Neuroendocrine Carcinoma with an Adenocarcinoma Component on the Ampulla of Vater Causing Acute Pancreatitis: A Case Report
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1 CASE REPORT Neuroendocrine Crcinom with n Adenocrcinom Component on the Ampull of Vter Cusing Acute Pncretitis: A Cse Report Reiko Ymd 1, Kenichiro Nishikw 2, Msshi Kishiwd 3, Hiroyuki Inoue 1, Tkshi Skuno 1, Tetsuro Hrd 1, Nohiko Yoshizw 1, Shinichi Kojim 1, Hiroshi Miur 1, Miski Nkmur 1, Mski Ktsurhr 4, Ysuhiko Hmd 4, Kyosuke Tnk 4, Noriyuki Horiki 4, Yoshiyuki Tkei 1, Shuji Isji 3 Deprtment of 1 Gstroenterology nd Heptology, Mie University Grdute School of Medicine, Tsu, Jpn Deprtment of 2 Gstroenterology, Mtsusk City Hospitl, Mtsusk, Jpn Deprtment of 3 Heptoiliry Pncretic nd Trnsplnt Surgery, Mie University Grdute School of Medicine, Tsu, Jpn Deprtment of 4 Endoscopy, Mie University Grdute School of Medicine, Tsu, Jpn ABSTRACT We encountered rre cse in which 14 mm mpullry tumor hd oth components of neuroendocrine crcinom nd denocrcinom, which cused cute pncretitis. A Sixty-one-yer-old womn ws referred to our hospitl for evlution nd tretment of pncretitis due to n unknown cuse. After vrious imging exmintions, the cuse of pncretitis ws found to e duodenl ppillry tumor. We performed endoscopic retrogrde pncretic duct dringe y inserting dringe tue; susequently, her dominl pin ws relieved, nd the pncretic enzyme levels normlized. As the pthologicl findings showed poorly differentited neuroendocrine crcinom, pncreticoduodenectomy ws performed. As liver nd lymph node metstses were found 3 months postopertively, she underwent chemotherpy. Although she chieved complete remission once, metstses relpsed nd she died of progressive disese 28 months postopertively. Histologicl exmintion showed tht the tumor comprised two elements: the min component (99.5%) ws neuroendocrine crcinom, nd the minor component ws denocrcinom. The denocrcinom component ws oserved only in the mucosl lyer, wheres the neuroendocrine component invded the sumucos or deeper lyer. It is speculted tht denocrcinom hd risen first from the epithelium, nd then it cquired neuroendocrine differentition cpilities during growth. Although some reports hve proposed tht neuroendocrine components hve more ggressive fetures thn denocrcinom components, it is still uncler whether the neuroendocrine or denocrcinom component is the min driving force of disese progression. Neuroendocrine crcinom with n denocrcinom component is highly ggressive nd ssocited with high risk for distnt metstsis nd poor prognosis, s in the present cse. INTRODUCTION Neuroendocrine crcinoms (NECs) with n denocrcinom component on the mpull of Vter re very rre. The 2010 edition of the World Helth Orgniztion clssifiction of tumors of the digestive system proposed concept clled mixed denoneuroendocrine crcinoms (MANECs); MANECs re defined s hving two mlignnt components, neuroendocrine nd glnd-forming epithelil cells, nd ech component exceeds 30% of the tumor [1]. The cse we discuss herein hd neuroendocrine Received Mrch 25th, 2017-Accepted April 26th, 2017 Keywords Adenocrcinom; Ampull of Vter; Crcinom, Neuroendocrine; Pncretitis Arevitions MANECs mixed denoneuroendocrine crcinoms; NECs neuroendocrine crcinoms Correspondence Reiko Ymd Deprtment of Gstroenterology Mie University Grdute School of Medicine Edoshi, Tsu, Mie, , Jpn Tel Fx E-mil reiko-t@clin.medic.mieu.c.jp nd denocrcinom components, lthough the neuroendocrine component occupied 99.5% of the whole tumor. Even if tumor does not meet the criteri, n mpullry tumor with oth NEC nd denocrcinom components is rre. The common symptom of mlignncy on the mpull of Vter is pinless jundice or dominl pin [2]. We found tht NEC with n denocrcinom component triggered cute pncretitis in our ptient. It is reltively rre for duodenl ppillry tumor to cuse cute pncretitis [3]. Herein, we descrie our experience with rre ptient with 14 mm mpullry tumor tht hd oth components of NEC nd denocrcinom, which cused cute pncretitis. CASE REPORT A Sixty-yer-old womn ws referred to our hospitl for evlution of cute pncretitis. She hd presented to the referring hospitl with severe, continuous dominl pin. Results of initil lortory tests showed incresed mylse (783 IU/L) nd lipse (1540 U/L) levels, s 297
