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1 J Korean Surg Soc 2010;79: DOI: /jkss 증 례 간내담관에유두상점액종양을동반한원발성미분화담낭암 을지대학교의과대학을지병원외과학교실, 1 병리학교실, 2 소화기내과학교실 김동희ㆍ김은경 1 ㆍ손병관 2 Synchronous Undifferentiated Carcinoma of Gallbladder in a Patient with Intrahepatic Intraductal Papillary Mucinous Neoplasia (b-ipmn) Dong Hee Kim, M.D., Eun Kyung Kim, M.D. 1, Byung Kwan Son, M.D. 2 Departments of Surgery, 1 Pathology, 2 Gastroenterology, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea Simultaneous development of intrahepatic bile duct and gallbladder carcinoma is extremely rare. We report herein the case of an 86-year-old man found to have double cancer of the gallbladder and intrahepatic bile duct. Computed tomography and magnetic resonance cholangiopancreatography revealed a polypoid mass in the gallbladder and dilatation of the intrahepatic bile duct with intraductal papillary tumor in the left side of the liver. The patient underwent left hepatectomy, cholecystectomy with lymphadenectomy around the hepatoduodenal ligament. Pathological examination of the gallbladder revealed undifferentiated giant cell type carcinoma invading the muscularis propria. On the other hand, the liver tumor was intrahepatic intraductal papillary mucinous carcinoma in situ. Therefore, this was an extremely rare case of synchronous carcinoma of the gallbladder associated with intrahepatic cholangiocarcinoma. (J Korean Surg Soc 2010;79: ) Key Words: Gallbladder cancer, Intrahepatic bile duct cancer, Synchronous cancer 중심단어 : 담낭암, 간내담관암, 중복암 서 최근에진단기술의발달및인구의고령화로인하여동일한환자에서서로다른조직학적특성을가진다발성원발성종양에대한보고가증가하고있다. 최근문헌보고에의하면담도계에서도담도암환자의 5 9% 정도에서중복암이발생한다고보고하였다.(1) 그러나대부분췌담관합류이상 (anomalous junction of pancreaticobiliary duct) 을동반한간외담도계에서발생한중복암이대부분이며, 담낭암과동시에간내담관에서발생하는중복암에관한보고는 책임저자 : 김동희, 서울시노원구하계 1 동 , 을지대학교을지병원외과 Tel: , Fax: kdh2109@eulji.ac.kr 접수일 :2009 년 12 월 8 일, 게재승인일 :2010 년 1 월 25 일 론 국내문헌에서찾을수없었으며, 외국에서도매우드물게보고하고있다.(2,3) 이에저자들은서로다른조직학적특성을가진간내담관암과담낭암이동시에발견된환자에대하여외과적치료를경험하였기에문헌고찰과함께보고하고자한다. 증례 86세고령의남자환자로내원한달전부터발생한식후상복부동통으로본원소화기내과외래를통해입원하였다. 과거력상 10여년전총수담관내담석으로인한담도염으로타병원에서치료받은경력이있으나담낭결석에대한자세한병력은알수없었으며그밖에고령임에도불구하고심폐기능의활동은비교적양호하였다. 이학적소견상만성병색의소견을보였으나황달이나복부팽만등의소견은없었고촉지되는림프절종대도관찰할수없었다. 415

416 J Korean Surg Soc. Vol. 79, No. 5 Fig. 1. Contrast enhanced CT. (A) shows multiple intraductal papillary mucinous tumor in dilated left intrahepatic duct (arrow). (B) shows 2.6 3.

Magnetic resonance cholangiopancreatography shows intraluminal polypoid mass in the gallbladder (arrow) and diffuse dilated biliary system with multifocal intraductal polypoid mass in left side

5 mg/dl, alkaline phosphatase (ALP) 293 IU/L, γ- GTP 81 IU/L로폐쇄성황달이나간염을시사하는특이한소견이없었으며종양표지자검사상 CEA 1.34 ng/ml, CA19-9 23.3 U/ml, AFP 1.40 ng/ml로임상적으로의미있는상승을보이지않았다.

7) at left hepatic lobe and two prominent lower density mass with intensely increased FDG uptake (SUVmax of 8.3 at gallbladder, SUVmax of 6.

