Introduction. Patients and methods

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1 J Heptobiliry Pncret Surg (2003) 10: DOI /s Surgicl tretment of intrductl ppillry-mucinous tumor (IPMT) of the pncres: opertive indictions bsed on surgico-pthologic study focusing on invsive crcinom derived from IPMT Mkoto Seki 1, Akio Yngisw 2, Hirotoshi Oht 1, Ysuro Ninomiy 1, Yoshihiro Skmoto 1, Junji Ymmoto 1, Toshihru Ymguchi 1, Eiji Ninomiy 3, Koichi Tkno 3, Akiko Arug 4, Keiko Ymd 4, Keiko Sski 2, nd Yo Kto 2 1 Deprtment of Surgery, 2 Deprtment of Pthology, 3 Deprtment of Internl Medicine, 4 Deprtment of Rdiology, Cncer Institute Hospitl, Kmi-Ikebukuro, Toshim-ku, Tokyo , Jpn Abstrct Bckground/Purpose. Between 1979 nd 2000, 51 ptients with intrductl ppillry-mucinous tumor (IPMT) of the pncres underwent surgicl resection. Methods. The ptients were reviewed to disclose the surgicl pthology of invsive crcinom derived from IPMT nd to determine the surgicl indictions for IPMT on the bsis of the pthologic findings. Results. The incidence of invsive crcinom derived from IPMT ccording to the locliztion of the tumor ws s follows: 4/9 (44%) in the min pncretic duct (MPD type), 4/9 (44%) showing ductl spred from the MPD to brnch ducts (mixed type), nd 2/33 (6%) in the 2 brnch duct (brnch type). The mximl size of the intrductl spred of invsive crcinoms (8 of 18 cses in the MPD nd mixed type together nd 2 of 33 cses in the brnch type) ws s follows: 6/8 (75%) in the MPD nd mixed type were over 6cm in size, nd the 2-brnch-type invsive crcinoms were within the 3-cm size rnge. Conclusions. We concluded tht for both invsive nd noninvsive IPMTs, surgicl resection ws necessry for ny MPD or mixed-type IPMTs, nd tht surgicl resection ws pproprite for brnch-type lesions lrger thn or equl to 3cm in dimeter, or for lesions smller thn 3cm showing rpid growth on clinicl imges. Key words Intrductl ppillry-mucinous tumor (IPMT) Invsive crcinom derived from IPMT Opertive indiction Introduction In 1982, Ohhshi et l. 1 nmed pncretic crcinom showing mrked diffuse dilttion of the min pncretic duct, cused by intrductl mucin ccumultion, Offprint requests to: M. Seki Received: April 14, 2002 / Accepted: My 12, 2002 nd widely opened orifice of the ppill of Vter, ccompnied by hypersecretion of mucin cliniclly, mucus-secreting pncretic cncer. This ws the first report in the world nd they noted tht this type of pncretic crcinom showed high resectbility rte nd fvorble prognosis fter resection. Lter, it cme to be known tht tumors showing the bove clinicl findings included not only mucus-secreting pncretic cncer but lso denom or borderline tumor between denom nd crcinom, nd so these tumors were summrized s pthologicl entity, i.e., intrductl ppillry tumor of the pncres. In recent yers, this concept hs rpidly spred ll over the world, nd, consequently, this entity ws included s n item in the World Helth Orgniztion (WHO) clssifiction of exocrine pncretic tumors, i.e., intrductl ppillrymucinous tumor (IPMT). 2 In generl, IPMTs contin invsive crcinoms derived from IPMTs; sometimes it is hrd to differentite these invsive crcinoms from other commonly seen invsive crcinoms. It is necessry to review the histopthologic findings of invsive crcinom derived from IPMT in order to elucidte modes of growth in IPMT nd to differentite invsive crcinoms derived from IPMT from those not derived from IPMT. The present study ws undertken to determine the opertive indictions for IPMTs on the bsis of their surgicopthologic findings. Ptients nd methods From 1979 to 2000, 51 ptients underwent pncretic resection for IPMT, which corresponded to 20.3% of totl of 251 pncretic resections for pncretic neoplsms t our institution. The sex rtio of the 51 ptients ws 18 femle/33 mle, nd the ptients ges rnged from 49 to 78 yers, with n verge of 65.4 yers.

