2012 년대한간학회춘계 Single Topic Symposium 샘종에비하여 3-10 배정도흔하며유병률은성인에서 % 로알려져있다. 1,2 남녀구분없이모든 연령에서발생가능하나20-50세의여자에서가장흔하게발견된다. 여자에서흔하게발생하나남녀비의보고는연구방법에따

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1 Focal Nodular Hyperplasia and Hepatic Adenoma 고신대학교의과대학내과학교실 윤병철 Liver tumors are often asymptomatic. The widespread use of high-resolution imaging modalities has increased the detection of liver lesions. Although some of these incidentally detected masses are malignant, most are benign and must be included in the differential diagnosis. Focal nodular hyperplasia (FNH) and hepatic adenoma (HA) represent the most frequent non-vascular benign liver tumors. The management of these benign tumors ranges from conservative to aggressive, depending on the nature of the lesions. Deciding on the most adequate management requires a reliable diagnosis, and also demands good understanding in the etiology of the disorder and its pathological behavior. In this paper focuses on the epidemiology, natural history and management of FNH and HA. Key words: Focal nodular hyperplasia; Hepatic adenoma; Benign liver tumor 서 론 간종양은흔히무증상이거나증상이거의없으므로우연하게발견되는경우가흔하다. 최근건강검진의증가와영상의학기술의발달로간결절의발견빈도가증가되고있다. 이러한간결절은악성종양이나전암성병변, 양성결절일수있다. 이결절들에대하여적절한치료를결정하기위해서는정확하게진단뿐만아니라이질환에대한발생원인과병리학적성질에대한적절한이해가필요하다. 악성종양과양성종양을구분하는것도중요하지만다양한양성병변을정확하게구분하는것은적절한치료를선택하는것에중요하다. 이연제에서는양성간종양중국소결절과형성 (FNH, Focal nodular hyperplasia) 와간샘종 (HA, Hepatic adenoma) 의역학, 자연경과및치료등에중점을두어임상적관점에서설명하고자한다. 국소결절과형성 1. 역학 FNH 는간혈관종다음으로흔한양성간종양으로전체원발성간종양중 8% 를차지한다. FNH 는간 1

2 2012 년대한간학회춘계 Single Topic Symposium 샘종에비하여 3-10 배정도흔하며유병률은성인에서 % 로알려져있다. 1,2 남녀구분없이모든 연령에서발생가능하나20-50세의여자에서가장흔하게발견된다. 여자에서흔하게발생하나남녀비의보고는연구방법에따라 2:1에서 12:1까지다양하게보고되고있다. 3-5 성인을대상으로한영상연구에서단독병변은주로우측간에위치하며약 20% 에서 2-5개의결절이발견되었다. 4 크기는다양하여 mm까지보고되고있으나진단당시평균크기는 40-50mm로알려져있다. 4,6 국내에서보고된 FNH에대한연구에서진단당시연령은재태기간 36주에서 67세로전연령층에서발견되었으며대부분 (76.3%) 이 20-50대연령층으로평균발생연령은 34세이었다. 총 38예의환자중남자 21명, 여자 17명으로남녀성비는 1.2:1로국내보고에서는남성이더많이보고되었다. 이는보고된논문들을분석한연구로 FNH는여자에서호발하는것으로알려져있어남자에서발생하는경우증례보고가더활발했기때문이라판단하였다 발생기전 FNH 의발생기전은아직명확히알려져있지않지만병소중심에발생한동맥기형으로인하여국소 적인과다혈류가발생하고이로인한간세포의과증식반응으로보고있다. 5 FNH 의면역조직화학분 석을시행한연구에서동맥혈의과관류에의해서과산소상태가발생하고이로인해간성상세포가활성화되어중심반흔이형성되는것으로보고하였고증가된산소분압에의해활성화된혈관내피성장인자가비정상적인혈관의증식에관여할것이라고설명하였다. 7 에스트로겐이나프로게스테론이 FNH의발생이나증식에관여하는역할에대하여는아직논란이있다. FNH의발생에경구피임제의역할에대한의견은다양하다. 경구피임제의복용이 FNH의발생과밀접한관계가있고경구피임제의복용시결절크기가더커지고출혈경향이증가한다고생각하였으나 2000년대이후보고들에서는이전의결과와는상이한결과를보였다. 최근경구피임제가 FNH의크기및개수에관련이없으며추적관찰시크기의변화도없었다는보고들이있다. 8,9 이는 1980년대이전의경구피임제는현재에비하여매우높은에스트로겐 (>50mcg) 용량이포함된것과관계가있을것으로생각되나현재까지의연구들로는 FNH에대한경구피임제의영향은결론을내리기힘들다. 현재는 FNH가있는환자는경구피임제를복용하지않도록하는것이안전할것으로생각된다. 3. 병리소견 전형적인 FNH 의육안소견은피막을형성하지않고주위의정상간과명확한경계를가지는종괴를 2

