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Case Report Ewha Med J 2012;35(1):44-48 pissn 2234-3180 / eissn 2234-2591 고등급이형성을보인편평톱니샘종 권경주ㆍ정성애ㆍ심기남ㆍ정정화ㆍ강석형ㆍ송도경ㆍ전승정ㆍ김혜인 이화여자대학교의학전문대학원내과학교실 Sessile Serrated Adenoma with High-grade Dysplasia

1 Case Report Ewha Med J 2012;35(1):44-48 pissn / eissn 고등급이형성을보인편평톱니샘종 권경주ㆍ정성애ㆍ심기남ㆍ정정화ㆍ강석형ㆍ송도경ㆍ전승정ㆍ김혜인 이화여자대학교의학전문대학원내과학교실 Sessile Serrated Adenoma with High-grade Dysplasia Kyoung-Joo Kwon, Sung-Ae Jung, Ki-Nam Shim, Jung-Hwa Chung, Seok-Hyung Kang, Do-Kyeung Song, Seung-Jung Jun, Hye-In Kim Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea Until recently, colorectal polyps were classified predominantly as hyperplastic or adenomatous. While adenomatous polyps are well-characterized precursor lesions of adenocarcinomas, hyperplastic polyps have been considered as benign lesion. However, some hyperplastic polyps with serrated morphology of the crypts have been recognized to have distinctive features and these polyps were termed serrated adenomas. Recent data show that sessile serrated adenomas (SSA) might be the precursors of serrated colonic cancers, underlining the necessity of identifying them. SSA is approximately 3% of all polyps, commonly appears as flat or sessile and yellowish due to mucus production. In the pathogenesis of SSA, progression to high grade dysplasia or early invasive carcinoma may be associated with serrated neoplasia pathway different from adenoma-carcinoma sequence. We report a case with a colon polyp diagnosed as sessile serrated adenoma with high grade dysplasia after endoscopic submucosal dissection. (Ewha Med J 2012;35(1):44-48) Key Words: Sessile serrated adenoma; Colorectal polyp; Hyperplastic polyp; Dysplasia 서론 대장의상피성폴립은크게증식폴립 (hyperplastic polyp) 과샘종 (adenoma) 으로나눌수있다 [1]. 증식폴립은일반적으로악성화경향이없는양성병변으로알려져있으나하나의폴립내에증식성과선종성이동반될수있다는것이보고되고있고, 심지어혼합되어관찰되기도한다 [1,2]. 톱니샘종 (serrated adenoma) 은형태학적으로증식폴립의전형적인톱니모양구조에세포학적이형성을보이는샘종으로, 하나의샘와 Received: August 1, 2011, Accepted: September 2, 2011 Corresponding author: Sung-Ae Jung, Department of Internal Medicine, Ewha Womans University School of Medicine, 1071 Anyangcheon-ro, Yangcheon-gu, Seoul , Korea Tel: , Fax: jassa@ewha.ac.kr 를구성하는상피세포가증식성및선종성상피의특징을갖는경우를 1990년 Longacre와 Fenoglio-Preiser [1] 가처음톱니샘종으로명명하였고특히, 이런톱니샘종이악성화하는경향이있다는보고가있은후더욱주목을받고있다. 톱니샘종과증식폴립, 그리고관상샘종 (tubular adenoma) 간의관계에대해서는아직명확하게밝혀져있지않지만모두암종 (carcinoma) 으로변할수있는것으로알려져있다 [3,4]. 우리나라에서대장암은식생활, 환경변화등의요인으로인해발생빈도가증가하고있어이에대한관심이고조되고있다. 하지만악성화경향이보고되고있는톱니샘종의역학과대장내시경적특징등에대한연구는드물다. 저자들은, 대장내시경검사에서폴립이발견되어내시경시술로절제한결과고도의이형성이동반된톱니샘종이확인된증례가있어이에 44

Kyoung-Joo Kwon, et al: Sessile Serrated Adenoma with High-grade Dysplasia 문헌고찰과함께보고한다. 증례 53세여자가건강검진에서발견된대장의거대한병변으로인해본원으로전원되었다. 환자는직장출혈이나복통, 배변습관변화, 후중감, 체중감소등의증상은호소하지않았다. 과거력, 가족력및사회력에서특이사항은없었다.

