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1 The Korean Journal of Gastrointestinal Endoscopy Case Report 십이지장샘암종과동반된악성췌관내유두상점액종양 1 예 박경석ㆍ조재희ㆍ박태운ㆍ고근준ㆍ우명렬ㆍ정진호 * ㆍ오화은 관동대학교의과대학내과학교실, * 외과학교실, 병리학교실 A Case of Malignant Intraductal Papillary Mucinous Neoplasm of the Pancreas with Duodenal Adenocarcinoma Kyoung Suk Park, M.D., Jae Hee Cho, M.D., Tae Woon Park, M.D., Geun Jun Ko, M.D., Myoung Lyeol Woo, M.D., Jin Ho Jeong, M.D.* and Hwa Eun Oh, M.D. Departments of Internal Medicine, *Surgery and Pathology, College of Medicine, Kwandong University, Goyang, Korea Intraductal papillary mucinous neoplasm of the pancreas (IPMN) is a precancerous lesion with a well-described adenocarcinoma sequence. The rate of progression of IPMN appears to be very slow; however, patients with IPMN may be at increased risk for extrapancreatic malignancies. A 55-year-old female was diagnosed with IPMN of the pancreas and a duodenal polyp in After an approximate 3 year loss to follow-up, she was readmitted for managing abdominal pain and underwent Whipple s operation. Herein, we report a case of a patient with malignant IPMN accompanied by duodenal adenocarcinoma arising from a duodenal polyp. (Korean J Gastrointest Endosc 2011;42: ) Key Words: Pancreatic neoplasm, Duodenal neoplasm, Multiple primary neoplasms 교신저자. 조재희관동대학교의과대학내과학교실 ( ), 경기고양시덕양구화정동 전화 : 팩스 : 이메일 : jhcho9328@kd.ac.kr 접수 년 12 월 1 일승인 년 4 월 1 일 서론 증례 췌관내유두상점액종양 (intraductal papillary mucinous neoplasm of pancreas, IPMN) 은 1982년에주췌관의확장, 바터팽대부구멍의개방과점액성분비의 3가지특징을가진예후가양호한췌장암이처음보고 1 되면서알려졌다. IPMN은샘종에서샘암종으로분화하는진행이 15년에서 20년으로매우느리고췌장샘암종 (pancreatic ductal adenocarcinoma, PDAC) 보다좋은예후를보인다. 2,3 또다른주목할만한특징은 IPMN 자체가췌장외악성신생물과연관이있다는점이며, 4-12 이러한 IPMN 질환의자연사를고려할경우, 동반신생물에대한조기진단및치료가필요하다. 십이지장의악성신생물은그자체로도드문경우이며 IPMN 과동반된췌장외악성신생물이십이지장에서보고된경우는흔치않기때문에저자들은악성 IPMN과동반된십이지장샘암종 1예를문헌고찰과함께보고한다. 55세여자가 2주전부터발생한우상복부통증을주소로내원하였다. 환자는 4년전에도복통으로주췌관타입의 IPMN으로진단받고수술적치료를권유받았으나, 거부하고자의로추적관찰하지않았다. 6년전부터당뇨병을진단받아 glimepiride 1 mg 투약중이었으며음주및흡연의과거력은없었다. 신체검사에서혈압 100/80 mmhg, 맥박 70회 / 분, 호흡수 20회 / 분, 체온 36.3 o C였고급성병색을보였으며, 의식은명료하였다. 호흡음과심음은정상이었으며복부는부드럽고장음은정상이었으며우상복부에압통은있었으나반발통은없었다. 일반혈액검사에서백혈구 11,200/mm 3 ( 중성구 76.9%), 혈색소 11.5 g/dl, 혈소판 327,000/mm 3 이었으며혈청생화학검사에서나트륨 meq/l, 칼륨 4.3 meq/l, 염소 meq/l, 혈액요소질소 10.1 mg/dl, 크레아티닌 0.9 mg/dl, 혈당 146 mg/dl, 총빌리루빈 1.2 mg/dl, ALT 82 IU/L, AST 215 IU/L, 알칼리포스파타제 449 U/L, γ-gt 1,011 U/L, 아밀라제 12 U/L, 리파아제 14 U/L, CA U/mL, 알파태아단백 The Korean Journal of Gastrointestinal Endoscopy

십이지장 샘암종과 동반된 악성 췌관 내 유두상 점액 종양 1예 박경석 외 Figure 1. Arterial phase of abdomino-pelvic computed tomography (CT).