3 윤병철 Focal Nodular Hyperplasia and Hepatic Adenoma 보이는것이일반적이다. 이종괴는중심반흔에서방사상으로뻗어나간섬유격막에의해여러개의결절로나뉘어져있다. FNH는전형적인형태 (70-80%) 와비전형적인형태 (20-30%) 로나눌수있다. 10 전형적인형태는비정상적인결절구조를가지며기형혈관과쓸개세관증식이있는것이특징이다. 비전형적인형태는쓸개세관의증식은보이나결절구조나기형혈관이동반되지않으며중심반흔이보이지않는것을특징으로한다. 간세포판이위축되면서굴모양혈관 (Sinusoid) 의심한확장을보이는혈관확장형 (Telangiectatic), 간세포샘종과비슷한소견이동반되는혼합증식샘종형과결절내대세포형성이상이있는비정형세포를동반하는 FNH 등 3가지아형으로나눌수있다. 최근 FNH의발생기전에대한클론분석에집중한분자수준의연구들이시행되었다. 대부분의연구들은 FNH는과형성으로발생한병변으로다클론기원이라고보고된다. 비전형적 FNH의아형중혈관확장형 FNH(tFNH, telangiectatic FNH) 은간샘종과유사하게 100% 에서단클론기원을보인다는보고가있다. 11,12 4. 임상증상및진단 FNH는증상이없는환자에서우연히발견하는경우가일반적이다. 혈청간기능검사의이상을보이는경우는 12-13% 정도에서보고되고있고혈청 α-fetoprotein은정상범위이다. 증상을보이는경우는흔하지않으며 2-4% 환자에서복부종괴로촉진되며 1% 이하의환자에서간비대와발열등이관찰된다. 10 FNH의영상진단는초음파, CT, MRI에서특징적인소견을보이는경우진단을할수있는데 MRI는높은민감도 (~70%) 와특이도 (98-100%) 를보인다. 13 많은환자가가임기의여성이므로진단에 CT보다방사선노출을피할수있는 MRI가선호된다. MRI는대부분의경우에서 FNH와다른간의국소병변을적절하게구분할수있다. 최근조영증강초음파가진단에유용하게이용되고있으나아직임상에서광범위하게사용하는것에는한계점이있다. 임상적이나혈청학적으로간질환의증거가없는젊은환자에서영상진단이불분명한경우에는간조직검사를시행한다. 5. 자연경과및치료 FNH와간세포암종이동시에발견된산발적인증례보고외에는조직학적으로확인된 FNH 환자에서악성변화의발생은보고된경우가없다. 조직학적으로확진된 FNH 환자의장기추적연구들에서도악성변화는없다고알려져있다. 30명의 FNH 환자에서초음파를이용하여평균 42개월기간동안추적 3

