Giant insulinoma: report of a case and review of published reports

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1 Ued et l. Surgicl Cse Reports (2016) 2:136 DOI /s z CASE REPORT Gint insulinom: report of cse nd review of pulished reports Open Access Kzumitsu Ued *, Tetsuro Tir, Hiroyuki Hkod, Shoko Nkt, Shiny Okt, Tkeshi Ngi, Shigeo Aoki, Hideyuki Mishim, Akihiko Sko, Tsunehiko Mruym nd Minoru Okumur Astrct Bckground: Lrger insulinoms re reportedly more likely to e mlignnt; however, their iologicl ehvior hs not een clerly elucidted. We here report the chrcteristics nd tretment of gint insulinom with locl invsion nd lymph node metstsis. We lso review pulished reports concerning the clinicl fetures of gint insulinoms nd compring their grding with tht of pncretic neuroendocrine tumors. Cse presenttion: A 71-yer-old mn ws referred to our hospitl for investigtion of persistent hypoglycemi. On the current presenttion, lortory tests showed serum glucose, immunorective insulin, nd C peptide concentrtions of 45 mg/dl, 17.2 μiu/ml nd 4.1 ng/ml, respectively. Dynmic mgnetic resonnce imging showed hypervsculr tumor mesuring 13.5 cm in the hed of the pncres. Computed tomogrphy scnning demonstrted locl invsion nd lymph node involvement. He thus hd Whipple s trid, which is ssocited with mlignnt insulinom. No distnt metstses hving een identified, pncreticoduodenectomy ws performed. Intropertively, three seprte tumors were identified in the pncretic hed. Pthologicl exmintion showed ll three tumors were pncretic neuroendocrine tumors; the tumor cells in the lrgest mss were strongly immunorective for insulin. The Ki-67 index ws 2 5% in most prts of the lrgest tumor nd over 20% in the poorly differentited res. This tumor ws clssified s neuroendocrine crcinom in ccordnce with the 2010 World Helth Orgniztion clssifiction of pncretic endocrine neoplsms. He remins free of evidence of recurrence 2 yers postsurgery. A review of pulished reports indicted tht gint insulinoms re more mlignnt thn smller ones, nd metsttic disese is found on presenttion in 56% of ptients with gint insulinoms; however, we were unle to identify ny correltion etween grde of pncretic neuroendocrine tumor nd iologicl ehvior of gint insulinoms. Conclusions: Gint insulinoms more frequently exhiit mlignnt ehvior, such s locl invsion, lymph node involvement, nd liver metstsis, thn smller ones. However, there ws no reltionship etween grde nd rte of metstses or survivl in this smll cse series. Identifiction of useful iologicl mrkers is necessry. Keywords: Gint insulinom, Mlignnt insulinom, Pncretic neuroendocrine tumor, Ki-67 index, Grde Bckground Insulinoms re the commonest functioning pncretic neuroendocrine tumor (pnet); their estimted nnul incidence eing one to three cses per million [1]. Approximtely 10% re multiple nd pproximtely 5% re ssocited with multiple endocrine neoplsi type 1 (MEN1) syndrome [2]. Their men size is 1.5 cm; 24% re smller thn 1 cm, 42% 1 2 cm, 30% 2 3 cm, nd pproximtely 4% >3 cm [3]. Mlignncy is defined y the presence of * Correspondence: kfureyuhryo@gmil.com Deprtment of Surgery, Hitchi Generl Hospitl, Jonn-cho, Hitchi, Irki , Jpn metstses, most commonly in lymph nodes or the liver; the clinicl presenttion chrcteristiclly does not enle differentiting enign from mlignnt disese [4]. Clinicopthologicl evidence of mlignnt ehvior (gross locl invsion or metstses) is extremely rre in insulinoms, occurring in only 5 10% of ll insulinoms; thus, most cn e surgiclly cured [2]. Lrger insulinoms re more likely to e mlignnt [5]; however, their iologicl ehvior hs not een clerly elucidted. Some uthors hve defined gint insulinoms s 9 cm in lrgest dimension [6, 7]. We here report the chrcteristics nd tretment of gint insulinom with The Author(s) Open Access This rticle is distriuted under the terms of the Cretive Commons Attriution 4.0 Interntionl License ( which permits unrestricted use, distriution, nd reproduction in ny medium, provided you give pproprite credit to the originl uthor(s) nd the source, provide link to the Cretive Commons license, nd indicte if chnges were mde.