(B) In 2008, main pancreatic duct was more dilatated and the solid nodule is more enlarged compared to previous CT scan.

내시 경 및 EUS에서 바터 팽대부 하방 1 cm에 점액으로 덮여 있는 이형 반향 용종(heteroechoic polyp)이 있었으며, 그 내부에는 줄기(stalk)가 동반된 혈관성 구조가 있었다.

이후 ERCP와 동시에 조직검사를 시행하 였으며 췌관 조영에서 2004년 췌관조영술과 비교하여 더욱 악 화된 췌관 확장소견과 점액에 의한 담관과 췌관의 충만 결손이 관찰되었다(Fig. 3).

종 괴는 고분화 이형성이 있는 유두모양샘종으로 점막 내 암종으 Figure 2. Endoscopic finding and endoscopic ultrasonography (EUS) findings.

2 십이지장 샘암종과 동반된 악성 췌관 내 유두상 점액 종양 1예 박경석 외 Figure 1. Arterial phase of abdomino-pelvic computed tomography (CT). (A) In 2004, main pancreatic duct was diffusely dilated and solid nodule is on ampulla portion. (B) In 2008, main pancreatic duct was more dilatated and the solid nodule is more enlarged compared to previous CT scan. ng/ml, 혈청 검사에서 CRP는 9.06 mg/dl이었다. 복부 CT에서 이전 영상과 비교하여 췌관 확장의 악화와 바 터 팽대부 부근 용종의 크기가 증가되어 있었다(Fig. 1). 내시 경 및 EUS에서 바터 팽대부 하방 1 cm에 점액으로 덮여 있는 이형 반향 용종(heteroechoic polyp)이 있었으며, 그 내부에는 줄기(stalk)가 동반된 혈관성 구조가 있었다. 또한 주췌관은 18 mm 정도로 확장되어 있었고 내부에 약 9 mm 크기의 벽내 결 절이 있었다(Fig. 2). 이후 ERCP와 동시에 조직검사를 시행하 였으며 췌관 조영에서 2004년 췌관조영술과 비교하여 더욱 악 화된 췌관 확장소견과 점액에 의한 담관과 췌관의 충만 결손이 관찰되었다(Fig. 3). 조직검사에서 십이지장의 종괴는 관상선종 에 중증도의 이형성이 있었으며, 췌관의 조직검사에서는 경도 에서 중증도 이형성을 보이는 IPMN이었다. 악성 십이지장용종 및 악성 IPMN으로 Whipple씨 수술을 하였다. 육안적으로 가 로 4 cm, 세로 2.5 cm, 높이 2 cm의 폴립형태의 종괴가 IPMN 과 약 3 mm의 경계를 두며 관찰되었으며 조직학적으로는 IPMN은 악성 변화가 관찰되며 십이지장 벽과 바터 팽대부와 총담관에 침윤되어 있는 소견이었고 십이지장의 폴립형태의 종 괴는 고분화 이형성이 있는 유두모양샘종으로 점막 내 암종으 Figure 2. Endoscopic finding and endoscopic ultrasonography (EUS) findings. (A) On endoscopy, There is an about 4 cm sized and mucin covered mass on distal 1 cm from ampulla. (B) On EUS, heteroechoic mass has stalk with vascular structure. (C) On EUS, there are 18 mm sized dilation (green crossed line) of main pancreatic duct and 14 mm sized dilation (yellow crossed line) of bile duct. (D) On EUS, there is 9 mm sized intramural node in main pancreatic duct. Vol. 42, No. 4 April, 2011 ( ) 269

Figure 3. Endoscopic retrograde cholangio pancreatography (ERCP) and duodenoscopic findings.

orifice and duodenal mass is located beside the papilla.

