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1 대한내과학회지 : 제 90 권제 3 호 종설 (Review) 위선종의치료전략 충남대학교의학전문대학원내과학교실 강선형 정현용 Treatment Strategy of Gastric Adenoma Sun Hyung Kang and Hyun Yong Jeong Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea Gastric adenoma is a precancerous lesion. While some adenomas regress spontaneously, others progress as invasive carcinomas. Simple follow-up of gastric adenoma may be possible considering the possibility of spontaneous regression. However, several studies have reported discrepancies between the results of endoscopic forceps biopsies and post-resection biopsies. These studies showed that the pathological findings are more severe in biopsies performed after endoscopic resections. We suggest that endoscopic resections should be planned for cases of gastric adenoma. After endoscopic resection, regular endoscopic surveillance and Helicobacter pylori eradication may reduce the occurrence of gastric cancer. (Korean J Med 2016;90: ) Keywords: Stomach; Adenoma; Endoscopic; Resection; Surveillance 서론위암은 2011년국가암등록사업연례보고서에따르면남자에서는첫번째, 여자에서는네번째로흔하게발생하는암으로남녀전체로보았을때두번째로많이발생하는암이다 [1]. 소화기내시경검사의보편화및국가암검진사업에힘입어많은사람들이내시경검사를받고있으며이는위암의조기발견에크게기여하고있고, 위선종의진단역시늘어나고있다. 위선종 (gastric adenoma) 혹은위의이형성증 (gastric dysplasia) 은위의상피세포에서기원하는비전형적인변화로서위암의전구병변으로정의할수있다. Correa [2] 는위의만성염증이헬리코박터균이나다른요인에의해만성위축성위염이발생하고장상피화생, 위의이형성증, 위의선 암으로이어지는일련의모델을제시한바있다. 그러나대장에비해위에서는선종이암으로이어지는 adenoma-carcinoma sequence 의증명이공고하지못하다 [3]. 다양한관찰연구에서선종이암으로진행하지않고그대로존재하는경우가존재하여서과연위선종은치료를해야하는것인지, 지켜보아도되는것인지혼동이있을수있다 [4-8]. 본고에서는위선종의자연경과부터조직검사의해석, 치료후조직검사를통해알수있는점을살펴보고, 이를통해위선종의치료전략에대해논해보고자한다. 위선종의자연경과위선종의자연경과는연구자및인종에따라다양하게보 Correspondence to Hyun Yong Jeong, M.D., Ph.D. Department of Internal medicine, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea Tel: , Fax: , jeonghy@cnu.ac.kr Copyright c 2016 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 90, No. 3, 고하고있다. 9만 2,000명을추적한네덜란드의코호트연구에서는진단후 5년이내에저도혹은중등도이형성증 (mild to moderate dysplasia) 에서는 0.6%, 고도이형성증 (high grade dysplasia) 에서는 6% 가암으로진행한다고보고하였고 [4], 118 명에서내시경추적검사를시행한 Rugge 등 [5] 의연구에서는 48% 에서병변이없어졌고 30% 에서는그대로있었으며 17% 만이위암으로진행하였다고보고하였다. 