2 148 M. Seki et l.: Surgico-pthologic study of IPMT-derived invsive crcinom All resected pncres sections were fixed in 10% formlin nd were sliced serilly t 5- to 8-mm intervls in plne t right-ngles to the min pncretic duct. 3 All the slices were processed ccording to stndrd procedures for hemtoxylin nd eosin-stined histologic preprtions nd were exmined microscopiclly. The lrgest dimeter of the tumor, which corresponded to the mximl size of intrductl spred of the tumor, whether it ws crcinom or denom, ws precisely clculted in ll the slices. Whether the invsive crcinom ws derived from IPMT or not ws defined by the following histologic findings: (1), whether there ws continuity of the tumor from IPMT nd (2), whether the tumor ws independent of IPMT; i.e., the IPMT could be evidently differentited from the nonppillry crcinom sometimes seen round common-type invsive crcinom of the pncres. 4 IPMT ws clssified by locliztion into three subtypes: (1), min pncretic duct (MPD) type, i.e., intrductl tumor spred ws loclized within the MPD; (2), mixed type, i.e., the tumor ws spreding from the MPD to side brnches; nd (3), brnch type, i.e., the tumor ws loclized within brnch ducts. In this study, the incidence of denom, noninvsive crcinom, nd invsive crcinom for ech tumor size ws nlyzed seprtely for ech histogic type. Results The histologic dignoses of ll 51 IPMTs re shown in Tble 1 by locliztion. The incidence of invsive crcinom in ech locliztion ws s follows: 4/9 (44%) in the MPD type, 4/9 (44%) in the mixed type, nd 2/33 (6%) in the brnch type. The overll incidence of invsive crcinom in ll the tumor type ws 10/51 (20%). The incidence of denom nd crcinom in IPMTs of the MPD type nd the mixed-type, together (n 18), ccording to size, is shown in Tble 2. The incidence of invsive crcinoms in tumors of these two types lrger thn 4cm in dimeter ws 6/11 (55%), while there ws 1 cse of invsive crcinom in the 2 IPMTs tht were less thn 2cm nd 1 cse of invsive crcinom in the 3 IPMTs tht were 2cm in dimeter. As indicted in Tble 3, the incidence of crcinom in brnch-type IPMTs ccording to size ws s follows: 0/6 in those smller thn 2cm in dimeter, 1/11 (9%) in those 2cm in dimeter, nd 4/16 (25%) in those lrger thn 3cm. In the 33 brnch-type IPMTs, there were 2 (6%) crcinoms tht were invsive crcinoms 3cm in dimeter. The surgico-pthologic findings of ten ptients with invsive crcinoms derived from IPMT re shown in Tble 4. Four ptients hd the MPD type, four hd the Tble 1. Intrductl ppillry-mucinous tumors (IPMTs) of the pncres Crcinom Locliztion Adenom Noninvsive Invsive Totl Min pncretic duct type 1 (11%) 4 (44%) 4 (44%) 9 (100%) Mixed type 2 (22%) 3 (33%) 4 (44%) 9 (100%) Brnch type 28 (85%) 3 (9%) 2 (6%) 33 (100%) , CIH Surgery 31 (60%) 10 (20%) 10 (20%) 51 (100%)

3 M. Seki et l.: Surgico-pthologic study of IPMT-derived invsive crcinom 149 Tble 2. Incidence of denom nd crcinom in min-pncretic duct-type nd mixed-type IPMTs ccording to tumor size Tumor size (cm) Histology Adenom 0 1 (33%) 0 2 (18%) Noninvsive Crcinom 2 (100%) 2 (67%) 2 (100%) 9 (82%) Invsive Totl 2 (100%) 3 (100%) 2 (100%) 11 (100%) , CIH Surgery IPMT, intrductl ppillry-mucinous tumor Mximl size of intrductl spred of the tumor Tble 3. Incidence of denom nd crcinom in brnch-type IPMTs