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1 The Korean Journal of Helicobacter and Upper Gastrointestinal Research Vol. 12, No. 3, , September 위식도접합부암의진단 Diagnosis of Adenocarcinoima of the Esophageal Junction Soon Young Ko, Jeong Hwan Kim 건국대학교의학전문대학원내과학교실 Department of Internal Medicine, Konkuk University School of Meidicine, Seoul, Korea The two most common types of esophageal cancer are squamous cell cancer and adenocarcinoma. Although squamous cell cancer has been the commonest type of esophageal cancer worldwide, there has been an upward trend in the incidence of esophageal and esophagogastric junction adenocarcinoma. Numerous endoscopic techniques have evolved over the past decade for endoscopic detection of early esophageal cancer. For the diagnosis of esophageal cancer, the usage of endoscopic imaging method has increased in conjunction with chromoscopy, narrow band imaging, and/or magnifying imaging. These newer endoscopic modalities enable the endoscopist to differentiate subtle mucosal patterns in the cancerous lesions. The prognosis of esophageal cancer depends on the depth of tumor invasion and lymph node metastasis. EUS, CT and/or PET are currently used for staging esophageal cancer. We will review diagnostic and staging modalities for esophageal and esophagogastric junction adenocarcinoma. (Korean J Helicobacter Up Gastrointest Res 2012;12: ) Key Words: Esophageal neoplasms; Adenocarcinoma; Diagnosis 고순영, 김정환접수일 :2012년 8월 8일승인일 :2012년 9월 1일연락처 : 김정환서울시광진구능동로 120 우편번호 : 건국대학교병원내과 Tel: Fax: sefamily@kuh.ac.kr 서론식도암조직형태중편평세포암과선암이 95% 이상을차지하고있으며, 이중편평세포암이 90% 이상으로식도암에서원발성선암은매우드문것으로여겨져왔다. 그러나최근선암의발생빈도가증가추세이며 1997년부터 2002년까지발생빈도가 4배이상증가하였다. 1-3 편평세포암과선암은침범부위와위험요인등에있어서차이를보인다. 편평세포암의경우중부식도에호발하며흡연과음주와관련이있으나선암의경우하부식도에호발하며바렛식도와관련이있는것으로알려져있다. 4 식도암의치료는병기에근거하여이루어진다. 식도암의병기는미국암병기분류기준인 2010년 American Joint Committee on Cancer에서제시한 TNM staging 방법을사용하고있다. 5 편평세포암과선암은역학, 병리, 종양생물학, 예후에있어서차이를보이며 2010년에제시된 TNM staging에서도이두가지암을따로분류하고있다. 식도암의예후는침윤정도와림프절전이와관련이있으며, 조직검사결과와상관없이 50 60% 의식도암환자는수술을할수없는환자들로, 치료를위해선정확한진단과병기평가가중요하다. 이번원고에서는식도암의진단방법과병기평가에사용되는검사방법들을살펴보고자한다. 본론 1. 진단적검사 1) Barium study: 내시경검사의증가로식도조영술로식도암의유무를확인할수는있으나확진을위한조직검사를할수없으므로, Double-contrast barium radiograph를이 145

146 Korean J Helicobacter Up Gastrointest Res: 제 12 권제 3 호 2012 Fig. 1. Endoscopic pictures of esophageal cancer. (A) Conventional view.

6 하지만, 병변의크기를측정함에있어서내시경검사에비해더유용할수있으며암종에의한이차성이완불능증의진단시, 위식도접합부암의발견시위분문부로의침범유무확인시, esophagorespiratory fistula 유무확인시, 내시경적으로식도에스텐트를삽입시해부학적인구조확인시에도내시경검사에비해유용할수있다.

조기식도암은내시경적으로판 (plaques) 형태의표재성병변, 결절 (nodules), 궤양 (ulcerations) 으로보이기도하므로진단을위해조직검사를통한확인이필요하다 (Fig. 1A). 진행된식도암의경우엔협착 (strictures) (Fig.

9 (1) Conventional chromoendoscopy: 식도점막표면에직접색소를뿌려서점막의색조변화를관찰하는식도점막에대한 in vivo staining 방법으로이를통해조직검사부위를결정할수있고병변의범위를정할수있다. 10 색소내시경에는흡수법, 대조법, 반응법등이있다.

