대한소화기내시경학회지 2007;35(Suppl. 1):308-313 췌장낭성병변 (Cystic Lesion) 의감별진단 : EUS-FNA 대구가톨릭대학교의과대학소화기내과학교실 김은영 서론최근건강에대한관심이높아지면서정기복부초음파 (abdominal ultrasound, US) 검진등의검사빈도가늘어나고전산화단층촬영술 (computed tomography, CT), 자기공명영상 (magnetic resonance imaging, MRI) 등다양한영상진단방법이발전함에따라무증상의췌장낭성병변이빈번하게발견되고있다. 양성병변으로부터전암성병변그리고악성병변까지다양한양상을가지는이들췌장낭성병변을수술전에명확히감별할수있는방법은아직없는실정이다. 최근활발하게사용되고있는내시경초음파 (endoscopic ultrasound, EUS) 검사는췌장을자세히관찰하는데유용하며그와더불어실시할수있는내시경초음파유도하세침흡인검사 (endoscopic ultrasound-guided fine-needle aspiration, EUS-FNA) 는병변으로부터조직이나낭액을쉽게채취할수있는편리한검사방법이다. 본고에서는여러가지췌장낭성병변의감별진단에서 EUS-FNA의활용과그유용성에대해알아보고자한다. 췌장낭성병변에서의 EUS-FNA 1. 왜 EUS-FNA가필요한가? 우연히발견된췌장낭성종양에대한적절한관리 방법을결정하기위하여서는정확한감별진단이필수적이나영상검사를이용한형태학적특징에의한감별은정확도가낮아서가장흔히사용되는 US나 CT 등의경우, 췌장낭종의수술전감별진단율은 30 60% 정도이다. 1,2 EUS 검사의감별진단율은그에비해더높다고알려져있고민감도 91%, 정확도 82% 에이른다는보고도있지만 3 완벽한검사법이라고할수는없다. 4 과거로부터췌장낭성종양에대하여세침흡인검사를실시하여낭액을얻어생화학적분석과세포학적검사를실시하여감별진단율을높이고자하는노력이있어왔다. 5,6 US나 CT를통한경피적접근방법에비하여 EUS-FNA (Fig. 1) 는해상도가우수하여작은병변에서사용하기용이하므로 3 cm 이하의병변에서 US- FNA나 CT-FNA에비하여높은정확도를보이는이점이있다. 7 또한실시간으로접근하고도플러를이용할수있으므로혈관구조물이많은지역에서쉽게사용할수있다. 8 그리고병변에보다더근접하여직접시술하므로짧은바늘통과거리를가져, 과거복벽을통한세침흡인시세침을통해종양이파급되는것을가장우려하였으나 5,9 EUS-FNA의경우에는그빈도가지극히낮다. 보고에의하면췌장암의경우, EUS-FNA를시행하였을때 2.2% 의복막전이가발생한반면경피적접근시에는 16.3% 에서복막전이가발생하여복막전이 Figure 1. Endoscopic ultrasound-guided fine-needle aspiration of pancreatic cystic lesion. (A) Septated cystic mass lesion with small nodule is seen. (B) Needle inserted into the cystic pancreatic mass under the guidance of curved linear array echoendoscope is visible. 308
김은영 : 췌장낭성병변 (Cystic Lesion) 의감별진단 : EUS-FNA 309 율이통계적으로유의하게차이가있다고하였다. 10 또한췌두부악성낭종이의심스러울경우에는 EUS-FNA 천자경로가수술시제거되는십이지장을통과하므로세침경로를통한종양의파급은걱정하지않아도된다는장점이있다. 2. 채취한검체에서무엇을검사할것인가? 세침흡인을통하여얻은검체에서세포진검사 (cytology) 를실시하여악성세포의존재를확인하면확진을얻을수있으나그정확도에대해서는보고자에따라큰차이가있다. 이는낭액천자검체에서충분한세포검체가얻어지지않는경우가많기때문이며이경우병리의사의역할이중요할것이다. EUS-FNA의악성췌장낭종감별민감도가 50% 라고낮게보고하였던연구에서는병리의사가 30% 의시술에서만참여하였지만, 11 모든시술에서병리의사가검체의적정성을평가하고검체를더얻어야할필요성이있는지여부를그자리에서조언한경우에는 93% 의진단적가치를보고하였다. 12 낭액의점성은악성위험도를가지는점액성낭성종양 (mucinous cystic tumor) 의감별에중요하다. 가성낭종 (pseudocyst) 과장액성낭선종 (serous cystadenoma) 의낭액은점도가낮지만점액성낭성종양의내용물은점액분비로높은점도로보이며점액염색에서양성이다. 