were as follows: the serum potassium was 2.1 mmol/L (normal3.5-5.5 mmol/L), serum calcium was 3.17 mmol/L (normal range 2.11-2.62 mmol/L), serum sodium 130 mmol/L (normal range 137-147 mmol/L).Serum chlorine and phosphorus was normal and urinary potassium and calcium were normal, and serum calcitonin was 0.948 pmol/L (normal range1.575-6.825 pmol/L). Serum alkaline phosphatase, glucose, amylase, lipase, total protein, and albumin were normal. Tumor markers of serum CEAwas 10.2 ng/mL (normal range 0-52 ng/mL), serum CA125 was 48.62 U/mL (normal range 0-35 U/mL), CA199, AFP, NSE, and ProGRP were in thenormal range. Serum aldoster one was 362.7 ng/mL (abo ve the normal range), and 24h urine VM A was 214 (abo ve the normal range), other hormonessuch as thyroid hormones, growth hormone, ACTH, serum cortisol, serum metanephrine and methoxy norepinephrine were all in the normal range.Abdominal CT scanning revealed abnormal thickness in the intestinal wall of duodenal decreased segment, and the structure of head of pancreaswas unclear. There were multiple low-d ensity lesions in the liver. Findings suggested of duodenal carcinoma invading the head of pancreas with livermetastasis (Figure 1). Somatostatin receptor scintigraphy showed abnormal radioactiv e uptake of the intestinal wall of duodenal descendingsegment, head of pancreas and multiple intra-hepatic lesions, which are both considered high expression of somatostatin receptor

histopathology of the liv er biopsy confirmed the diagnosis of neur oendocrine tumor, positive staining for CK, Syn and VIP .

The patient was treated with short-acting octreotide and potassium supplement, after which the symptom of diarrhea was significantly relieved, andserum potassium was maintained in range of 3-3.5 mmol/L. On November 11, 2016, the patient underwent pancreaticoduodenectomy plus hepaticmultiple nodular resection and intraoperativ e radiofrequency ablation. The pathological section of pancreatic duodenum and liver was performed.The primary tumor was neuroendocrine tumor, 5*3 cm, located in the head of pancreas and invaded in the duodenum, with no vessel and nerveinvasion. Lymph node metastasis was 2/18. Immunohistochemistr y (IHC) showed positive staining for CgA, Syn and SSTR2, and VIP positive, Ki-67proliferation index was 3%. Then the diagnosis of this patient was confirmed as neuroendocrine tumor (VIPoma) with lymph node and livermetastasis (G2, T3N1M1, stage IV ).

The serum potassium was back to normal after the operation, and the patient no longer had diarrhea or fatigue. Long- acting octreotide was theninjected every 4 weeks for 6 months, and a follow-up one year post operation showed normal serum potassium and stable disease in livermetastasis on abdominal MRI (Figure 3). The patient was symptom free. After six cycles of long- acting octreotide, the patient refused to receivefurther treatment because of financial issue. The patient was still under positive follow-up.

(Figure 2). The

Authors Heli Gao, Kaizhou Jin, Xianjun Yu

E- mail yuxianjun@fudanpci.org

Institute Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai MedicalCollege, Fudan University, Shanghai 200032, P.R. China; Shanghai Pancreatic Cancer Institute; Pancreatic Cancer Institute,Fudan University

City/Nationality Shanghai, China

Category Case

Upper GI Lower GI Pancreatobiliary tract Others

Title of Case

A case of vasoactive intestinal polypeptide tumor (VIPoma)

DISCUSSION

VIPoma (vasoactive intestinal peptide tumor), also known as Vemer-Morriso n syndrome, is a rare neuroendocrine neoplasm with the incidence rateof one per 10,000,000 per year. Its clinical feature is diarrhea-based disease, caused by the secretion of vasoactive intestinal peptide (VIP). VIP is avasodilator; the biological activity of VIP is activating VIP receptor of intestinal epithelial cells, promoting intestinal C-AMP synthesis, causingintestinal secretion of water and electrolytes, and bile secretion. 80%-90% of VIPoma occurs in the pancreas, especially the tail of the pancreas, so itis also known as " pancreatic cholera”. 1/3 to 1/2 of VIP oma is malignant, and liv er is the major metastasis organ.1