4 2012 년대한간학회춘계 Single Topic Symposium 관찰한연구에서 71% 병변에서크기변화가없었고 27% 병변은크기가감소하였고 3% 병변만이직경이 30% 이상증가하였다. 14 다른연구에서도추적관찰중 80% 의병변이크기변화가없었고 7% 의병변은 크기가감소하였다. 15 대부분의 FNH 은크기변화가없거나연령이증가할수록크기가감소되는것으로 악성화가능성은거의없으며출혈이나파열등의합병증의위험도는매우낮은것으로알려져있다. 대부분의 FNH는양성경과를보이므로특징적인방사선학적소견을보이는무증상의 FNH 환자는특별한치료가필요없다. 일부환자는여러가지영상검사 ( 초음파, CT, MRI, 핵의학검사 ) 등을시행해도양성결절인것같으나 FNH의비전형적인소견을보이는경우가있다. 이런경우는호르몬환경이변동되는폐경기에가까운 40대의여성에서흔히발생한다. 고령의여성에서는 FNH가발견되지않은것은흥미로운사실로폐경기이후에많은수의 FNH 병변이소실될수있다. 비전형적이지만양성의방사선학적특징을가진환자의경우는다른위험한소견이동반되지않은경우는 3-4개월간격으로주기적인관찰이합당하며관찰기간동안영상의변화가있거나크기가증가하거나, 증상이나타나는경우는진단및치료의목적으로외과적치료를시행한다. 대부분의 FNH 환자는무증상이나병변의크기가크거나피막하에위치하는경우증상이나타날수있고이런환자는수술적절제가필요하다. 비전형적인방사선학적특징을가지며악성화를완전히배제하지못하는병변은즉시수술적제거를시행하여야한다. 저용량의경구피임제복용과 FNH 발생의상관관계에대한자료가한정되어있으나 FNH가진단된환자는경구피임제복용을중단하여야한다. 임산부나임신을원하는 FNH 환자는병변의제거가필요하지않고대부분의환자는임신기간동안조심스럽게초음파를시행하면서관찰할수있다. 간샘종 1. 역학 HA는주로경구피임약을복용하는젊은여자에서진단되며여러보고들에서유병률은다양하여 100 만명당 1명에서 1% 정도로보고되고있으나 4,16 정확한발생률과유병률은알려져있지않다. 경구피임제를장기간사용하는경우 HA의연간발생률이 10만명당 3-4명으로발생률이 30-40배증가하는것으로알려져있다. 17 FNH가 HA에비하여 3-10배흔하게발생하다. 1 남자에서는 HA는아주드물게보고된다. 2. 발생기전 여성과남성호르몬의복용이 HA 의발생과연관된확실한발병인자로알려져있다. HA 는 1960 대에 4

5 윤병철 Focal Nodular Hyperplasia and Hepatic Adenoma 경구피임제가사용되기전에는아주드물게발생하였으나경구피임제의사용후부터발생이증가하기시작하였다. 정확한기전은아직명확하지않으나경구피임제의용량, 복용기간에비례하여 HA의발생율과샘종의크기가증가한다고알려져있다. 운동선수들과재생불량성빈혈환자에게단백동화스테로이드를복용하는것같이남성호르몬제를복용하는경우 HA가발생하는것이보고되었다. 18,19 정확한발생기전은알려져있지않으나당원병과 HA의발생과는연관되어있다. 당원병 I형과 III형에서환자의 50% 와 25% 에서다발성 HA가발생하는것으로보고되고있으며특히당원병 I형에서발생하는 HA에서는악성변화위험이현저하게증가하는것으로보고된다 병리소견대부분의 HA는단독병변 (70-80%) 으로나타나며진단시종양의크기는 1cm 미만부터 15-20cm 이상까지다양하다. HA는피막이없거나불완전하게존재하여경계를알수없는경우가있고이특징으로종양내에서출혈이발생하면주위간조직이나복막강으로쉽게퍼지는것을설명할수있다. 조직학적으로는굴모양혈관에의해나뉜간세포의판이 3개의층이상으로구성된 cord로구성되어있다. 문맥이없어간동맥으로부터혈액을공급받으며쓸개세관이없어담즙을배출할수없다. 21 중심반흔, 문맥, 쓸개세관이없는것으로 FNH와구분된다. 유전자검사등을시행하여 HA를 HNF1α activated, Inflammatory, β-catenin activated HA 등크게 3개의소그룹으로나눌수있다. 22 이분류에따르면 HA의 90-95% 가이 3군의소그룹에속하며이분류에따라합병증의발생을평가할수있다 (Table 1). 4. 임상증상및치료복부불쾌감이 30-40% 에서나타나는흔한증상이며 2-4% 환자에서는복부종괴가만져지기도한다. 7% 정도에서혈청간기능검사의이상이나타나며혈청 α-fetoprotein 같은종양표지자검사는정상범위이다. 15 출혈과악성변화가중요합병증으로종양의파열에의한출혈은약 30% 에서나타난다. 23 HA 의악성변화위험성에대해서는아직논란이있으나 5% 로보고된다. 23 종양의크기가크거나다발성인경우악성화가능성이높을것으로추정된다. 진단은 CT나 MRI의특징적인소견으로진단할수있다. 침생검에의한조직검사는출혈의위험과진단을위한충분한양의조직을얻지못하는경우가있어진단에한계점을가진다. HA와유사한 FNH 를구분하기위해서는외과적절제후조직을관찰하는것이필요할수도있다. 5

