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1 대한내과학회지 : 제 78 권제 3 호 2010 특집 (Special Review) - 췌장의낭종성질환 췌장의낭종성질환의감별진단 대구가톨릭대학교의과대학내과학교실 김호각 Differential diagnosis of cystic diseases of pancreas Ho Gak Kim, M.D., Ph.D. Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Korea Cystic diseases of pancreas are increasingly detected because of high quality of imaging modality. Most of pancreatic cysts are discovered incidentally. Differential diagnosis of pancreatic cysts is very important because they include wide range of pathologic disease such as inflammation, benign neoplasm, borderline and malignant neoplasm. The most common cystic disease of pancreas is post-inflammatory pseudocyst, but in recent decades the incidence of neoplastic cysts, such as serous cyst neoplasm, mucinous cyst neoplasm, intraductal papillary mucinous neoplasm has increased. Among the cystic neoplasms, mucinous cystic neoplasm, intraductal papillary mucinous neoplasm are premalignant, and serous cystadenoma has no malignant potential. Patient s age, symptoms and a possible history of acute or chronic pancreatitis together with cross-sectional imaging modalities are mainstay for differential diagnosis of cystic diseases of pancreas. Cystic fluid cytology and analysis for CEA, mucin stain, and viscosity are providing additional information for differentiation. But cross-sectional images have overlapping findings in various cystic diseases and cystic fluid aspiration has still lack of sensitivity. The purpose of this review article is to provide the overview of the differentiation of pancreatic cystic lesions. (Korean J Med 78: , 2010) Key Words: Cystic disease; Pancreas; Diagnosis, differential 서론췌장의낭종성질환 (cystic disease) 은낮게는초음파선별검사에서 0.2% 로보고되며, 높게는부검에서 24.3% 까지보고되고있다 1). 영상진단에서췌장낭종의발견은그진단방법에따라그차이가크며최근영상진단기기나기술의발전으로그보고빈도가점차높아지고있다 2,3). 대부분의췌장낭종성질환은증상이없이우연히발견되며 2~3년이지나도변화가없이지속된다 4). 다른한편으로는췌장낭성질환중일부는악성변화를할수있으며, 발전된영상진단에의해발견당시에악성이의심되어서수술치료를받는경우가증가하고있다. 그러나수술전낭성질 환의정확한진단이어려운경우가있으며수술전과수술후의진단이불일치하는경우도많다. 이논평에서는췌장낭종성질환중에서비교적흔한종류인가성낭 (pseudocyst), 점액성낭종 (mucinous cyst neoplasm), 장액성낭종 (serous cyst neoplasm), 관내유두상점액성종양 (intraductal papillary mucinous neoplasm, IPMN) 그리고고형가성유두상종양 (solid pseudopapillary tumor) 을중심으로췌장낭종성질환의감별을알아보고자한다. 췌장낭종성질환의분류췌장의낭종성질환의분류는여러방법이있으나임상적

