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1 대한내과학회지 : 제 72 권부록 2 호 2007 간내원발병소가뚜렷하지않고폐전이로확진된간세포암종 1예 연세대학교의과대학내과학교실, 병리학교실 2 문희선 백용한 장진혁 황성준 문종태 이관식 권지은 2 =bstract= case of lung metastasis from unknown primary hepatocellular carcinoma Hee Sun Mun, M.D., Yong Han Paik, M.D., Jin Hyuck Chang, M.D., Seoung Joon Hwang, M.D., Jong Tae Moon, M.D., Kwan Sik Lee, M.D. and Ji Eun Kwon, M.D. 2 Departments of Internal Medicine and Pathology 2, Yonsei University College of Medicine, Seoul, Korea Hepatocellular carcinoma (HCC) is a common malignancy and hepatitis infection is known to be its most common etiologic factor. The most common metastatic site of extrahepatic spread is the lung. We report here on a case of a patient who presented with pulmonary metastasis as the first clinical manifestation of HCC. 62-year-old-male patient showed an elevated α-fetoprotein level during follow up for chronic hepatitis and liver cirrhosis. The existence of HCC was suspected and an empirical imaging diagnosis was performed. However, repeated computer tomography (CT), magnetic resonance imaging and hepatic angiography failed to detect any HCC. fter 12 months, chest CT and PET (positron emission tomography) revealed lung nodules. Histologically, the resected lesion was confirmed as metastatic tumor from HCC. The establishment of the diagnosis of metastatic HCC can occasionally be problematic, particularly when the primary tumor has not been identified. systemic approach to diagnosis and treatment should be followed.(korean J Med 72:S149-S155, 2007) Key Words : Carcinoma, hepatocellular; Neoplasm, unknown primary; Neoplasm metastasis 서론간세포암종은우리나라 3대암중의하나로 형간염바이러스감염에의한만성간질환이가장중요한원인이다 1-3). 간세포암종은 1990년대에와서는감소추세로들어서고있으나, OECD 국가중에서우리나라의간세포암종사망률은최고수치를기록하고있으며, 2005년 9월통계청발표에따르면폐암 (27.5%), 위암 (23.2%) 에이어세번째암사망률 (22.6%) 을기록하고있다. 최근간세포암종의진단과치료법이발전하여장기 생존이증가함에따라간외장기로원격전이가증가하는추세이다. 간세포암종은혈행성경로, 임파선을통하여또는직접적인침윤으로전이되며, 혈행성전이로는폐전이가가장흔하고골, 부신등의순서로흔히발생한다 4). 또한원발병소가뚜렷하지않은원격전이도드물게보고되고있다. 그러나국내에서는원발병소없이발견된간세포암종의원격전이에대한보고는아직없었다. 이에저자등은간내원발병소는뚜렷하지않고, 원격전이된폐부위에대한수술적절제후조직학적으로확진된간세포암종 1예를경험하였기에 Received : ccepted : Correspondence to : Yong Han Paik, M.D., Department of Internal Medicine, Yongdong Severance Hospal, Dogok-dong, Gangnam-gu, Seoul , Korea yhpaik@yumc.yonsei.ac.kr - S149 -

- 대한내과학회지 : 제 72 권부록 2 호 2007 - C D Figure 1. Initial and follow up abdominal dynamic CT. ( and ). The initial abdominal dynamic CT (: arterial phase, : delayed phase).

2 - 대한내과학회지 : 제 72 권부록 2 호 C D Figure 1. Initial and follow up abdominal dynamic CT. ( and ). The initial abdominal dynamic CT (: arterial phase, : delayed phase). Tiny areas of low attenuation density in the liver dome S8 show suspicious marginal contrast enhancement on the portal and delayed phase images and no contrast enhancement in the central area. (C and D). bdominal dynamic CT after 1 year (C: arterial phase, D: delayed phase). The hepatic fibrosis in the anterior and upper portions of the Lt. and Rt. lobes of the liver shows no significant interval change. No size variation was seen in the S8 lesion. 보고하는바이다. 증례환자 : 62세, 남자주소 : 지속적인혈청태아단백상승및 2개의폐우상엽종괴현병력 : 11년전 형간염보균자, 1년전간경변증으로진단받고외래추적관찰중혈청태아단백수치가 16.7 ng/ml로증가하여복부전산화단층촬영및자기공명영상을시행하였으나, 간내에는섬유화를동반한국소지방축적의소견만을보였다 ( 그림 1, 2). 6개월후 시행한복부전산화단층촬영에서도간내악성종괴의소견이뚜렷하지않았으나, 혈청태아단백및 PIVK-II 수치가각각 ng/ml, 313 U/mL로상승되어, 간내섬유화부위에서간생검을시행하였으나악성화소견없는거대결절성간경변으로진단되었다 ( 그림 3). 9 개월후간동맥조영술시행하였으며고혈관성간내병소는확인되지않았으나 ( 그림 4), 경동맥화학주사요법 (TCI; transarterial chemoinfusion therapy) 시행후추적관찰하였다. 12개월후시행한흉부단순촬영및흉부전산화단층촬영상 2개의새로생긴종괴가폐우상엽에서발견되었다 ( 그림 5). - S150 -