5 g/dl, 백혈구 5,000/mm 3 였고, 혈청생화학검사에서총단백 6.6 g/dl, 알부민 4.1 g/dl, AST 26 IU/L, ALT 28 IU/L, BUN 13 mg/dl, 크레아티닌 0.7 mg/dl, 나트륨 143 meq/l, 칼륨 4.1 meq/l이었다. 종양표지자검사는 CEA 0.9 ng/ml, CA 19-9 13.6 U/mL였다.

복부전산화단층촬영에서복강내림프절종대나복수, 간전이소견은관찰되지않았으며대장전벽이두꺼워진소견이나관강의종괴가의심되는소견은없었고 (Fig. 2), 전신 PET 촬영에서도대사가증가한병변은보이지않았다 (Fig. 3). 폴립의크기가 2 cm 이상이면서관상모양의선구형태를보여암성변화의가능성이있었으므로, 병변의일괄절제를위해내시경점막하박리술을시행하였다 (Fig. 4).

2 Kyoung-Joo Kwon, et al: Sessile Serrated Adenoma with High-grade Dysplasia 문헌고찰과함께보고한다. 증례 53세여자가건강검진에서발견된대장의거대한병변으로인해본원으로전원되었다. 환자는직장출혈이나복통, 배변습관변화, 후중감, 체중감소등의증상은호소하지않았다. 과거력, 가족력및사회력에서특이사항은없었다. 신체검사에서내원당시혈압 130/80 mmhg, 맥박 60회 / 분, 호흡수 20회 / 분, 체온 36.5 o C이었다. 병색은보이지않았고의식은명료하였다. 결막은정상색깔이었으며공막의황달은관찰되지않았고, 두경부및흉부진찰에서특이사항은없었고복부의압통이나만져지는종괴는없었다. 내원했을때시행한전혈검사결과는혈색소 12.5 g/dl, 백혈구 5,000/mm 3 였고, 혈청생화학검사에서총단백 6.6 g/dl, 알부민 4.1 g/dl, AST 26 IU/L, ALT 28 IU/L, BUN 13 mg/dl, 크레아티닌 0.7 mg/dl, 나트륨 143 meq/l, 칼륨 4.1 meq/l이었다. 종양표지자검사는 CEA 0.9 ng/ml, CA U/mL였다. 대장내시경검사에서항문연 25 cm 상방의구불결장에직경 3.3 cm 크기의무경성폴립이관찰되었다. 폴립은약간붉은색을띄고있는과립결정형이었으며, 편평한병변위에다시짙은붉은색의유경성폴립이솟아있는양상이었다 (Fig. 1). 폴립의표면에는 다양한크기의관상모양의선구형태가관찰되었다. 복부전산화단층촬영에서복강내림프절종대나복수, 간전이소견은관찰되지않았으며대장전벽이두꺼워진소견이나관강의종괴가의심되는소견은없었고 (Fig. 2), 전신 PET 촬영에서도대사가증가한병변은보이지않았다 (Fig. 3). 폴립의크기가 2 cm 이상이면서관상모양의선구형태를보여암성변화의가능성이있었으므로, 병변의일괄절제를위해내시경점막하박리술을시행하였다 (Fig. 4). 시술후특별한합병증은관찰되지않았다. 절제된검체에대한병리조직검사결과저배율에서많은부분의상피가톱니모양으로관찰되었으며구조적인이형성이없어서증식폴립을연상할수있었으나 (Fig. 5A), 고배율소견 Fig. 2. Abdominal computed tomography show no evidence of apparent wall thickening or intraluminal mass-like lesion in the colon. Fig. 1. The colonoscopy reveals broad-based sessile polyp of 3.3 cm in size on sigmoid colon. Its surface shows large tubular pit pattern. There is a reddish papillomatous polypoid lesion arising from the surface of the polyp. Fig. 3. PET findings shows no abnormal hypermetabolic lesion. THE EWHA MEDICAL JOURNAL 45