2 - The Korean Journal of Medicine: Vol. 78, No. 3, Table 1. WHO classification of cystic neoplasms of the pancreas Serous microcystic adenoma Serous oligocystic adenoma Serous cystadenocarcinoma Mucinous cystadenoma Mucinous cystic tumor-borderline Mucinous cystadenocarcinoma Non-invasive Invasive Intraductal papillary mucinous adenoma Intraductal papillary mucinous neoplasm- borderline Intraductal papillary mucinous carcinoma Non-invasive Invasive 으로흔히쓰이는유용한분류로는낭종의병리학적구분에따라잔류낭종 (retension cyst), 가성낭 ( 거짓낭 ) 그리고낭종성종양으로나누며, 낭종성종양은구체적으로 WHO 분류가있다 ( 표 1) 5,6). 잔류낭종혹은진성낭종 (true cyst) 은정상췌관세포나췌장선방세포 (centroacinar cell) 로구성되고췌액이고인적은크기의낭을말하며임상적으로문제가없다 ( 그림 1). Von Hippel-Lindau 병도일종의선천성의진성낭종으로다발성으로췌장에여러크기의낭종이동반된다 ( 그림 2). 가성낭은췌장의염증이나괴사의결과로췌장실질안이나밖으로염증성삼출액이나췌액이고이는것으로췌장효 소를많이함유하고있으며낭벽은점막세포가없이섬유조직, 육아조직으로되어있다. 낭종성종양은 WHO 분류을중심으로일반적으로단순히점액성낭선종 (mucinous cystadenoma) 혹은점액성낭선암 (mucinous cystadenocarcinoma), 췌장의관내유두상점액성종양, 장액성낭종, 고형가성유두상종양으로나눈다 ( 표 2) 6). 이중장액성낭종은췌장의선방세포에서발생하는양성종양으로낭종의내면이얇은점막으로구성되며낭내에맑은장액이고이게되며 ( 그림 3), 점액성낭종은점액을분비하는원주상피세포 (mucin-producing columnar epithelium) 로구성되며난소형기질 (ovarian type stroma) 을가지는경우가있으며낭종의내층세포가점액을분비하여낭내에점액이고이게되며 ( 그림 4), 관내유두상점액성종양은췌관에서발생한유두상종양에서점액이분비되어역시췌관에점액이고여서낭모양으로확장되는것이며 ( 그림 5), 고형가성유두상종양은고형의종양이낭성병성 (cystic degeneration) 혹은괴사에의해낭종으로변하면서내면이유두양을보이는것으로낭종의내면은유두양세포와점액양기질 (myxoid stroma) 을가진다 ( 그림 6). 이중서양에서는점액성낭종이가장흔하며 7), 일본이나우리나라에서는 IPMN 이흔하며국내의다기관조사에서도 IPMN 이가장흔하고이어서가성낭, 점액성낭종, 장액성낭종순의빈도였다 8). 여기서는췌장의낭종성질환중흔한형태인가성낭, 점액성낭종, 장액성낭종, IPMN 그리고고형가성유두상종양의감별해보고자한다. Figure 1. Retension cyst of pancreas body. Figure 2. Pancreas cysts in the patient with von Hippel-Lindau disease. There are multiple cysts in body of pancreas

3 - Ho Gak Kim. Differential diagnosis of cystic diseases of pancreas - Table 2. Cystic lesions of pancreas classified according to lining of cyst No lining Pseudocyst Mucinous epithelium Mucinous cyst neoplasm Intreductal papillary mucinous neoplasm Serous (clear cell) epithelium Serous cystadenoma Von Hippel-Lindau syndrome Acinar cell Acinar cell carcinoma (cystic endocrine tumor) Degenerative changes of solid tumor Solid pseudopapillary tumor Cystic ductal adenocarcinoma 췌장낭종성질환의감별진단 1. 임상특성과증상에의한감별 1) 성별과연령에의한감별가성낭은지역과연령에따라차이가있지만췌장의낭종성질환중가장흔한것으로대부분알코올성췌장염에서생기므로음주력이있는남자에서흔하며담석증등다른원인의췌장염이나췌장손상의병력이있는사람에서도의심할수있다. 장액성낭종은양성종양으로악성변화를거의하지않는것으로남성에서도생길수있으나주로고령층의여성에흔하다. 