ccording to tumor size Tumor size (cm) Histology Adenom 6 10 (91%) 9 (75%) 3 (75%) Noninvsive Crcinom 1 (9%) 3 (25%) 1 (25%) Invsive Totl 6 11 (100%) 12 (100%) 4 (100%) , CIH Surgery Mxil size of intrductl spred of the tumor mixed type, nd 2 hd brnch type. Three fourths of the MPD nd mixed types were lrger thn 6cm in dimeter, while the two brnch types were 3cm in dimeter. Lymph node metstses were seen in 50% of ech type. The histologic types of invsive crcinoms, indicted s slnted lines in Tble 4, ws s follows: five were mucinous (colloid) nd the other five were tubulr. The overll 5-yer survivl of eight ptients excluding the two who died of nother disese, ws 46.9%, nd there were three postopertive 5-yer survivors. Cse reports Cse 1: 62-yer-old womn (ptient 5 in Tble 4) Enhnced computed tomogrphy (CT) (Fig. 1) demonstrted low-ttenuting, round mss, which ws 1.5cm in size, in the hed of the pncres. Endoscopic retrogrde cholngiopncretogrm (ERCP; Fig. 1b) demonstrted brupt interruption of the min pncretic duct (MPD) nd spotty ccumultions of contrst medium round the obstruction of the MPD in the hed of the pncres. The MPD proximl to the re of obstruction ws mrkedly dilted on postopertive pncretocholngiogrm of the resected specimen (Fig. 1c). Moreover, there ws remrkble nrrowing in the common bile duct (CBD). We demonstrte schemtic illustrtion of the specimen nd mgnified view of cross-section 6 in Fig. 1d,e. There ws intrluminl ppillry growth in the MPD through the brnch duct. Both low- nd high-power views demonstrted tumor invsion into the CBD (Fig. 1f,g). Cse 2: 67-yer-old mn (ptient 8 in Tble 4) Enhnced CT (Fig. 2) demonstrted heterogeneously low-ttenuting, round mss in the hed of the pncres. ERCP (Fig. 2b) demonstrted diffusely dilted MPD, which ws irregulrly shped in the hed nd ws ccompnied by severl filling defects in the body nd til. There were mny filling defects in the dilted MPD on postopertive pncretocholngiogrm of the resected specimen (Fig. 2c). We demonstrte schemtic illustrtion of the specimen nd mgnified view of cross-section 13 in Fig. 2d,e. Almost ll of the pncretic duct were impcted by intrluminlly growing tumors (Fig. 2e). Both low- nd high-power views demonstrted intrductl ppillry denocrcinom nd invsive crcinom into the interstitil tissue (Fig. 2f,g). Cse 3: 65-yer-old mn (ptient 9 in Tble 4) Enhnced CT (Fig. 3) demonstrted guitr-shped, low-ttenuting mss, which ws 3cm in size, in the hed of the pncres. ERCP (Fig. 3b) demonstrted diffusely dilted MPD, which hd communiction with cyst-like dilted brnch duct ccompnied by n intrluminl filling defect. There ws filling defect in the cystic mss, which communicted with the slightly dilted MPD, on postopertive pncretocholngiogrm of

4 150 M. Seki et l.: Surgico-pthologic study of IPMT-derived invsive crcinom Tble 4. Ptients with invsive crcinom derived from IPMT Ptient Age/ Loction Size Schem of the Schem of representtive Histology of Locliztion no. Sex of tumor (mm) N resected specimen cross-section invsive crcinom Outcome Min pncretic 1 63/M Body ( ) muc 6 Yers, 1 Month duct type Ded Invsive crcinom of pncres hed 2 64/F Body-til ( ) muc tub (mod) 9 Months Ded Myocrdil infrction 3 57/F Whole ( ) tub (por-mod) 16 Yers Ded Wekness 4 77/M Whole ( ) muc 2 Months Ded Cncer deth