- 문희선외 6 인 : 간내원발병소없는폐전이간세포암종 - Figure 2. Initial and follow up liver MRI. (). Initial liver MRI. (). Liver MRI after 1 year.

Histology of the liver biopsy. Liver biopsy was performed after 6 months of follow up.

과거력 : 11년전 형간염보균자, 1년전간경변증으로진단받고외래추적관찰중이다. 가족력 : 특이가족력없음. 이학적소견 : 입원시활력징후는혈압 140/90 mmhg, 맥박은분당 60회, 호흡수는분당 20회, 체온 36.1 이었다.

복부진찰소견상장음은정상이었고, 복부의압통과반사통은 없었으며간, 비장, 신장은만져지지않았다. 상지나하지의함요부종은관찰되지않았고, 늑골척추각압통도없었다. 검사실소견 : 내원당시시행한말초혈액검사상백혈구 6,040/mm 3 ( 호중구 49.

3 - 문희선외 6 인 : 간내원발병소없는폐전이간세포암종 - Figure 2. Initial and follow up liver MRI. (). Initial liver MRI. (). Liver MRI after 1 year. Comparing to the previous MRI, a 1.9 cm localized SPIO defect on the area of the liver dome shows no interval change. Figure 3. Histology of the liver biopsy. Liver biopsy was performed after 6 months of follow up. Macronodular inactive cirrhosis was observed and there was no evidence of malignancy ( 50)(), ( 400)(). 과거력 : 11년전 형간염보균자, 1년전간경변증으로진단받고외래추적관찰중이다. 가족력 : 특이가족력없음. 이학적소견 : 입원시활력징후는혈압 140/90 mmhg, 맥박은분당 60회, 호흡수는분당 20회, 체온 36.1 이었다. 의식은명료하였고, 피부는따뜻하였으며, 황달소견을포함한비정상적인피부병변은보이지않았고, 공막에황달은관찰되지않았다. 흉부진찰소견상호흡음은정상이었고, 수포음은청진되지않았으며, 심음은규칙적이었고, 심잡음은청진되지않았다. 복부진찰소견상장음은정상이었고, 복부의압통과반사통은 없었으며간, 비장, 신장은만져지지않았다. 상지나하지의함요부종은관찰되지않았고, 늑골척추각압통도없었다. 검사실소견 : 내원당시시행한말초혈액검사상백혈구 6,040/mm 3 ( 호중구 49.8%), 혈색소 13.4 g/dl, 헤마토크릿 39.5%, 혈소판 101,000/mm 3 이었고, 혈청생화학검사상총단백 / 알부민 7.9/4.9 g/dl, ST/LT 26/29 IU/L, UN 15.4 mg/dl, Cr 0.8 mg/dl, gamma-gt 29 IU/L, 총빌리루빈 0.7 mg/dl, LP 53 IU/L, 특수혈액검사상 PT 101% (INR 0.99), aptt 31.9 sec, 혈청태아단백 (0.5-7) IU/mL, PIVK II 642 (0-40) - S151 -

- 대한내과학회지 : 제 72 권부록 2 호 2007 - Figure 4. Hepatic angiogram performed after 9 months.

2 cm sized lobulated nodule in the anterior segment of the Rt.

apex area () are highly suggestive of metastatic lesion. Figure 6. spiration cytology of the pulmonary nodule.

2) ng/ml, SCC g 0.87 (0-1.5) ng/ml 이었다. 치료및경과 : 폐의종괴에대하여세침흡인검사시행후비소세포폐암으로진단되었다 ( 그림 6).