점액성낭종은대부분중년여성에서생기며크기가커지면서악성화의가능성이매우크다. IPMN 은남녀의발생이비슷하며증상이없이서서히커지므로고령에서발견이많이되고서양의보고보다우리나라 Figure 3. Cartoon of serous cyst neoplasm of pancreas. Cystic mass are composed of clusters of multiple small cysts with stellate scar in septa (quoted from The Pancreas, Berger HG, eds, Blackwell Science, London 1998). Figure 4. Cartoon of mucinous cyst neoplasm of pancreas. Cystic mass are surrounded by thick irregular wall and divided with thick septa (quoted from The Pancreas, Berger HG, eds, Blackwell Science, London 1998). Figure 5. Cartoon of intraductal papillary mucinous neoplasm of pancreas. Mucing producing papillary mass are arising along epithelium of pancreatic duct with cystic dilatation (quoted from The Pancreas, Berger HG, eds, Blackwell Science, London 1998). Figure 6. Cartoon of solid pseudopapillary tumor in pancreas. The mass has solid and cystic portions concomitantly (quoted from The Pancreas, Berger HG, eds, Blackwell Science, London 1998)

4 - 대한내과학회지 : 제 78 권제 3 호통권제 595 호 Table 3. Differential diagnosis of pancreatic cystic diseases Type Age Gender Cyst fluid Serous cystadenoma Older F>M Tin, serous, often bloody Mucinous cystic neoplasm Intraductal papillary mucinous neoplasm Solid pseudopapillary tumor Pseudocyst Middle age F>>M Mucoid, often viscus Older M=F Mucoid, often viscus Amylase activity Cystic fluid analysis CEA Viscosity Mucin stain Cytology Negative Glycogen-rich cell Positive Mucinous cell Positive Mucinous cell Young F>M Bloody Negative Epithelial cell, necrotic cell Variable range M>F Prune color, often bloody Negative, decrease mildly;, increased markedly;, increased moderately;, increased mildly;, normal range. Inflammatory cell Table 4. Clinical features of cystic lesions of pancreas Etiology Type Malignant potential Communication with duct Congenital Retention cyst None Seldom Post-inflammatory Pseudocyst None Frequent Neoplastic Serous cysadenoma Very low Rarely Mucinous cystadenoma High Occasionally IPMN High Yes Solid pseudopapillary neoplasm Moderate Occasionally IPMN, intraductal papillary mucinous neoplasm. 에서더흔하다 8). 고형가성유두상종양은비교적드문종양으로고형유두상상피종양 (solid papillary epithelial neoplasm) 으로도불리며젊은여성에서상당히큰종괴로발견되는경우가많다 ( 표 3). 2) 증상에의한감별대부분의췌장낭종성질환은증상이없이우연히발견된다. 낭종성병변자체가복통, 췌장염, 염증에의한고열, 담관폐쇄에의한황달을일으킬수있으나대부분증상이없다. 가성낭은최근의췌장염의병력이있는경우나혈청아밀라제나리파제가증가한경우에의심하여야하며, 이미만성췌장염으로진단된환자이거나영상진단에서췌장에서만성췌장염에합당한소견인췌장의석회화, 췌관의협착과확장및췌관결석이있는경우도가성낭을의심할수있다. 관내유두상점액성종양도때로는점액에의한췌관폐쇄로췌장염이생길수있다. 점액성낭종과장액성낭종도크기가매우커서췌관이나담관을막을경우에는췌장염이나 폐쇄성황달이생길수있다. 점액성낭종과관내유두상점액성종양이악성변화를하여췌장에악성종괴를형성하거나주변조직으로의침윤이나전이가있으면복통, 식욕부진, 체중감소등증상이있을수있다 ( 표 4). 2. 영상학진단에의한감별췌장의낭성병변을진단하기위한여러가지영상진단법으로는비침습적으로단면상 (cross-sectional image) 을얻는것으로복부초음파, 전산화단층촬영 (computed tomogram, CT), 자기공명영상 (magnetic resonance imaging, MRI) 이있으며침습적인방법으로내시경역행담췌관조영술 (endoscopic retrograde cholangiopancreatography, ERCP) 및내시경초음파 (endoscopic ultrasonography, EUS) 가있다여기에서는복부초음파, CT, MRI 및 ERCP 소견으로췌장의낭종성질환을감별하는것을알아보겠다 ( 표 4, 5)