2 416 J Korean Surg Soc. Vol. 79, No. 5 Fig. 1. Contrast enhanced CT. (A) shows multiple intraductal papillary mucinous tumor in dilated left intrahepatic duct (arrow). (B) shows cm sized polypoid mass in gallbladder with diffuse enhanced wall thickening (arrow). Fig. 2. Magnetic resonance cholangiopancreatography shows intraluminal polypoid mass in the gallbladder (arrow) and diffuse dilated biliary system with multifocal intraductal polypoid mass in left side intrahepatic duct (arrow head). 내원시시행한임상병리검사상 alanine aminotransferase (ALT) 23 IU/L, aspirate aminotransferase (AST) 46 IU/L, total bilirubin 0.5 mg/dl, alkaline phosphatase (ALP) 293 IU/L, γ- GTP 81 IU/L로폐쇄성황달이나간염을시사하는특이한소견이없었으며종양표지자검사상 CEA 1.34 ng/ml, CA U/ml, AFP 1.40 ng/ml로임상적으로의미있는상승을보이지않았다. 복부단층촬영을시행한결과좌측간담관의확장과함께담관내다발성의유두상종양이관찰되었고, 담낭내에는 cm의담낭내종괴가관찰되었으며간문맥과대정맥사이에림프절종대가관찰되었으나그외총간동맥이나대동맥주위의림프절종대는명확하지않았다 (Fig. 1). 전체적인담관내종양의위치및침범 Fig F-FDG PET scan shows fine lower density mass with slightly increased FDG uptake (SUVmax of 3.7) at left hepatic lobe and two prominent lower density mass with intensely increased FDG uptake (SUVmax of 8.3 at gallbladder, SUVmax of 6.2 at portocaval area), suggesting intensely FDG-avid malignant gallbladder cancer with metastasis. 범위를알아보기위하여 magnetic resonance cholangiopancreatography를시행한결과좌측간담관에국한된담관내유두상종양과원발병소와떨어져서담낭내종양이관찰되었으나총담관과우측간담관에는특이한소견이없었다 (Fig. 2). 전신적인전이여부를판단하기위하여저자들은 18 F-FDG PET scan을촬영한결과좌측간내담관, 담낭, 간문맥과대정맥사이에종대된림프절에서만서로다르게증가된 FDG 섭취 (uptake) 를보이고있었다 (SUVmax 3.7; 간내담관, 8.3; 담낭, 6.2; 림프절 ) (Fig. 3). 고령의환자로담낭

Dong Hee Kim, et al Double Cancer Occurred on Hepatobiliary System 417 Fig. 4. Gross and histologic findings of liver.

The adjacent hepatic ducts are dilated and have impacted black pigment stones.

epithelium (H&E stain, 200; inset, H&E stain, 400). Fig. 5. Gross and histolgic findings of gallbladder.

(B) The tumor cells of the gallbladder are diffusely arranged and focally syncytial large and pleomorphic

The giant tumor cells demonstrate hyperchromatic nuclei with prominent nucleoli and severe mitotic activity

3 Dong Hee Kim, et al Double Cancer Occurred on Hepatobiliary System 417 Fig. 4. Gross and histologic findings of liver. (A) The cut surface of liver shows an ill-defined multilocular whitish tumor containing mucus. The adjacent hepatic ducts are dilated and have impacted black pigment stones. (B) The microscopic findings of liver shows intraductal papillary proliferation of tall columnar mucus epithelium (H&E stain, 200; inset, H&E stain, 400). Fig. 5. Gross and histolgic findings of gallbladder. (A) The gallbladder shows a cm sized hemorrhagic and necrotic polypoid tumor filling the lumen. (B) The tumor cells of the gallbladder are diffusely arranged and focally syncytial large and pleomorphic tumor giant cells. The giant tumor cells demonstrate hyperchromatic nuclei with prominent nucleoli and severe mitotic activity (H&E stain, 200; inset, H&E stain, 400). (C) On immunohistochemistry, tumor cells are strongly positive for epithelial membrane antigen (EMA) (Immunohistochemical stain, 200) and focally positive for CK (inset, immunohistochemical stain, 200).