Mixed type 5 62/F Hed ( ) tub (well) 3 Yers, 5 Months Ded Cncer deth 6 67/M Body-til ( ) muc 2 Yers, 6 Months Alive 7 75/M Hed ( ) tub (mod-por) 4 Months Ded Pneumoni 8 67/M Whole ( ) tub (por-mod) 2 Yers, 4 Months Ded Cncer deth Brnch type 9 65/M Hed ( ) muc 8 Yers, 3 Months Ded Wekness 10 73/M Hed ( ) tub (mod-por) 7 Months Ded Cncer deth , CIH Surgery IPMT, intrductl ppillry-mucinous tumor; N, lymph node metstsis; MPD, min pncretic duct; CBD, common bile duct; muc, mucinous; tub, tubulr; mod, modertely differentited; por, poorly differentited; dotted or blck res, noninvsive crcinom; striped res, invsive crcinom

5 b c d e g Fig. 1 g. Ptient 5 in Tble 4. Enhnced computed tomogrphy (CT) demonstrtes low-ttenuting mss (rrow) in the hed of the pncres. b Endoscopic retrogrde cholngio pncretogrm (ERCP) demonstrtes brupt interruption of the min pncretic duct (MPD) nd spotty ccumultion of contrst medium (rrow). c The MPD proximl to the obstruction (rrow) is dilted on postopertive pncretocholngiogrm of the resected specimen. d Schemtic illustrtion of the resected specimen. e Mgnified view of cross-section 6 demonstrtes intrluminl ppillry growth in the MPD through the brnch duct. CBD, Common bile duct. f Low-power view of the rectngle in e demonstrtes tumor invsion into the CBD. INV, invsive crcinom. H&E, g High-power view of the rectngle in f discloses invsive crcinom derived from intrductl ppillrymucinous tumor (IPMT). H&E, 40 f

6 b d c f e g Fig. 2 g. Ptient 8 in Tble 4. Enhnced CT demonstrtes lowttenuting mss (rrow) in the hed of the pncres. b ERCP demonstrte diffusely dilted MPD, which is irregulrly shped in the hed (rrow) nd is ccompnied by severl filling defects (rrowheds) in the body nd til. c There re mny filling defects (rrowheds) in the dilted MPD on postopertive pncretocholngiogrm of the resected specimen. d Schemtic illustrtion of the resected specimen. e Mgnified view of cross-section 13 demonstrtes lmost ll of the pncretic ducts impcted by intrluminlly growing tumors. f Low-power view of the rectngle in e demonstrtes intrductl ppillry denocrcinom nd invsive crcinom into the interstitil tissue. H&E, g High-power view of the rectngle in f discloses invsive crcinom. H&E, 40

7 b d c e f g Fig. 3 g. Ptient 9 in Tble 4. Enhnced CT demonstrtes guitr-shped, low-ttenuting mss (rrow) in the hed of the pncres. b ERCP demonstrtes diffusely dilted MPD which hs communiction with cyst-like dilted brnch duct (rrow). c There is filling defect (rrow) in the cystic mss on postopertive pncretocholngiogrm of the resected specimen. d Schemtic illustrtion of the resected specimen. e Mgnified view of crosssection 6 demonstrtes intrductl or geltinous tumor in the cystic lesion. f Low-power view of the rectngle in e discloses IPMT nd invsive crcinom derived from it. H&E, g High-power view of the rectngle in f demonstrtes colloid crcinom. H&E, 100