2 Ued et l. Surgicl Cse Reports (2016) 2:136 Pge 2 of 7 peripncretic locl invsion nd lymph node metstsis nd present review of pulished reports. Cse presenttion A 71-yer-old mn ws referred to our hospitl for investigtion of hypoglycemi. Two yers efore, he hd ttended the emergency deprtment with cute-onset loss of consciousness fter trffic ccident. Hypoglycemi ws identified s the cuse; however, ecuse his condition hd quickly improved, he ws not extensively investigted nd ws dischrged without definitive dignosis. Since then, he hd recurrent hypoglycemi ssocited with impired consciousness. In the four preceding months, his serum glucose concentrtions hd een less thn 67 mg/dl nd he hd een given intrvenous glucose, which resulted in grdul resolution of symptoms. On this presenttion, his serum glucose, immunorective insulin nd C peptide concentrtions were 45 mg/dl, 17.2 μiu/ml, nd 4.1 ng/ml, respectively. MEN-1 syndrome ws excluded y norml serum intct prthyroid hormone, clcium, nd prolctin concentrtions. He thus hd Whipple s trid (symptoms known or likely to e cused y hypoglycemi, low serum glucose t the time of the symptoms, relief of symptoms when the glucose hs incresed to norml). To confirm the dignosis of endogenous hyperinsulinemi cused y insulinom, the ptient underwent supervised overnight fst during which he developed symptomtic hypoglycemi with serum glucose of 50 mg/dl. Dynmic mgnetic resonnce imging showed 13.5 cm 12 cm 8 cm hypervsculr tumor contining necrotic res in the pncretic hed (Fig. 1). Mgnetic resonnce cholngiopncretogrphy showed no involvement of the pncretoiliry systems (Fig. 1). Computed tomogrphy scn demonstrted heterogenous, enhncing, prtly necrotic mss prtilly replcing the hed of the pncres (Fig. 2). There ws no evidence of heptic metstsis; however, locl invsion of the surrounding dipose tissues nd duodenum nd lymph node involvement were identified (Fig. 2). This ptient s pncretic ody nd til were slender, mesuring 2 cm 1.5 cm 5 cm; no other tumors were identified in them (Fig. 2c). No distnt metstses hving een identified; extended pncretic resection ws performed. Intropertively, one ulky tumor nd two dditionl undignosed tumors were identified in the hed of the pncres. Mnul plption y n experienced surgeon reveled no tumor in the pncretic ody nd til. One 3.5-cm dimeter pedunculted lesion ws suspended from the surfce of the uncinte process of the pncres, nd nother 2-cm dimeter tumor ws ttched to the duodenum. The ptient underwent sutotl stomchpreserving pncreticoduodenectomy. Fig. 1 Dynmic mgnetic resonnce imge showing cm hypervsculr tumor contining necrotic res in the pncretic hed (). Mgnetic resonnce cholngiopncretogrphy showing no evidence of involvement of pncretoiliry trees () Mcroscopiclly, the lrgest tumor mesured cm nd ws firmly dherent to the retroperitoneum (Fig. 3). Cut sections showed solid lesion with evidence of hemorrhge (Fig. 3). All three tumors were composed of uniform lnd cuoidl cells with grnulr eosinophilic cytoplsm nd round nuclei. Most of the lrgest mss comprised well-differentited tumor cells (Fig. 4); however, poorly differentited tumor cells were identified in smll prt of it (Fig. 4). The retroperitonel ft tissues nd duodenum were involved, nd metstses were identified in two of four peripncretic lymph nodes. Immunohistochemiclly, the tumor showed strong diffuse expression of chromogrnin A, insulin, nd glucgon nd wek expression of somtosttin. The Ki-67 index ws 2 5% in most of the lrgest tumor (Fig. 4c) ut over 20% in the poorly differentited res (Fig. 4d). This tumor ws clssified s NEC in ccordnce with the 2010 World Helth Orgniztion (WHO) clssifiction of pncretic endocrine neoplsms. Postopertively, moderte pncretic fistul developed. This resolved with conservtive tretment nd he ws dischrged on postopertive dy 35. At routine