Ewha Med J Vol. 35, No. 1, 2012 에서는일부고도의이형성을보이는핵이관찰되었다 (Fig. 5B). 환자는최종적으로국소적인고도의이형성을지닌톱니샘종으로진단하였으며, 현재외래에서추적관찰중이다. 고찰 대장내의증식폴립은일반적으로양성으로알려졌으나증식성과선종성이혼합된형태인톱니샘종에서 Fig. 4.

전통적톱니샘종은표면의상피세포샘와에이형성을보이며, 혼합형톱니샘종은증식성폴립같은톱니모양의구조에샘종의특징인이형성을동반한다. 편평톱니샘종은가장최근에 Torlakovic과 Snover[5] 에의해밝혀졌는데, 증식폴립과전통적톱니샘종의중간적인형태적특징을보인다.

특히, 조직학적소견에서세포이형성을보이는경우샘암종으로빠르게진행할가능성이있어완전절제를하는것이좋으며, 이형성이없는경우에도가능하다면병변을모두제거하되만약내시경을통한절제가어려울경우에는지속적으로내시경적추적관찰을하도록권하고있다. 이에비해전통적톱니샘종은이형성여부에따라예후에차이가있지는않으며일반샘종처럼치료한다 [8].

3 Ewha Med J Vol. 35, No. 1, 2012 에서는일부고도의이형성을보이는핵이관찰되었다 (Fig. 5B). 환자는최종적으로국소적인고도의이형성을지닌톱니샘종으로진단하였으며, 현재외래에서추적관찰중이다. 고찰 대장내의증식폴립은일반적으로양성으로알려졌으나증식성과선종성이혼합된형태인톱니샘종에서 Fig. 4. Endoscopic findings during endoscopic submucosal dissection. 대장암의발생이보고되면서이러한증식성과선종성폴립의혼합형이주목을받게되었다 [1,3]. 조직학적으로톱니모양의형태학적특징이있는톱니샘종은과거증식폴립으로분류되었지만, 현재는톱니샘종을전통적톱니샘종, 편평톱니샘종, 혼합형태의톱니샘종으로분류하고있다 [4]. 전통적톱니샘종은표면의상피세포샘와에이형성을보이며, 혼합형톱니샘종은증식성폴립같은톱니모양의구조에샘종의특징인이형성을동반한다. 편평톱니샘종은가장최근에 Torlakovic과 Snover[5] 에의해밝혀졌는데, 증식폴립과전통적톱니샘종의중간적인형태적특징을보인다. 증식폴립처럼무경성형태를유지하지만, 기저부위의샘와는확장되어있으며분지화되어있고점막근층과평행하게가장자리로자라나는형태를띤다. 편평톱니샘종은샘암종을일으키는원인으로알려진이형성톱니샘종의전구단계라고보고되고있다 [6,7]. 특히, 조직학적소견에서세포이형성을보이는경우샘암종으로빠르게진행할가능성이있어완전절제를하는것이좋으며, 이형성이없는경우에도가능하다면병변을모두제거하되만약내시경을통한절제가어려울경우에는지속적으로내시경적추적관찰을하도록권하고있다. 이에비해전통적톱니샘종은이형성여부에따라예후에차이가있지는않으며일반샘종처럼치료한다 [8]. 대부분의대장암과직장암은유전적이지않고, 산발적으로발생하는데, 이곳에서발생하는샘암종의 80% 가 adenomatous polyposis coli (APC ) gene과관계 Fig. 5. Pathologic findings. (A) The polyp is measured cm in size. Its surface is granular, villous and focally had polypoid mass with long stalk (H&E stain, 100). (B) Serrated adenoma with focal high grade dysplasia is noted with clear resection margin (H&E stain, 200). 46 THE EWHA MEDICAL JOURNAL

