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1 측방발육형종양의병리학적및분자생물학적특성 국립암센터병리과 장희진 서 론 소화기계의표재성종양은발육형태상크게용종형과비용종형으로나누고있으나, 내시경학적으로비용종형은다시편평형과궤양형으로나누며, 편평형은다시표면융기형, 표면편평형, 표면함몰형으로세분하고있다. 1 대장점막의표재성병변중 94% 가용종형또는표면융기형으로, 나머지유형은 6% 미만으로보고되고있다. 2 Kudo는편평형의종양중장벽을기준으로수직방향이아닌수평방향, 즉장내강을따라측방으로성장하는종양은비교적크기가커도점막하침윤은비교적드물기때문에내시경적절제가가능하다는사실에주목하여이들을 측방발육형종양 (laterally spreding tumor; LST) 으로분류할것을제안한바있다. 3 측방발육형종양은내시경적으로절제된대장의선종의약 2% 를차지하는드문병변이나, 4 Kudo의보고이후로일본을중심으로측방발육형종양에대한관심이높아져이종양에대한임상병리학적연구및분자생물학적연구가이루어져왔으며, 본연제에서는이들연구결과에대한문헌고찰을위주로측방발육형종양의병리학적및분자생물학적특성에대해살펴보기로한다. 본 론 LST의정의와분류 LST는대장의내강을따라측방으로성장하며, 높이가낮은 10 mm 이상크기의종양을일컫는다. 3 유사한병변에대해서 carpet lesion, 5 creeping villous tumor, 6 granular cluster type, assembled nodular type, short villous tumor, large flat tumor 7 등의명칭으로보고된바있으나, Kudo의기술이후로현재는 LST라는용어가일본및국내에서는보편적으로사용되고있다. 그러나서구에서는아직까지 LST의정의및분류가타 Subtypes of LST Classification of type 0 Granular (LST-G) Homogenous Nodular mixed Nongranular (LST-NG) Elevated Pseudodepressed Table 1. LST 의분류 * 76 0-IIa 0-IIa, 0-Is+IIa, 0-IIa+Is 0-IIa 0-IIa+IIc, 0-IIc+IIa *Kudo S et al, Gastrointestinal Endoscopy 2008; 68: S3-S47 (reference 9).

2 장희진 : 측방발육형종양의특성 유형의종양과혼돈될수있다는점을들어비용종형종양에포함시키고있다. 1,2 LST는점막형태에따라과립결절형또는고르지않은표면을보이는 과립형 과편편하고매끄러운표면을보이는 비과립형 으로분류된다. 8 최근에는다시과립형을 균질형 (homogenous type) 과 결절혼합형 (nodular mixed type), 그리고비과립형은 융기형 (elevated type) 과 가성함몰형 (psedodepressed type) 으로세분하고있으며 (Table 1) 9, 결절혼합형에서결절의크기가큰경우와가성함몰형에서는점막하침윤및악성화가능성이각각높다는보고들이발표되고있다 그러나, LST의세분류기준은형태학적인소견에의존하고있기때문에가성함몰형 LST의경우일반적인표면함몰형병변과의감별이어렵다는지적이나오고있으나, 전자의경우함몰된부위의경계가불분명하며종양의변연부에서위족과같은형태를보이는반면후자의경우함몰된부위의경계가보다명확하다고기술되어있으며, 4,10 조직학적으로도전자는치환성성장을보이는반면후자는팽창성성장을보이는것으로보고되어있다. 4 LST 의병리 LST는직장및 S자결장, 그리고맹장및상행결장에호발하는것으로보고되어있다. 12,13 LST의정의자체가내시경적육안소견이므로조직학적으로일반적인용종형혹은비용종형병변과다름없이관상, 관융모상, 융모상, 거치상 (serrated) 선종및선암종까지다양한병변을보일수있으나, 11,14 대다수의 LST 관련연구가일본에서이루어졌고, 거치상선종의개념이서구에서먼저소개되어최근정의및분류가정착되어가고있는단계이기때문에보고된 LST 관련연구결과에서거치상선종의빈도는매우낮으며, 실제로거치상용종의진단이간과되었을가능성이있다. 2002년에발표된류등의연구결과에의하면 46예의 LST의 65% 에서관상선종, 26% 에서관융모상선종, 9% 에서융모상선종성성분이관찰되었던반면에, 년에발표된 Takahashi 등의연구결과에는 101예의 LST 중 3예 (3%) 의거치상선종이포함되어있다. 14 전체 LST에서고도이형성및악성화의빈도는연구자간각각 20 50%, 4 60% 로큰차이를보이고있는데, 11-13,15 이는대상환자군의차이및병리의사의진단기준의차이등에의할것으로추정된다. LST의육안분류즉과립형과비과립형으로나누어비교해보았을때과립상 LST의크기가 mm 로비과립형 LST (24 26 mm) 에비해크지만 11,15,16 침윤암의발생빈도는비과립형에서높은것으로보고되어있다 (Table 2). 11,16 가성함몰형의 LST와함몰형 (IIc, IIc+IIa, IIa+IIc) 종양의임상병리학적특성을비교한연구에서가성함몰형 LST 16예중 14예 (87%), 함몰형종양 14예중 14예 (100%) 에서악성화가관찰되었는데, 가성함몰형 LST 는함몰형에비하여크기가컸으나 ( 가성함몰형 LST 13.5 mm vs. 함몰형종양 11.2 mm) 침윤깊이는상대 LST subtype Table 2. LST 의분류에따른악성화의빈도 Ryu et al Hurlstone et al (n=46) Ref. 11 Ref. 16 (n=82) ptis+pt1 carcinoma pt1+pt2 carcinoma Granular 5/31 (16%) 29/56 (52%) Homogenous 2/17 (12%) Nodular mixed 3/14 (21%) Nongranular 4/15 (27%) 23/26 (88%) 77

