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1 Small gastric SMT: Careful observation may be enough 성균관대학교의과대학내과학교실 김은란 이준행 서 본 점막하종양은임상에서흔히볼수있는질환으로발생률에대한정확한보고는없으나 90년대초에시행된외국의한보고에의하면상부위장관내시경을시행받은환자의 0.36% 에서발견된다고하였다. 1 그러나최근내시경기기가발달하고조기건강검진에대한인식이높아지면서위내시경검사에대한수요는꾸준히증가하고있으며, 무증상성인에서우연히발견되는점막하종양의빈도또한증가하고있어실제발생률은더욱높을것으로생각한다. 점막하종양에대한치료는소화불량, 출혈또는폐쇄등의증상이있는경우수술적치료가우선이다. 그러나앞서언급했듯이근래에는무증상성인에서건강검진상우연히발견되는크기가작은점막하종양이대부분으로, Hassan 등 2 이위장관간질종양환자를대상으로한연구에서증상의존재유무가환자의예후와연관이있다는보고를참고로하더라도이전의수술적치료만을고수하기에는무리가있다. 실제임상에서도이들에대한적절한치료방침에대한합의점을찾지못한상태로의료기관에따라수술적또는내시경적절제를해야한다는의견과경과관찰만으로충분하다는의견등혼선을빚고있는실정이다. 이러한혼선의근본적이유는점막하종양의정확한진단을위한비침습적이면서민감도와특이도가높은검사법의부재와이들종양의자연경과에대한자료의부족때문이다. 본고에서는위점막하종양을중심으로이들의자연경과를살펴보고, 무증상성인에서발견된크기가작은점막하종양의치료방침에대해논의해보고자한다. 위점막하종양의종류및진단 점막하종양은위장관내강으로돌출된융기성병변으로, 병변이점막의하층에존재하고정상점막으로덮혀있는경우를말한다. 3-4 그러나내시경소견만으로벽외성압박을정확히구분하기어렵고, 상피층에가까운부위에병변이발생하기도하므로상피하종양이라고표현하기도한다. 위점막하종양은크게양성병변과악성또는악성화의가능성이있는병변으로나누어볼수있는데 (Table 1) 실제임상에서진료방침을정하는데있어이들병변에대한정확한진단은중요한부분을차지한다. 양성병변인지방종, 평활근종, 이소성췌장, duplication cyst 등은추가적인검사가필요하지않거나내시경을통한경과관찰만으로충분한반면, 악성화의가능성이있는위장관간질종양이나유암종등에대해서는합당한치료또는경과관찰이필요하기때문이다. 이들병변에대한감별진단은일차적으로내시경검사시모양, 색조, 경도, 이동성등을살펴봄으로써어느정도가능하다. 지방종의경우, 표면색조가노랗게보이는경우가많고생검겸자로눌렀을때 pillow sign이라하여표면이쉽게눌러지는것을보고진단할수있으며, 이소성췌장의경우는주로위전정부에위치하며병변의중양에작은함몰을동반하는경우가많고, duplication cyst 는생검겸자로눌렀을때표면이쉽게눌러지면서점막표면이투명하게비치는경우가많다. 그러나이러한소견들이항상전형적인것은아니어서내시경검사만으감별진단에어려움이많다. 5-7 점막하종양의진단에있어내시경초음파검사는중요한검사법으로종양의크기와내부성상, 기원된층벽등을관찰함으로써감별에도움을얻을 26

2 김은란 이준행 : Small gastric SMT: Careful observation may be enough Table 1. Differential diagnosis of intramural gastric subepithelial masses based on EUS feature Subepithelial lesion EUS layer a Echogenicity Benign Leiomyoma 2, 3 or 4 Hypoechoic Neural origin tumors Schwannoma 3 or 4 Hypoechoic Neuroma Neurofibroma Lipoma 3 Intensely hyperechoic Duplication cyst Any or extramural Anechoic Pancreatic rest 2 or 3 Hypoechoic Inflammatory fibroid polyp 3 or 4 Hypoechoic Granular cell tumor 2 or 3 Hypoechoic Varices 2 or 3 Anechoic Malignant or with malignant potential GIST 4 (rarely 2 or 3) Hypoechoic Lymphoma 2, 3 or 4 Hypoechoic Carcinoid 2 or 3 Hypoechoic Metastatic carcinoma Any Hypoechoic Glomus tumor 3 or 4 Hypoechoic a Layer 1 is the interface of luminal fluid and mucosa, layer 2 represents, the deep mucosa, layer 3 is largely due to the submucosa, layer 4 represents the muscularis propria, and layer 5 is adventitia or serosa with adjacent fatty or fibrous tissue. 수있다. 최근위점막하종양의진단에있어내시경초음파검사와내시경검사를비교한한연구에서내시경초음파검사와병리학적진단을비교한결과 43%(10/23) 에서만일치한반면, 일치하지않은 10예중 9예의병리학적진단과내시경검사에의한추정진단이일치하였다는결과를보고하였는데, 내시경초음파검사상오진된 10예는모두초음파상제 3층이나 4층에위치하는저에코병변으로위장관간질종양과유암종으로진단하였으나다른종류의양성또는악성의병변이었다. 