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1 pissn eissn X Cse Report Clinicl nd Moleculr Heptology 2018;24: Complete cure of dvnced heptocellulr crcinom with right drenl glnd metstsis nd portl vein thrombosis by multiple pplictions of n interdisciplinry therpy: Cse report with 8-yer follow up Hojung Jung 1, yung Ik Kim 1, Yong Kyun Cho 1, Woo Kyu Jeon 1, Hong Joo Kim 1, nd Hyun Pyo Hong 2 1 Division of Gstroenterology, Deprtment of Internl Medicine nd 2 Rdiology, Kngbuk Smsung Hospitl, Sungkyunkwn University School of Medicine, Seoul, Kore Heptocellulr crcinom (HCC) is the sixth most common cuse of deth worldwide nd the min cuse of primry liver cncer. The principle problem of HCC is the poor prognosis, since dvnced HCC reportedly hs medin survivl of only 9 months. The stndrd therpies re sorfenib nd regorfenib, but the outcomes remin uncler. We report 60-yer-old mn with dvnced HCC with right drenl glnd metstsis nd portl vein tumor thrombosis, who showed complete response to multiple pplictions of n interdisciplinry therpy. (Clin Mol Heptol 2018;24: ) Keywords: Heptocellulr crcinom; Adrenl glnd; Portl vein thrombosis INTRODUCTION Heptocellulr crcinom (HCC) is the 6th most common cuse of cncer nd the second most common cuse of cncer-relted deth worldwide. 1 Incidence dt from 1999 to 2014 were collected from the Kore Ntionl Cncer Incidence Dtbse. 2 Estimted 15,593 new cses nd 1,057 deths re occurred during the period of study. 3 However, the min problem is poor prognosis of HCC. A medin survivl of dvnced HCC is 9 months, nd Sorfenib is the first pproved systemic therpy for dvnced HCC. 4 And regorfenib is pproved by Food nd Drug Administrtion (FDA) on April 27, In this study, we report cse of 60-yer-old mn with dvnced HCC with right drenl glnd metstsis nd portl vein tumor thrombosis who chieved complete response fter multiple nd interdisciplinry therpies, mintined recurrence free for 8 yers of follow up. CASE REPORT A 60-yer-old mn visited the hospitl with febrile sense over the prior 7 dys. He hd no pst history of relevnt medicl record. He socilly consumed lcohol bout 1-2 times for month. Lbortory tests reveled white blood cell count of 5,500/μL, with 70.1% neutrophils, pltelet level of 160,000/μL, nd prothrombin time (interntionl normlized rtio, INR) of The Abbrevitions: CT, computed tomogrphy; FDA, Food nd Drug Administrtion; HCC, heptocellulr crcinom; PET-CT, positron emission tomogrphy computed tomogrphy; PVTT, portl vein tumor thrombosis; TACE, trnsrteril chemoemboliztion Corresponding uthor : yung Ik Kim Division of Gstroenterology, Deprtment of Internl Medicine, Kngbuk Smsung Hospitl, Sungkyunkwn University School of Medicine, 29 Semunn-ro, Jongno-gu, Seoul 03181, Kore Tel: , Fx: E-mil: Received : Jun. 4, 2017 / Revised : Jul. 14, 2017 / Accepted : Aug. 2, 2017 Copyright 2018 by Koren Assocition for the Study of the Liver This is n Open Access rticle distributed under the terms of the Cretive Commons Attribution Non-Commercil License ( which permits unrestricted non-commercil use, distribution, nd reproduction in ny medium, provided the originl work is properly cited.