5 - 김호각. 췌장의낭종성질환의감별진단 - Table 5. Differentiation of cystic lesion of pancreas according to cyst morphology Cyst morphology Diagram of cyst Included cystic diseases Unilocular Pseudocyst Cystic degeneration of ductal adenocarcinoma Cystic endocrine tumor Retention cyst, von Hippel-Lindau syndrome Microcystic Serous cystadenoma Cystic endocrine tumor von Hippel-Lindau syndrome Macrocystic Mucinous cystadenoma Intraductal papillary mucinous neoplasm Serous macrocystic adenoma Solid component in cyst Solid pseudopapillary tumor Cystic degeneration of malignant neoplasm Figure 7. CT scan of pancreatic pseudocyst. There is large exophytic cystic lesion at body of pancreas with severe inflammation at tail of pancreas. Figure 8. CT scan of serous cystadenoma. There is microcystic cystic mass with central stellate septa at body of pancreas. 1) 가성낭가성낭은췌장내에생기는모든낭종성병변의 70% 를차지한다 9). 초음파나 CT에서췌장에급성췌장염혹은만성췌장염의소견이있으면서주로단방성 (unilocular) 의낭성종괴가췌장밖으로돌출해있는형태이며, 낭벽은보통 4 mm 미만으로얇게 CT에서조영되며주변에염증소견이같이있다 ( 그림 7). 종괴에고형부분이없으며낭액은내용물 이없는췌액이거나찌꺼기가아래쪽에침전되어있거나출혈이동반되어있기도한다. ERCP나 MRI에서주췌관과교통이있는경우가 65~70% 이다 9). 2) 장액성낭종장액성낭종은췌장머리에서많이생기지만췌장몸체, 꼬리에서도관찰된다. 가장흔한형태로는 70% 에서 2 cm 미

6 - The Korean Journal of Medicine: Vol. 78, No. 3, Figure 9. Endoscopic retrograde pancreatography of serous cystadenoma. Main pancreatic duct was displaced by large cystic mass at head of pancreas. Figure 10. CT scan of mucinous cystic neoplasm. There is medium-sized cystic mass with thick wall and eccentric septum at tail of pancreas. Figure 11. CT scan of intraductal papillary mucinous neoplasm. Main pancreatic duct was dilated with enhancing mural mural at head of pancreas. 만의작은낭들이 6~7개이상여러개가뭉쳐서 5 cm 미만의하나의다방성 (multilocular) 낭을만들어 (microcystic serous cystadenoma) 스폰지모양을하고있으며특징적으로가운데에별모양의석회화가동반된반흔을가지고있다 ( 그림 8) 10). 태양불꽃 (sunburst) 모양의가운데의석회화가장액성낭종의 30% 에서볼수있으며이는장액성낭종의진단적특징이다 11). 장액성낭종의장벽은얇고낭액은내용물이없는장액으로되어있다. 장액성낭종의 20% 에서는 1 mm 이하의낭들이뭉쳐서영상진단에서하나하나의낭을구별하기가어려워서벌집모양혹은고형종양처럼보이지만초음파및 CT에서는저에코및저음영으로보이며 MRI에서 T2- 조영증강에서높은신호강도를보인다. 각각낭의크기가 0.5~1.0 cm 이상인여러낭이모여서된장액성낭종 (macrocystic 혹은 oligicystic serous cystadenoma) 는 10% 미만으로형태적로는점액성낭종이나중격이있는가성낭과구별이어렵다. 장액성낭종은췌장내에있으며주변췌장조직과경계가명확하고췌관과교통이없으며크기가크면췌관이나담관을외부에서압박할수있다 ( 그림 9). 3) 점액성낭종점액성낭종은췌장의몸체나꼬리에주로있으며 4~5 cm 이상의비교적큰크기이며때로는 25 cm까지되기도한