2 146 Korean J Helicobacter Up Gastrointest Res: 제 12 권제 3 호 2012 Fig. 1. Endoscopic pictures of esophageal cancer. (A) Conventional view. (B) Chromoendoscopic view using lugol s solution spraying. Fig. 2. Endoscopic pictures of esophageal cancer. (A) Conventional view. (B) Narrow band imaging. 용한식도암진단빈도는감소하고있다. 6 하지만, 병변의크기를측정함에있어서내시경검사에비해더유용할수있으며암종에의한이차성이완불능증의진단시, 위식도접합부암의발견시위분문부로의침범유무확인시, esophagorespiratory fistula 유무확인시, 내시경적으로식도에스텐트를삽입시해부학적인구조확인시에도내시경검사에비해유용할수있다. 7,8 2) Endoscopic biopsy: 식도의점막병변을직접관찰할수있고의심병변에대한조직검사를할수있으므로내시경을통한조직검사는식도암진단에필수적인검사이다. 조직검사횟수가증가할수록진단의정확도는증가하는것으로알려져있다. 조기식도암은내시경적으로판 (plaques) 형태의표재성병변, 결절 (nodules), 궤양 (ulcerations) 으로보이기도하므로진단을위해조직검사를통한확인이필요하다 (Fig. 1A). 진행된식도암의경우엔협착 (strictures) (Fig. 2A), 궤양을동반한종괴 (ulcerated mass), 원주상종괴 (circumferentiial mass) (Fig. 3A) 등으로나타난다. 3) 조기식도암의내시경검사 : 최근기술의발전으로색소내시경, 확대내시경등다양한내시경적진단기술들이보급및연구되어조기식도암진단에유용하게사용되고있다. 9 (1) Conventional chromoendoscopy: 식도점막표면에직접색소를뿌려서점막의색조변화를관찰하는식도점막에대한 in vivo staining 방법으로이를통해조직검사부위를결정할수있고병변의범위를정할수있다. 10 색소내시경에는흡수법, 대조법, 반응법등이있다. 이중식도의병변유무검사에주로이용하는흡수법은특정색소가특정한세포내로흡수되어염색되는방법으로루골용액, 메틸렌블루등이있다. 11 루골용액은정상평편상피로이루어진점막의글리코겐과반응하여흑갈색을나타내게되는반면암조직에는글리코겐이없으므로염색이되지않는다 (Fig. 1B). 요오드가염색이되지않는부분이있으면감별질환으로식도암, 식도염, 미란이나궤양과같은식도상피결손이있다. 비록식도암의스크리닝검사에서색소내시경의역할은아직입증이되지않았으나음주, 흡연력, 두경부영역의암환자등식도암의고위험군에선내시경을통한통상적관찰과함께색소검사법을시행하는것이도움이될수있다는보고가제한적이지만제시되고있다. (2) Electronic chromoendoscopy: Narrow band imaging (NBI) 와같이내시경에내장된광학필터의분광투과율특성을짧은파장으로변환시켜, 관찰광의전파심도를표층점막미세구조나모세혈관상을강조해서관찰할수있도록

고순영, 김정환 : 위식도접합부암의진단 147 Fig. 3. Radiologic pictures of esophgogastric junction cancer. (A) Conventional endoscopic imaging.

(C, D) Computed tomography/ positron emission tomography scan with fluorine-18 fluorodeoxyglucose in a patent with adenocarcinoma of the esophagogastric junction (arrow). 하는전자내시경의화상처리기술을지칭한다.

11 따라서, 기존의색소내시경과유사한결과를얻을수있는것으로보고되고있으며, 표재성식도암의병변관찰을향상시킬수있고, 암성병변에서동반되는혈관의변화를관찰하는데도 NBI가효과적일수있다 (Fig. 2B). 9 (3) High-resolution endoscopic imaging: 식도에발생하는선암의경우하부식도에호발하며바렛식도와관련이있는것으로알려져있다.

9 이중확대내시경 (magnification endoscopy) 은기존의내시경에비해서 100배에서 150배까지병변을확대하여관찰할수있는방법으로장상피화생, 형성이상또는암의발견 목적으로사용할수있을것으로보고되고있다.