5,8 내시경초음파유도하세침흡인술은원하는부위에직접세침을천자하고흡인하여세포를얻거나경우에따라조직절편검체를얻어세포검사를시행함으로써양성과악성병변의감별에유용한검사이나, 점막하종양의진단의확진이나악성여부판정에필수적인유사분열의수를측정하는데는한계가있다. 9,12 그러나세침흡인술로얻은검체에면역조직화학염색을시행함으로써제 3층이나 4층에위치하는저에코종양, 특히위장관간질종양의감별진단에도움이될수있다 위점막하종양의자연경과위점막하종양의자연경과에대한연구는아직충분하지않은상태로대부분은대상환자수가적고경과관찰기간이길지않다는제한점을가지고있으나, 최근까지보고된몇몇연구들을살펴봄으로써자연경과에대한이해에도움을얻고자한다. Melzer 등은 4 cm 이하의고유근층에서기원하는위점막하종양 16예를 6개월간격으로평균 19개월간내시경초음파검사로추적관찰한결과, 1예에서만 17개월후초음파상변화를동반한크기증가를 (3 cm에서 3.8 cm) 발견하여수술을시행하였고조직검사상고도의악성도를갖는위장관간질종양임을확인하였으며이러한결과를바탕으로 4 cm 이하의위점막하종양의경우수술적절제없이추적관찰하여도안전할것이라고주장하였다. 15 또 Gill 등은 51명의무증상의제 2층또는 4층에서기원하는 3 cm이하의상부위장관점막하종양환자를평균 29.7개월간 (3 84개월) 추적관찰한결과이들중 7예에서크기변화또는초음 27

3 파상에코의변화가있었고크기와에코상변화둘다있었던 2예가수술후위장관간질종양으로진단되었음을 16 보고하면서 3 cm 이하의점막하종양을갖는무증상환자에서 2년마다내시경초음파검사를통한경과관찰이면충분할것이라고주장하였다. Sawaki 등은내시경초음파유도하세침흡인술로진단된평균 1.8 cm 크기 ( cm) 의위장관간질종양이있는환자 16명을중앙값 4.9년간내시경초음파검사로추적관찰한결과 2예에서만크기증가가있었다고보고하였다. 17 이중 1예는두배로크기가증가 (1.0 cm에서 2.3 cm) 하는데 8년이소요되었고, 다른 1예는첫진단시크기가 1.8 cm이었으나내시경초음파검사상악성의가능성이있어수술을권유하였으나증상이없다는이유로환자가수술을거부하였다가 2년만에 10 cm으로크기가증가하여내원하였던경우로위장관간질종양이악성의가능성이있긴하지만크기가작은위장관간질종양의경우, 악성화의가능성은낮으며내시경적으로경과관찰할수있을 Table 2. Patients undergoing serial endoscopic ultrasound (EUS) for suspected gastrointestinal stromal tumors (GIST) (n=28) Median Range Duration of follow-up 4.5 years years Number of procedures Inter-procedure interval 18 months 6-84 months Initial size 13 mm 3-44 mm Growth velocity 0 mm/year 0-5 mm/year No change in size n=23 것이라고주장하였다. Humphis 등도내시경초음파검사상위장관간질종양으로추정되는 28예를추적관찰한결과정기적추적검사가수술을대체할수있을것이라고하였다 (Table 2). 3 그밖에국내보고로, 내시경초음파검사상 3.0 cm 이하의양성중간엽종양으로진단된 26예를 2년이상추적관찰한결과 1예에서만크기증가 (2.6 cm에서 3.4 cm) 가있었는데초음파검사상변화는동반하지않았으며수술후조직검사상평활근종으로진단되어저자는양성중간엽종양의기준을만족하는 3 cm 미만크기의종양의경우추적관찰이가능할것이라고주장하였다18. 내시경초음파검사상양성의소견을보인 3 cm이하의상부위장관점막하종양 60예를추적관찰하였던또다른연구에서도 10예에서크기의증가가있었으나조직을확인하였던 3예모두양성병변이었다고보고하였다. 19 위점막하종양의치료방침에대한여러견해 현재까지위점막하종양의치료에있어증상이있는경우수술적또는내시경적치료를시행해야한다는데에는이견이없는상태다. 그러나무증상환자에서발견된점막하종양에대한적절한치료방침에대해서는임상경험과자료에제한이있어표준화된지침이마련되어있지않다. 최근미국소화기학회 (American Gastroenterological Association) 에서는여러연구들을바탕으로위점막하종양에대한가이드라인을제시하였는데내시경초음파상 3 cm이상의위장관간질종양이나 3형의유암종은수술적절제를, 3 cm이하의 위장관간질종양이나사구종양의경우는추적관찰할수있다고하였다 (Table 3). 4 Eckardt 등도위 Table 3. Summary of the recommendations for the management of asymptomatic gastric subepithelial masses No further investigation or follow-up Follow with periodic endoscopy and/or EUS or Resection resection Normal extramural organ GIST < 3 cm in diameter GIST > 3 cm in diameter Lipoma Glomus tumor carcinoid tumor (type III) Duplication cyst Pancreatic rest Inflammatory fibroid polyp Seural origin tumor (Schwannoma) 28