2 Hojung Jung, et l. Complete cure of dvnced HCC Figure 1. Liver computed tomogrphy (CT) findings. An rteril-phse imge reveled n enhnced mss of size cm t S6/7 of the liver (A), while delyed-wshout imge reveled n 8-cm lesion t the sme loction (). A tumor thrombus ws noticed in the right min portl vein (C). c ptient s blood chemistry profile ws s follows: fsting glucose 88 mg/dl; totl protein, 7.6 g/dl; lbumin, 3.6 g/dl; totl bilirubin, 0.83 mg/dl; sprtte minotrnsferse, 96 U/L; lnine minotrnsferse, 104 U/L; lkline phosphtse, 189 U/L; gmm-glutmyl trnsferse, 101 U/L. Serologic tests for tumor mrkers were s follows: lph-fetoprotein, 1,200 ng/ml (norml rnge, 0-7); CA 19-9, U/mL (0-37). Serologic tests for virl mrkers were s follows: Hs Ag, positive; He Ag, negtive; heptitis virus DNA 854,515 IU/mL; nd nti-heptitis C virus, negtive. A computed tomogrphy (CT) scn of the bdomen reveled n pproximtely 8 cm sized huge ovoid shpe heterogenous rteril enhncement nd delyed wsh out mss lesion. We observed suggested HCC in the liver S6/7 with direct invsion of right drenl glnd. Moreover, n pproximtely 3 cm sized rteril enhncing lesion nd delyed wsh out lesion were observed in the liver S8. This lesion invded directly the right min portl vein nd formed the tumor thrombus t right min portl vein. This result suggests HCC in the liver S6/7 with direct invsion on right portl vein (Fig. 1). One cm sized lymph node ws noticed t port heptis. A positron emitting tomogrphy-computed tomogrphy (PETCT) scn noticed 8.5cm sized hypermetbolic mss in the right liver S6/7, which directly invdes the right drenl glnd. There were no significnt incresing of bnorml Fludeoxyglucose uptke in scn (Fig. 2). Portl vein thrombus ws not noticed on PET-CT scn t initil work up. Considering the imging test nd elevtion of tumor mrker, we dignosed HCC with invsion of right drenl glnd nd right portl vein. Trnsrteril chemoemboliztion (TACE) ws performed in October Lrge tumor stining reveled in right lobe of liver supplied by right heptic rtery nd right phrenic rtery. 2nd TACE ws done t We considered rdiotherpy bout right drenl glnd mss. Rdiotherpy (dose: 33cGy; number of session: 11 times) ws performed for trgeting liver S6/7/8, right drenl glnd, nd right portl vein during on month. We considered opertion rther thn rdiofrequency bltion, becuse colon ws ner the suspicious lesion of subtle tumor stining. After first TACE, the right min portl vein thrombus ws still found, l- 425

3 Clin Mol Heptol Volume_24 Number_4 December 2018 Figure 2. Combined positron-emission tomogrphy nd computed tomogrphy reveled n 8.5-cm hypermetbolic mss in the right liver t S6/7 tht directly invded the right drenl glnd. Figure 3. Computed tomogrphy of the liver showed lesion with n incresed Lipiodol uptke nd decresed tumor volume (A). The tumor thrombus ws not observed in the right min portl vein (). though they were reduced in size for 1 cm. ut no tumor stining ws found in the right min portl vein fter second TACE. We conducted CT for follow up, fter third TACE. CT scns were performed to rule out the recurrence or progression t Mrch 2010 nd July Portl vein thrombosis ws lso not observed in CT scn fter rdiotherpy nd third TACE (Fig. 3). Therefore, we concluded tht the portl vein thrombosis observed t bseline CT ws tumor thrombosis. efore the opertion, We exmined the PET-CT to rule out distnce metstsis. There ws no significnt increse in bnorml fludeoxyglucose uptke from the scn. Lbortory tests reveled white blood cell count of 5,400/μL, with 60.6% neutrophils, pltelet level 106,000 of /μl, nd INR The ptient s blood chemistry profile ws s follows: lbumin, 4.4 g/dl; totl bilirubin, 0.65 mg/dl; sprtte minotrnsferse, 31 U/L; lnine minotrnsferse, 31 U/L. Therefore, we concluded the ptient s sttus s stble disese. The ptient ws reluctnt to undergo surgery, however fter our medicl tem s dvice, opertion ws performed on ptient consent. Heptic segmentectomy (S6/7), cholecystectomy nd right drenl resection ws performed t Jnury 20, Dissection ws difficult becuse of severe dhesion fter TACE nd rdiotherpy, but ll suspicious gross tumor ws resected. After the opertion, Microscopic pthology of the resected liver, gllbldder, right d

4 Hojung Jung, et l. Complete cure of dvnced HCC Figure 4. Microscopic pthology reveled heptocellulr crcinom surrounding the drenl glnd (A). It ws impossible to evlute the tumor grding nd pttern since the tumor ws undergoing totl necrosis fter trnsrteril chemoemboliztion nd rdiotherpy (). c Figure 5. Liver computed tomogrphy imges fter surgicl resection in the rteril (A), portl (), nd delyed (C) phses. renl glnd, nd right drenl LN shown ischemic necrosis nd fibrosis formtion without tumor cell. There were reveled necrosis nd fibrosis chnges without mlignncy (Fig. 4). Prtil lipiodol lden mss ws removed fter opertion t liver S6/7 nd right drenl glnd. However prtil lipiodol lden mss ws noticed t remnnt right drenl glnd. We decided to follow up this re