2 well s incresed totl iliruin (1.3 mg/dl), sprtte minotrnsferse (61 IU/L), lnine minotrnsferse (81 IU/L), lkline phosphtse (727 IU/L), nd C-rective protein levels (2.13 mg/dl). Initil serum tumor mrkers showed norml serum level of crcinoemryonic ntigen (CEA; 1.9 ng/l), pro-gstrin-relesing peptide (Pro-GRP; 64.4 pg/ml), slightly elevted neuron-specific enolse (NSE; 10.8ng/mL), nd elevted crohydrte ntigen 19-9 (CA19-9; U/mL). The dynmic contrstenhnced computed tomogrphy (CT) scn showed pncretic swelling with slight peripncretic fluid effusion. The CT scn lso showed hypervsculr lesion locted in the mpullry region, with diltion of the common ile duct (CBD) nd min pncretic duct (MPD) (Figure 1). The endoscopic ultrsonogrm showed 14 mm 10- mm low echoic mss in the mpullry lesion, which ws round nd well-defined (Figure 2). Upper gstrointestinl endoscopy showed the reddish, swollen ppill with n irregulr surfce nd esy-touch leeding (Figure 3). The endoscopic retrogrde cholngiopncretogrm showed tht the CBD nd MPD were mrkedly dilted (Figure 4); therefore, we presumed tht the tumor of the mpull of Vter cused ostructive jundice nd cute pncretitis. Thus, n endoscopic retrogrde ile duct dringe (ERBD) tue nd endoscopic retrogrde pncretic duct dringe (ERPD) tue were inserted. After ERPD insertion, her dominl pin ws relieved, nd the pncretic enzyme levels normlized. Pthologicl findings of the endoscopic iopsy of the mpull showed poorly differentited NEC. Immunohistochemiclly, the tumor stined positive for chromogrnin A nd synptophysin. The 18F-fluorodeoxyglucose (FDG)- positron emission tomogrphy comined with CT scn showed 18F-FDG ccumultion in the mpull mss (mximum stndrdized uptke vlue, 4.3) with no metstses. Following the preopertive dignosis of NEC, pncreticoduodenectomy ws performed. A cross-section of the resected specimen showed tht the tumor ws well-circumscried, whitish-yellow solid mss occupying the mpull, which ws suspected to hve generted from the common chnnel since the tumor ws loclized round the mpullry orifice (Figure 5). The histologicl exmintion showed tht the tumor comprised two elements (Figure 6): 1) the min component (99.5%) ws NEC rrnged in nest, nd ech cell hd undnt cytoplsm nd nucler hyperchromtism (Figure 6); nd 2) the minor component (0.5%) ws the well-differentited denocrcinom (Figure 6c), nd the denocrcinom component ws lso found in the epithelium of mpullry duodenl (Ad) re (Figure 6d). The tumor ws loclized minly t Ad re, nd prt of tumor spred to the common chnnel re (Figure 7). The denocrcinom component ws found to e slightly exceeded sumucosl lyer of Ad re (Figure 7). However, there ws no superficil extension of tumor to mpullry ile duct (A) re nd no invsion to the duodenum nd pncretic prenchym. The epithelium t A re ws found to hve hyperplstic chnge nd it ws thought to e the rective epithelil hyperplsi due to ERBD plcement (Figure 7c). Results of immunohistochemicl stining showed tht the neuroendocrine component ws positive for chromogrnin A, synptophysin, nd CD56, nd the Ki-67 index ws 63% (Figures 8cd); the denocrcinom component ws negtive for these forementioned tumor mrkers. The stge of the tumor ws clssified s pt1n0m0, stge IA sed on the TNM clssifiction (Union for Interntionl