7 - Ho Gak Kim. Differential diagnosis of cystic diseases of pancreas - A B Figure 12. CT scan and magnetic resonance cholangiopancreatography of branch-type intraductal papillary mucinous neoplasm. There is cystic dilatation of branch ducts at uncinate process of pancreas on CT scan (A). On magnetic resonance cholangiopancreatography, dilated ducts look like bunch of grape having communication with main pancreatic duct (B). 다 11). 낭은두껍고불규칙한섬유성벽으로둘러싸여있으며중격에의해여러개의방으로나누어져있으나일반적으로 6개미만이며주변에작은크기의인접한낭들이있기도하다 ( 그림 10) 12,13). 점액성낭종은보통췌관과교통이없으며크기가커서췌관을막을수있다. 장액성낭종과크기로감별은어려우나불규칙하고두꺼운낭벽에유두양돌기가있고낭내로뻗어있는중격과같은내부구조로점액성낭종을진단할수있다. 가성낭과의감별은낭종주변에염증소견이없으며췌실질에도급성췌장염이나만성췌장염의소견이없고대신에중격이흔히보이고낭액이점액이어서내용물의에코나밀도가높다. 점액성낭종에서낭내에조영이되는종괴가있거나낭벽에서계란모양의석회화가있으면점액성낭선암을의심할수있다 14,15). 4) 췌장의관내유두상점액성종양 IPMN 은췌관내의점액분비성종양세포에서분비되는점액의높은점성때문에췌관이미만성혹은국소적으로확장되며때로는췌관이낭종의형태로확장되는특징이있다. IPMN 은주췌관형 IPMN 과분지관형 IPMN 으로분류되며 16,17) 주췌관형은주췌관을미만성으로혹은국소적으로침범하며주로췌장의머리쪽에서시작하며몸체와꼬리방향으로진행한다. 분지관형은더젊은나이에발생하고췌장머리의갈고리돌기 (uncinate process) 에서잘생기며꼬리에 Figure 13. Fish-eye appearance of major papilla in intraductal papillary mucinous neoplasm. Clear mucin is dropping from patulous major papilla. 서발생하기도한다. 주췌관형과분지관형이합쳐진경우도있다. 췌장조영 CT는췌관의확장이나낭성종양을확인할수있어서 IPMN 의선별에가장좋은진단방법이며종양세포들이종괴를형성하고있어서조영이되는벽성결절 (mural nodule) 을볼수도있다 ( 그림 11). 분지형 IPMN 에서는주췌관의확장이없이도분지관의확장을볼수있다 ( 그림 12A)

8 - 대한내과학회지 : 제 78 권제 3 호통권제 595 호 A B Figure 14. CT scan and endoscopic retrograde pancreatography of malignant intraductal papillary mucinous neoplasm. There is enhancing mass in the dilated main pancreatic duct on CT (A) and filling defect at endoscopic retrograde pancreatography (B) at body and tail of pancreas. 자기공명담췌관조영술 (magnetic resonance cholangiopancreatography, MRCP) 은점액이고여있어서확장되어있는췌관의범위를 ERCP보다는더민감하게보여주며분지관형의경우도쉽게주췌관과교통하는지알수있다. 분지형의경우는 MRCP에서낭성종양이포도송이모양으로보인다 ( 그림 12B). IPMN 의진단에서 MRCP 는 CT와같거나더우월하며 18), IPMN 의상태의판단에서도 ERCP에서는점액마개 (mucus plug) 에의해췌관이막히므로 MRCP가더민감하다 19). IPMN 의특징적인 ERCP 소견은주로 IPMN 병소가있는부분의하류쪽, 즉유두방향의췌관이특별한협착이없이점액의저류로인한미만성혹은국소적으로확장되어있으며심해지면근처의분지까지확장된다. 점액이나벽성결절로인해충만결손이보이기도한다. 내시경소견에서유두가확장되어물고기눈모양 (fish-eye) 모양을하며때로점액이흘러나오기도한다 ( 그림 13). 