76예를치료없이분석한호주연구에서는 18예에서암이발생하여 25.7% 의암발생을보고하였고 [6], 40만명이상을분석한스웨덴의대단위코호트연구에서는위선종의경우 19예중 1예의비율로 20 년이내에위암이발생한다고보고하여정상점막에비해위선종의위암발생위험도 (hazard ratio) 를 10.9로제시하였다 [7]. 우리나라의경우소규모이긴하지만평균 58개월 (20-112개월 ) 로비교적긴시간추적해보았던후향적연구에서는 26예의위선종을추적하였을때 8예에서진행함을보였고총 4예의위암을보고한바있다 [8]. 이자료들은해석하기에따라서위선종을반드시치료해야하는지, 지켜봐도되는지혼동이있을수있다. 모든선종이반드시위암이나더진행된형태의이형성증으로변하지는않기때문이다. 여기서반드시우리가생각하고넘어가야할점은과연내시경시시행한조직검사가정확한지, 그병변전체를대변할수있는지의문제이다. 위선종의조직진단및해석역사적으로서구와일본에서는위선종혹은위의이형성증을서로다른병리학적분류체계를가지고기술해왔던터라위선종의병리학적정의에혼돈이있을수있지만요약하자면위선종은위의선구조 (glandular structure) 를유지하면서관상 (tubular) 혹은유두상 (papillary) 의구조를가지고있는선종성상피세포 (adenomatous epithelium) 의증식으로정의할수있다 [9]. 일본과우리나라병리학자간의관찰자간일치도 (Interobserver variation) 을살펴본연구에서는크진않지만우리나라와일본학자들사이에서도진단기준에어느정도간격이있음을확인할수있었다 [10]. 최근우리나라병리학회에서는이런혼선을줄이고자좀더발전된형태의위선종의병리학적분류체계를제시하였다 [11]. 이가이드라인에서는암은침윤이있어야진단할수있고, 저도이형성증 (low grade dysplasia) 은규칙적인선와구조 (regular distribution of crypts) 를기본으로하며심한이형성 (atypia) 이있을경우침윤하는부분이있는지좀더자세한관찰이필요하다고주장하였고, 이 진단기준을적용할경우관찰자간일치도 (Interobserver variation) 를어느정도향상시킬수있었다. 하지만아직도전세계적으로공히사용할수있는확고한분류체계의부재, 관찰자간의불일치는선종의진단에있어서여전히해결해야할숙제로남아있다. 조직검사의판독기준자체의모호성뿐만아니라우리가또고려해야할문제는내시경생검에서나온조직이그전체를반영하는가하는문제이다. 상당히분화된암인데조직검사에서선구조가잘보존되어있다면선종처럼해석될가능성이있으며, 선종과암이함께있는경우에선종부분만조직검사에서채취되어이것이선종으로오인될가능성이다. 중국의연구에서는내시경조직검사와수술혹은내시경절제술후조직검사의불일치가무려 62.07% 로보고되어이런우려를뒷받침하는결과를보여주었다 [12]. 우리나라의연구역시내시경조직검사와치료후최종조직검사의차이를 44% 까지보고하였다 [13]. 내시경절제술전후의조직검사간불일치우리나라및일본에서위선종에대한내시경적절제술이광범위하게이루어지고있고많은자료들이나오고있어서이에대한연구는상당히많은편이다. Nam 등 [14] 의연구에서는 534명의환자에서 554예의내시경적절제술을분석하였는데시술전저도이형성증의 11% 가고도이형성증으로, 5.8% 가조기위암으로시술후병리에서다르게진단되어상당수의위선종에서조직검사간의불일치를보여주었다. 같은연구에서고도이형성증의 55% 가시술후조기위암으로병리결과가승격되어서내시경시겸자를이용한조직검사를완전히신뢰하기는어렵다는결과를보여주었다. 이런결과는대개선종내에서암세포의위치에따른것이라고분석하였는데, 선종내암이있는경우조직검사시선종부분만조직검사를할경우암이선종으로오인될수있음에주목하여이를원인으로제시하였다. 이연구에서 1차의료기관에서의뢰된환자를다시내시경하여조직검사를한경우나, 재조직검사를한경우횟수를많이할수록최종진단이암으로나올확률이높았다고밝혀서이러한가설의신빙성을더해준다. 또다른해석은위에서언급하였듯이 1차의료기관에근무하는병리의사와 2차판독혹은절제술후판독을시행한병리의사간에다른병리기준을가지고진단하였을때이런일이발생할수있다. 아직까지도다양한병리기준이혼재되어있는상황에서같은병변을두고다른해석이충분히일어날여