8 154 M. Seki et l.: Surgico-pthologic study of IPMT-derived invsive crcinom the resected specimen (Fig. 3c). We demonstrte schemtic illustrtion of the specimen nd mgnified view of cross-section 6 in Fig. 3d,e. Intrductl ppillry or geltinous tumor could be seen in the cystic lesion. A low-power view (Fig. 3f) demonstrted intrductl ppillry denocrcinom nd mucinous crcinom simultneously. A high-power view (Fig. 3g) demonstrted mucinous (colloid) crcinom. Discussion At present, the mucus-secreting pncretic cncer nmed by Ohhshi et l. 1 in 1982, bsed on the clinicl concepts of ductecttic type mucinous cystdenom or cystdenocrcinom defined pthologiclly by Yngisw et l. 5 in 1984 hs been summrized s one pthologic concept, i.e., intrductl ppillry tumor of the pncres by recent efforts of numerous clinicins nd pthologists from Jpn nd other countries fter lpse of 20 yers. Since this concept ws dded to the ctegory of exocrine pncretic tumors in the WHO interntionl histologicl clssifiction of tumors s intrductl ppillry-mucinous tumor (IPMT) in 1996, the concept of the entity spred rpidly ll over the world, nd now it hs ttrcted much ttention becuse it shows much better prognosis thn the invsive ductl crcinom of the pncres tht is commonly seen. But s the number of resected IPMTs hs incresed, it hs been found tht IPMTs include not only noninvsive crcinom or denom but lso invsive crcinom. In the study by Cuillerier nd collegues 6 nd tht by Flconi nd collegues, 7 the rte of invsive crcinom in ll of the resected IPMTs ws 19/45 (42.2%) nd 19/51 (37.3%), respectively, while Mguchi 8 reported rte of 5/29 (17.2%), which is close to the rte of 10/51 (19.6%) t our institution. Although it is difficult to explin the discrepncies between these results, it cn be guessed tht differences in the pthologic criteri of invsive crcinom derived from IPMTs hs led to this discrepncy. It is histologiclly controversil whether invsive crcinom ccompnied by IPMT is derived from IPMT itself or not. It is commonly ccepted tht the histologicl type of invsive crcinom derived from IPMT is mucinous (colloid) or tubulr crcinom. In the study by Loftus nd collegues, 9 3 invsive crcinoms, derived from IPMT, within 14 IPMTs were ll colloid crcinoms. If prt of colloid crcinom is histologiclly much lrger thn the IPMT, it is problemtic whether the colloid crcinom cn be dignosed s being derived from IPMT or ccompnied by IPMT. Moreover, it is difficult to dignose whether invsive crcinom is derived from IPMT or not in ptients in whom the noninvsive crcinom communicting with n invsive prt is nonppillry. Now we believe tht both the former, wht IPMT except for invsive prt lcks independency s tumor nd looks like n ttendnt lesion on invsive crcinom, nd the ltter should be excluded from the entity of invsive crcinom derived from IPMT. The incidence of invsive crcinom in IPMT is distinct in terms of the locliztion of tumor, i.e., whether it exists in the min pncretic duct (MPD) or the brnch duct. In the study by Kobri nd collegues, 10 the incidence of invsive crcinom ws 3/13 (23%) in the MPD type nd 1/16 (6%) in the brnch type. Similrly, Terris nd collegues 11 reported n incidence of 11/30 (37%) in the MPD type nd n incidence of 0/13 (0%) in the brnch type. In the present study, the incidence of invsive crcinom ws 8/18 (44%) in the MPD type nd mixed type together, 2/33 (6%) in the brnch type. It is generlly ccepted tht the incidence of crcinom nd tht of invsive crcinom in IPMT re both much higher in the MPD type thn in the brnch type, nd the reson for this is under investigtion by moleculr biologicl methods t our institution. In conclusion, it is pprent from the bove results for the