3 Ued et l. Surgicl Cse Reports (2016) 2:136 Pge 3 of 7 c Fig. 3 Mcroscopic findings. Three seprte tumors re present in the hed of the pncres, nmely, the lrgest, which ws firmly dherent to the retroperitoneum, 2 2 cm tumor, which ws dherent to the duodenum (rrow), nd cm pedunculted tumor tht ws suspended from the surfce of the uncinte process of the pncres (rrowhed) (). The lrgest mss mesured cm nd the cut surfce showed solid tissue with hemorrhgic res () Fig. 2 Computed tomogrphy scn imge demonstrting heterogenous enhncing mss with res of necrosis replcing the hed of the pncres (). Computed tomogrphy scn imge demonstrting locl invsion into the peripncretic retroperitoneum nd duodenum (rrowhed) nd lymph node involvement (rrow) (). No other hypervsculr insulinoms were identified in the pncretic ody nd til (rrow) (c) follow-up visit 3 months postopertively, he reported no hypoglycemic symptoms, nd he remins free of evidence of recurrence 2 yers nd 3 months fter surgery. Discussion Becuse it hs een difficult to differentite etween enign nd mlignnt insulinoms on the sis of histologic findings, mlignnt insulinoms hve een dignosed sed on metstsis to liver, lymph nodes, or other orgns [2]. However, the new 2010 WHO Clssifiction of Tumors of the Digestive System considers ll insulinoms of 0.5 cm or greter mlignnt tumors [8]. According to the 2010 Europen Neuroendocrine Tumor Society guidelines, the most criticl prognostic fctors re the prolifertive rte (mitotic index or Ki-67 leling index) nd the presence of distnt metstses [9]. Surgery is the only potentilly curtive tretment for mlignnt insulinom dignosed t loclly dvnced stge [10]. The medin disese-free survivl fter curtive resection is 5 yers; recurrence occurs in more thn 60% of ptients t medin intervl of yers [2]. Ptients with distnt metstses from insulinoms to the liver, one, nd lymph nodes hve medin survivl of <2 yers [11]. Cllcondo et l. [12] reviewed 35 cses of gint insulinom nd reported tht they re more likely to e mlignnt thn non-gint insulinoms; however, the reltionship etween clinicl fetures, pnets grding, nd G1/G2/ NECs hs not een elucidted. In ll, we reviewed 45 cses

4 Ued et l. Surgicl Cse Reports (2016) 2:136 Pge 4 of 7 c d Fig. 4 Well-differentited tumor cells were oserved in most prts of the tumor (); however, poorly differentited tumor cells were identified in smll proportion of it ().TheKi67indexws2 5% in most of the tumor (c); however, the poorly differentited re hd Ki67 of over 20% (d) of gint insulinom comprising the 35 cses of Cllcondo et l., n dditionl 9 cses [4, 5, 13 19] nd the present cse (Tle 1). We lso investigted the reltionship etween recurrence rtes nd grde in reported cses (Tle 2). We performed PuMed serch nd Jpnese MEDLINE dtses (during the period of ) using the keywords: gint insulinom, mlignnt insulinom, nd pncretic neuroendocrine tumor nd limited our review to reports in English- nd Jpneselnguge pulictions, including cse reports. The men ge t presenttion of the 45 ptients with gint insulinom ws 57 yers (rnge, yers), nd Tle 1 Clinicl fetures of 45 reported pncretic gint insulinoms Vriles Age (men) (57) yers Sex (M:F) 1.14:1 Tumor dimeter (men) 9 21 (12) cm Loction H/HB/B/BT/T/HBT/NA 3/1/2/13/22/1/3 Tretment for primry disese DP (+/ S)/DP+ RLM/DP+ ALM 23/2/2 PD/TP/E/TR/iopsy/NO/NA 3/1/1/4/3/5/1 Metsttic sites Generlized/liver/LN, surround 6/7/12 Recurrences/remnnt/none 8/11/26 Recurrent sites Generlized/liver/locl 2/4/1 Tretment of recurrences or remnnt Surgery/Syst chemo/hace/rt/none/na 3/2/2/2/1/7 Outcome (n) Durtion of follow-up (men) months No disese recurrence (24) (18) Alive with disese (6) (48) Died of metsttic disese (10) (24) Died of other disese (1) NA NA (4) NA H hed, HB hed nd ody, B ody, BT ody nd til, T til, HBT hed, ody nd til, NA not ville, DP distl pncretectomy, +/ with/without, S splenectomy, RLM resection for liver metstses, ALM ltion of liver metstses, PD pncreticoduodenectomy, TP totl pncretectomy, E enucltion, TR tumor resection, Biopsy iopsy of pncretic or liver tumor, NO no opertion, Generlized involvement of the liver nd one or more of the following orgns: drenl glnds, spleen, stomch, nd colon, LN lymph node, Surround surrounding tissue, Remnnt remnnt disese, Syst chemo systemic chemotherpy, HACE heptic rteril chemoemoliztion, RT rdition therpy