Cncer Control, 8th ed). Three months postopertively, multiple liver metstses nd lymph node metstses were found, despite performing resection t n erly stge. The ptient hd een undergoing chemotherpy consisting of comintion of cispltin nd etoposide (VP16). Although she chieved complete remission, which ws ttriuted to the first regimen, the liver metstses relpsed 12 months lter. Then, she received cropltin plus VP16 s the second regimen, irinotecn s the third, nd mruicin s the fourth. She died of progressive disese 28 months postopertively. DISCUSSION In the present cse, tumor of the mpull of Vter ws detected s the cuse of cute pncretitis. The coexistence of cute pncretitis nd mlignncies of the duodenl ppill is rre [3]. The common presenttion of mlignncy of the duodenl ppill is pinless jundice. Regrding neuroendocrine tumors of the mpull of Vter, including Figure 1. Contrst-enhnced computed tomogrphy scn showing (). hypervsculr lesion locted in the mpullry region (). with diltion of the common ile duct nd min pncretic duct. 298
3 Figure 2. Endoscopic ultrsonogrm showing mm low echoic mss in the mpullry lesion. Figure 3. (, ). Upper gstrointestinl endoscopic imge showing the reddish, swollen ppill with n irregulr surfce nd esy-touch leeding. composite neuroendocrine nd denomtous crcinom, jundice (60%) nd dominl pin (40%) re the most frequent symptoms [2]. The ptient descried in this rticle presented with pncretitis ecuse of ostruction of the pncretic duct y the tumor, nd then ERPD insertion ws very effective. When the cuse of pncretitis is uncler, tumor of the duodenl ppill should e considered s one of the differentil pthogeneses. Regrding the development of ech neuroendocrine or denocrcinom component, the widely ccepted theory is tht the denocrcinom component exists minly in the mucosl surfce lyer, wheres the component of NEC is often locted deeper thn the mucosl lyer [4]. Hrd et l. lso reported tht they experienced the cses of MANEC tht the denocrcinom components were predomintely locted t the surfce of the tumors, wheres the mjority of stroml nd vsculr invsion nd lymph node metstsis involved neuroendocrine components [5]. The present ptient hd the sme invsive pttern s forementioned. Therefore, we speculted tht the denocrcinom hd risen first from the epithelium round the common chnnel of the ppill, nd then it cquired neuroendocrine differentition cpilities during growth. However, it is uncler which component rose first nd whether oth components will originte from common cells. Woischke et l. investigted genetic dt on colorectl NECs, nd found evidence for common clonl origin of colorectl NECs nd djcent glndulr tumor components. Moreover, they suggested the possiility of erly seprtion of glndulr nd neuroendocrine components during mlignnt trnsformtion with susequent independent muttionl evolution [6]. Their findings lso support our hypothesis. 299
4 Figure 4. Endoscopic retrogrde cholngiopncretogrm showing tht the common ile duct nd min pncretic duct re mrkedly dilted. Figure 5. Cross-section of the resected specimen showing tht the tumor is well-circumscried, whitish-yellow solid mss occupying the mpull. c d Figure 6. Histologicl exmintion showing tht (). the tumor comprises two elements: neuroendocrine crcinom (NEC) nd denocrcinom. (). The min component is NEC rrnged in nest, nd ech cell hs undnt cytoplsm nd nucler hyperchromtism; nd (c). the minor component is the welldifferentited denocrcinom. (d). The denocrcinom component is lso found in the epithelium of mpullry duodenl (Ad) re. 300