(B) In 2008, duodenal mass and papilla are increased in size and orifice of papilla is larger than before.

환자는수술후 18개월이지난현재재발이나특이소견은없었으며주기적으로경과관찰중에있다. 고찰췌장의낭성신생물중하나인 IPMN은그진행이매우느려일반적인췌장샘암종보다좋은예후를보인다고알려져있다.

13 임상적인증상은주로점액성물질이췌관에막혀서발생된만성췌장염의증상이대부분이나무증상인경우도많다. 진단으로는일반적인복부 CT나복부초음파로는감별이어려워 EUS, MRCP, ERCP 등이진단에보조적으로많이사용된다.

낭종이 30 mm 이상커져있는경우, 벽내결절이있는경우에는악성의위험도가증가하여수술적인치료가권고되고있다.

3 Figure 3. Endoscopic retrograde cholangio pancreatography (ERCP) and duodenoscopic findings. (A) In 2004, duodenoscopy shows that the papilla is patulous and resembles a fish-eye with mucus extruding form orifice and duodenal mass is located beside the papilla. The pancreatogram shows multiple filling defects by mucin and pancreatic duct dilation. (B) In 2008, duodenal mass and papilla are increased in size and orifice of papilla is larger than before. On pancreatogram, main pancreatic duct is more dilated compared to previous pancreatogram. 로의변화와고유판침윤도보이고있었다 (Fig. 4). 환자는수술후 18개월이지난현재재발이나특이소견은없었으며주기적으로경과관찰중에있다. 고찰췌장의낭성신생물중하나인 IPMN은그진행이매우느려일반적인췌장샘암종보다좋은예후를보인다고알려져있다. IPMN은해부학적으로침윤된췌관에따라주췌관형과분지췌관형으로나누며주췌관형이전체 IPMN의 75% 정도를차지하며주로췌두부에서시작하여원위부로진행하며분지췌관형보다조직학적으로악성도가더높은것으로되어있다. 13 임상적인증상은주로점액성물질이췌관에막혀서발생된만성췌장염의증상이대부분이나무증상인경우도많다. 진단으로는일반적인복부 CT나복부초음파로는감별이어려워 EUS, MRCP, ERCP 등이진단에보조적으로많이사용된다. IPMN은 3년생존율이 60 80% 로양호하며대개침습적이지않거나진행이매우느려모두수술적인치료가필요하지않으나내시경적으로고도의이형성증이나암종이진단되면수술적인치료가반드시필요하고췌장의주췌관이 10 mm 이상확장된경우, 낭종이 30 mm 이상커져있는경우, 벽내결절이있는경우에는악성의위험도가증가하여수술적인치료가권고되고있다. 14 본증례는주췌관의확장이 18 mm였고, 벽내결절이동반되었으며, 2004년주췌관조영술과비교해악화되어수술이필요하였다. 또다른 IPMN의특징은췌장외악성종양과의병발이많다는점이며아직까지구체적인권고사항은없으나일반적으로위내시경과대장내시경이감별을위해흔히시행되며본증례의경우는병발하는종양을감별하기위해대장내시경과 PET (positron emission tomography) 을시행하여다른부위에병발된종양이없는것을확인하였다. 다발성중복암은 1889년 Billroth가처음으로보고하였고 Billroth가제시한중복암의진단기준은서로다른조직에서 270 The Korean Journal of Gastrointestinal Endoscopy

Figure 4. Gross findings and microscopic findings. (A) The specimen consists of mucin covered duodenal polyp, measuring 4 2.5 2 cm in dimension (red circle).

(C) On section of the main pancreatic duct, the mucin covered duodenal mass (red circle) lies on the 3 mm sized free border on intraductal papillary mucinous neoplasm of

Intraductal proliferation of tall columnar cells and the foci of invasion are noted (H&E stain, 20, 200). Table 1.