5 Tle 2 Clinicopthologicl fetures nd grde of gint insulinoms in reports pulished since 2001 Author [ref]/yer Age Sex Size (cm) Loction Surgery Ki-67 (%) Mitosis Differentition Grde Met site t dignosis Recurrences Follow-up (months) Konno [14]/ F 10.5 Til DP, S <2 NA NA 1 None None NDR (24) Mittendorf [6]/ F 9 Til Tumor resection >2 <1 W 2 None None NDR (6) Esten [12]/ F 10 Til DP 20 NA W NEC None None NDR (31) Reg [12]/ M 15 Body/til DP, S 5.4 NA WDEC 2 Surround, LN None NDR (3) Sugiym [7]/ M 12 Hed PD W 1 Surround None NDR (12) Mtkri [12]/ M 11 Hed E >2 NA W 2 None None NDR (12) Prmodh [12]/ M 9.8 NA NO <5 NA WDEC 2 None None DOD (NA) Oerheim [21]/ F 13.5 Hed/ody PpPD <1 1 W 1 None None NDR (12) Cllcondo [12]/ F 15 Til DP, S, RLM <1 <1 W 1 Liver Liver AD (60) Cllcondo [12]/ M 10 Til DP, S <2 5 W 1 LN Liver NDR (43) Cllcondo [12]/ M 11 Til DP, S, RLM <2 3 W 2 Spleen, liver Liver DMD (156) Ielpo [13]/ F 14 Til DP >20 NA Por NEC NA None NDR (72) Eguchi [16]/ F 12 Til DP, S NA NA NA 1 None NA NDR (4) Fenech [17]/ F 16 Til DP, S NA <2 W 1 Surround None NA Present cse/ M 15 Hed SSpPD >20 >20 Por NEC Surround, LN, duodenum None NDR (24) Krvis [5]/ F 17 Body/til DP, S, RMD NA 10 NA 2 Lt-kidney, Lt drenl, PALN, None NDR (60) liver, omentum Vsiksin [18]/ M 12.5 Til DP, S NA 1 None None NDR (6) Mrtino [19]/ F 21 Hed/ody/til Deulking >15 15 NA 2 Surround, LN, liver, xillry, nd medistinl Remnnt AD (36) Ki-67 Ki-67 index, Mitosis mitoses per 10 high-power fields, Met Site metsttic sites, DP distl pncretectomy, S splenectomy, NA not ville, W well-differentited neuroendocrine tumor, NDR no disese recurrence, NEC neuroendocrine crcinom, WDEC well-differentited neuroendocrine crcinom, Surround surrounding dipose tissue, LN lymph node, PD pncreticoduodenectomy, E enucltion, NO no opertion, DOD died of other disese, PpPD pylorous-preserving PD, RLM resection of liver metstses, AD live with disese, DMD died of metsttic disese, Por poorly differentited neuroendocrine tumor, SSpPD sutotl stomch-preserving PD, PALN pr-ort LN, Deulking totl pncretectomy with splenectomy, prtil gstrectomy, nd cholecystectomy, RMD resection of metsttic diseses, Remnnt remnnt liver, xillry, nd medistinl metstses Ued et l. Surgicl Cse Reports (2016) 2:136 Pge 5 of 7

6 Ued et l. Surgicl Cse Reports (2016) 2:136 Pge 6 of 7 there ws slight mle prepondernce (mle/femle rtio, 1.14:1). Those ptterns re similr to those of non-gint insulinoms. Tumor loction within the pncres ws ville for 42 ptients. Tumors in single segment of the pncres hd predilection for the til (n = 22); involvement of oth the ody nd til ws seen in 12 ptients. Gint tumors occur more frequently in the ody nd til of the pncres ecuse they cn grow freely there without cusing mss effects or mechnicl ostruction [12]. Even huge msses in the hed of the pncres rrely present with gstric outlet ostruction or ostructive jundice ecuse insulinoms generlly enlrge slowly nd do not mssively invde djcent vitl orgns. Surgicl resection hd een performed in 36 (81.8%) of ll cses studied; the procedures comprising distl pncretectomy (comined with resection or ltion of heptic metstses) in 23 (4) cses, pncreticoduodenectomy in 3, tumor resection in 5, nd totl pncretectomy in 1 cse. No ptient hd undergone comined resection