3 적으로낮아가성함몰형 LST에서발생한암종의 71% 가 ptis, 29% 가 pt1 (sm1) 였던반면에, 함몰형종양은 ptis가 21%, pt1이 79% 로이중 sm3 침윤암이 64% 였다. 4 LST 의분자생물학적특성 LST에대한분자생물학적연구는주로일본에서이루어졌으며, 서구문헌에서는편평형 (flat) 혹은비용종형 (nonpolypoid) 대장종양을대상으로한연구결과들도보고되어있지만 편평형혹은비용종형에는 LST외에다른병변도포함되므로본연제에서는 LST에관한연구결과만국한시키도록한다. LST에대한분자생물학적연구는 K-ras 돌연변이, 메틸화분석 14,19,20 등이주로이루어졌으며, 그외 p53 돌연변이, 17 β-catenin, 20 Matrix metalloproteinase-7 (MMP-7), 21 cyclooxygenase-2 (COX-2), 18 gastrin 18 등에대한면역조직화학적발현에대한연구결과가발표되었으며, 그결과는 Table 3에요약되어있다. K-ras 돌연변이가 LST에서융기형선종에비해높다는결과가있으나, 18,19 또다른결과에서는 IIa 형에비해서는높으나용종형에비해서는높지않은것으로나타났다. 17 또한 LST를과립형과비과립형으로나누어융기형선종과비교분석한연구결과에서는과립형 LST가비과립형 LST나융기형선종에비하여유의하게높다는결과가 Mukawa 등 18 과 Hiraoka 등 19 에의해발표되었다 (77 78% in LST-G vs % in LST-NG vs % in protruded adenoma). 메틸화분석도 LST 유형을나누어융기형선종과비교분석한연구결과가 Nosho 등 14 과 Hiraoka 등 19 에의해발표되었는데, Hiraoka 등의결과에서는과립형에서비과립형 LST나융기형선종에비하여 CpG island methylator phenotype (CIMP)-high의빈도가유의하게높은것으로나타났으나 (61% in LST-G vs. 8% in LST-NG vs. 25% in protruded adenoma), 19 Nosho 등의결과에서는 CIMP-low와 CIMP-high의빈도는세그룹간차이가없었으며 CIMP-0 (no methylator phenotype) 의경우오 Table 3. LST 에서분자생물학적연구결과요약 Frequency in LST Mutation K-ras BRAF p53 β-catenin Methylation MGMT CDKN2A (p16) MLH1 CACNA1G CRABP1 NEUROG1 CIMP*-0 CIMP-low CIMP-high Immunohostochemistry β-catenin MMP-7 COX-2 Gastrin *CpG island methylator phenotype % Ref % Ref.20 25% Ref.17 3% Ref.20 28% Ref % Ref.14,19, % Ref.14,19 25% Ref.14 36% Ref.14 34% Ref % Ref % Ref.14, % Ref.14,19 20% Ref.21 13% Ref.21 58% Ref.18 53% Ref.18 78