The clinical manifestations of VIPoma are as follows2: ① prolonged watery diarrhea, with fasting stool volume > 750-1,000 mL/day. The diarrhea isnot septic, the onset is slowly and gradually increased for a duration of up to several years, and diarrhea begins as episodes and then graduallybecomes persistent to mor e than 10 times per da y. Severe diarrhea can lead to dehy dration and uncontr ollable electr olyte imbalance and acidosis; ②hypokalemia: due to severe diarrhea, VIPoma can lead to potassium loss from the stool (150~500 mmol/L). ③ No or low stomach acid: VIP caninhibit gastric acid secretion. Other syndromes include muscle weakness, nausea, vomiting and achlorhydria. The lab test of VIPoma includes bloodchemistry tests (electrolyte and comprehensive metabolic panel), stool examination for the cause of diarrhea, and electrolyte and VIP levels in theblood. CT or MRI scan and somatostatin receptor scintigraphy are used to localize the tumor site, which is usually metastatic at diagnosis. In thiscase, we failed to test the VIP level in blood because of the examination limitation. However, The patient’ s signs and symptoms made the clinicalteam consider the extremely rare diagnosis of VIPoma. Somatostatin receptor scintigraphy and abdominal CT showed the primary site of pancreasand liver metastasis. And the IHC of tissue showed the positive of VIP staining.

The treatment for localized VIPoma is surgery to remove the tumor. If the tumor has not spread to other organs, surgery can often cure the condition.For patients who do not accept surgery or are not suitable for surgery, somatostatin analog can also slow the diarrhea and control the diseaseprognosis. Octreotide blocks the action of VIP, and relieves 80%-88% of VIP-caused syndrome, including diarrhea and hypokalemia. 3 For metastaticdisease, traditional hepatic-dir ected therapies, including resection, ablation, hepatic artery embolism, and liver transplantation, are used for livermetastasis. New therapies such as peptide receptor radionuclide therapy (PRRT) can be highly effective, and combined chemotherapy ofcapecitabine and temozolomide seems to show response for some VIPoma patients. 4 Sunitinib and everolimus are also the most promisingtreatments for metastasis disease. 5 Other treatments include correcting dehydration; fluids are often given through a vein (intravenous fluids) toreplace fluids lost in diarrhea. There is no report of surgery in VIPoma patients with liver metastasis. In this case, the patient was diagnosed asVIPoma with type II liver metastasis. Our multidisciplinary team considered the metastasis sites to be resectable. With the resection of primary siteand metastasis sites, the patient recovered well from related syndr ome. We need more cases to study the role of surgery in stage IV VIPoma.

FIGURES

FIGURE 1 Abdominal CT scan before operation A. Mass in the head of pancr eas and duodenum, B. Metastases of the liver, C. Metastases of the liver

 

FIGURE 3 Abdominal MRI scan after operation A. Liver metastases after six months (T2), B. Liv er metastases after one year (T2)

 

FIGURE 2 Somatostatin receptor scintigraphy showed the metastases in the liver (arrow)

REFERENCES

01 Lam S, Liew H, Khor H T, et al. VIP oma in a 37-y ear-old man. Lancet. 2013;382(9894):832

02 Solcia E, Capella C, Riva C, Polak JM. The morphology and neuroendocrine profile of pancreatic epithelial VIPomas andextrapancreatic, VIP-pr oducing, neur ogenic tumors. Ann N Y Acad Sci. 1988;527:508–517.

03 Lebowitz-Amit R, Mete O, Asa SL, Ezzat S, Joshua AM. Malignant pheochromocytoma secreting vasoactive intestinal peptide andresponse to sunitinib: a case r eport and literatur e review. Endocrine Practice. 2014;20(8):145–150.

04 Belei OA, Heredea ER, Beriu E, et al. V erner–Morrison syndr ome. Literatur e review. Rom J Morphol Embryol. 2017;58(2):371–376.

05 de Mestier L, Walter T, Brixi H, Lombard-Bohas C, Cadiot G. Sunitinib achieved fast and sustained control of VIPoma symptoms . Eur JEndocrinol. 2015;172(1):K1–K3.