Colon (38%), esophagus (10%) 1999 Sugiyama and Atomi 5 42 15 (36%) Colon (33%), stomach (27%) 2000 Yamaguchi et al 6 48 13 (27%) Stomach (38%), liver (13%) 2004 Suzuki et al 7

(25%) 2006 Choi et al 10 61 18 (30%) Stomach (44%), colorectum (22%) 2006 Eguchi et al 11 69 32 (46%) Colorectum (12%), stomach (6%) 2008 Yoon et al 12 210 77 (37%) Stomach

발생한조직학적으로상이한종양이서로다른전이과정을가져야한다는것 15 이었으나현재에와서는일반적으로는 2000년 International Association Cancer Registries에따라서두개이상의원발성종양이각기다른원발병소에발생하여각각이서로에대하여확장, 재발혹은전이가아닌경우로정의하고있다.

4 Figure 4. Gross findings and microscopic findings. (A) The specimen consists of mucin covered duodenal polyp, measuring cm in dimension (red circle). (B) There is papillary intestinal type duodenal adenoma with high grade dysplasia and intramucosal carcinoma change with lamina propria invasion (H&E stain 40, 100). (C) On section of the main pancreatic duct, the mucin covered duodenal mass (red circle) lies on the 3 mm sized free border on intraductal papillary mucinous neoplasm of pancreas and 5 5 cm sized whitish firm tumor (blue circle) is shown on pancreatic head. (D) There are intraductal papillary mucinous carcinomas. Intraductal proliferation of tall columnar cells and the foci of invasion are noted (H&E stain, 20, 200). Table 1. Cases of Extrapancreatic Tumors Associated with IPMN Year Authors Total IPMN Extapancreatic cases malignancy (%) Major associated sites (%) 1996 Jiang et al (71%)* Colon (38%), esophagus (10%) 1999 Sugiyama and Atomi (36%) Colon (33%), stomach (27%) 2000 Yamaguchi et al (27%) Stomach (38%), liver (13%) 2004 Suzuki et al 7 1, (19%) Stomach (33%), colorectum (22%) 2005 Jang et al (5%) Colon (27%), stomach (27%), liver (18%) 2005 Kamisawa et al (35%) Stomach (43%), colon (25%) 2006 Choi et al (30%) Stomach (44%), colorectum (22%) 2006 Eguchi et al (46%) Colorectum (12%), stomach (6%) 2008 Yoon et al (37%) Stomach (38%), colorectum (21%) IPMN, intraductal papillary mucinous neoplasm of pancreas; *Extrapancreatic neoplasm (benign and malignant tumor). 발생한조직학적으로상이한종양이서로다른전이과정을가져야한다는것 15 이었으나현재에와서는일반적으로는 2000년 International Association Cancer Registries에따라서두개이상의원발성종양이각기다른원발병소에발생하여각각이서로에대하여확장, 재발혹은전이가아닌경우로정의하고있다. 16 본증례는십이지장의샘암종과악성 IPMN이육안적으로도약 3 mm의뚜렸한경계가있었으며조직학적으로십이지장샘암종은전체적으로유두모양샘종으로내부에암종으로 의변화가보이고있어 IPMN에의한확장이나전이가아닌샘종에서샘암종으로의변화에의한것으로중복암으로생각하였다. 중복암의발생원인은일반적으로선행유전적결함에의한것이거나이른바 Field carcinogenesis 의개념으로인식되고있다. 17 IPMN의병인및유전적인원인은아직명확하게밝혀진바는없으나 IPMN이췌장외의다른악성종양과병발할확률이높다는것이여러논문에서통계적으로입증되고있다 (Table 1). 1996년 Jiang 등 4 이처음으로 21예의 IPMN환자에서 Vol. 42, No. 4 April, 2011 ( ) 271