분지관형의경우는조영제가채워지면서낭성확장을볼수있다. IPMN 에서악성변화를시사하는소견으로는 (1) 주췌관형에서 10 mm 이상의췌관확장이있거나 (2) 분지관형에서전체낭종의크기가 30 mm 이상이거나중격이불규칙하거나두꺼워져있거나 (3) 벽성결절이 3 mm 이상으로보이는경우다 ( 그림 14) 20,21). IPMN 을점액성낭종과감별하는방법으로는주췌관이나분지관이확장되어있으며확장된췌관에점액마개나벽성결절이보이며분지형에서도 MRCP나 ERCP에서낭성으로확장된분지관이주췌관과교통이있는것으로진단할수 Figure 15. CT scan of large solid pseudopapillary tumor at tail of pancreas. The mass has large degenerative cyst and solid component with calcification. 있다. 5) 고형가성유두상종양고형가성유두상종양은고형종양으로시작하여낭성변성을초래하는것으로낭내에는출혈, 괴사조직, 탐식세포등이있으며, 영상조영에서 10 cm 이상의비교적큰크기의경계가명확한종괴가췌장의어느부위에서나발견될수있다 ( 그림 15) 15). 종괴내에는고형과낭성부분이같이있는경우가많으며석회화가흔히동반된다. 혈류가풍부하여출혈이동반되기도한다. 고형부분과낭성부분이교차로존재

9 - 김호각. 췌장의낭종성질환의감별진단 - 하는것이진단에특징적이다. 3. 낭액의천자에의한감별췌장의낭종성질환은낭액을천자하여낭액의육안적소견, 생화학적분석, 점도검사, 종양표지자검사, 세포검사등으로감별을시도할수있다. 췌장낭종의천자는복부초음파나 CT를이용한경피적천자로할수도있으며최근에는 EUS를이용한세침흡입술 (fine needle aspiration, FNA) 로낭액의분석이나세포검사를많이하고있다 ( 표 3). 1) 세침흡인액의세포검사췌장낭종의천자액세포검사의가장큰단점으로는췌장낭종액에는세포수가적어서진단이어렵고민감도가낮다 14). 악성변화가있을때에민감도가올라가지만악성점액성낭종에서도 29% 정도이다 23). 그러나악성낭종에서특이도는매우높다. 낭액의천자액에서가성낭과점액성낭종의감별은점액소염색 (mucin stain) 이나점도 (viscosity) 의측정에서양성이나오면점액성낭종으로진단할수있다. 가성낭에서는염증세포가있으나상피세포는보이지않고점액과점도도없다. 낭종의감별을위한천자액의세포검사에서점액세포가보이지않고일정한모양의췌관의선방근처의세관세포 (ductule cell) 에해당하는상피세포가끊어져보이면장액성낭종으로진단할수있으며점액세포가보이면점액성낭종이나 IPMN 으로진단할수있지만대부분감별이어렵다. 2) 세침흡인액의분석췌장낭성병변에서의낭액의분석은어느정도진단적가치가있다 ( 표 3). 가성낭의낭액은아밀라제치가매우높을수있으나점액소염색에서음성이며점도측정에서양성을보이지않는다. 장액성낭종은점액소가없으며글리코겐 (glycogen) 에대한 PAS 염색에서양성을보인다. 낭액은아밀라제나 CA19-9, CEA의증가가없다. 점액성낭종과 IPMN 에서는천자액에서점액소염색이양성이며 CEA가증가한다. 특히 CEA가 250 ng/ml 이상이면점액성낭종을진단할수있으며 5 ng/ml 미만이면제외할수있다 24,25). 차단 (cut-off) 수치를 400 ng/ml으로하면점액성낭종을가성낭과감별할때민감도가 57%, 특이도가 100% 였다 25). 다른종양표지자인 CA 19-9, CA 125, CA 72-4 등도점액상낭종에서증가되어있으나진단가치는낮다. 낭액의 CA19-9 나 CEA의증가는양성보다악성점액성낭종이나악성 IPMN 에서더흔히볼수있다 26). 천자액의아밀라제치는감별진단에서낭종의감별에큰감별은되지않으나아밀라제치가많이높은경우는가성낭을강하게의심할수있으나 IPMN 에서도역시많이증가되어있으며점액성낭종이췌관과교통하고있는경우도증가하며, IPMN 도췌관과교통이없이오래지속된경우는아밀라제치가증가하지않는다. 췌장낭의천자액에서점도의증가는점액소의존재를의미하며점액성낭종이나 IPMN 을의미한다. 맺음말췌장낭종성질환은염증성질환에의한낭종부터악성낭종까지그범위가다양하지만여러가지방사선및내시경진단방법이개선되고, 낭액의 FNA와같은새로운진단방법이소개되어도정확한진단과감별이어려운경우가있다. 췌장낭종성질환이증상의유무와관계없이영상진단에서발견되면다음과같은사항을염두에두어야하겠다. 첫째, 췌장의낭종은크기나증상의유무에관계없이진단을위한평가를시행하여야한다. 둘째, 췌장의낭종성질환중점액성낭종과 IPMN 은악성화의가능성이있으며드문질환인고형가성유두상종양도악성이될수있다. 셋째, 췌장낭종성질환의영상진단의첫째선택은조영증강 CT이며추가감별을위해서 EUS나 MRCP가가능한 MRI 를추천할수있다. 넷째, 낭액의세포검사는낭종의감별에도움이되지않으나, 점액성낭종이의심되면 EUS-FNA를이용한낭액의 CEA 검사, 점액소염색, 점도검사로감별에도움을준다. 다섯째, IPMN 이의심이되는경우는 MRCP, ERCP를통해췌관과의교통을확인할수있으며 ERCP에서유두에서점액분비를확인하는것이진단특이성이되며 MRCP에서는 IPMN 의범위를알수있다. 여섯째, 여러가지진단방법을동원하여도감별이불가능한경우가있으며장액성낭종이나잔류낭종이라고확신하지않는경우는정기적인추적이필요하다. 중심단어 : 췌장 ; 낭종성질환 ; 감별진단

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