- Sun Hyung Kang, et al. Treatment of gastric adenoma - 지가있는것이다. Nam 등 [14] 의연구에서연구를주로시행했던기관내에서도 2명의병리의사가있었는데, 전문분야가위암인병리의사가좀더많은조기위암을진단하였다. 경험및진단기준의차이가이런현상을만든것으로보인다.

두연구모두최종결과가암으로나올경우에대한위험인자를분석하였는데, 첫조직검사에서고도이형성증으로나온경우, 발적을동반한경우, 크기가 2 cm 이상인경우, 함몰이있는경우를그위험인자고하였다 [14,15]. 저자들이경험한증례에서도저도이형성증으로내시경점막절제술을시행후깊은점막하침윤을가진조기위암으로진단되어서추가 A B C Figure 1.

(B) Endoscopic resection was done, (C) and post-resection biopsy revealed adenocarcinoma with submucosal invasion (H&E stain, 200). Table 1.

3 - Sun Hyung Kang, et al. Treatment of gastric adenoma - 지가있는것이다. Nam 등 [14] 의연구에서연구를주로시행했던기관내에서도 2명의병리의사가있었는데, 전문분야가위암인병리의사가좀더많은조기위암을진단하였다. 경험및진단기준의차이가이런현상을만든것으로보인다. 또다른연구에서 Choi 등 [15] 은 282예의위선종을내시경적점막하박리술 (endoscopic submucosal dissection) 을시행한후그결과를분석하였는데첫조직검사에서저도이형성증으로진단된경우의 11.8%, 고도이형성증에서 55.2% 가위암으로 최종진단되어서 Nam 등 [14] 의연구와비슷한결과를보여주었다. 두연구모두최종결과가암으로나올경우에대한위험인자를분석하였는데, 첫조직검사에서고도이형성증으로나온경우, 발적을동반한경우, 크기가 2 cm 이상인경우, 함몰이있는경우를그위험인자고하였다 [14,15]. 저자들이경험한증례에서도저도이형성증으로내시경점막절제술을시행후깊은점막하침윤을가진조기위암으로진단되어서추가 A B C Figure 1. A case of gastric adenoma. 73-year-old male patient presented with gastric mass. (A) About 1.5 cm sized polypoid lesion with depression was found. Initial biopsy revealed low grade dysplasia. (B) Endoscopic resection was done, (C) and post-resection biopsy revealed adenocarcinoma with submucosal invasion (H&E stain, 200). Table 1. Diagnostic discrepancy between endoscopic forcep biopsy and final diagnosis after resection Treatment method Number of patients Upgrade of final pathology Risk factors Lee et al. [13] Gastrectomy, polypectomy, EMR Category 3 a (70) Category 4 a (56) Nam et al. [14] EMR, ESD No grading 92 LGD 382, HGD 80 Choi et al. [15] ESD LGD 195 HGD (8), 3 5 (4) 4 5 (29) LGD HGD 42 LGD CA 22 HGD CA 44 LGD HGD 15 LGD CA 23 HGD CA 48 Choi et al. [17] ESD LGD 218 LGD HGD 14 LGD CA 24 Kim et al. [18] EMR, ESD LGD 285 LGD HGD 22 LGD CA 24 Goo et al. [19] ESD, gastrectomy Indefinite dysplasia, atypia, Indefinite CA 26 atypical gland 119 Cho et al. [20] EMR, strip biopsy ESD LGD 236 LGD HGD 71 LGD CA 9 HGD, depression, surface redness, size > 2 cm HGD, depression, surface redness, size > 2 cm Surface redness, surface nodularity, size > 1 cm Erythema, depression, Size > 2 cm Size > 1 cm, Surface redness Depression, surface erythema, size > 1 cm EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; LGD, low grade dysplasia; HGD, high grade dysplasia; CA, carcinoma. a adopted from Vienna classification