nd reconstruction of the portl vein or heptic rtery. Complete resection should e performed; however, removing 90% of the tumor is cceptle. Surgery is justified for functionl dvnced neuroendocrine tumors, the ims eing to control symptoms, improve qulity of life, nd extend survivl rte compred with conservtive tretment [19]. Seven of 19 ptients with metstses or recurrence hd received sequentil multimodl therpy (systemic chemotherpy, chemoemoliztion, ltion, nd resection of liver metstses). These ggressive therpies cn prolong the survivl of ptients with mlignnt insulinom, even in the presence of liver metstses [20]. The dimeter of these ptient s tumors rnged etween 9 nd 21 cm (medin, 12 cm). Most insulinoms ecome symptomtic when very smll, llowing erly detection nd prompt surgicl tretment, possily efore they cn metstsize. The severity of hypoglycemi vries from ptient to ptient nd hs no direct reltionship with tumor urden [10]. Sugiym et l. [7] suggested tht gint insulinom initilly dignosed s non-functioning pnets my secondrily ecome functioning. Twenty-five (55.6%) of the cses of gint insulinom reviewed hd metstses t presenttion, this percentge eing higher thn the 10% reported in most insulinom series [2]. At the first surgery, six ptients hd involvement of the multiple orgns, seven hd liver metstses only, nd 12 hd loclly dvnced disese such s invsion of the surrounding dipose tissues or/nd lymph node involvement. Eight cses hd developed recurrences, the mjor site of metstses eing the liver. Follow-up dt were ville for 41 of the pulished cses. Durtion of follow-up of 24 cses who hd no recurrences rnged etween 3 months nd 23 yers (medin 18 months). Seven cses of the 11 ftl cses were reported efore The overll survivl of ll ptients who died with disese rnged etween 1 month nd 13 yers (medin, 2 yers), wheres ptients of non-gint mlignnt insulinom with distnt metstses hd medin survivl of <2 yers [11]. Six cses live with disese hd een followed-up for 15 months to 17 yers (medin, 4 yers). Since 2001, the mitotic ctivity, Ki-67 index, nd grde hve een reported for 17 ptients with gint insulinoms (Tle 2) [5 7, 12 14, 16 19, 21]. We compred the grde, the rte of metstses nd durtion of follow-up of 18 cses, including the present cse. The Ki-67 index ws <2% in eight cses; the only three cses with Ki- 67 index of 20%weredignosedshvingNECs.Four, three, nd one ptient hd no metstses from G1/G2/ NEC t surgery, respectively, wheres four, four, nd one hd synchronous metstses, respectively. Unexpectedly, there ws no difference in proportion of G1/ G2/NEC in ptients with versus without synchronous metstses. The medin durtions of follow-up y grde were s follows: 12 months (G1), 12 months (G2), nd 31 months (NEC); the durtion of follow-up for NECs eing longer thn expected. We nticipted tht ptients with gint insulinom nd higher Ki-67 indexes would hve worse prognoses; however, we identified no reltionship etween grde nd survivl. In our smll cse series, we were unle to identify ny correltion etween grde nd iologicl ehvior of gint insulinoms. Conclusions Gint insulinoms more frequently exhiit mlignnt ehvior, such s locl invsion, lymph node involvement, nd liver metstsis, thn smller ones. Metsttic disese is present t surgery in 56% of cses of gint insulinom. Unexpectedly, there ws no reltionship etween grde of pnet nd rte of metstses or survivl in this smll cse series. Identifiction of useful iologicl mrkers is necessry, s is development of nti-tumor gents for liver metstses. Authors contriutions KU nd TM performed the opertion. KU, TT, HH, SN, SO, TN, SA, HM, AS, TM, nd MO were involved in the tretment of the ptient. KU nd TT prepred the mnuscript conducted the literture serch. All uthors red nd pproved the finl mnuscript Competing interests The uthors declre tht they hve no competing interests. Consent for puliction Written informed consent ws otined from the ptient for puliction of this cse report nd ll ccompnying imges. Received: 10 August 2016 Accepted: 11 Novemer 2016