4 418 J Korean Surg Soc. Vol. 79, No. 5 암의좌측간담관의전이및림프절전이를배제할수없었으나환자및보호자의적극적인치료의지로진단적개복술을시행하였다. 수술소견상복강내복막에전이소견은없었으며좌측간에국한된만성적인간담도염소견과함께종양을의심할만한종괴가촉지되었으나우측간은비교적양호한표면을보였다. 담낭은내강에종양이꽉찬소견을보였으며주변간조직이나간십이지장인대에암종의침범이보이지않았다. 간문맥과대정맥사이에 4 3 cm 크기의림프절이촉지되었고그외에림프절종대는관찰되지않았다. 수술은좌측간엽절제술을시행한후절제된말단부의간담관조직에서응급동결조직검사를시행한결과종양침범이보여추가로간담관을절제하여종양이없음을확인하였고절제된간담관의개구부를통해담도경으로팽대부까지확인한후말단부의간담관을봉합하였다. 이후담낭절제술및간문맥과대정맥사이의종대된림프절을포함하여간십이지장인대및총간동맥주변의림프절곽청술을시행하였다. 수술후병리조직학적검사상좌측간엽에는흑색결석을동반한간담관의협착과확장된모양을띠는만성적인간담도염의소견을보였으며확장된간담관내에는점액을포함한 cm 크기의담관내유두상종양이관찰되었다 (Fig. 4A). 현미경소견상담관내로기둥모양의종양세포들이유두상증식을보였으나간실질로는침범되지않은담관내유두상점액성상피내암 (intraductal papillary mucinous carcinoma in situ) 으로진단되었다 (Fig. 4B). 절제된담낭의육안적소견은담낭내강에 cm 크기의출혈을동반한괴사성의용종모양의종양이전체내강을채우고있었으며종양은담낭벽의근육층까지침범하였으나장막층의침윤은보이지않았다 (Fig. 5A). 현미경소견상종양조직의광범위한괴사와미만성으로분포된다양한형태의여러개의핵을가진거대세포가관찰되었고, 이들거대세포는두드러지게관찰되는핵소체와심한유사분열성을보이는과색소의핵으로구성된종양세포로미분화거대세포형담낭암으로진단이가능하였다 (Fig. 5B). 면역조직화학염색을시행한결과상피암을암시하는 epithelial membrane antigen, cytokeratin에양성소견을보였으며중간엽기원 (mesenchymal origin) 을암시하는 vimentin 염색에는음성소견을보였다 (Fig. 5C). 절제된림프절에서는수술중림프절종대가확인된한개의림프절 (No.12p) 에서만담낭암과같은세포의전이소견이관찰되었다. 환자는수술후특이합병증없이 2주후퇴원하였으며고령인관계로보조적항암치료없이현재 외래추적관찰중이다. 고찰 원발성중복암이란한환자에서 2개이상의원발성악성종양이발생하는것을의미하며진단되는시기에따라진단당시동시에발견되거나첫번째악성종양이진단된후 6개월이내에다른악성병변이발견되는동시성중복암 (synchronous multiple malignancy) 과첫번째악성병변이발견된후 6개월이상경과된후다른병변이발견되는속발성중복암 (metachronous multiple malignancy) 으로구분할수있다. Warren과 Gates(4) 는다발성원발성악성종양의진단기준을 1) 각각의종양은명확한악성의특징이있어야하고 2) 명확한병리조직학적차이가있어야하며 3) 종양상호간에전이의가능성이없어야한다고하였다. 담도계에서발생하는원발성중복암의진단기준에대하여 Gertsch 등 (5) 은 1) 종양상호간에직접적인연결이없어야하며 2) 각각특징적인종양성장의유형이있어야하고 3) 두종양간의분명한조직학적차이가있어야한다고하였다. 그러나담도계에서중복암의발생기전대하여다발성발암화 (multicentric carcinogenesis) 와원발병소의전이 (metastasis of primary malignancy) 에대한가설은현재까지논란이되고있다. 임상적으로담도계에서발생하는동시성중복암의 65%, 속발성중복암의 100% 가췌담관합류이상으로췌즙의담도내역류로인한다발성발암화를병리기전으로보고하고있다.(2) 반면에췌담관합류이상을동반하지않은담도계의중복암에대하여 Fahim 등 (6) 은담도암의 4% 정도에서담관내종양세포의전이가다발성중복암을유발한다고보고하였다. 실제적으로담도암의중복암이다발성발암화혹은원발병소의전이에의한발생인지를구분하기는쉽지않다. 최근에는폐암이나두경부암에서종양의유전자정보를통해일명 field cancerization 으로불리는다발성발암화과정을확인하기도하였으나,(7,8) 반면에요관세포암의경우 p53, c-erb B2 발현을통해요관내다발성종양의원인이종양세포의요관내전이에의한것임을보고하였다.(9) 담도계의다발성중복암에서는유전자검사에관한연구로현미부수체불안전성 (microsatellite instability) 에의한유전자의 loss of heterozygosity를암종에서분석함으로써중복암의발생기전을연구한보고가있다.(10) 결론적으로담도계에서중복암의진단은기존의병리학적기준과더불어유전자검사, 면역조직화학염색