4 - 대한내과학회지 : 제 72 권부록 2 호 Figure 4. Hepatic angiogram performed after 9 months. No definite tumor staining was seen in the liver. Figure 5. Chest CT after 1 year. 2 cm sized lobulated nodule in the anterior segment of the Rt. upper lobe () and another 5 mm sized tiny nodule in the Rt. apex area () are highly suggestive of metastatic lesion. Figure 6. spiration cytology of the pulmonary nodule. Diagnosis was non-small cell carcinoma ( 100). U/mL, NSE 6.4 ( ) ng/ml, Cyfra (0-3.2) ng/ml, SCC g 0.87 (0-1.5) ng/ml 이었다. 치료및경과 : 폐의종괴에대하여세침흡인검사시행후비소세포폐암으로진단되었다 ( 그림 6). 원발성폐암과전이성폐암의감별이어려워양전자방출단층 촬영을시행하였고, 폐이외의병소는발견되지않아 ( 그림 7) 폐우상엽절제술을시행하였고, 조직검사결과 2 개의결절모두간세포암종의폐전이소견으로확인되었다 ( 그림 8). 수술후 3개월째혈청태아단백은 ng/ml까지감소추세이며복부전산화단층촬영및흉부전산화단층촬영상종괴의재발소견없이외래추적관찰중이다. 고찰간세포암종은간에서발생하는원발성악성종양중에서가장흔하다 5). 보통 50~60대에나타나며가장흔한병인은만성바이러스성간염, 특히간경변증이동반된경우이다. 가장흔한원인은만성 형간염이며 1-3), - S152 -

- 문희선외 6 인 : 간내원발병소없는폐전이간세포암종 - Figure 7. PET after 1 year. The known pulmonary nodule in the RUL shows an increased FDG uptake and this is consistent with malignancy.

4% 로 7) 남자대여자비는 3:1~6:1로보고된다 6). 간세포암종은간내혈관을통하거나임파선의침투, 직접적인침윤으로전이되고혈행성전이의경우간정맥, 간문맥또는대정맥을통해이루어진다 4). 혈행성으로파종된원격전이는폐 (49%), 골 (16%), 부신 (15%), 췌장 (4%), 신장 (3%), 비장 (2%) 순으로호발된다 8).

5 - 문희선외 6 인 : 간내원발병소없는폐전이간세포암종 - Figure 7. PET after 1 year. The known pulmonary nodule in the RUL shows an increased FDG uptake and this is consistent with malignancy. 바이러스성간염의호발지역에서는모든암의 20~ 40% 를차지한다 6). 간세포암종은아시아와사하라사막이남아프리카에서는흔한암종으로매해인구 100,000만명당 500명의발생률을보이고있으며, 서유럽과미국에서는상대적으로흔치않고악성종양의 1~2% 를차지한다 7). 증상이발현된간세포암종의 5년생존율은남자의경우 0.8%, 여자의경우 4.4% 로 7) 남자대여자비는 3:1~6:1로보고된다 6). 간세포암종은간내혈관을통하거나임파선의침투, 직접적인침윤으로전이되고혈행성전이의경우간정맥, 간문맥또는대정맥을통해이루어진다 4). 혈행성으로파종된원격전이는폐 (49%), 골 (16%), 부신 (15%), 췌장 (4%), 신장 (3%), 비장 (2%) 순으로호발된다 8). 그러나간내원발병소가뚜렷하지않은상태에서골 9), 흉곽 4, 7, 10), 부신 11) 등으로의원격전이는간세포암종에서드물게 보고된바있다. 이경우혈청태아단백의상승, 세침흡 C D Figure 8. Gross findings and histology of the resected lung. ( and ). Gross findings of the resected lung. (). Metastatic hepatocellular carcinoma was seen as a mass-like lesion in the anterior segment. (). The other metastatic HCC was seen as a nodular lesion in the apical segment. (C and D). Microscopic pathology of the resected lung. (C). The tumor cells form trabecular cords that are separated by variably dilated sinusoidal spaces, showing hepatocellular carcinoma ( 100). (D). The tumor cells have round to oval hyperchromatic nuclei with moderate to ample eosinophilic granular cytoplasm. The sinusoidal spaces are lined by a single layer of flattened endothelial cells ( 400). - S153 -