5 c Figure 7. The tumor is loclized minly t mpullry duodenl Ad re, nd (). prt of tumor spred to the common chnnel re. Yellow rrow shows sumucosl lyer of Ad re, (). nd the denocrcinom component is found to e slightly exceeded sumucosl lyer of Ad re. The epithelium of mpullry ile duct (A) re is found to hve hyperplstic chnge, nd (c). there is no superficil extension of tumor to A re. c d Figure 8. Imges of immunohistochemicl stining of the resected specimen showing tht the neuroendocrine component is positive for (). chromogrnin A, (). synptophysin, nd (c). CD56. The (d). Ki-67 index is 63%. It is lso still uncler whether the NEC or denocrcinom component is the min driving force of disese progression. There re severl conflicting reports tht one of these components, the neuroendocrine component [5, 7] or denocrcinom component, initites tumor progression [8]. Yet, Volnte et l. reported tht the clinicl ehvior of these tumors depends on the denocrcinom component if the ssocited endocrine component is well-differentited, wheres the prognosis depends on the neuroendocrine component if it is poorly differentited [9]. However, there re no systemtic dt to indicte which component ffects the prognosis nd which tretment is effective. Generlly, NEC nd MANECs on the mpull of Vter re highly ggressive tumors ssocited with high risk for distnt metstsis nd poor prognosis [3, 10]. Thus, estlishment of multidisciplinry tretment, including opertion, chemotherpy nd rdiotherpy, nd iologicl trgeted therpy, requires further investigtions. CONCLUSION In conclusion, we reported hs proposed tht neuroendocrine components hve more ggressive fetures thn denocrcinom components, it is still uncler whether the neuroendocrine or denocrcinom component is the min driving force of disese progression. Neuroendocrine crcinom with n denocrcinom component is highly ggressive nd ssocited with high risk for distnt metstsis nd poor prognosis, s in the present cse. Acknowledgments We thnk Dr. Msy Fujiwr from the Deprtment of Pthology nd Mtrix Biology, Mie University for his kind support. 301
6 Conflict of Interests The uthors declre no conflict of interest nd no finncil rrngement with ny compny. References 1. Rindi G, Petrone G, Inzni F. The 2010 WHO clssifiction of digestive neuroendocrine neoplsms: criticl pprisl four yers fter its introduction. Endocr Pthol 2014; 25: [PMID: ] 2. Tsukgoshi M, Hosouchi Y, Arki K, Mochid Y, Aihr R, Shire K, Kuwno H. Neuroendocrine tumor of the mpull of Vter with distnt cystic lymph node metstsis: cse report. Surg Cse Rep 2016; 2:73. [PMID: ] 3. Petrou A, Brmis K, Willims T, Pplmros A, Mntonkis E, Felekours E. Acute recurrent pncretitis: possile clinicl mnifesttion of mpullry cncer. JOP 2011; 2: [PMID: ] 4. Kto S, Mguchi H, Osni M, Tkhshi K, Ktnum A, Yne K, et l. A cse of denoendocrine cell crcinom on the mpull of Vter. Nihon Shokkiyo Gkki Zsshi 2013; 110: Jpnese. [PMID: ] 5. Hrd K, Sto Y, Iked H, Mylee H, Igrshi S, Okmur A, et l. Clinicopthologic study of mixed denoneuroendocrine crcinoms of heptoiliry orgns. Virchows Arch 2012; 460: [PMID: ] 6. Woischke C, Schf CW, Yng HM, Vieth M, Veits L, Geddert H, et l. Indepth muttionl nlyses of colorectl neuroendocrine crcinoms with denom or denocrcinom components. Mod Pthol 2017; 30: [PMID: ] 7. Mkino A, Serr S, Chetty R. Composite denocrcinom nd lrge cell neuroendocrine crcinom of the rectum. Virchows Arch 2006; 448: [PMID: ] 8. Zhng L, DeMy RM. Cytologicl fetures of mixed denoneuroendocrine crcinom of the mpull: Two cse reports with review of literture. Dign Cytopthol 2014; 42: [PMID: ] 9. Volnte M, Rindi G, Ppotti M. The grey zone etween pure (neuro) endocrine nd non-(neuro) endocrine tumours: comment on concepts nd clssifiction of mixed exocrine-endocrine neoplsms. Virchows Arch 2006; 449: [PMID: ] 10. Mx N, Rothe A, Lngner C. Mixed denoneuroendocrine crcinom of the mpull of Vter: A cse report. Mol Clin Oncol 2016; 5:95-8. [PMID: ] 302
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