4 김은란 이준행 : Small gastric SMT: Careful observation may be enough Step 1: Endoscopy Identification of a subepithelial lesion (Wide based, sessile tumors with a sloping contour and normal overlying mucosa) Biopsy of the overlying mucosa (rules out epithelial lesion: avoid if lesion appears vascular or cystic) Estimation of size (with biopsy forceps) Lesion > 1 cm Identification of a pillow sign Negative pillow sign Lesion < 1 cm Positive pillow sign May consider endosoopic follow up in 1 year 3 Lipoma Step 2: EUS (obtain consent for possible tissue acquisition prior to the procedure) Identification of intra- or extramural location Intramural Identification of echo-features. Doppler-features size Hyperechoic Anechoic Hypoechoic Size < 3 cm Extramural Doppler positive Doppler negative Size > 3 cm Extramural orgen structure or extramural mass (work-up as clinically Indicated) Lipoma Vascular lesion Cyst or lymphangloma Surgery Step 3: Histology (dependent on clinical availability and risk) EMR (especially when located in layers 1-3) FNA (in conjunction with immunohistochemistry, especially if located in layer 4) Other (jumbo forceps, large bore FNA, enucleation, surgery etc.) Fig. 1. Stepwise evaluation of subepithelial mass lesions 점막하종양의진단및치료에대해여러연구들을토대로진단및치료에대한지침을제시하였는데, 병변의크기가 1 cm 이하인경우는주기적인경과관찰을, 1 cm 이상인경우는내시경초음파검사를시행하여크기가 3 cm 이상이면서내시경초음파상저에코병변인경우는수술을, 3 cm 미만의경우는내시경초음파세침흡인술을시행하거나제 1-3층에위치하는경우는내시경적절제술을고려할수있고조직학적진단을하지못한경우는주기적인경과관찰을시행할수있다고제안하였다 (Fig. 1). 3,8 반면, 2007년 NCCN (National Comprehensive Cancer Network) 가이드라인에서는 2 cm이상의모든위장관간질종양은절제되어야하고 2 cm 이하의우연히발견된종양에대해서는아직일치된의견이없다고하였으며, 1 cm 이하의간질종양에대해서도자료가충분하지않아가이드라인을정할수없다고하였다. 20 결 지금까지위점막하종양의자연경과에대한여 29

5 러연구및치료방침에대한의견들을살펴보았다. 그러나아직까지위점막하종양의장기적인경과관찰에대한자료들이부족하여치료방침에대한통일된합의점을얻지못하고있다. 특히위점막하종양중가장많은위장관간질종양의경우악성화의가능성이있는병변으로현재까지마련된지침으로는조직을채취하여야만악성화의위험도를결정할수있어내시경시행중첫진단된경우치료방침을결정하는데어려움이있다. 그러나여러연구에서살펴보았듯이크기가작은위점막하종양의경우, 경과관찰중대부분크기에변화가없었고크기가증가한경우에도내시경초음파검사상악성의소견이없는경우수술후조직검사상대부분양성의병변임을확인할수있었으며, 이러한연구결과들을고려할때증상없이우연히발견된크기가작은위점막하종양의경우조심스럽게추적관찰을해볼수있을것으로생각한다. 다만적절한추적검사의시기와검사방법에대해서는좀더논의가되어야하겠으며확고한치료방침을결정하기위해서는좀더많은환자수를대상으로한장기간추적관찰에대한연구가있어야겠다. 참고문헌 1. Hedenbro JL, Ekelund M, Wetterberg P. Endoscopic diagnosis of submucosal gasric lesions. The results after routine endoscopy. Surg Endosc 1991;5: Hassan I, You YN, Shyyan R, et al. Surgically managed gastrointestinal stromal tumors: a comparative and prognostic analysis. Ann Surg Oncol 2008;15: Humphris JL, Jones DB, Subepithelial mass lesion in the upper gastrointestinal tract. J Gastroenterology and Hepatology 2008;23: Hwang JH, Rulyak SD, Kimmey MB. American Gastroenterological Association Institute technical review on the management of gastric subepithelial masses. Gastroenterology 2006; 130: Hwang JH, Saunders MD, Rulyak SJ, Shaw S, Nietsch H, Kimmey MB. A prospective study comparing endoscopy and EUS in the evaluation of GI subepithelial masses. Gastrointest Endosc 2005;62: 김형길. 