6 - 대한내과학회지 : 제 72 권부록 2 호 인또는절제후조직학적으로확진하였다. 간내원발병소가뚜렷하지않은경우는미세한간세포암종으로부터의전이, 면역체계가손상된경우, 이소성간조직에서발생하는간세포암종, 드물게는간세포암종의자발적인퇴화로설명되었다 12-15). 본증례의경우에는미세한간세포암종또는자발적으로퇴화한간세포암종의전이가가능성이높다고생각된다. 원발성간내병변이뚜렷하지않은경우, 전이성간세포암종의확진은어려울수있다. 그러나만성간질환이있는상태에서혈청태아단백의상승이있는경우는간세포암종을의심하고진단하기위한체계적인접근이필요하다 4, 16). 기본적으로는이학적검사, 혈액학적검사및혈청학적검사 ( 간염바이러스표지자검사, 혈청태아단백등 ), 방사선학적검사 ( 복부초음파, 컴퓨터단층촬영 ) 등을시행해야한다. 자기공명영상및혈관조영술은진단및치료에도움이되며세침흡인또는절제를통해조직학적으로진단할수있다. 양전자방사단층촬영은암의진단및병기설정에도움이되는영상학적도구이나원발성간세포암종에서는다양한정도의 18 F-FDG 흡수로인해그유용성이떨어진다. 그러나간외전이부위를찾는데있어서 1 cm 이상인경우 83%, 특히폐전이의경우 100% 의발견율이보고된바있다 17). 간세포암종의전이에대한치료로는수술적절제, 항암화학요법, 방사선치료, 간동맥화학색전술등이있다. 폐전이의경우에는일부의선택된환자에서쐐기절제술, 구역절제술, 폐엽절제술등의수술이장기적인생존율향상에도움이되며다른폐엽또는반대쪽폐등다발성폐전이의경우에도완전절제를할수있는경우에는적극적인절제를고려할수있다 8, 12, 18). 요약최근간세포암종의진단과치료법이발전하여장기생존이증가함에따라간외장기로의원격전이가증가하는추세이다. 간세포암종은혈행성경로를통한간외전이의경우폐전이가가장흔하고그다음부신, 골, 등의순서로흔히발생한다. 저자등은간내원발병소는뚜렷하지않은가운데원격전이된폐전이에대한수술적절제후확진된간세포암종 1예를경험하여보고하는바이다. 62세남자환자가 11년전 형간염보균자, 1년전간경변증으로진단받고외래추적관찰중혈청태아 단백수치가증가하여복부전산화단층촬영, 자기공명영상, 간동맥조영술및간생검을시행하였으나간내원발병소는뚜렷하지않았다. 외래추적관찰중시행한흉부단순촬영및흉부전산화단층촬영상 2개의새로생긴종괴가발견되어세침흡인검사시행후비소세포폐암으로나타나폐우상엽절제술을시행하였고, 조직검사결과 2개의결절모두간세포암종의폐전이소견으로확인되었다. 만성간질환이있는환자에서혈청태아단백의상승이있는경우는간세포암종을의심하여먼저간내종괴를찾기위한검사를하는것이일반적이나간내종괴없이지속적으로혈청태아단백의상승이있는경우간이외의다른장기에전이성종괴가있을가능성에대해서도고려가필요하다. 중심단어 : 간세포암종, 뚜렷하지않은원발병소, 폐전이 REFERENCES 1) efeler S, di isceglie M. Hepatocellular carcinoma: diagnosis and treatment. Gastroenterology 122: , ) Katyal S, Oliver JH 3rd, Peterson MS, Ferris JV, Carr S, aron RL. Extrahepatic metastasis of hepatocellular carcinoma. Radiology 216: , ) Tang ZY. Hepatocellular carcinoma: cause, treatment and metastasis. World J Gastroenterol 7: , ) Coban S, Yksel O, Koklu S, Ceyhan K, aykara M, Dkmeci. typical presentation of hepatocellular carcinoma: a mass on the left thoracic wall. MC Cancer 4:89, ) nthony PP. Hepatocellular carcinoma: an overview. Histopathology 39: , ) osch FX. Global epidemiology of hepatocellular carcinoma. In: Okuda K, Tabor E, eds. Liver cancer. p , New york, Churchill livingstone, ) Hofmann HS, Spillner J, Hammer, Diez C. solitary chest wall metastasis from unknown primary hepatocelleular carcinoma. Eur J Gastroenterol Hepatol 15: , ) Raoul JL, le Simple T, le Prise E, Meunier, en Hassel M, retagne JF. one metastasis revealing hepatocellular carcinoma: a report of three cases with a long clinical course. m J Gastroenterol 90: , ) Suterwala SS, Volk EE, Danforth RD. spiration biopsy of osseous metastasis of occult hepatocellular - S154 -

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김범수

김범수 Analysis of Outcomes after Resection of Sarcomatous Hepatocellular Carcinoma Purpose: Sarcomatous hepatocellular carcinoma (HCC) is rare. Therefore, the clinicopathologic characteristics and prognosis