3 고순영, 김정환 : 위식도접합부암의진단 147 Fig. 3. Radiologic pictures of esophgogastric junction cancer. (A) Conventional endoscopic imaging. (B) Computed tomography imaging showing circumferential thickening of the wall of the esophagogastic junction (arrow). (C, D) Computed tomography/ positron emission tomography scan with fluorine-18 fluorodeoxyglucose in a patent with adenocarcinoma of the esophagogastric junction (arrow). 하는전자내시경의화상처리기술을지칭한다. 이기법은빛의파장이짧을수록, 투과하는깊이가짧을수록투과하는깊이가더얕다는광학원리를이용한방법이다. 11 단파장은조직투과성이떨어지고헤모글로빈에잘흡수되어점막과표층혈관의뚜렷한대조를보여주므로미세혈관관찰에용이하다. 11 NBI로관찰시고도이형성부위는불규칙한점막과혈관패턴을보여서이형성발견에유용한것으로알려져있다. 11 따라서, 기존의색소내시경과유사한결과를얻을수있는것으로보고되고있으며, 표재성식도암의병변관찰을향상시킬수있고, 암성병변에서동반되는혈관의변화를관찰하는데도 NBI가효과적일수있다 (Fig. 2B). 9 (3) High-resolution endoscopic imaging: 식도에발생하는선암의경우하부식도에호발하며바렛식도와관련이있는것으로알려져있다. 바렛식도는하부식도점막이원주상피로치환된상태로장상피화생으로된부분에서형성이상이나암성변화를수반하는것으로알려지고있어서이부위의발견이중요하다. 따라서바렛식도에대한내시경적검사방법에대한많은논의가이루어지고있는실정이다. 9 이중확대내시경 (magnification endoscopy) 은기존의내시경에비해서 100배에서 150배까지병변을확대하여관찰할수있는방법으로장상피화생, 형성이상또는암의발견 목적으로사용할수있을것으로보고되고있다. 정상식도에서는점막하측의정맥에서분지된세혈관이점막근판의상하에수지상혈관망을형성하며여기서분지된상피유두내혈관루프 (intra-papillary capillary loop, IPCL) 를구성하는데, 기존의내시경으로는 IPCL을관찰할수없으나확대내시경으로관찰할경우 IPCL까지관찰이가능하므로식도의형성이상이나암과동반되는 IPCL의확장이나형성불균일과같은혈관의변화들을관찰할수있다. 9 4) 바렛식도의위식도접합부암으로진행과관련된분자생물학 : 바렛식도에서위식도접합부암으로의진행과관련된복잡한분자생물학적연구가이루어지고있으며이들연구를살펴보면산의역류와담즙에대해만성적으로노출과 tumor necrosis factor (TNF)-α, interleukin-1b와같은사이토카인들의일련의염증반응들이활성화되는데기인하는것으로추정하고있다. 8 사이토카인들의활성화로 CDX1, CDX2 homeobox 단백질들의이소성발현이증가하게되고배아단계의장상피의발생을유도하여장피화생 (intestinal metaplsia) 을유발하게된다는것이다. 8 이러한장피화생이이형성 (dysplasia) 을거쳐위식도접합부암으로발생하는데는유전적및후생유전학적 (epigenetic) 요인들이관련이있을것으로보고있으나정확한기전에대해선아직명확하게밝혀져있지는않다. p16 이상과 cyclin D1의

4 148 Korean J Helicobacter Up Gastrointest Res: 제 12 권제 3 호 2012 과발현및 telomerase가이상의세포주기의초기단계와관련이있다는보고가있다. 8 TNF-α와 cyclooxygenase-2와같은성장인자들의발현또한이형성으로의진행을증가시키는것으로알려져있으며이러한표지자들에대한생물표지자 (biomarker) 로서의유용성에대해선추가적인평가가 필요할것으로보인다. 8 앞으로게놈분석기술, 줄기세포신호전달경로, 단백질체학 (proteomics), microarray analysis 의발전은위식도접합부암으로진행할수있는병변을이형성단계에서감별해낼수있는검사도구및암의치료물질의개발로이어질수있을것으로기대가되고있다. Table 1. AJCC TNM Staging of Esophageal an Esophagogastric Junction Adenocarcinoma (7th ed, 2010) Primary tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis High-grade dysplasia T1 Tumor invades lamina propria, muscularis mucosae, or submucosa T1a Tumor invades lamina propria or muscularis mucosae T1b Tumor invades submucosa T2 Tumor invades muscularis propria T3 Tumor invades adventitia T4 Tumor invades adjacent structures T4a Resectable tumor invading pleura, pericardium, or diaphragm T4b Unresectable tumor invading other adjacent structures, such as aorta, vertebral body, trachea, etc. *High-grade dysplasia includes all noninvasive neoplastic epithelia that was formerly called carcinoma in situ, a diagnosis that is no longer used for columnar mucosae anywhere in the gastrointestinal tract. Regional lymph nodes (N) NX Regional lymph nodes cannot be assessed No regional lymph node metastasis N1 Metastasis in 1 2 regional lymph nodes N2 Metastasis in 3 6 regional lymph nodes N3 Metastasis in seven or more regional lymph nodes Distant metastasis (M) No distant metastasis M1 Distant metastasis Stage Stage 0 Stage IA IB T Tis (HGD) T1 T1 T2 Stage IIA T2 IIB T3 T1 2 Stage IIIA T1 2 T3 T4a IIIB T3 IIIC T4a T4b Stage IV Histologic grade (G) GX Grade cannot be assessed stage grouping as G1 G1 Well differentiated G2 Moderately differentiated G3 Poorly differentiated G4 Undifferentiated - stage grouping as G3 squamous N N1 N2 N1 N2 N1 2 N3 AJCC, American Joint Committee on Cancer; HGD, high-grade dysplasia. M M1 Grade 1, X 1 2, X 3 1 2, X 3

