The diagnosis of a metastatic breast tumor from ovarian cancer by the succession of a p53 mutation: a case report

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1 Mori et l. World Journl of Surgil Onology (2017) 15:117 DOI /s CASE REPORT Open Aess The dignosis of metstti rest tumor from ovrin ner y the suession of p53 muttion: se report Ryutro Mori 1*, Mnu Futmur 1, Ksumi Morimitsu 1, Chiemi Sigo 2, Ttsuhiko Miyzki 3 nd Kzuhiro Yoshid 1 Astrt Bkground: Metstti rest tumors from other orgns re very rre. We herein desrie the se of ptient with metstti rest tumor due to ovrin ner who ws dignosed y the suession of p53 muttion. Cse presenttion: The ptient ws 59-yer-old womn with sigmoid olon stenosis. Dignosti imging reveled pelvi mss, multiple liver tumors, sites, nd multiple swollen pr-orti lymph nodes, suggesting n dvned ovrin tumor. Trnsverse loop olostomy nd prtil resetion of the greter omentum ws performed followed y six yles of plitxel with ropltin hemotherpy (TC therpy). Her ner lmost disppered, with the exeption of smll tumor in her pelvis. Simple hysteretomy with ilterl slpingo-oophoretomy ws performed. Two yers nd 5 months fter the seond surgery, mss ws deteted in her right rest nd simple mstetomy ws performed. A histologil exmintion of the tumors from the first surgery reveled infiltrting ppillry denorinom nd the solid nest prolifertion of typil ells with omedo nerosis nd psmmom odies. The findings of n immunohistohemil nlysis were s follows: ner ntigen 125 (CA125 (+)), ytokertin 7 (CK7 (+)), ytokertin 20 (CK20 ( )), p53 (+) nd CDX2 ( ), estrogen reeptor (ER (slightly +)), progesterone reeptor (PR (slightly +)), nd humn epiderml growth ftor reeptor 2 (HER2 (1+)). The rest tumors presented similr morphologil fetures (ER ( ), PR ( ), HER2 ( ), CA125 (+), CK7 (+), CK20 ( ), p53 (+), mmmgloin ( ), nd GCDFP15 ( )), whih were not hrteristi of rest ner. A diret sequening nlysis of p53 reveled p.v173m muttion in exon 5 in oth the rest tumor nd the ovrin ner. It ws not deteted in norml tissue, suggesting tht the rest tumors were metstti serous denorinoms from ovrin ner. Conlusions: A diret sequening muttion nlysis of p53 ws useful for distinguishing the primry tumor from the metstti tumor. We should reset metstti rest tumors to the extent tht is possile euse the prognosis of suh ptients is reltively good. Keywords: Seondry rest neoplsm, Ovrin neoplsm, p53 muttion Bkground The survivl of ptients with metstti ner hs improved due to dvnes in its mngement [1]. Beuse ptients live longer, unusul metstses suh s pnreti metstses, renl metstses, nd rest metstses hve een identified [2]. Advned ovrin ner typilly develops into peritonel dissemintion or lymph node metstsis in the dominl vity; distnt metstses re rre. * Correspondene: moriry52@gmil.om 1 Deprtment of Surgil Onology, Grdute Shool of Mediine, Gifu University, 1-1 Yngido, Gifu , Jpn Full list of uthor informtion is ville t the end of the rtile However, ovrin ner osionlly develops into distnt metstses to the liver, pleur, or lung, nd the prognosis of ovrin ner ptients with distnt metstsis is poor [3]. The mjority of rest tumors originte from the mmmry glnd, nd most metstti rest tumors originte from the ontrlterl rest [4]. Metstti rest tumors from other orgns re very rre. We herein desrie the se of ptient with metstti rest tumor due to ovrin ner who ws dignosed y the suession of p53 muttion. The Author(s) Open Aess This rtile is distriuted under the terms of the Cretive Commons Attriution 4.0 Interntionl Liense ( whih permits unrestrited use, distriution, nd reprodution in ny medium, provided you give pproprite redit to the originl uthor(s) nd the soure, provide link to the Cretive Commons liense, nd indite if hnges were mde. The Cretive Commons Puli Domin Dedition wiver ( pplies to the dt mde ville in this rtile, unless otherwise stted.