6 2012 년대한간학회춘계 Single Topic Symposium Table 1. Epidemiological, Clinical, Pathological, and Imaging Features of 3 Major Subtypes of Hepatic adenoma Epidemiology Clinical features Pathological features Imaging features MDCT/MRI CEUS Inflammatory HA (I-HCA) HA With HNF-1α Gene Mutation HA With β-catenin Activation 40-55% of HAs; majority are women; rarely seen in men. History of OC use in >90% cases. Increased risk of bleeding and small risk of malignant transformation. Associated with obesity, alcohol abuse, and inflammatory syndrome % of HAs; almost 10-18% of HAs. exclusively in women. History of Affects men and women. OC use in >90% cases. May bleed; no risk of malignant transformation. Tend to develop familial adenomatosis and MODY-3 diabetes mellitus Marked sinusoidal No inflammatory infiltrates or dilatation/peliosis, significant peliosis. polymorphous inflammatory Excessive lipid accumulation infiltrates, thick tortuous within the tumor hepatocytes arteries. No portal tract elements. Less extensive and variable No cytologic and nuclear atypia. steatosis. Lack of expression of liver fatty Prominent ductular reaction. acid binding protein on Previously misclassified as immunohistochemistry. telangiectatic FNHs. No cytologic and nuclear atypia. Strong expression of serum amyloid-associated protein A2 (SAA-2) and CRP on immunohistochemistry Hyperintense on T2-weighted image; intense arterial enhancement that persists on venous and delayed phases Arterial hypervascularity with centripetal filling; peripheral rim of sustained enhancement with delayed central washout J Comput Assist Tomogr 2011;35:159. Diffuse steatosis within the lesion; arterial enhancement that does not persist into the venous phase Homogeneously hyperechoic on grayscale imaging with mild to moderate arterial hypervascularity; becomes isoechoic on the portal venous phase. Definite increased risk of malignancy. Associated with androgen therapy and glycogen storage disease No significant peliosis or steatosis. No portal tract elements. Cytological and nuclear atypia may be seen (in malignant HCA). Strong diffuse overexpression of glutamine synthetase and nuclear A-catenin staining on immunohistochemistry. Arterial enhancement with portal venous washout. 5. 치료 HA의치료지침은종양의숫자보다조직학적소그룹의형태와크기에따라결정된다. 종양의크기가 5 cm 이상이면출혈의위험이있고 8 cm 이상이며악성화가능성이있다. 24 악성화위험성은당원병에동반된종양이나남자에서발생한경우에높다. HNF1α activated HA는악성화가능성은없으나출혈이발생할수있다. 6