5 Clin Mol Heptol Volume_24 Number_4 December 2018 mined prtil lipiodol lden mss. Moreover, smll mount of fluid collection ws observed t opertion site, which we considered s postopertive chnge. There ws no bnorml rteril enhncing lesion t CT imnge study (Fig. 5). The ptient ws dischrged from the hospitl fter surgery. lood test reveled normlized lph fetoprotein s 0.7 ng. Lbortory tests for PIVKA-II were s follows: initil result, 495 mau/ml; fter third TACE, 20 mau/ml; brefore opertion, 21 mau/ml. The lst check of PIVKA-II ws reveled 20 mau/ml t We underwent follow-up monitoring the ptient with dynmic liver CT nd tumor mrker levels every 4-6 months. In recent study t Jnury 2017, CT scn of liver reveled no recurrence nd intervl chnges thn lst study. The ptient completely cured nd no evidence of recurrence with 8 yer follow up. report cse of 60 yer-old mn with HCC ccompnied by metstsis of Rt. drenl glnd nd PVTT, who showed complete remission for 8 yers fter multiple nd interdisciplinry therpy, nd mintined recurrence free for 8 yers of follow up. Due to the ptient s conserved liver function, nd good ECOG performnce, we conducted other options thn sorfenib. As in this cse, if the ptients hve positive liver function, we cn consider other tretment options such s TACE, rdiotherpy, nd opertion over sorfenib. Therefore, we suggest HCC my be cured completely even with n dvnced stge with other tretment options nd combintion therpy rther thn monotherpy. Authors contribution Authors give finl pprovl of the version to be submitted nd ny revised version. DISCUSSION HCC stge cn be clssified into very erly, erly, intermedite, dvnced, nd end stge ccording to their size, number, ECOG performnce, existence of portl vein tumor thrombosis (PVTT). 5 According to the rcelon Clinic Liver Cncer stging system, HCC with PVTT is clssified s n dvnced stge. Mlignnt portl vein thrombosis is the leding cuse of poor prognosis, resulting in medin survivl time of 2-4 months without tretment. As it is impossible to tret surgicl resection, there re no other tretment methods thn systemic chemotherpy. Sorfenib is the first pproved systemic therpy nd regorfenib ws pproved by FDA for dvnced HCC. 6,7 And regorfenib is pproved by FDA on April 27, Sorfenib hs been cknowledged s stndrd therpy in ptients with dvnced HCC, but it only provides limited survivl benefits nd tretment responses. 8,9 In the clinicl fields, heptologists re considering to find other tretment methods, other thn sorfenib. According to review rticle of non-opertive Tretments for HCC with PVTT in Journl of Clinicl nd Trnsltionl Heptology, the medin survivl times is 0.78 yers (95% CI, ) in ptients of HCC ccompnied by right PVTT (Vp3). The medin survivl times of Vp3 ptients in the TACE nd supportive cre group ws 11.0 nd 1.43 months, respectively (P<0.01), indicting tht the TACE hd significnt longer survivl thn the supportive tretment. 10 According to cse report on Gstroenterology, 56 yer old mn with HCC ccompnied by PVTT who chieved complete remission for 8 yers fter receiving conventionl TACE. 11 Herein, we Finncil support This work ws supported in prt by Smsung iomedicl Reserch Institute grnt nd Medicl Reserch Funds from Kngbuk Smsung Hospitl (Seoul, Kore). Conflicts of Interest The uthors hve no conflicts to disclose. REFERENCES 1. Ferly J, Soerjomtrm I, Dikshit R, Eser S, Mthers C, Rebelo M, et l. Cncer incidence nd mortlity worldwide: sources, methods nd mjor ptterns in GLOOCAN Int J Cncer 2015;136:E Jung KW, Won YJ, Oh CM, Kong HJ, Cho H, Lee JK, et l. Prediction of cncer incidence nd mortlity in Kore, Cncer Res Tret 2016;48: Siegel RL, Miller KD, Jeml A. Cncer sttistics, CA Cncer J Clin 2016;66: Allire M, Nult JC. Advnces in mngement of heptocellulr crcinom. Curr Opin Oncol 2017;29: Gom AI, Wked I. Recent dvnces in multidisciplinry mngement of heptocellulr crcinom. World J Heptol 2015;7: Kim DW, Tlti C, Kim R. Heptocellulr crcinom (HCC): beyond sorfenib-chemotherpy. J Gstrointest Oncol 2017;8: Llovet JM, Ricci S, Mzzferro V, Hilgrd P, Gne E, lnc JF, et l. Sorfenib in dvnced heptocellulr crcinom. N Engl J Med 2008;359: Keting GM, Sntoro A. Sorfenib: review of its use in dvnced heptocellulr crcinom. Drugs 2009;69:

6 Hojung Jung, et l. Complete cure of dvnced HCC 9. Lu LC, Chen PJ, Yeh YC, Hsu CH, Chen HM, Li MS, et l. Prescription ptterns of sorfenib nd outcomes of ptients with dvnced heptocellulr crcinom: ntionl popultion study. Anticncer Res 2017;37: Moriguchi M, Furut M, Itoh Y. A review of non-opertive tretments for heptocellulr crcinom with dvnced portl vein tumor thrombus. J Clin Trndl Heptol 2017;5: Kim S. Diffuse infiltrtive heptocellulr crcinom with portl vein tumor thrombosis completely cured by trnsctheter rteril chemoemboliztion: cse report with 8-yer follow-up. Cse Rep Gstroenterol 2016;10:

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