4 - 대한내과학회지 : 제 90 권제 3 호통권제 667 호 로수술적절제술을시행한예가있었다 (Fig. 1). 최근의메타연구에서는저도이형성증의경우 25%( 고도이형성증 16.7%, 위암 6.9%) 가절제술후조직검사가진행된형태의이형성증혹은위암으로승격된다고보고하였고위두연구와마찬가지의위험인자를제시하였다 [16]. 이외에도다양한연구들에서비슷한연구결과들이제시가되어서시술전조직검사만가지고서는위선종의치료여부를결정하기어렵다는점을알수가있다 (Table 1) [13-15,17-20]. 선종의치료전략현재까지의선종치료의근간은내시경적절제술이다. 위선종이나위암에서내시경적절제술은역사가오래되었을뿐아니라안정성도여러연구에서입증이되었다. 위에서언급하였듯이선종과암이공존하고있을가능성, 추후좀더진행된형태로변할가능성, 또시술후정확한병리를알수있어서진단과치료를동시에가능케해줄수있다는점에서내시경적절제술은매력적이다 [21,22]. Kwon 등 [23] 의연구에서위선종을내시경적점막절제술로치료하였을때 7.1% 정도의재발을보여서점막절제술이효과적임을증명하였으며, Lee 등 [24] 의연구에서는 17.7% 의재발을보였는데주로장상피화생을포함한중등도이상의위축성위염을위험인자로제시하였다. 두연구모두약 10% 정도의출혈을보고하였고 Kwon 등 [23] 의연구에서 1예의천공을, Lee 등 [24] 의연구에서는천공이발생하지않아서안전한시술임을입증할수있었다. Nishida 등 [25] 은저도이형성증의경우에관찰혹은내시경적절제를, 고도이형성증과조기위암의경우내시경적절제를권고하였는데, 앞에서언급한대로, 저도이형성증의일부에서절제후고도이형성증이나조기위암으로진단되며고도이형성증의경우절제후절반정도에서조기위암으로진단된다는점을고려하면매우합리적인제안으로보인다. 내시경점막절제술과내시경적점막하박리술모두가능한데점막하박리술이점막절제술에비해출혈이나천공등의합병증발생률이높긴하지만넓고깊은병변을일괄절제할수있어서첫조직검사에서고도이형성증, 육안적으로함몰이나발적이있는경우, 크기가큰경우에조기위암일가능성을염두에둔다면좀더적합한방법이라하겠다. 저도이형성증의경우점막절제술이나점막하박리술보다빠르고간편하며합병증이덜발생하면서병변을제거할수있는방법으로아르곤플라스마응고술 (argon plasma coagulation) 이있다. 이방법은탐침 (probe) 을점막에직접대지않고아 르곤가스를통해고주파의전류를흘려병변을소작하는방법으로저도이형성증에서점막하박리술과아르곤플라스마응고술을비교한연구에서국소재발률이약간더높았으나 (3.8% vs. 0.5%), 재발예모두에서추가로소작술을시행하여병변을제거할수있어서효과를입증하였다 [26]. 이연구에서아르곤플라스마응고술의경우 102예중 2건의출혈이발생하였고천공은발생하지않아서안전성면에서점막하박리술과큰차이가없었으나시술시간에서불과 8분가량밖에걸리지않아서 (7.8 min vs min) 많은양의시술을소화해야하는우리나라의실정에서매력적인방법으로보인다. 다만내시경적절제와는달리조직을얻을수없기때문에절제후조직이 upgrade 될것으로예상되는고위험환자군 ( 고도이형성증, 2 cm 이상의크기, 발적이나함몰이동반된경우 ) 에서는신중하게시행여부를결정해야한다. 모든선종이암이나고도이형성증으로진행하지않는다는점을고려할때, 선종을반드시제거해야한다고는말할수없다. 여명이얼마남지않은고령의환자이거나심각한동반질환을가지고있는경우, 치료에비협조적인환자에서합병증을감수하면서내시경적치료를진행하기는어려운일일것이다. 하지만현재의의료환경을비추어볼때선종이암으로진행될경우의료분쟁으로진행할가능성이높으므로상황이허락하는한적극적인치료를하는것이바람직할것이다. 내시경치료후환자관리및추적검사선종의내시경적치료전후에주의해야할점은동시성병변 (synchronous lesion) 혹은이시성병변 (metachronous lesion) 의존재이다. Jang 등 [27] 은 512 예의조기위암과위선종을내시경적점막하박리술로치료후추적하였는데, 이중 12.9% 의동시성병변과 2.5% 의이시성병변이있었음을발표하였다. 또다른우리나라연구에서는 20.8% 와 20.1% 의동시성및이시성병변이있음을발표하여치료전후로다른병변의유무를면밀히살펴야함을시사하였다 [28]. 선종과조기위암의치료후위암발생률을비교한연구에서는위암의이시성재발이양군간의차이를보이지않아서선종을치료한후에는조기위암에준하여내시경추적 (endoscopic surveillance) 이필요함을주장하였다 [29]. 미국의코호트연구에서도내시경절제술후매년추적내시경을하는것이위선종환자에서평생의위암발생률을 90% 가량감소시키는것으로밝혀져시술후추적검사를하는것의중요성을강조하였다 [30]. 저자들은최근위선종치료후이시성위암재발을경험하였는데 73세

- 강선형외 1 인. 위선종의치료전략 - A B C D Figure 2. A case of metachronus cancer. 64-year-old female patient presented with gastric mass.

(C, D) After 10 years, early and advanced gastric cancer recurred at other site of remnant stomach. 여자환자로 2006년유문륜의선종으로내시경절제술을시행하였다.

우리나라의높은위암유병률을고려한다면저자들은 1-2년간격이적절할것으로판단한다. Correa [2] 는위암의발생모델에서헬리코박터균의역할을제시하였고, 약 75% 의위암발생이헬리코박터균과연관이있는것으로알려져있다 [31]. 일본의전향적연구에서조기위암의내시경적치료후헬리코박터제균을시행하면이시성재발의감소를보고한바있다 [32].

이보다적은숫자이지만 129명을대상으로한국내연구역시헬리코박터제균이내시경절제술후위선종의재발을줄이는것으로발표하여위선종의내시경절제술후헬리코박터제균의필요성을뒷받침하는결과를보여주었다 [34]. 위선종환자에서대장선종의유병률이높다는몇몇연구들도있다.