점액염색양성여부로점액성낭종을장액성낭종과구별하면그민감도는 78%, 특이도는 100% 였다. 13 또낭액의점성과아래에서언급할 CEA (carcinoembryonic antigen) 를함께고려하면 97% 이상의높은감별정확도를보였다. 14 낭액의아밀라아제수치는상당히중복이되어유용성에는약간의의문이있으나매우높은수치 (>10,000 IU/L) 는가성낭종과선관내유두상점액성종양 (intraductal papillary mucinous tumor, IPMT) 에서보이며낮은수치의아밀라아제는거의모든유형의낭성종양에서보인다. 15 다양한종양표지자를이용한췌장낭성종양에대한감별노력이있었으며그중가장중요한표지자는 CEA (carcinoembryonic antigen) 로생각된다. 13,16,17 그러므로채취한검체의양이충분하지않을경우에는 CEA 검사를우선적으로실시하여야할것이다. 높은 CEA 수치는점액성낭선종 (mucinous cystadenoma) 을의심할수있는중요한소견이며 CA (carbohydrate antigen) 15-3, CA 72-4 등도높게측정된다. 18 점액성낭성종양에서 CEA의증가는대부분의보고에서일치되는소견 이나그 cut-off 농도에대해서는검사기관에따라차이가있다. 점액성낭선암종 (mucinous cystadenocarcinoma) 의경우에서는 TPA (tissue polypeptide antigen) 함량이높다. 장액성낭선종은무색또는연황색의액체로차있으며출혈이있는경우혈액이함유될수있다. 장액성낭선종의낭액은점도가낮고풍부한글리코겐을함유하고있으며 CEA, CA 15-3, CA 72-4, TPA 등의종양표지자농도도낮고세포검사에서는글리코겐에염색되는입방형상피세포를확인할수있다. 그러나작은낭들로구성되어흡인될수있는낭액이적으며혈관분포가높아서검사의합병증이높고만족스러운검사가되지못할수도있다. 19 가성낭종은상피세포에싸여있지않으므로세포학적검사에서항상염증성괴사조직이관찰된다. 고형성가유두상종양 (solid pseudopapillary tumor) 은 EUS-FNA 세포검사에서종양세포들은입방세포를가지며불규칙한육주 (trabeculae) 를형성하거나유두상배열을하고곳곳에서혈관을함유한풍부한점액양 (myxoid) 또는부종성기질을갖는특징적소견을보여진단율이높다. 20 최근에는낭액의분자분석 (molecular analysis) 을통하여악성낭종을진단할수있다는보고들이나오고있다. 낭종천자를통하여얻은낭액에서 DNA의양과질을측정하고유전자의변이를검사하였을때 K-ras 유전자변이와연속되는대립유전자소실 (allelic loss) 이췌장의악성낭종을예견하는데가장예민하며 91% 의민감도와 93% 의특이도를보인다는보고가있다. 21 지난 2007년미국소화기학회 (Digestive Disease Week) 에서도유사한내용의단일기관및다기관연구결과가보고되었으며향후이분야의연구및임상에서의활용이더욱증가하리라기대한다. 22,23 이상에언급한여러가지췌장낭종에서낭액의각각의특징을요약하면 Table 1 24-26 과같다. 3. EUS-FNA의정확도는어느정도기대할수있는가? 연구자에따라 EUS-FNA의정확도는다양하다. 췌장낭성종양의수술후최종조직과 EUS, EUS-FNA의결과를비교한한연구에서 EUS의정확도는 73% 인반면 EUS-FNA의정확도는 97% 라고하였고 27 또다른보고에서는 EUS는 51%, EUS-FNA 세포검사는 59%, 낭액의 CEA 검사는 79% 의정확도를보였다. 16 점액성췌장낭성종양의 EUS-FNA 검체에대한점액염색의민감도, 특이도, 정확도는각각 69%, 66%, 63% 이며악성낭성
310 대한소화기내시경학회지 2007;35(Suppl. 1):308-313 Table 1. Analysis of Aspirated Fluid of Pancreatic Cystic Lesions Diagnostic features Serous cystadenoma Mucinous cystic neoplasm IPMT Pseudocyst Appearance of fluid Small volume, thin, clear, Often large volume, Small volume, viscous, Large volume, thin, dark, nonmucinous, bloody viscous, clear, with clear, with mucin opaque, blood-stained, mucin nonmucinous Cytologic