위장관점막하종양의치료와관리. 대한소화기내시경학회지 2008;37: 박찬국. 점막하종양. 대한소화기내시경학회지 2004;29: Eckardt AJ, Wassef W. Diagnosis of subepithelial tumors in the GI tract. Endoscopy, EUS, and histology: bronze, silver, and gold standard? Gastrointest Endosc 2005;62: Hwang JH, Kimmey MB. The incidental upper gastrointestinal subepithelial mass Gastroentetology 2004;126: Williams DB, Sahai AV, Aabakken L, et al. Endoscopic ultrasound guided fine needle aspiration biopsy: a large single centre experience. Gut 1999;44: Gu M, Ghafari S, Nguyen PT, Lin F. Cytologic diagnosis of gastrointestinal stromal tumors of the stomach by endoscopic ultrasound-guided fine-needle aspiration biopsy: cytomorphologic and immunohistochemical study of 12 cases. Diagn Cytopathol 2001;25: Wiersema MJ, Wiersema LM, Khusro Q, Cramer HM, Tao LC. Combined endosono graphy and fine-needle aspiration cytology in the evaluation of gastrointestinal lesions. Gastrointest Endosc 1994;40: Okubo K, Yamao K, Nakamura T, et al. Endoscopic ultrasoundguided fine needle aspiration biopsy for the diagnosis of gastrointestinal stromal tumors in the stomach. Gastroenterol 2004;39: Rader AE, Avery A, Wait CL, McGreevey LS, Faigel D, Heinrich MC. Fine-needle aspiration biosy diagnosis of gastrointestinal stromal tumors using morphology, immunocytochemistry, and mutational analysis of c-kit. Cancer 2001;93: Melzer E, Fidder H, The natural course of upper gastrointestinal submucosal tumors: an endoscopic ultrasound survey. IMAJ 2000;2: Gill KR, Camellini L, Conigliaro R, et al. The natural history of upper gastrointestinal subepithelial tumors(sets): a multicenter endoscopic ultrasound(eus) survey. Gastrointest Endosc 2008;67:AB Akira Sawaki, Nobumasa Mizuno, Kuniyuki Takahashi, et al. Long-term follow up of patients with small gastrointestinal stromal tumors in the stomach using endoscopic ultrasonography-guided fine-needle aspiration biopsy. Digestive Endoscopy 2006;18: 이수정, 김진오, 은수훈등. 상부위장관양성중간엽종양의내시경초음파검사를이용한추적관찰. 대한소화기내시경학회지 2007;35: 원태경, 김은영, 서창진등. 상부위장관상피하병변의내시경초음파검사. 대한소화기내시경학회지 2006;32: Demetri GD, Benjamin RS, Blanke CD, et al. NCCN task force report: Management of patients with gastrointestinal stromal tumors (GIST)-Update of the NCCN clinical practice guidelines. J Natl Compr Canc Netw 2007;5:s1-s40. 30

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<C1A63530C8B820BCBCB9CCB3AA2DC6EDC1FD2E687770> C-IV. 흥미로운하부위장관질환증례 Room C 김진오 이용섭 순천향대학교의과대학내과학교실, 소화기연구소 Subepithelial Lesions Jin-Oh Kim, Yong-Sub Lee Institiute for Digestive Research, Department of Internal Medicine, Soonchunhyang University College