5 Dong Hee Kim, et al:double Cancer Occurred on Hepatobiliary System 419 등다양한보조적방법이필요하리라본다. 본증례에서간내담관암의경우간담관내로점액을함유하며유두상성장을하는점액성유두상종양중상피내암의단계로간내담관에국한되어정상적인좌, 우총간관을유지하고있는비교적예후가양호한종양이었다. 반면에담낭암의경우전체담낭암의 10% 전후를차지하는미분화암중매우희귀한거대세포형미분화담낭암으로아직정확한병리기전이밝혀지지않았으나종양은담낭에국한되어정상적인담낭관을유지하고있었으며, 비록복강내림프절전이 (No.12p) 를보이고있으나간문부림프절및담관주변신경절침범이나미세혈관침범의소견이없으며, 면역조직화학검사상간내담관의종양과는다른종양세포로확인되었다. 따라서임상병리학적으로두암종은서로다른병리조직학적특징을가지고있으며상호간의연결이없는담도계의동시성중복암이라할수있다. REFERENCES 1) Kurosaki I, Watanabe H, Tsukada K, Hatakeyama K. Synchronous primary tumors of the extrahepatic bile duct and gallbladder. J Surg Oncol 1997;65: ) Fujii T, Kaneko T, Sugimoto H, Okochi O, Inoue S, Takeda S, et al. Metachronous double cancer of the gallbladder and common bile duct. J Hepatobiliary Pancreat Surg 2004;11: ) Taniai N, Onda M, Tajiri T, Yoshida H, Naitou Z. Synchronous carcinoma of the gallbladder in a patient with intrahepatic bile duct carcinoma. Hepatogastroenterology 2000; 47: ) Warren S, Gates O. Multiple primary malignant tumors. A survey of the literature and a statistical study. Am J Cancer 1932;16: ) Gertsch P, Thomas P, Baer H, Lerut J, Zimmermann A, Blumgart LH. Multiple tumors of the biliary tract. Am J Surg 1990;159: ) Fahim RB, McDonald JR, Richards JC, Ferris DO. Carcinoma of the gallbladder: a study of its modes of spread. Ann Surg 1962;156: ) Sozzi G, Miozzo M, Pastorino U, Pilotti S, Donghi R, Giarola M, et al. Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res 1995;55: ) Nees M, Homann N, Discher H, Andl T, Enders C, Herold-Mende C, et al. Expression of mutated p53 occurs in tumor-distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors. Cancer Res 1993;53: ) Habuchi T, Takahashi R, Yamada H, Kakehi Y, Sugiyama T, Yoshida O. Metachronous multifocal development of urothelial cancers by intraluminal seeding. Lancet 1993;342: ) Ogawa A, Sugo H, Takamori S, Kojima K, Fukasawa M, Beppu T, et al. Double cancers in the common bile duct: molecular genetic findings with an analysis of LOH. J Hepatobiliary Pancreat Surg 2001;8:374-8.

(49-54)Kjhps004.hwp

(49-54)Kjhps004.hwp Biliary Cystadenoma and Cystadenocarcinoma of the Liver Jae Hoon Lee, M.D., Dong Ho Choi, M.D. 1, Kyeong Geun Lee, M.D., Hwon Kyum Park M.D. and Kwang Soo Lee, M.D. Department of Surgery, College of Medicine,