4 장희진 : 측방발육형종양의특성 히려과립형 LST에서많은것으로나타났으며, 14 Takahashi 등도 LST에서는융기형선종에비하여메틸화가드물다고보고하였다. 20 이와같이메틸화에대한연구결과가서로상이하게나온이유는분석한유전자가다르고, CIMP-high와 CIMP-low에대한분류기준도상이했으며, 거치상선종의포함유무도달랐기때문으로추정되기때문에 LST에서메틸화에대한분석결과는추가연구가필요하다. 요 약 LST는내시경적소견에의한진단이우선되는병변으로서점막표면형태및발육양상에따라과립형과비과립형으로나뉘나두유형간의병리학적및분자생물학적특성을고려해볼때서로다른악성화과정을밟는상이한 (heterogenous) 종양일가능성이있으며, 따라서두유형에대한치료도달라야할것으로생각된다. 참고문헌 1. The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon. Gastrointest Endosc 2003;58(Suppl 6):S Endoscopic Classification Review Group. Update on the Paris Classification of superficial neoplastic lesions in the digestive tract. Endoscopy 2005;37: Kudo S. Endoscopic mucosal resection of flat and depressed types of early colorectal cancer. Endoscopy 1993;25: Ohno Y, Terai T, Ogihara T, Hirai S, Miwa H. Laterally spreading tumor; Clinicopathological study in comparison with the depressed type. J Gastroenterol Hepatol 2001;16: Rubesin SE, Saul SH, Laufer I, Levin MS. Carpet lesions of the colon. Radiographics 1985;5: Strekalovsky VP, Odaryuk TS, Veselov VV. Endoscopic surgery for creeping villous tumors of the colon. Gastroenterol Endosc 1986;28: Hurlstone D, Korulla C, Lobo A. Colorectal laterally spreading tumors: clinical evaluation and endoscopic strategies updated. J Gastroenterol Hepatol 2002;17: Okamoto T, Tanaka S, Haruma K, et al. Clinicopathologic evaluation on colorectal laterally spreading tumor (LST). Nippon Geka Gakkai Zasshi 1996;93: Kudo S, Lambert R, Allen J, et al. Nonpolypoid neoplastic lesions of the colorectal mucosa. Gastrointest Endosc 2008; 64:S3-S Kudo S, Takemura O, Ohsuka K. Flat and depressed types of early colorectal cancers: From east to west. Gastrointest Endoscopy Clin N Am 2008;18: Ryu KH, Jang JY, Cha SW, et al. Clinicopathologic characteristics of laterally spreading tumors in colorectum. Korean J Gastrointest Endosc 2002;25: Saito Y, Fujii H, Kondo H, et al. Endoscopic treatment for laterally spreading tumors in the colon. Endoscopoy 2001;33: Su MY, Hsu CM, Ho YP, et al. Endoscopic mucosal resection for colonic non-polypoid neoplasms. Am J Gastroenterol 2005;100: Nosho K, Yamamoto H, Takahashi T, et al. Correlation of laterally spreading type and JC virus with methylator phenotype status in colorectal adenoma. Hum Pathol 2008;39: Hurlstone DP, Sanders DS, Cross SS, et al. Colonoscopic resection of lateral spreading tumours: a prospective analysis of endoscopic mucosal resection. Gut 2004;53: Tanaka S, Haruma K, Oka S, et al. Clinicopathologic features and endoscopic treatment of superficially spreading colorectal neoplasms larger than 20 mm. Gastrointest Endosc 2001;54: Noro A, Sugai T, Habano W, Nakamura SI. Analysis of Ki-ras and p53 gene mutations in laterally spreading tumors of the colorectum. Pathol International 2003;53:

5 18. Mukawa K, Fujii S, Takeda J, et al. Analysis of K-ras mutations and expression of cyclooxygenase-2 and gastrin protein in laterally spreading tumors. J Gastroenterol Hepatol 20051;20: Hiraoka S, Kato J, Tatsukawa M, et al. Laterally spreading type of colorectal adenoma exhibits a unique methylation phenotype and K-ras mutations. Gastroenterology 2006;131: Takahashi T, Nosho K, Yamamoto H, et al. Flat-type colorectal advanced adenomas (laterally spreading tumors) have different genetic and epigenetic alterations from protruded-type advanced adenomas. Mod Pathol 2007;20: Hashimoto S, Higaki S, Amano A, et al. Relationship between molecular markers and endoscopic findings in laterally spreading tumors. J Gastroenterol Hepatol 2007;22: Uronis JM, Herfarth HH, Rubinas TC, Bissahoyo AC, Hanlon K, Threadgill DW. Flat colorectal cancers are genetically determined and progress to invasion without going through a polypoid stage. Cancer Res 2007;67: Postma C, Hermsen MA, Coffa J, et al. Chromosomal instability in flat adenomas and carcinomas of the colon. J Pathol 2005;205: Richter H, Slezak P, Walch A, et al. Distinct chromosomal imbalances in nonpolypoid and polypoid colorectal adenomas indicate different genetic pathways in the development of colorectal neoplasms. Am J Pathol 2003;163: van Wyk R, Slezak P, Hayes VM, et al. Somatic mutations of the APC, KRAS, and TP53 genes in nonpolypoid colorectal adenomas. Genes Chromosomes Cancer 2000;27:

549_561_특집- 장동경

549_561_특집- 장동경 DOI: 10.5124/jkma.2010.53.7.549 pissn: 1975-8456 eissn: 2093-5951 http://jkma.org Focused Issue of This Month Endoscopic Diagnosis and Treatment of Colorectal Cancers Dong Kyung Chang, MD Department of