4 Kyoung-Joo Kwon, et al: Sessile Serrated Adenoma with High-grade Dysplasia 되어 adenoma-carcinoma sequence라고불리는유전적메커니즘을따라발생한다 [5,9,10]. 반면 serrated pathway는전통적인 adenoma-carcinoma sequence와는달리, BRAF, KRAS 등의돌연변이와관계되는데, 이를통해샘종과는구조적으로다른톱니모양의샘암종전구병변을만든다. Serrated pathway를통한대장암이흔하지는않으나, 산발적인대장암발생원인의 20% 를차지한다. BRAF oncogene은이과정에서가장흔한유전적변이로 high CpG-island methylation phenotype (CIMP-H), high microsatellite instability (MSI-H ) 와연관된다 [11,12]. BRAF 돌연변이는편평톱니샘종과혼합톱니샘종과연관이있는데, 각각 MLH1의표현이결여되어있으며, 전체톱니샘종의 2/3에서발견된다 [13]. 편평톱니샘종은임상적으로중년여성의우측대장에서많이발견되고, 형태학적으로는창백하고납작하며, 확장된샘와의바닥은톱니모양의기하학적구조를보인다 [14]. 전통적톱니샘종은 KRAS 돌연변이와관계되며, 전체톱니샘종의 30% 에서발견된다. 병변은흔히대장왼편의말단부위에많이발생하며, 구조는일반적인샘종과비슷하나샘와의톱니화가적거나줄어든양상을보인다 [15]. 톱니샘종에대한치료는결론이나지않은상태로, 현재까지이런폴립에대한자료가많지않기때문이다. 또한, 톱니샘종의생활사에대해서도밝혀지지않은부분이많다. 아직까지재발률이나, 샘암종으로의진행비율에대해서는구체적으로알려진바없으나, 톱니샘종이대장암과직장암의전암병변이라는것은확실하며 [16-18], 악성화의빈도는약 13% 로보고되고있다 [1]. 따라서일반적인샘종처럼톱니샘종역시치료할것을권장하고있다 [19,20]. 치료에대한권고사항들을보면, 톱니샘종은내시경적으로최대한제거해야하며, 추적관찰을하도록권유하고있다 [21]. 일단완전하게제거한뒤에는내시경시술자의판단과환자의위험요소, 즉폴립의크기와갯수, 대장암의과거력이나가족력등에따라추적관찰기간을차별화할수있다. 왼쪽대장이나말단에서발견되는톱니샘종은대부분크기가작으므로용종절제를통해제거할수있으며, 병변의수와크기, 이형성을고려하여 1년에서 10년간격으로추적내시경을시행하도록권유하고있다 [21-23]. 본증례의경우, 국소적인고도의이형성을보이는병변으로내시경시술을통해완전절제가되어추가적인치료는필요하지않지만, 대장내시경추적은치료후최소 1년내에시행해야한다 [24]. 톱니샘종에서발생한샘암종의장기생 존율은일반적인대장샘암종과비슷한것으로알려져있으며, 근위부톱니샘종에서발생한샘암종이원위부톱니샘종에서발생한샘암종보다예후가좋다고보고되었다 [3]. 이번증례는구불결장의이형성을동반한톱니샘종을내시경점막하박리술로치료하였는데, 톱니샘종에서발생하는대장샘암종의빈도가향후증가할것으로기대되므로이에대한내시경의사들과병리의사들의관심이필요하다. 참고문헌 1. Longacre TA, Fenoglio-Preiser CM. Mixed hyperplastic adenomatous polyps/serrated adenomas: a distinct form of colorectal neoplasia. Am J Surg Pathol 1990;14: Fenoglio CM, Pascal RR. Colorectal adenomas and cancer: pathologic relationships. Cancer 1982;50: Makinen MJ, George SM, Jernvall P, Makela J, Vihko P, Karttunen TJ. Colorectal carcinoma associated with serrated adenoma: prevalence, histological features, and prognosis. J Pathol 2001;193: Aust DE, Baretton GB. Serrated polyps of the colon and rectum (hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed polyps)-proposal for diagnostic criteria. Virchows Arch 2010;457: Torlakovic E, Snover DC. Serrated adenomatous polyposis in humans. Gastroenterology 1996;110: Goldstein NS, Bhanot P, Odish E, Hunter S. Hyperplasticlike colon polyps that preceded microsatellite-unstable adenocarcinomas. Am J Clin Pathol 2003;119: Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 2010; 138: Snover DC. Update on the serrated pathway to colorectal carcinoma. Hum Pathol 2011;42: Leggett BA, Devereaux B, Biden K, Searle J, Young J, Jass J. Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 2001;25: Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med 1988;319: Chan TL, Zhao W, Leung SY, Yuen ST. BRAF and KRAS mutations in colorectal hyperplastic polyps and serrated adenomas. Cancer Res 2003;63: Koinuma K, Shitoh K, Miyakura Y, Furukawa T, Yamashita Y, Ota J, et al. Mutations of BRAF are asso- THE EWHA MEDICAL JOURNAL 47