incidence of invsive crcinom in IPMT tht ptients with tumors of the MPD type or the mixed type should be operted urgently, nd the intrductl spred of the tumor should be exmined closely. However, the incidence of invsive crcinom in brnch-type IPMTs ws reltively low, t 6%, t our institution, lthough, when tumors in brnch-type IPMTs were lrger thn or equl to 3cm in dimeter, 4/16 (25%) of them were crcinoms. Consequently, surgicl resection is bsiclly necessry for lesions lrger thn or equl to 3cm in brnch-type IPMTs nd for lesions smller thn 3cm showing rpid growth of tumor, murl nodule in dilted pncretic duct, or extrductl tumor invsion on clinicl imges during surveillnce. Acknowledgments. The uthors thnk Dr. Kzuhiko Ohhshi, Deprtment of Internl Medicine, Aichi Cncer Center, Aichi, Jpn, nd Dr. Kunio Tkgi, Hyshi Surgicl Hospitl, Tokyo, Jpn, for their invluble dvice. References 1. Ohhshi K, Murkmi Y, Mruym M, Tkekoshi T, Oht H, Ohshi I, Tkgi K, Kto Y (1982) Four cses of mucous secreting pncretic cncer (in Jpnese with English bstrct). Shokki Nishikyo No Shinpo (Prog Dig Endosc) 20: , Klöppel G, Solci E, Longnecker DS, Cpell C, Sobin LH (1996) Histologicl typing of tumours of the exocrine pncres. In: World Helth Orgniztion interntionl histologicl clssifiction of tumours. Springer, Berlin Heidelberg New York Tokyo, pp 12 19

9 M. Seki et l.: Surgico-pthologic study of IPMT-derived invsive crcinom Yngisw A, Kto Y (1991) Min duct involvement in common type pncretic crcinom: study to ssess the efficiency of pncretoscopy (in Jpnese with English bstrct). Shokki Nishikyo (Dig Endosc) 3: Hrubn RH, Adsy NV, Albores-Svedr J, Compton C, Grrett ES, Goodmn SN, Kern SE, Klimstr DS, Klöppel G, Longnecker DS, Lüttges J, Offerhus GJA (2001) Pncretic intrepithelil neoplsi: new nomenclture nd clssifiction system for pncretic duct lesions. Am J Surg Pthol 25: Yngisw A, Kto Y, Sugno H, Ohhshi K, Tkekoshi T, Tkgi K (1984) Clssifiction of the pncretic cyst with typicl epithelium (in Jpnese). 5: Cuillerier E, Cellier C, Plzzo L, Devière J, Wind P, Rickert F, Cugnenc PH, Cremer M, Brbier JP (2000) Outcome fter surgicl resection of intrductl ppillry nd mucinous tumors of the pncres. Am J Gstroenterol 95: Flconi M, Slvi R, Bssi C, Zmboni G, Tlmini G, Pederzoli P (2001) Clinicopthologicl fetures nd tretment of intrductl ppillry mucinous tumour of the pncres. Br J Surg 88: Mguchi H (1994) Clinicopthologicl nd dignostic study of mucin producing pncretic tumors (in Jpnese with English bstrct). Nippon Syokkibyo Gkki Zsshi (Jpn J Gstroenterol) 91: Loftus EV, Olivres-Pkzd BA, Btts KP, Adkins MC, Stephens DH, Srr MG, Dimgno EP (1996) Intrductl ppillrymucinous tumors of the pncres: clinicopthologic fetures, outcome, nd nomenclture. Gstroenterology 110: Kobri M, Egw S, Shibuy K, Shimmur H, Sunmur M, Tked K, Mtsuno S, Furukw T (1999) Intrductl ppillry mucinous tumors of the pncres comprise two clinicl subtypes: differences in clinicl chrcteristics nd surgicl mngement. Arch Surg 134: Terris B, Ponsot P, Pye F, Hmmel P, Suvnet A, Mols G, Berndes P, Belghiti J, Ruszniewski P, Fléjou JF (2000) Intrductl ppillry mucinous tumors of the pncres confined to secondry ducts show less ggressive pthologic fetures s compred with those involving the min pncretic duct. Am J Surg Pthol 24: