Clinicopathological analysis and prognosis of extrahepatic bile duct cancer with a microscopic positive ductal margin

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1 DOI: /hpb HPB ORIGINAL ARTICLE Clinicopthologicl nlysis nd prognosis of extrheptic bile duct cncer with microscopic positive ductl mrgin In Woong Hn 1 *, Jin-Young Jng 2 *, Kyoung Bun Lee 3, Mee Joo Kng 2, Wooil Kwon 2, Je Woo Prk 2, Ye Rim Chng 2 & Sun-Whe Kim 2 1 Deprtment of Surgery, Dongguk University College of Medicine, Goyng, 2 Deprtment of Surgery & Cncer Reserch Institute, nd 3 Deprtment of Pthology, Seoul Ntionl University College of Medicine, Seoul, South Kore Abstrct Bckground: The fte of microscopic positive ductl mrgin (MPDM) of extrheptic bile duct (EHBD) cncer is uncler. The purpose of this study ws to nlyse the clinicopthologicl fetures of EHBD cncer with MPDM nd to identify the prognostic fctors ssocited with survivl. Methods: Between 1995 nd 2007, retrospective nlysis of 464 ptients who hd undergone surgicl resection for EHBD cncer ws conducted. Clinicopthologicl fctors likely to influence survivl were ssessed using univrite nd multivrite nlysis. Results: One hundred twenty-four ptients hd MPDM which included invsive crcinom (IC) (n =85) nd crcinom in situ (CIS)/ high-grde dysplsi (HGD) (n = 39). The medin survivl (MS) of R0, R1 s CIS/ HGD, nd R1 s IC were 41 months, 29 months, nd 18 months, respectively. Adverse prognostic fctors were IC on the resection mrgin [HR = 1.66, 95% confidence intervls (CIs) , P = 0.026], nd no use of djuvnt chemordiotherpy (HR = 1.57, 95% CIs , P = 0.033). Adjuvnt chemordiotherpy ws beneficil in ptients with MPDM s IC (5-yer survivl rte 19.7 compred with 2.8%, P = 0.011). Conclusions: The presence of MPDM is n importnt prognostic fctor in EHBD cncer. When ductl resection mrgin is positive, discrimintion between IC nd CIS/ HGD is importnt. Received 31 July 2013; ccepted 1 October 2013 Correspondence Sun-Whe Kim, Deprtment of Surgery, Seoul Ntionl University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul , South Kore. Tel.: Fx: E-mil: sunkim@snu.c.kr Introduction A surgicl resection hs been the minsty of curtive tretment for extrheptic bile duct (EHBD) cncer. Overll, 5-yer survivl rtes (5YSR) of 20 35% hve been reported fter resection of EHBD cncer. 1 3 In ddition, most ptients who undergo resection die of locl tumour recurrence. 4,5 This is becuse complete surgicl resection with tumour-free histologicl mrgins is difficult to obtin. Antomiclly, EHBD cncers re clssified s perihilr nd distl bile duct cncers. 4 However, tumours re rrely confined to *I.W. Hn nd J.Y. Jng eqully contributed to this rticle. This mnuscript ws presented t the 10th World IHPBA Congress, Pris, 1 5 July the short segment s bile duct cncer tends to longitudinlly spred long the bile duct wll. 6,7 Recent dvnces in imging modlities nd surgicl strtegies hve improved the outcome of the surgicl tretment for EHBD cncer. A surgicl resection for EHBD cncer is determined by the loction nd extent of the tumour. 3,6 13 Although pre-opertive dignosis for the extension of EHBD cncer hs improved in recent yers, it is difficult to decide the surgicl resection mrgin pre-opertively. 13,14 In some ptients, mrgin positive resection ws inevitble considering the opertive risk. A positive resection mrgin hs been considered n dverse prognostic fctor; 6,15 24 however, the reported incidence of positive surgicl resection mrgin in ptients who hve undergone resection with curtive intent hs vried from 9% to s high s 74%. 20,24,25 This could be explined by vrition

2 576 HPB between institutions or investigtors on the principle of the opertion or the definition of positive resection mrgin. However, there re few reports on the long-term outcome nd fctor nlysis ssocited with survivl in ptients with positive resection mrgin. The purpose of this retrospective study ws to nlyse the clinicopthologicl fetures of EHBD cncer with microscopic positive ductl mrgin (MPDM) fter surgicl resection, nd to explore the prognostic fctors in ptients with EHBD cncer with MPDM. The clrifiction of whether residul crcinom in situ (CIS)/high-grde dysplsi (HGD) t ductl resection mrgins differs prognosticlly from residul invsive ductl disese in ptients with EHBD cncer ws lso ssessed. Ptients nd methods Ptients nd surgicl procedures With the pprovl from the institutionl review bord, ll ptients with EHBD cncer who underwent resection t Seoul Ntionl University Hospitl (SNUH) were entered into prospectively mintined dtbse between 1995 nd Pre-opertively, the predominnt loction of the tumour nd the extent of the tumour long the biliry trct were evluted using imging studies, including n enhnced computed tomogrphy (CT) scn, ultrsonogrphy, mgnetic resonnce imging (MRI), cholngiogrphy nd sometimes choledochoscopy. Surgicl procedures were decided by ech ttending surgeon with considertion of the blnce between the tumour extent nd the sfety of ech procedure. Distnt metstsis, extensive lymph node metstsis such s pr-ortic lymph node involvement, bilterl extensive intrheptic duct infiltrtion, involvement of mjor vessels except focl portl vein invsion nd other systemic poor opertive risk fctors were contrindictions of curtive resection. After lprotomy nd the exclusion of distnt metstsis, ll of the following surgicl procedures including regionl lymphdenectomy t the right side of the celic rtery, nd ll tissues in the heptoduodenl ligment except the portl vein nd the heptic rtery, were removed (skeletoniztion of the heptoduodenl ligment). 6 The type of resection ws determined by the loction nd extent of the tumour. In ptients with loclized bile duct cncer in the heptoduodenl ligment, n EHBD resection (BDR) ws dopted, especilly in ptients in poor generl helth condition or with high-risk fctors. As the tumour ws minly locted in the perihilr bile duct or involved in the liver prenchym, unilterl heptic rtery, or portl vein, n extended hemiheptectomy including cudte lobectomy combined with bile duct resection (HBR) ws performed. 6 When the tumour ws chiefly locted in the distl bile duct, pncretoduodenectomy (PD) ws usully performed. Since 1991, pylorus preservtion hs been ttempted in ll ptients undergoing PD, except when duodenl ischemi, duodenl ulcer or duodenl tumor infiltrtion ws present. A heptopncretoduodenectomy (HPD) ws indicted in ptients with diffuse bile duct cncer. 6 Dignosis nd definition of surgicl mrgins A R0 resection ws defined s no residul ductl disese. Intropertive evlution of the proximl (heptic)-side nd/or distl (duodenl)-side ductl mrgins ws performed using frozen sections mong ll ptients. Opertive specimens were submitted for permnent histopthology. On the bsis of the type of resection procedure performed, the pproprite proximl nd distl bile duct mrgins were identified, nd cross-section of ech ws submitted for histology. When the distl-side ductl mrgin ws positive, dditionl resection of the intr-pncretic bile duct or PD ws performed, s fr s possible in principle.when the proximl-side ductl mrgin ws positive, dditionl resection of the heptic duct or n dditionl heptectomy ws performed where possible. Positive surgicl mrgins were clssified into two ctegories: invsive crcinom (IC) nd CIS/ HGD. In the present study, HGD ws included in the ctegory of CIS owing to the extreme difficulty if distinguishing between the two epithelil lesions. 20 Rdil mrgins were defined s surgicl mrgins other thn the ductl mrgins of the resected specimen, but there were no isolted positive rdil mrgins without MPDM. Microscopic positive ductl mrgins were confirmed by permnent pthologicl exmintion of resected mrgin. Comprison of clinicopthologicl vribles in ptients with MPDM nd ptients follow- up Resected specimens were submitted to the Deprtment of Pthology in SNUH for histologicl evlution, in which experienced heptobiliry pthologists exmined ll the specimens without knowledge of ny previous dignoses nd clinicl detils. Clinicopthologicl vribles including ge, gender, loction of positive mrgin, histologicl grde nd type of ptient with MPDM were evluted. Histologicl findings were described in ccordnce with the 7 th edition TNM stging of the Americn Joint Committee on Cncer (AJCC). 26 Ptients were followed regulrly in outptient clinics every 3 6 months, nd the informtion during follow-up for ll ptients ws obtined. The sites of initil disese recurrence were determined from cross-sectionl imging studies, such s computed tomogrphy or mgnetic resonnce imging. They were clssified s locl disese recurrence (resection mrgin, bilioenteric nstomosis, or port heptis), regionl disese recurrence (retroperitonel lymph nodes) nd distnt disese recurrence (intrheptic, peritoneum, or extr-bdominl sites). The overll survivl ws nlysed from the dte of surgicl resection to the dte of deth from ll cuses. The cuses of deth were determined from the medicl records. The follow-up period ws defined s the intervls between the dte of surgicl resection nd tht of the lst follow-up. Adjuvnt tretment Other thn for poor performnce sttus or refusl to the chemoor chemordition, djuvnt tretment ws performed fter the ptients were informed of the prognosis nd of the effects of ech tretment modlity. Decisions were mde fter thorough discussions with ptients, physicins nd ech ttending surgeon.

3 HPB 577 Tble 1 Ptients chrcteristics fter curtive intended resection Chrcteristics Tumour loction Totl (n = 464) P-vlue Perihilr (n = 208) Distl (n = 246) Diffuse (n = 10) Age (yers) 61.3 ± ± ± ± Gender (M : F) 154:54 175:71 6:4 335: Mrgin sttus negtive/ positive (%) 118/90 (43.3) 216/30 (12.2) 6/4 (40.0) 340/124 (26.9) <0.001 Histologicl grde 44:147 44:186 2:7 90: PP +WD/ MD + PLD Opertion type (n, %) <0.001 HBR 118 (56.7) (25.4) BDR 67 (32.2) 11 (4.5) 2 (20.0) 80 (17.2) PD 14 (6.7) 234 (95.1) 7 (70.0) 255 (55.0) HPD 9 (4.3) 1 (0.4) 1 (10.0) 11 (2.4) Medin follow-up (months) 29.0 (rnge ) 38 (rnge ) 22.0 (rnge ) 32.0 (rnge ) <0.001 PP, ppillry crcinom; WD, well- differentited; MD, moderte- differentited; PLD, poorly- differentited crcinom; HBR, extended hemiheptectomy combined with bile duct resection; BDR, EHBD resection with lymphdenectomy; PD, pncretoduodenectomy; HPD, heptopncretoduodenectomy. Fluorourcil (5-FU)-bsed concomitnt chemo-rdiotherpy (CCRT) consisted of up to 40 Gy t 2 Gy/frction with 2-week plnned rest, nd n intrvenous bolus of 5-FU (500 mg/m 2 /dy) given on dy 1 to 3 of ech split course. 27 Some ptients received 5-FU monthly for 1 yer fter rdiotherpy. 28 In ptients treted with chemotherpy lone, vrious fluoropyrimidines including 5-FU, S-1, cpecitbine or urcil-tegfur were used. 28 Sttisticl nlysis The dt ws nlysed using SPSS version 19.0 (SPSS Inc., Chicgo, IL, USA). Continuous nd normlly distributed vribles re presented s the medins nd rnge. Continuous prmeters in ech group were compred using the independent t-test or the Mnn Whitney U-test, nd ctegoricl prmeters using the χ 2 test or Fisher s exct test. Medicl records nd survivl dt were obtined for ll ptients. Survivl curves were constructed using the Kpln Meier method nd differences in survivl were evluted using the log-rnk test. Multivrite nlysis for prognostic fctors used Cox s proportionl hzrds model. Probbility (P)- vlues of 0.05 or less were considered sttisticlly significnt. Results Clinicopthologicl nlysis of EHBD cncer with curtive-intended resection The clinicopthologicl findings in ptients with EHBD cncer with curtive-intended resection re listed in Tble 1. Clinicopthologicl nlysis of EHBD cncer with MPDM A totl of 124 ptients were identified for MPDM fter reviewing the pthologicl dignosis of resected mrgin, the results of which re shown in Tble 2. Survivl nlysis of EHBD cncer with MPDM The medin survivl (MS) nd 5-yer survivl rte (5YSR) of R0, R1 s CIS/ HGD, nd R1 s IC were 41 months nd 44.5%, 29 months nd 20.7%, nd 18 months nd 12.0%, respectively (Fig. 1). In the univrite nlysis, the outcome fter surgicl resection ws better in ptients with CIS/HGD ductl mrgin thn in those with IC ductl mrgin (Tble 3 nd Fig. 1). Age 60 yers or older, lymph node metstsis (N stge) nd no use of djuvnt tretment including CCRT hd mrginlly significnt dverse effect on survivl (Tble 3). After multivrite nlysis, there were two independent dverse prognostic fctors: invsive crcinom on the resection mrgin [hzrd rtio (HR) = 1.66, 95% confidence intervls , P = 0.026] nd no use of djuvnt CCRT (HR = 1.57, 95% confidence intervls , P = 0.033). Ductl mrgin sttus nd recurrence Fifty-three with IC nd 25 out of 124 ptients with CIS/ HGD hd disese recurrence during follow-up. There were no significnt differences in locl disese recurrence (25 of 85 ptients, versus 14 of 39 ptients, P = 0.820), regionl disese recurrence (9 of 85 ptients versus 6 of 39 ptients, P = 0.629), distnt disese recurrence (31 of 85 ptients versus 15 of 39 ptients, P = 0.616) between IC nd CIS/ HGD. Nturl course of MPDM Figure 2 shows the clinicl course of ptients with MPDM. As previously noted, the 5YSR of CIS/HGD ws higher thn tht of IC (Tble 3 nd Fig. 1). In ddition, the disese-free (DF) (5YSR) of the CIS/HGD group ws higher thn tht of the IC group with sttisticlly mrginl significnce. When subdividing the IC

4 578 HPB Tble 2 Ptients chrcteristics of microscopic positive ductl mrgin mong curtive intended resection Chrcteristics Tumour loction Totl P vlue Perihilr (n = 90) Distl (n = 30) Diffuse (n = 4) (n = 124) Age (yers) 62.3 ± ± ± ± Gender (M : F) 64:26 19:11 1:3 84: Loction of mrgin (+) 57/5/28/5 30/0/0/0 3/0/1/0 85/5/29/ PRM/ DRM/ Both/ RM Histologicl Grde 24:60 6:21 1:2 31: PP +WD/ MD + PLD Op type (n, %) <0.001 HBR 39 (43.3) (31.5) BDR 41 (45.6) 2 (6.7) 1 (25.0) 44 (35.5) PD 6 (6.7) 28 (93.3) 2 (50.0) 36 (29.0) HPD 4 (4.4) 0 1 (25.0) 5 (4.0) Medin follow-up (months) 21 ( ) 18 ( ) 9 ( ) 20 ( ) Five of PRM (+) mong ptients with perihilr bile duct cncer were reveled s combined rdil mrgin positivity. PRM, proximl resection mrgin; DRM, distl resection mrgin; RM, rdil resection mrgin; PP, ppillry crcinom; WD, well- differentited; MD, moderte- differentited; PLD, poorly-differentited crcinom; HBR, extended hemiheptectomy combined with bile duct resection; BDR, EHBD resection with lymphdenectomy; PD, pncretoduodenectomy; HPD, heptopncretoduodenectomy R0-CIS/HGD: P < R0-IC: P < CIS/HGD-IC: P = group s treted djuvnt tretment including or excluding CCRT, the 5YSR nd DF-5YSR of the ptients with djuvnt tretment were higher thn tht without djuvnt tretment (5YSR 19.7 versus 2.8%, P = 0.011; DF-5YSR 16.6 versus 0%, P = 0.012) (Fig. 2). Survivl rte (%) 60 R0 (n = 340) 40 CIS/HGD (n = 39) 20 IC (n = 85) Follow-up durtion (months) No. of ptients t risk R0 CIS/HGD IC Figure 1 Overll survivl in ptients with extrheptic bile duct cncer with curtive intended resection. IC, invsive crcinom; CIS, crcinom in situ; HGD, high-grde dysplsi Discussion The most consistent independent determinnt for long-term survivl fter potentilly curtive resection of EHBD cncer is the surgicl mrgin sttus of the resected bile duct. In considertion of few studies insisting tht the presence of MPDM my not hve n effect on the overll men survivl, 29 numerous studies hve reported n ssocition of MPDM with mjor decrese in survivl rtes nd n increse in recurrence rtes. 6,15,18 21,24 This present study dded MPDM s n dverse prognostic fctor (Fig. 1). There re severl reports showing some ptients undergoing resection with microscopic tumour involvement t the bile duct mrgin survive longer thn expected. 6,11,20,30,31 Among these, severl studies reported CIS/HGD t the bile duct mrgin ws prognosticlly better thn residul IC in ptients undergoing surgicl resection for EHBD cncer. 12,20,30,32,33 However, there re few studies on the long-term fte nd on detiled nlysis for fctor ssocited survivl in ptients with positive resection mrgin. In the present study, in spite of concerns bout significnt correltion with IC nd other fetures of tumour extension, IC on the resection mrgin ws reveled s one of the independent prognostic fctors fter multivrite nlysis. This cn be explined by the biologicl nture of the min tumours displying extensive superficil spred, which is likely to be responsible for the remnnt CIS/HGD t the bile duct stump, tends to be less mlignnt compred with tht of conventionl IC. 33

5 HPB 579 Tble 3 Survivl nlysis of microscopic positive ductl mrgin (MPDM) mong curtive intended resection in ptients with extrheptic bile duct (EHBD) cncer Vrible No. of ptients Medin survivl (months) P-vlue Age <60/ 60 38/86 23 ( )/20 ( ) Gender Mle/Femle 84/40 25 ( )/18 ( ) T stge T1/T2/T3 19/53/52 29 ( )/20 ( )/18 ( ) N stge N0/N1 89/35 25 ( )/16 ( ) Tumour loction Perihilr/Distl/Diffuse 90/30/4 21 ( )/18 ( )/9 ( ) b Differentition PP + WD/MD + PLD 33/86 32 ( )/18 ( ) Perineurl invsion Not identified/present 41/83 36 ( )/20 ( ) Resection mrgin IC/CIS + HG 85/39 18 ( )/29 ( ) Type of opertion HBR/BDR/PD/HPD 39/44/36/5 20 ( )/25 ( )/ ( )/13 ( ) Adjuvnt tretment No/Yes 54/70 18 ( )/21 ( ) Chemotherpy lone No/Yes 54/6 18 ( )/16 ( ) CCRT No/Yes 61/63 18 ( )/21 ( ) Vlues in prenthesis re rnge of follow-up. AJCC 7 th edition. b The pthologicl reports of five ptients did not contin the histologicl differentition. PP, ppillry crcinom; WD, well-differentited; MD, moderte-differentited; PLD, poorly-differentited crcinom; HBR, extended hemiheptectomy combined with bile duct resection; BDR, EHBD resection with lymphdenectomy; PD, pncretoduodenectomy; HPD, heptopncretoduodenectomy; CCRT, concomitnt chemo-rdiotherpy. Microscopic mrgin positive No. of ptients = 124 5YSR =13.6% DF-5YSR = 13.1% No. of ptients = 85 5YSR = 12.0% DF-5YSR = 10.8% Invsive crcinom P = P = Crcinom in situ or high-grde dysplsi No. of ptients = 39 5YSR = 20.7% DF-5YSR = 19.5% Adjuvnt tretment No djuvnt tretment Adjuvnt tretment No djuvnt tretment No. of ptients = 48 5YSR = 19.7% DF-5YSR = 16.6% P = P = No. of ptients = 37 5YSR = 2.8% DF-5YSR = 0% No. of ptients = 21 5YSR = 22.9% DF-5YSR = 20.3% P = P = No. of ptients = 18 5YSR = 21.5% DF-5YSR = 15.2% Figure 2 Clinicl course of ptients with microscopic positive ductl mrgin. 5YSR, 5-yer survivl rte; DF-5YSR, disese-free 5-yer survivl rte In spite of the slower growth, remnnt CIS/HGD hs the potentil to develop into lethl IC. In this study, regrdless of the prolonged survivl compred to MPDM s IC, survivl of MPDM s CIS/HGD hd worse prognosis thn tht of the R0 resection (Fig. 1). Thus, CIS/HGD should be completely resected to chieve long-term survivl if possible. However, when CIS/ HGD spreds too widely, extended surgery such s HPD my be required. For ptients in poor generl condition or with high opertive risk, limited resection of the min invsive cncer with CIS/HGD remining t the ductl stumps, s n lterntive procedure, might bring considerble survivl benefits. Mny other clinicopthologicl fctors hve been reported to hve positive or negtive impct on survivl, including lymph node metstsis, 6,15,23,25,34 AJCC pt, 34 histopthologicl grding 6,8 nd gender 35 in resected EHBD cncer. In this study, there were no significnt differences with respect to survivl bsed on the loc-

6 580 HPB tion of the tumour or resection type, suggesting tht once the microscopic remnnt tumour hs occurred, the prognoses of different loctionl types re similr (Tble 3). These results were similr to Jng et l. 6 where they reported on the ctul long-term outcome of EHBD cncer fter surgicl resection. There hs been controversy whether remnnt CIS/HGD t the bile duct stump develops into IC. Jng et l. 6 previously reported tht, in ttempted curtive surgery, microscopic tumor involvement in the resection mrgin did not lwys men erly recurrence. However, there re severl reports tht show significnt reltionship between locl recurrence nd ductl mrgin sttus. 12,20,30,32,33 Furthermore, some studies suggested residul CIS my cuse lte locl disese recurrences, wheres residul invsive ductl lesions cuse erly locl recurrences. 20,36 In this study, 14 out of 39 ptients with CIS/HGD showed locl recurrence t the bile duct stump, such s, bilioenteric nstomosis, or port heptis. However, this result did not hve ny sttisticl difference in the locl recurrence rte in ptients with IC (25 out of 85 ptients, P = 0.820). As result, it could be possible tht CIS/HGD hs the potentil to progress to IC. Even lthough there is possibility for CIS/HGD to develop into IC, there re differences in their biologicl behviours. Remnnt CIS/HGD is likely to develop into IC in the lte phse fter surgery. In this study, the DF-5YSR of the CIS/HGD group ws significntly higher thn tht of the IC group (Fig. 2), suggesting tht CIS/ HGD hd less mlignncy nd showed slower growth thn IC. In spite of the similr incidence of recurrence, it is noteworthy tht ductl mrgin with CIS/ HGD resulted in prolonged disese-free survivl thn tht of ductl mrgin with IC. Therefore, s mentioned bove, for ptients in poor generl condition or with high opertive risk, limited resection of the min invsive cncer with CIS/ HGD remining t the ductl stumps, s n lterntive procedure, my bring considerble survivl benefits. 37 Gwk et l. 31 suggested tht djuvnt rdiotherpy might be useful in ptients with EHBD cncer, especilly for those ptients with microscopic residul tumours nd positive lymph nodes fter resection for incresing locl control In this study, there ws no survivl benefit with djuvnt chemotherpy lone but n increse in survivl in ptients with MPDM who received CCRT with mrginl significnce (Tble 3), especilly the ptients with n IC resection mrgin (Fig. 2). In spite of this study hs the limittion tht the post-opertive djuvnt tretment ws given to selected ptients nd the tretment regimens differed significntly mong the individuls, some subsets of ptients with positive mrgin could hve better prognosis if chemordiotherpy is combined with surgicl resection. 6,10,31 In conclusion, mong ptients undergoing surgicl resection for EHBD cncer, IC t the ductl resection mrgins ppers to hve more dverse effect on survivl, wheres residul CIS or HGD does not. It is therefore cler tht when the ductl resection mrgin sttus is positive upon pthologicl exmintion, discrimintion between CIS/ HGD nd IC is cliniclly importnt, nd resection should be considered nd efforts should be mde to obtin n IC-free mrgin. For MPDM, especilly IC, djuvnt chemordition cn be beneficil. Acknowledgements This study ws supported by grnt from the Ntionl R&D Progrm for Cncer Control, Ministry of Helth & Welfre, Republic of Kore (No ). 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