5 Ewha Med J Vol. 35, No. 1, 2012 ciated with extensive hmlh1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer 2004;108: Iino H, Jass JR, Simms LA, Young J, Leggett B, Ajioka Y, et al. DNA microsatellite instability in hyperplastic polyps, serrated adenomas, and mixed polyps: a mild mutator pathway for colorectal cancer? J Clin Pathol 1999;52: Jass JR. Hyperplastic-like polyps as precursors of microsatellite-unstable colorectal cancer. Am J Clin Pathol 2003;119: Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM. Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 2003;27: Sheridan TB, Fenton H, Lewin MR, Burkart AL, Iacobuzio-Donahue CA, Frankel WL, et al. Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions "caught in the act". Am J Clin Pathol 2006;126: Gurudu SR, Heigh RI, De Petris G, Heigh EG, Leighton JA, Pasha SF, et al. Sessile serrated adenomas: demographic, endoscopic and pathological characteristics. World J Gastroenterol 2010;16: Lu FI, van Niekerk de W, Owen D, Tha SP, Turbin DA, Webber DL. Longitudinal outcome study of sessile serrated adenomas of the colorectum: an increased risk for subsequent right-sided colorectal carcinoma. Am J Surg Pathol 2010;34: Snover DC. Serrated polyps of the large intestine. Semin Diagn Pathol 2005;22: Snover DC, Jass JR, Fenoglio-Preiser C, Batts KP. Serrated polyps of the large intestine: a morphologic and molecular review of an evolving concept. Am J Clin Pathol 2005;124: Bauer VP, Papaconstantinou HT. Management of serrated adenomas and hyperplastic polyps. Clin Colon Rectal Surg 2008;21: Noffsinger AE. Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol 2009;4: Winawer SJ, Zauber AG, Fletcher RH, Stillman JS, O'Brien MJ, Levin B, et al. Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society. Gastroenterology 2006;130: Rex DK, Kahi CJ, Levin B, Smith RA, Bond JH, Brooks D, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and US Multi-Society Task Force on Colorectal Cancer. CA Cancer J Clin 2006;56: THE EWHA MEDICAL JOURNAL

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untitled 대한내과학회지 : 제 71 권부록 3 호 2006 거치상선종에서발생한대장의점액성선암 2 예 부산대학교의과대학내과학교실 정효진 김태오 김광하 허정 강대환 송근암 조몽 =Abstract= Two cases of colonic mucinous adenocarcinoma originating from serrated adenomas Hyo Jin Jung, M.D.,