7 Ued et l. Surgicl Cse Reports (2016) 2:136 Pge 7 of 7 References 1. Vnderveen K, Grnt C. Insulinom. Cncer Tret Res. 2010;153: de Herder WW, Niederle B, Scozec J-Y, Puwels S, Klöppel G, Flconi M, et l. Well-differentited pncretic tumor/crcinom: insulinom. Neuroendocrinology. 2006;84: Psiek JL, McLeod MK, Thompson NW, Burney RE. Surgicl pproch to insulinoms: ssessing the need for preopertive locliztion. Arch Surg. 1992;127: Ferrer-Grci JC, Gonzlez-Cruz VI, Nvs-DeSolis S, Civer-Andres M, Morills-Arino C, Merchnte-Alfro A, et l. Mngement of mlignnt insulinom. Clin Trnsl Oncol. 2013;15: Krvis D, Heos I, Mroulis I, Klogeropoulou C, Tsmnds A, Chveles I, et l. Gint mlignnt insulinom. Ann Surg Tret Res. 2015;88: Mittendorf EA, Liu YC, Mcheny CR. Gint insulinom: cse report nd review of the literture. J Clin Endocrinol Met. 2005;90: Sugiym T, Kouym R, Tni Y, Izumiym H, Akshi T, Kishimoto S, et l. Gint mlignnt insulinom which developed from non-functioning pncretic tumor over long period of time. Inter Med. 2010;49: Rindi G, Arnold R, Bosmn FT, Cpell C, Klimstr DS, Klöppel G, et l. Nomenclture nd clssifiction of neuroendocrine neoplsms of the digestive system. In: Bosmn FT, Crneiro F, Hrun RH, editors. WHO clssifiction of Tumors of the Digestive System. Lyon: IARC; p Klimstr DS, Modlin IR, Coppol D, Lloyd RV, Suster S. The pthologic clssifiction of neuroendocrine tumors: review of nomenclture, grding, nd stging system. Pncres. 2010;39: Budin E, Cron P, Lomrd-Bohs C, Trin A, Mitry E, Reznick Y, et l. Mlignnt insulinom: recommendtions for chrcteriztion nd tretment. Ann Endocrinol. 2013;74: Dnforth Jr DN, Gorden P, Brennn MF. Metsttic insulin-secreting crcinom of the pncres: clinicl course nd the role of surgery. Surgery. 1984;96: Cllcondo D, Arens JL, Gnoz AJ, Rojs-Cmyo J, Quesd-Olrte J, Roledo H. Gint insulinom. A report of 3 cses nd review of the literture. Pncres. 2013;42: Ielpo B, Cruso R, Ferri V, Quijno Y, Durn H, Diz E, et l. Gint pncretic insulinom. The igger the worse? Report of two cses nd literture review. Int J Surg Cse Rep. 2013;4: Konno F, Miur K, Kwri S, Sw N, Okmoto M, Ae K, et l. A cse of gint insulinom with physicl nd mentl growth deficiency [in Jpnese]. Gek Chiryo. 2001;84: Mori R, Misut K, Mtsuym R, Hsegw S, Ntori S, Hsegw S, Nkno A, et l. A cse of islet cell tumor with wide invsion to the spleen [in Jpnese]. Jpn J Gstroenterol Surg. 2004;37: Eguchi T, Miyuchi S, Ueno Y, Kiyochi H, Mtsukge S. A lrge insulinom in ptient with postopertive hyperglycemi due to decresed insulin: cse report [in Jpnese]. J Jpn Di Soc. 2013;56: Fenech VA, Ellul P, Ael A, Crun C, Cssr M, Lferl G. A rre finding of rre disese. A cse report of gint insulinom. Pncres. 2013;42: Vsiksin V, Wtthnthm J, Npthrtip P, Temmthurpoj S. Gint insulinom in 15-yer-old mn: cse report. Int J Surg Rep. 2016;24: Di Mrtino M, Grci Snz I, Delgdo Vlduez J, Mrtin-Perez E. Gint mlignnt insulinom. J Gstrointest Surg. 2016;20: Okyshi T, Shim Y, Sumiyoshi T, Kozuki A, Ito S, Ogw Y, et l. Dignosis nd mngement of insulinom. World J Gstroenterol. 2013;19: Oerheim NAE, Kim A, Frks RL, Run DT, Schoeniger LO, Schiffhuer LM, et l. Gint pncretic tumor with clinicl chrcteristics of insulinom ut without common pthologic fetures. Endocr Prct. 2011;17:e12 6. Sumit your mnuscript to journl nd enefit from: 7 Convenient online sumission 7 Rigorous peer review 7 Immedite puliction on cceptnce 7 Open ccess: rticles freely ville online 7 High visiility within the field 7 Retining the copyright to your rticle Sumit your next mnuscript t 7 springeropen.com

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