7 윤병철 Focal Nodular Hyperplasia and Hepatic Adenoma 출혈은종양내에국한되거나피막하혈종또는복강내로출혈될수있다. 흔하지않지만종양이파열된경우혈역학적불안정성이발생할수있고이런경우간동맥색전술을시행하는것만으로혈역학적안정성을회복할수있고종양의크기를감소시킬수있다 cm 이하의 HA는출혈과악성변화의위험이낮으므로특별한조치를하지않고주기적으로영상검사를시행할수있다. 26 영상감시검사의적절한기간과간격은명확하게정해져있지않으나폐경기까지매년 CT 또는 MRI를시행하는것이적절하다고알려져있다. 27 현재치료의지침은종양의크기가 5 cm 이상, 유발하는약제를중단한후에도종양이감소되지않는경우, 악성화가능성이있는경우, β-catenin activated HA, 남자에서발생한 HA는수술적치료가권장된다. 최근수술적치료외에도경동맥색전술과고주파열파괴술을시행하기도한다. HA 환자는임신이금기는아니지만임신기간중종양의크기가증가할수있고출혈의위험이증가한다. HA를가진젊은여자는더적극적인치료가필요하고 5 cm 미만의종양이라도임신을원하는경우는조기에치료를하는것을생각해야한다. Table 2. Characteristics of focal nodular hyperplasia and Hepatic Adenoma Focal nodular hyperplasia Hepatic adenoma Age All ages 2nd to 5th decade Gender Female > male Nearly exclusively female Prevalence 4 26/1, /100,000 Clinical presentation Asymptomatic Abdominal pain or asymptomatic Laboratory Normal or non-remarkable Normal AFP Normal or non-remarkable Normal AFP Imaging Spokes of wheel vascular pattern Circular vascular pattern around lesion Pathological mechanism Hyperplastic reaction to vascular abnormality Uncontrolled growth Possibly estrogen-induced Histopathological features Central scar Ductular reaction Fibrosis Liver cell plates No bile ducts (with the exception of inflammatory type ) No fibrosis Mutation analysis Polyclonal Monoclonal Gene expression β-catenin pathway activation Ang-1/Ang-2 mrna ratio elevated HNF-1α inactivation β-catenin pathway activation Ang-1/Ang-2 mrna ratio normal Complications None Bleeding Hepatocellular carcinoma Treatment of choice Classic FNH: expectative Diagnosis doubtful: consider excision Withdrawal of estrogen treatment Excision/partial liver resection 7

8 2012 년대한간학회춘계 Single Topic Symposium 요 약 FNH와 HA는혈관종다음으로흔한양성간종양이다. 최근의학의발달로인한유전자검사등으로이종양들의병태생리에대한이해가더향상되었으나아직발생원인과역학등이명확하게밝혀지지않았다. 이종양들은특징적으로여자에서호발하며발생에여성호르몬등이관여하는등많은부분에서유사점을가지고있으나종양에대한치료는같지않다. 영상또는조직학적특징적인소견으로적절하게감별하여환자에게적절한치료를시행해야하겠다 (Table 2). 참고문헌 1. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990;11: Wanless IR, Albrecht S, Bilbao J, Frei JV, Heathcote EJ, Roberts EA, Chiasson D. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol 1989;2: Luciani A, Kobeiter H, Maison P, Cherqui D, Zafrani ES, Dhumeaux D, Mathieu D. Focal nodular hyperplasia of the liver in men: is presentation the same in men and women? Gut 2002;50: Vilgrain V, Uzan F, Brancatelli G, Federle MP, Zappa M, Menu Y. Prevalence of hepatic hemangioma in patients with focal nodular hyperplasia: MR imaging analysis. Radiology 2003;229: Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 1985;5: Kang HY, La SS, Kong JH, Lee SS, Baek DS, Lim SS, et al. Clinical, radiological and pathological exploration of focal nodular hyperplasia of liver reported in Korea. Korean J Gastroenterol 2008;52: Sato Y, Harada K, Ikeda H, Fijii T, Sasaki M, Zen Y, Nakanuma Y. Hepatic stellate cells are activated around central scars of focal nodular hyperplasia of the liver--a potential mechanism of central scar formation. Hum Pathol 2009;40: Kapp N, Curtis KM. Hormonal contraceptive use among women with liver tumors: a systematic review. Contraception 2009;80: Mathieu D, Kobeiter H, Maison P, Rahmouni A, Cherqui D, Zafrani ES, Dhumeaux D. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 2000;118: Nguyen BN, Flejou JF, Terris B, Belghiti J, Degott C. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol 1999;23: Bioulac-Sage P, Rebouissou S, Sa Cunha A, Jeannot E, Lepreux S, Blanc JF, et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology 2005;128: Paradis V, Benzekri A, Dargere D, Bieche I, Laurendeau I, Vilgrain V, et al. Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma. Gastroenterology 2004;126: Cherqui D, Rahmouni A, Charlotte F, Boulahdour H, Metreau JM, Meignan M, et al. Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, 8