features Cuboidal cells with clear Columnar mucinous Columnar mucinous Inflammatory cells, cytoplasm, glycogen-rich cells, mucin-rich cells, mucin-rich histiocytes without mucin or epithelial cells Amylase Low Low High but variable High Viscosity Low High High Low Tumor markers CEA Low High High but variable Low but variable CA 72-4 Low High* High but variable Low but variable CA 19-9 Variable Variable Variable Variable CA 125 Low Variable Low Low CA 15-3 Low High Low Low *sometimes low, if benign. usually high. some authors reports as high. IPMT, intraductal papillary mucinous tumor; CEA, carcinoembryonic antigen; CA, carbohydrate antigen. 종양의진단에있어서 EUS-FNA의민감도, 특이도, 정확도는각각 79%, 100%, 89% 로보고하기도하였다. 28 이런연구결과의차이는표본추출오류 (sampling error) 와각표지자의 cut-off 수준을어떻게잡았느냐에따라그민감도와특이도가달라지는데있다. 다양한표지자와 cut-off 값이사용된몇몇보고를비교하면 Table 2와같다. 16,27,29 최근에는조직심 (tissue core) 을얻을수있는절단바늘을이용한 EUS-TCB (endoscopic ultrasound-guided trucut biopsy) 로낭종벽을조직검사하면 EUS-FNA에서적절한검체를얻지못하는경우보완적으로사용할수있다는연구가있었다. 30 우려했던바와는달리이검사법에서심각한합병증은없었다. EUS 단독검사에비하여 EUS-FNA 병합검사가진단정확도에아무런차이가없다는보고 3 로부터 EUS- FNA가현저하게도움된다는보고 12 에이르기까지 EUS-FNA의유용성에대한이견이있는것이사실이다 (Table 3). 일반적으로 EUS에서전형적인양성낭종의양상을보인경우는 EUS-FNA의대상이되지않는다. 또 EUS-FNA가실시된후에도이들증례중에서수술적방법으로최종조직을얻은경우만을대상으로정확도에대한분석이이루어지고수술대상이아니었던증례의결과는분석에서배제된다. 그러므로이들결과를해석함에있어서는이러한사실들을고려하여야할것이다. 대체로보아췌장낭성종양의감별진단에서 EUS-FNA의정확도는세포검사, 아밀라아제, 종양표지자, 점액염색, 분자분석등을조합하여판단할때 80 90% 정도의정확도를가지며, 26,31 EUS에서의형태학적검사만으로는진단이불확실한경우추가적인진단의단서를제공할수있다고생각한다. 29,32 4. EUS-FNA 시술시유의할사항은무엇인가? EUS-FNA의합병증은출혈, 감염, 천공, 급성췌장염등을들수있는데경험많은시술자에의해시술된다면그빈도는높지않아서 2% 내외의좋은결과를보여주고있다. 33 낭성병변은 EUS-FNA에따른합병증을줄이기위하여단한번만천자하고가능한한모든낭액을흡인해내는것이좋다. 감염을피하기위하여시술전후로예방적항생제투여가필요하다. 췌장염을피하기위해서는위장관벽으로부터천자침이병변에도달하기까지의거리가 1 cm를넘지않아야한다. EUS-FNA 시술전에는반드시이시술이필요한가하는점을생각해보아야한다. 특히기존의영상진단및임상소견에서이미종양의절제가필요하며가능하다고판단되면 EUS-FNA가불필요한검사일수있다. 가음성 (false negative) 결과로인해절제가능한종양의수술시기를놓치는경우와시술시동반될수있는주요합병증을고려하여수술가능하다고판단되는췌장종양의경우조직검사없이수술로바로진행하는것