2 Mori et l. World Journl of Surgil Onology (2017) 15:117 Pge 2 of 5 Cse presenttion The ptient ws 59-yer-old femle with history of holeystetomy due to gllstones, exision of firodenom in the right rest, nd duodenl uler. She suffered from stenosis of the sigmoid olon, nd lol dotor referred her to the gyneology nd gstroenterology division of our hospitl. Computed tomogrphy (CT) reveled loulted tumor in her pelvis, multiple tumors in her liver (S4, S6), sites round her liver, nd multiple swollen pr-orti lymph nodes (Fig. 1). Mgneti resonne imging (MRI) showed lrge pelvi tumor with ysti omponent involving the uterus, retum, nd sigmoid olon (Fig. 1). Positron emission tomogrphy/omputed tomogrphy (PET/CT) showed lrge tumor in her pelvis nd multiple swollen lymph nodes in her dominl vity (Fig. 1). Colonosopy reveled wll edem nd stenosis pproximtely 30 m from the nl verge (Fig. 1d). Aording to these findings, she ws dignosed with dvned ovrin ner, nd trnsverse loop olostomy nd prtil resetion of the greter omentum were performed (Fig. 1e). After the first surgery, she reeived six yles of plitxel with ropltin hemotherpy (TC therpy), nd her ner lmost disppered, with the exeption of smll pelvi tumor of 2.6 m in dimeter (Fig. 1f). Simple hysteretomy with ilterl slpingo-oophoretomy nd prtil resetion of the omentum were performed s seond surgery to remove the residul tumors (Fig. 1g). The pthologil dignosis of the residul tumors in her ilterl ovries ws serous denorinom. After the seond surgery, the ptient reeived one yle of TC therpy. Inidentlly, she developed n intestinl ostrution 2 months fter the seond surgery, nd prtil resetion of the smll owel ws performed. However, no residul tumor ws deteted in her dominl vity or the reseted speimen (Fig. 1h). Two yers nd 5 months fter the seond surgery, the ptient visited our division with mss in her right rest. Mmmogrphy did not revel tumor (Fig. 2); however, ultrsonogrphy (US) showed irumsried mss ner the retrommmry spe in her right mmmry glnd (Fig. 2). MRI (Fig. 2) nd PET/CT (Fig. 2d) showed two msses under the nipple nd ner the retrommmry spe in her right rest. The findings of histologil exmintion of ore needle iopsy speimen were onsistent with metstsis of serous denorinom. Beuse no other metstti mss ws deteted on PET/CT nd the ptient s serum ner ntigen 125 (CA125) level ws elow the upper limit (Fig. 2e), simple mstetomy of the right rest ws performed (Fig. 2f ). Aording to the findings of histologil exmintions, the tumors in the greter omentum tht were reseted in the first surgery demonstrted infiltrting ppillry denorinom nd the solid nest prolifertion of d e f g h Fig. 1 Imges nd the surgil speimens otined in the first nd seond surgeries. CT, MRI, nd PET/CT reveled pelvi tumor involving the sigmoid olon, multiple liver tumors, sites, nd swollen pr-orti lymph nodes. d Colonosopy showed wll edem nd stenosis. e A speimen otined y prtil resetion of the greter omentum. f MRI nd PET/CT fter TC therpy reveled smll pelvi tumor of 2.6 m in dimeter. g Speimens otined y simple hysteretomy with ilterl slpingo-oophoretomy nd prtil resetion of the omentum. h The findings t the third surgery for n inidentl intestinl ostrution

3 Mori et l. World Journl of Surgil Onology (2017) 15:117 Pge 3 of 5 d e f Fig. 2 Imges of the rest mss, the serum CA125 level, nd speimen otined y simple mstetomy. No mss ws oserved on mmmogrphy. However, msses under the nipple nd ner the retrommmry spe ould e deteted y US, MRI, nd d PET/CT. e The serum CA125 level ws under the upper limit. f A speimen otined y simple mstetomy typil ells with omedo nerosis nd psmmom odies. The findings of n immunohistohemil nlysis were s follows: CA125 (+), ytokertin 7 (CK7 (+)), ytokertin 20 (CK20 ( )), p53 (+), nd udl-type homeoox protein 2 (CDX2 ( )). This ws onsistent with metstti serous denorinom from ovrin ner. After mstetomy, the findings of n dditionl immunohistohemil nlysis of the tumor were s follows: estrogen reeptor (ER (slightly +)), progesterone reeptor (PR (slightly +)), nd humn epiderml growth ftor reeptor 2 (HER2 (1+)) (Fig. 3). Moreover, the rest tumors lso presented