9 윤병철 Focal Nodular Hyperplasia and Hepatic Adenoma radiological, and pathological correlations. Hepatology 1995;22: Kuo YH, Wang JH, Lu SN, Hung CH, Wei YC, Hu TH, et al. Natural course of hepatic focal nodular hyperplasia: a long-term follow-up study with sonography. J Clin Ultrasound 2009;37: Weimann A, Ringe B, Klempnauer J, Lamesch P, Gratz KF, Prokop M, et al. Benign liver tumors: differential diagnosis and indications for surgery. World J Surg 1997;21: ; discussion Karhunen PJ. Benign hepatic tumours and tumour like conditions in men. J Clin Pathol 1986;39: Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, Tyler CW, Jr. Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. JAMA 1979;242: Nakao A, Sakagami K, Nakata Y, Komazawa K, Amimoto T, Nakashima K, et al. Multiple hepatic adenomas caused by long-term administration of androgenic steroids for aplastic anemia in association with familial adenomatous polyposis. J Gastroenterol 2000;35: Socas L, Zumbado M, Perez-Luzardo O, Ramos A, Perez C, Hernandez JR, Boada LD. Hepatocellular adenomas associated with anabolic androgenic steroid abuse in bodybuilders: a report of two cases and a review of the literature. Br J Sports Med 2005;39:e Labrune P, Trioche P, Duvaltier I, Chevalier P, Odievre M. Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature. J Pediatr Gastroenterol Nutr 1997;24: Maillette de Buy Wenniger L, Terpstra V, Beuers U. Focal nodular hyperplasia and hepatic adenoma: epidemiology and pathology. Dig Surg;27: Shanbhogue A, Shah SN, Zaheer A, Prasad SR, Takahashi N, Vikram R. Hepatocellular adenomas: current update on genetics, taxonomy, and management. J Comput Assist Tomogr;35: Cho SW, Marsh JW, Steel J, Holloway SE, Heckman JT, Ochoa ER, et al. Surgical management of hepatocellular adenoma: take it or leave it? Ann Surg Oncol 2008;15: Dokmak S, Paradis V, Vilgrain V, Sauvanet A, Farges O, Valla D, et al. A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas. Gastroenterology 2009;137: Stoot JH, van der Linden E, Terpstra OT, Schaapherder AF. Life-saving therapy for haemorrhaging liver adenomas using selective arterial embolization. Br J Surg 2007;94: Zucman-Rossi J, Jeannot E, Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 2006;43: Bioulac-Sage P, Laumonier H, Couchy G, Le Bail B, Sa Cunha A, Rullier A, et al. Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology 2009;50:

388 The Korean Journal of Hepatology : Vol. 6. No COMMENT 1. (dysplastic nodule) (adenomatous hyperplasia, AH), (macroregenerative nodule, MR

388 The Korean Journal of Hepatology : Vol. 6. No COMMENT 1. (dysplastic nodule) (adenomatous hyperplasia, AH), (macroregenerative nodule, MR 6 3 2000 ; 387-392 (3) Dysplastic Nodule Young Nyun Park, M.D., Chanil Park, M.D. Department of Pathology, Yonsei University College of Medicine BRIEF HISTORY 56. AST/ALT 72/73 IU/L, total bilirubin 0.7