김은영 : 췌장낭성병변 (Cystic Lesion) 의감별진단 : EUS-FNA 311 Table 2. Sensitivity, Specificity, and Positive and Negative Predictive Values of Different Biochemical and Tumor Markers in Differentiation of Pancreatic Cystic Lesions: Reported by Different Authors Cut-off Sensitivity Specificity PPV NPV (%) (%) (%) (%) Frossard et al. 27 Pseudocysts Amylase >5,000 U/L 61 58 20 89 Lipase >2,000 U/L 41 56 13 84 Serous cysts Amylase <5,000 U/L 87 59 53 90 Lipase <2,000 U/L 78 52 46 82 CEA <5 ng/ml 54 77 52 79 Mucinous cysts CEA >400 ng/ml 13 75 13 72 CA 19-9 >50,000 U/mL 15 81 22 78 Cystadenocarcinoma CEA >400 ng/ml 86 85 40 98 Hammel et al. 29 Pseudocysts Amylase >5,000 U/L 94 74 85 88 Lipase >2,000 U/L 100 59 80 100 Serous cysts Amylase <5,000 U/L 100 77 41 100 CEA <400 ng/ml 100 16 18 100 Mucinous cysts CEA >400 ng/ml 50 100 100 86 CA 19-9 >50,000 U/mL 75 90 67 90 Brugge et al. 16 Mucinous cysts CEA >192 ng/ml 73 84 Linder et al. 15 Pseudocysts VIS <1.6 or lipase UL >6,000 and CEA <480 ng/ml 91 100 100 86 Serous cysts VIS <1.6 and lipase >6,000 UL 100 100 100 100 Mucinous cysts VIS 1.6 and CEA <6,000 ng/ml 86 100 100 96 Cystadenocarcinoma VIS 1.6 and CEA 6,000 ng/ml 100 92 84 100 PPV, positive predictive value; NPV, negative predictive value; CEA, carcinoembryonic antigen; CA, carbohydrate antigen; VIS, viscosity. Table 3. Accuracy of EUS-FNA in Differentiation of Pancreatic Cystic Lesions: Reported by Different Authors EUS-FNA EUS-FNA Studies diagnostic with surgical accuracy correlation accuracy Moparty et al. 12 (2006) 28/30 (93%) 10/11 (91%) Linder et al. 15 (2006) 55/71 (77%) 67/77 (94%) Brugge et al. 16 (2004) 64/109 (59%) 64/109 (59%) Frossard et al. 27 (2003) 98/127 (77%) 65/67 (97%) Sedlack et al. 3 (2002) 10/18 (55%) 10/18 (55%) Brandwein et al. 11 (2001) 23/26 (88.5%) 23/26 (88.5%) 이좋다. 34,35 또한절제가능한것으로보이는췌장종양환자에서복강경을통한복강세척액세포검사 (peritoneal cytology) 를실시하였을때 FNA를실시한군에서양성률이더높았다는보고 36 도있으므로, 혹시라도가능한 FNA를통한종양의파종가능성을염두에둔다 면진단이확실시되는절제가능한췌장종양의경우에는 EUS-FNA 시술자체의필요성유무를꼭숙고해야한다. 마찬가지로크기가작은단순낭종의경우주의깊은임상적, 영상적경과관찰만으로충분하므로 37 EUS- FNA의고려대상이되지않는다. 반면절제불가능한종양으로판단되는경우에는정확한조직진단을통하여확진하고치료방침을선택할필요가있다. 다음으로고려되어야할점은 EUS-FNA가최선인가하는문제이다. EUS-FNA가비교적덜침습적인시술이기는하지만 US-FNA, CT-FNA 혹은 ERCP (endoscopic retrograde cholangiopancreatography) 를시행하면서솔질세포검사 (brush cytology) 를시행하는등다양한검사방법들이있으므로이들을함께고려하여보고환자개개인의상황에따라가장알맞은방법을선택하여야할것이다.