5 고순영, 김정환 : 위식도접합부암의진단 병기평가를위한검사 2010년에제시된 TNM staging에서식도암은평편세포암과선암을따로분류하고있다. 이중선암의 TNM staging 은 Table 1에제시하였다. 12 1) Computed tomography: 기존의단일단면 CT (single detector CT) 는다른신체부위에비해상대적으로넓은범위의촬영이필요한복부영상은호흡을참아야하는시간이길어인공음영으로인한영상질저하가빈번하였으나이러한점을개선한다검출 CT (multidetector-row CT, MDCT) 의등장으로다양한영상구현기법들을통해진단과치료결정에큰도움을받게되었다. 11 MDCT의경우여러개의열로구성된검출기를이용하여한번의나선스캔으로여러단면의정보를동시에얻을수있는영상기법으로, 영상진단에서 MDCT를이용한 3차원영상과가상위내시경영상등의최신기법을이용해위장관내외의변화를총괄적으로이해하는데많은도움을주고있다. 13 따라서, 내시경을이용한조직검사에서식도암이진단된후원발성식도암및원격전이를포함한병기평가를위해통상적으로제일먼저흉부 CT와복부 CT를시행하게된다. CT 는간, 폐, 대동맥주변의림프절로의전이감별에유용하게이용되고있으며, 대동맥, 기관지, 심장주위로의침범을감별해내는데 90% 이상의정확성을보인다 (Fig. 3B). 그러나 5층으로이루어진식도벽의침윤정도를감별하는데에는어려움이있어서, CT만을이용한병기판정시 50 60% 로정확도가떨어진다. 8 2) Endoscopic ultrasonography: 5층으로이루어진식도벽에서식도암의침윤깊이를확인할수있으며복강동맥 (celiac trunk), 간의좌엽, 좌측부신 (adrenal gland), 흉부와복부의대동맥등식도주변을고해상도로관찰할수있는병기평가방법으로, 80 90% 의정확도를보이는 EUS는식도암의식도벽과식도주변혈관과장기로의침윤정도를판단할수있는병기판정 (locoregional staging) 에서가장정확한방법이다. 14 EUS를통한림프절전이는통상 1 cm 이상으로저음영의경계가분명한원형의병변이보이는경우진단할수있는데 65 86% 의정확도를보인다. EUS 를통한세침흡인검사시행시림프절전이유무를진단하는데정확도를높일수있다. 그러나진행성식도암에비해조기표재성식도암에서병기판정에있어서정확도는다소떨어질수있으나, 일반적으로 EUS는 CT, MRI, PET보다정확한 TNM tumor staging이가능하다 ) Positron emission tomography: 대부분암세포들이당분해 (glycolysis) 가활발한것을이용해서당분해가활발한세포들에침착하는 fluorine 18 fluoro-deoxyglucose (FDG) 의 양을측정해서암의유무를확인하는검사인 FDG-PET는, 원격전이평가를위해서는 CT보다민감도가높아병기판정방법으로의이용이증가하고있다 (Fig. 3C, 3D) 그러나현재사용중인 PET 스캐너의공간적인해상도에제한이있으며, 원발암주변으로 FDG의침착으로인한차폐효과 (masking) 로원발암근접부근림프절로의 FDG 침착감별이어려울수있으며, 조직분화도가나쁜식도암이나위식도접합부암에는 FDG 침착이적어국소적인병변을감별하는데는민감도가떨어질수있다. 12 또한, 암이외에염증성병변, 양성병변에서도 FDG 흡수율이증가할수있으므로이들병변과의감별이필요하다. 22 결 식도암은내시경을통한조직검사로진단을하며, 최근내시경과영상기술의발전으로색소내시경, NBI, 확대내시경과같은검사방법들이조기식도암의진단에점점더많이이용되는추세이다. 진단이후치료방법결정에중요한병기평가는 TNM staging system을따르게되는데, 식도암의경우편평세포암과선암 2가지로분류하여병기를정하게된다. 식도선암의병기평가에있어서식도암의침윤정도평가방법으로 EUS가정확도가높은것으로알려져있으며, 원격전이평가에있어서는 PET가유용한것으로제시되고있다. 최근에이용이증가하고있는내시경적검사법이진단방법으로서의역할을획득하기위해서는추가적인연구가병행되어야할것으로생각한다. 론 참고문헌 1. Daly JM, Karnell LH, Menck HR. National Cancer Data Base report on esophageal carcinoma. Cancer 1996;78: Younes M, Henson DE, Ertan A, Miller CC. Incidence and survival trends of esophageal carcinoma in the United States: racial and gender differences by histological type. Scand J Gastroenterol 2002;37: Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol 2007;17: Engel LS, Chow WH, Vaughan TL, et al. Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst 2003;95: Yang DH, Jung HY. Treatment of esophageal cancer. Korean J Gastroenterol 2008;52: Lightdale CJ. Esophageal cancer. American College of Gastroenterology. Am J Gastroenterol 1999;94: Levine MS, Rubesin SE. Diseases of the esophagus: diagnosis with esophagography. Radiology 2005;237: Sleisenger MS. Sleisenger & Fortran's Gastrointestinal and Liver Disease. 9th ed. Philadelphia: Sauders Elsevier, 2010:

6 150 Korean J Helicobacter Up Gastrointest Res: 제 12 권제 3 호 Lee SH, Ryu CB, Jang JY, Cho JY. Magnifying endoscopy in upper gastrointestinal tract. Korean J Gastroenterol 2006;48: Acosta MM, Boyce HW Jr. Chromoendoscopy--where is it useful? J Clin Gastroenterol 1998;27: Han JP, Hong SJ. Diagnosis of barrett's esophagus. Korean J Helicobacter Up Gastrointest Res 2012;12: Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 2010;17: Kim AY. Multidetector-row CT of the gastrointestinal tract. Korean J Gastroenterol 2006;48: Rösch T. Endosonographic staging of esophageal cancer: a review of literature results. Gastrointest Endosc Clin N Am 1995;5: Bar-Shalom R, Valdivia AY, Blaufox MD. PET imaging in oncology. Semin Nucl Med 2000;30: van Vliet EP, Heijenbrok-Kal MH, Hunink MG, Kuipers EJ, Siersema PD. Staging investigations for oesophageal cancer: a meta-analysis. Br J Cancer 2008;98: Flamen P, Lerut A, Van Cutsem E, et al. Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. J Clin Oncol 2000;18: Keswani RN, Early DS, Edmundowicz SA, et al. Routine positron emission tomography does not alter nodal staging in patients undergoing EUS-guided FNA for esophageal cancer. Gastrointest Endosc 2009;69: Flanagan FL, Dehdashti F, Siegel BA, et al. Staging of esophageal cancer with 18F-fluorodeoxyglucose positron emission tomography. AJR Am J Roentgenol 1997;168: Block MI, Patterson GA, Sundaresan RS, et al. Improvement in staging of esophageal cancer with the addition of positron emission tomography. Ann Thorac Surg 1997;64: Meyers BF, Downey RJ, Decker PA, et al; American College of Surgeons Oncology Group Z0060. The utility of positron emission tomography in staging of potentially operable carcinoma of the thoracic esophagus: results of the American College of Surgeons Oncology Group Z0060 trial. J Thorac Cardiovasc Surg 2007;133: Cook GJ, Fogelman I, Maisey MN. Normal physiological and benign pathological variants of 18-fluoro-2-deoxyglucose positron-emission tomography scanning: potential for error in interpretation. Semin Nucl Med 1996;26:

김범수

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