5 - 강선형외 1 인. 위선종의치료전략 - A B C D Figure 2. A case of metachronus cancer. 64-year-old female patient presented with gastric mass. (A) About 1 cm sized polypoid mass was found at great curvature side of pyloric ring. (B) Endoscopic resection was done and post-resection biopsy revealed low grade dysplasia. (C, D) After 10 years, early and advanced gastric cancer recurred at other site of remnant stomach. 여자환자로 2006년유문륜의선종으로내시경절제술을시행하였다. 추적이되지않고지내던중 2016년 1월타병원에서시행한위내시경상위각부의진행성위암, 전정부전벽에조기위암으로두군데암이발생하여의뢰되었다 (Fig. 2). 적절한내시경추적검사의간격에대해미국의코호트연구에서는내시경절제후 1-5년간격의추적을주장하였지만명확한근거가있지는않다 [30]. 적절한추적간격에대해서는추후더연구가필요할것이다. 우리나라의높은위암유병률을고려한다면저자들은 1-2년간격이적절할것으로판단한다. Correa [2] 는위암의발생모델에서헬리코박터균의역할을제시하였고, 약 75% 의위암발생이헬리코박터균과연관이있는것으로알려져있다 [31]. 일본의전향적연구에서조기위암의내시경적치료후헬리코박터제균을시행하면이시성재발의감소를보고한바있다 [32]. 그렇다면헬리코박터제균을하면위선종의발생을줄일수있을까? Shin 등 [33] 은위선종으로내시경적절제술을시행한 1,872명의환자중 2년이상추적한 282명의환자를대상으로조사한결과를최근발표하였는데, 헬리코박터균을제균치료한환자군에서치료하지않은환자군과헬리코박터균음성인환자군에비하여통계적으로유의하게적은이시성재발의감소를보고하였다. 이보다적은숫자이지만 129명을대상으로한국내연구역시헬리코박터제균이내시경절제술후위선종의재발을줄이는것으로발표하여위선종의내시경절제술후헬리코박터제균의필요성을뒷받침하는결과를보여주었다 [34]. 위선종환자에서대장선종의유병률이높다는몇몇연구들도있다. Bae 등 [35] 은 133명의위선종환자와 213명의건강검진환자들을비교하였는데, 대장선종은두군간의차이가없었으나진행된대장선종은위선종환자군에서더높게나타남 (odd ratio = 3.382, p = 0.000) 을발표하여위선종이대장선종의위험인자임을주장하였다. 186명의위선종군환자와같은환자의정상대조군을비교한연구에서는대장선종, 진행된대장선종, 대장암모두위선종군에서높게나타남을발표하여위선종이대장선종의위험인자임을밝혔다 [36]. 위선종의기왕력이있는환자에서는대장내시경을시행하는것을내시경의사들은고려해야할것이다. 결 위선종은위의상피세포에서기원하는비정상적인변화로서위암의전구병변이다. 모든위선종환자에서위암으로진행하는것은아니지만조직검사만으로이를예견할수없고내시경적절제술후첫조직검사보다더진행된형태의이형성증이나조기위암으로진단되는경우도상당수있어서가능하면적극적인치료를고려해야한다. 치료는내시경치료가기본이며내시경적점막절제술과내시경적점막하박리술, 아르곤플라스마응고술등을이용할수있고, 시술후에도이시성병변이나동시성병변이존재할수있기때문에추적내시경을꾸준히시행해야한다. 절제술후에는헬리코박터균을제균하는것이이시성재발을막는데도움이되며대장용종의발생도고려해야하는사항이다. 중심단어 : 위 ; 선종 ; 내시경 ; 절제술 ; 내시경추적검사 론 REFERENCES 1. Ministry of Health and Welfare. Annual report of cancer statics in Korea Sejong: Ministry of Health and Welfare, Correa P. A human model of gastric carcinogenesis. Cancer Res 1988;48: Kato M. Diagnosis and therapies for gastric non-invasive neoplasia. World J Gastroenterol 2015;21: de Vries AC, van Grieken NC, Looman CW, et al. Gastric cancer risk in patients with premalignant gastric lesions: a

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슬라이드 1

슬라이드 1 위선종 / 이형성 Gastric adenoma/dysplasia Jun Haeng Lee. Department of Medicine Sungkyunkwanuniversity School of Medicie, Seoul, Korea Dysplasia in Barrett s esophagus Ideally, the management of a disorder is