312 대한소화기내시경학회지 2007;35(Suppl. 1):308-313 결 증상을유발하는췌장낭성병변에대하여수술적치료가필요하다는것에는이견이없지만, 최근에는우연히발견된췌장의낭성병변이늘고있으며이들의치료방침에대한선택이임상의사에게중요한문제가되고있다. EUS-FNA는이들질환의감별진단에기존의검사방법에더불어추가적인정보를얻을수있는안전한검사방법이다. 32 EUS-FNA를통하여췌장낭성종양에서얻은낭액은점성검사, 점액염색, 세포진검사, 아밀라아제등효소와 CEA를포함한종양표지자검사, DNA와변이유무에대한분자분석등여러가지검사를실시할수있다. EUS-FNA의유용성정도에관한보고는연구자마다다소의차이가있기는하지만암성낭종이나전암성낭종으로분류될수있는점액성종양의감별에있어서비교적정확한정보를얻을수있다. 향후더나은표지자를찾기위한연구가지속되고많은경험과자료가축적되면그임상적유용성이더욱커질것으로기대한다. 론 참고문헌 1. Le Borgne J, de Calan L, Partensky C. Cystadenomas and cystadenocarcinomas of the pancreas. a multiinstitutional retrospective study of 398 cases. Ann Surg 1999;230:152-161. 2. Woo YM, Lee KY, Lee KU. Pancreatic Cystic Neoplasms: A Clinical Review. Korean J Gastroenterol 1995;27:110-119. 3. Sedlack R, Affi A, Vazquez-Sequeiros E, Norton ID, Clain JE, Wiersema MJ. Utility of EUS in the evaluation of cystic pancreatic lesions. Gastrointest Endosc 2002;56:543-547. 4. Ahmad NA, Kochman ML, Lewis JD, Ginsberg GG. Can EUS alone differentiate between malignant and benign cystic lesions of the pancreas? Am J Gastroenterol 2001;96:3295-3300. 5. Schwerk WB. Ultrasonically guided percutaneous puncture and analysis of aspirated material of cystic pancreatic lesions. Digestion 1981;21:184-192. 6. Lewandrowski KB, Southern JF, Pins MR, Compton CC, Warshaw AL. Cyst fluid analysis in the differential diagnosis of pancreatic cysts. A comparison of pseudocysts, serous cystadenomas, mucinous cystic neoplasms, and mucinous cystadenocarcinoma. Ann Surg 1993;217:41-47. 7. Volmar KE, Vollmer RT, Jowell PS, Nelson RC, Xie HB. Pancreatic FNA in 1000 cases: a comparison of imaging modalities. Gastrointest Endosc 2005;61:854-861. 8. Carlson SK, Johnson CD, Brandt KR, Batts KP, Salomao DR. Pancreatic cystic neoplasms: the role and sensitivity of needle aspiration and biopsy. Abdom Imaging 1998;23:387-393. 9. Warshaw AL, Compton CC, Lewandrowski K, Cardenosa G, Mueller PR. Cystic tumors of the pancreas. New clinical, radiologic, and pathologic observations in 67 patients. Ann Surg 1990;212:432-434. 10. Micames C, Jowell PS, White R, et al. Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA. Gastrointest Endosc. 2003;58:690-695. 11. Brandwein SL, Farrell JJ, Centeno BA, Brugge WR. Detection and tumor staging of malignancy in cystic, intraductal, and solid tumors of the pancreas by EUS. Gastrointest Endosc 2001;53:722-727. 12. Moparty B, Logrono R, Nealon WH, et al. The role of endoscopic ultrasound and endoscopic ultrasound-guided fineneedle aspiration in distinguishing pancreatic cystic lesions. Diagn Cytopathol 2007;35:18-25. 13. Shami VM, Sundaram V, Stelow EB, et al. The level of carcinoembryonic antigen and the presence of mucin as predictors of cystic pancreatic mucinous neoplasia. Pancreas 2007;34:466-469. 14. Breslin N, Wallace MB. Diagnosis and fine needle aspiration of pancreatic pseudocysts: the role of endoscopic ultrasound. Gastrointest Endosc Clin N Am 2002;12:781-790. 15. Linder JD, Geenen JE, Catalano MF. Cyst fluid analysis obtained by EUS-guided FNA in the evaluation of discrete cystic neoplasms of the pancreas: a prospective single-center experience. Gastrointest Endosc 2006;64:697-702. 16. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, et al. Diagnosis of pancreatic cystic neoplasms: a report of the cooperative pancreatic cyst study. Gastroenterology 2004;126: 1330-1336. 17. van der Waaij LA, van Dullemen HM, Porte RJ. Cyst fluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointest Endosc 2005;62:383-389. 18. Van Dam J. EUS in cystic lesions of the pancreas. Gastrointest Endosc 2002;56(suppl):91S-93S. 19. Torresan F, Casadei R, Solmi L, Marrano D, Gandolfi L. The role of ultrasound in the differential diagnosis of serous and mucinous cystic tumours of the pancreas. Eur J Gastroenterol Hepatol 1997;9:169-172. 20. Bardales RH, Centeno B, Mallery JS, et al. Endoscopic ultrasound-guided fine-needle aspiration cytology diagnosis of solid-pseudopapillary tumor of the pancreas: a rare neoplasm of elusive origin but characteristic cytomorphologic features. Am J Clin Pathol 2004;121:654-662. 21. Khalid A, McGrath KM, Zahid M, et al. The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology. Clin Gastroenterol Hepatol 2005;3:967-973. 22. Zolotarevsky E. Kwon RS, Piraka CR, et al. Endoscopic ultrasound with fine needle aspiration (EUS-FNA) with pancreatic cyst fluid DNA analysis influences clinical
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