solid nest formtion nd omedo nerosis with stroml invsion nd the following findings: ER ( ), PR ( ), HER2 ( ), CA125 (+), CK7 (+), CK20 ( ), p53 (+), mmmgloin ( ), nd gross ysti disese fluid protein 15 (GCDFP15 ( )) (Fig. 3). These findings re not hrteristi of rest ner ut were similr to the tumor of the omentum. We lso performed diret sequening muttion nlysis of p53 to onfirm the suession of the muttion. DNA ws extrted from formlin-fixed, prffin-emedded smples of the rest tumor, the ovrin tumor, nd norml rest tissue using NuleoSpin DNA FFPE XS system (Tkr Bio In., Jpn), nd exons 5 8 of the p53 were mplified y polymerse hin retion (98, 56, nd 72 C for 10, 30, nd 60 s, respetively) in Premix Ex Tq Hot Strt Version system (Tkr Bio In.) using speifi primers (Tle 1) tht were designed sed on the dt of previous studies [5]. The produts were sent to the Genomis Reserh division of Gifu University, nd diret sequening nlysis ws performed. The results showed tht oth the rest tumor nd the ovrin ner hd p.v173m muttion in exon 5, whih ws not deteted in norml tissue. The rest tumor lso hd n dditionl p.c176y muttion (Fig. 3). Aording to these findings, the rest tumors were onfirmed to e metstti serous denorinom from ovrin ner. Disussion We enountered ptient with metstti rest tumor from ovrin ner. This dignosis ws mde ording to the morphologil fetures, the results of n immunohistohemil nlysis, nd the suession of p53 muttion. Metstsis from other orgns ounts for only 0.43% of ll ses of mlignnt rest tumors [4]. However, Di Bonito et l. previously reported 12 ses with metstti rest tumors tht were deteted on utopsy. Only two ses were dignosed efore deth [6]. Thus, mny ses of metstti rest tumor my e missed efore deth. DeLir et l. reported 85 ses of metstti rest tumors, the origins of whih were srom (n =18), melnom (n = 18), ovrin ner (n = 14), lung ner (n = 11), nd gstrointestinl ner (n = 17) [7]. Crinom most ommonly origintes in the ovries. We performed PuMed dtse serh for se reports on metstti rest tumors nd identified 37 se reports. The mjority (25 reports) desried unilterl rest tumors. However, ilterl (four reports) [8], inflmmtory

4 Mori et l. World Journl of Surgil Onology (2017) 15:117 Pge 4 of 5 Fig. 3 The histopthologil nd immunohistohemil dignoses of the omentl tumor nd the diret sequening muttion nlysis of p53. The omentl tumor findings (HE, ER, PR, HER2, CA125, CK7, CK20, p53, nd CDX2). The rest tumor findings (HE, ER, PR, HER2, CA125, CK7, CK20, p53, mmmgloin, nd GCDFP15). A sequene nlysis of exon 5 from the rest tumor, the ovrin tumor, nd norml rest tissue. The rrows indite point muttions (six reports) [9], nd dutl rinom in situ-like (one report) [10] metstti rest tumors were lso desried. Krm et l. reported 10 ses of metstti rest tumor nd noted tht the men intervl etween the dignosis of ovrin ner nd rest/xill events ws 70.7 months nd tht the medin overll survivl fter rest event ws 26 months, suggesting tht metstti rest tumors Tle 1 The primer sequenes for the polymerse hin retion Exon Primer sequene 5 5 -TTCCTCTTCCTGCAGTACTCC-3 5 -GCCCCAGCTGCTCACCATCG CACTGATTGCTCTTAGGTCT-3 5 -AGTTGCAAACCAGACCTCAGG TCTCCTAGGTTGGCTCTGAC-3 5 -CAAGTGGCTCCTGACCTGGA CCTATCCTGAGTAGTGGTAA-3 5 -CCTGCTTGCTTACCTCG-3 from ovrin ner re not ssoited with poor prognosis [11]. The differentil dignosis etween primry rest ner nd metstti rest tumor from ovrin ner is not simple. Mmmgloin nd gross ysti disese fluid protein 15 (GCDFP15) re known to e rest ner-speifi mrkers. Bhrgv et l. reported tht the rtes of mmmgloin nd GCDFP positivity (inluding ny strength of stinility) were 93.1% (54/58) nd 84.5% (49/58), respetively, nd tht only two ses were negtive for oth mrkers. Furthermore, mong 40 ses of ovrin serous rinom, only one se showed mmmgloin positivity (pthy, moderte stining) [12]. CA125 is well-known tumor mrker of ovrin ner, nd rtes of CA125 positivity deteted in ovrin ner nd primry rest ner speimens y immunohistohemistry were 90% (38/42) (strong nd diffuse stining) nd 16% (6/36) (fol nd wek stining), respetively [13]. The expression pttern of mmmgloin, GCDFP15, nd CA125 re summrized in Tle 2.

5 Mori et l. World Journl of Surgil Onology (2017) 15:117 Pge 5 of 5 Tle 2 The expression pttern of mmmgloin, GCDFP15, nd CA125 Brest ner (%) Ovrin ner Negtive for oth mmmgloin 3 nd GCDFP15 Mmmgloin-positive GCDFP15-positive 84.5 CA125-positive In our se, the rest tumor ws negtive for mmmgloin nd GCDFP15, while oth the rest nd the ovrin ners were positive for CA125, suggesting tht the rest tumor hd metstsized from ovrin ner. The p53 gene hs vrious muttion points in exons 5 8, nd the suession of the p53 muttion pttern n e used to distinguish primry tumors from metstti tumors [14 16]. In our se, the p.v173m in the ovrin ner ws oserved to hve sueeded to the rest tumor, strongly suggesting tht the rest tumor hd metstsized from ovrin ner. Conlusion We enountered the se of ptient with rest tumor tht hd metstsized from ovrin ner. A diret sequening muttion nlysis of p53 ws useful for distinguishing the primry tumor from the metstti tumor. We should reset metstti rest tumors to the extent tht is possile euse the prognosis of suh ptients is reltively good. Arevitions CA125: Cner ntigen 125; CDX: Cudl-type homeoox protein 2; CK20: Cytokertin 20; CK7: Cytokertin 7; CT: Computed tomogrphy; ER: Estrogen reeptor; GCDFP15: Gross ysti disese fluid protein 15; HER2: Humn epiderml growth ftor reeptor 2; MRI: Mgneti resonne imging; PET/CT: Positron emission tomogrphy/omputed tomogrphy; PR: Progesterone reeptor Aknowledgements Not pplile. Funding Nothing to delre. Avilility of dt nd mterils All dt generted or nlyzed during this study re inluded in this pulished rtile. Authors ontriutions RM wrote the mnusript. RM, MF, nd KM prtiipted in the medil tretment for the se. CS nd TM performed the histologil nd immunohistohemil evlutions. RM nd TM performed diret sequening nlysis of p53. KY representedoursurgildeprtmentndsupervisedthewritingofthe mnusript. All uthors red nd pproved the finl mnusript. Authors informtion Not pplile. Ethis pprovl nd onsent to prtiipte All proedures performed in this study involving the ptient were pproved y the ethil ommittee of Gifu University, Grdute Shool of Mediine. Consent for pulition Ptient s onsent ws otined for the pulition of this se report. Competing interests Outside the sumitted work, K. Yoshid hs reeived grnts nd personl fees from Tiho Phrmeutil Co., Ltd., Pfizer In., Chugi Phrmeutil Co., Ltd., nd Ykult Honsh Co., Ltd.; grnts from Bristol-Myers Squi nd Kyow Hkko Kirin Co., Ltd.; nd honorri from Tiho Phrmeutil Co., Ltd., Pfizer In., Chugi Phrmeutil Co., Ltd., Kyow Hkko Kirin Co., Ltd., nd Ykult Honsh Co., Ltd., nd hd onsultnt or dvisory reltionship to Tiho Phrmeutil Co., Ltd., nd L Rohe, Ltd. All remining uthors delred tht they hve no onflit of interest. Pulisher s Note Springer Nture remins neutrl with regrd to jurisditionl lims in pulished mps nd institutionl ffilitions. Author detils 1 Deprtment of Surgil Onology, Grdute Shool of Mediine, Gifu University, 1-1 Yngido, Gifu , Jpn. 2 Deprtment of Pthology nd Trnsltionl Reserh, Grdute Shool of Mediine, Gifu University, 1-1 Yngido, Gifu , Jpn. 3 Pthology Division, Gifu University Hospitl, 1-1 Yngido, Gifu , Jpn. Reeived: 7 Novemer 2016 Aepted: 22 June 2017 Referenes 1. Gennri A, Conte P, Rosso R, Orlndini C, Bruzzi P. Survivl of metstti rest rinom ptients over 20-yer period: retrospetive nlysis sed on individul ptient dt from six onseutive studies. Cner. 2005;104: Disiio G, Frenh SW. Metstti ptterns of ners: results from lrge utopsy study. Arh Pthol L Med. 2008;132: Cormio G, Rossi C, Czzoll A, Rest L, Loverro G, Greo P, et l. Distnt metstses in ovrin rinom. Int J Gyneol Cner. 2003;13: Georginnos SN, Chin J, Goode AW, Sheff M. Seondry neoplsms of the rest: survey of the 20th entury. Cner. 2001;92: Hiyosi H, Noguhi M, Mtsuno Y, Kto H, Shimosto Y. 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