5 15명이췌장외의종양과동반되어있음을보고하였고국내에서는 2000년에처음으로 IPMN과동반된위암증례를보고한이후 Jang 등 8 및 Choi 등 10 이여러증례를모아 IPMN과췌장외악성종양의통계적유의성을보고하였으며, IPMN과동반된췌장외악성종양은주로대장암, 위암등의위장관의악성종양이었다. 특히 Eguchi 등 11 은여러가지췌장외악성종양중에특히대장암의발생빈도가통계적으로유의하게많음을보고하였다. 본증례와같이십이지장암과동반된 IPMN 한예를 2008년국내에서 Yoon 등 12 이 77예의보고에서간단하게언급된것이외에는보고가없었다. 십이지장을비롯한소장은악성신생물의발생이드문장기이며 18 정확한분자생물학적이나유전자적원인에대해서는대장암의경우처럼잘알려져있지않으나가족성샘종폴립증 (familial adenomatous polyposis) 과같은유전자배선돌연변이 (germline genetic mutation) 가있는질환에서호발한다. 18,19 최근국내에서 IPMN과연관된췌장외악성종양의배선돌연변이에대한연구 20 에서 P53 및 CDH-1 유전자배선유전자의돌연변이가관련이있으며 IPMN은이러한유전자변이에의해서발생되는다발성종양의하나의표현형일가능성을보여주기도하였다. 본증례는그자체로도드문십이지장의악성종양이 IPMN과동반된것으로이러한배선돌연변이가 IPMN의췌장외악성종양의기전에밀접하게관련되어있다는사실을간접적으로알려주고있으며추후소장의악성신생물의발생기전과 IPMN의췌장외악성종양의발생기전을아는데도도움을줄수있다. 저자들은십이지장악성신생물이악성 IPMN과동반된경우를수술을통해치료하였고 18개월째추적관찰중으로문헌고찰과함께보고한다. 요약 췌관내유두상종양은샘종에서샘암종으로분화하는전암성병변이나그진행이매우느리다. 췌관내유두상종양환자에서췌장외악성신생물의발생빈도가증가되는특징은환자의예후에있어서매우중요하다. 십이지장의악성신생물은그자체로도드문경우이며췌관내유두상종양과동반된췌장외악성신생물이십이지장에서보고된경우는흔치않기때문에저자들은악성 IPMN과동반된십이지장샘암종을수술을통해치료하였고 18개월째추적관찰중인증례를문헌고찰과함께보고한다. 색인단어 : 췌관내유두상종양, 소장의악성신생물, 췌장암 참고문헌 1. Ohashi K, Murakami Y, Maruyama M. Four cases of mucin producing cancer of the pancreas on specific findings of the papilla of Vater. Prog Dig Endosc 1982;20: Sessa F, Solcia E, Capella C, et al. Intraductal papillary mucinous tumours represent a distinct group of pancreatic neoplasms: an investigation of tumour cell differentiation and K-ras, p53 and c-erbb-2 abnormalities in 26 patients. Virchows Arch 1994;425: Z'graggen K, Rivera JA, Compton CC, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg 1997;226: Jiang ZL, Satoh K, Moriizumi S, Shimosegawa T, Koizumi M, Toyota T. An analysis of the diseases associated with mucin-producing tumors of the pancreas. J Jpn Panc Soc 1996;11: Sugiyama M, Atomi Y. Extrapancreatic neoplasms occur with unusual frequency in patients with intraductal papillary mucinous tumors of the pancreas. Am J Gastroenterol 1999;94: Yamaguchi K, Yokohata K, Noshiro H, Chijiiwa K, Tanaka M. Mucinous cystic neoplasm of the pancreas or intraductal papillary-mucinous tumour of the pancreas. Eur J Surg 2000;166: Suzuki Y, Atomi Y, Sugiyama M, et al. Cystic neoplasm of the pancreas: a Japanese multiinstitutional study of intraductal papillary mucinous tumor and mucinous cystic tumor. Pancreas 2004;28: Jang JY, Kim SW, Ahn YJ, et al. Multicenter analysis of clinicopathologic features of intraductal papillary mucinous tumor of the pancreas: is it possible to predict the malignancy before surgery? Ann Surg Oncol 2005;12: Kamisawa T, Tu Y, Egawa N, Nakajima H, Tsuruta K, Okamoto A. Malignancies associated with intraductal papillary mucinous neoplasm of the pancreas. World J Gastroenterol 2005;11: Choi MG, Kim SW, Han SS, Jang JY, Park YH. High incidence of extrapancreatic neoplasms in patients with intraductal papillary mucinous neoplasms. Arch Surg 2006;141: Eguchi H, Ishikawa O, Ohigashi H, et al. Patients with pancreatic intraductal papillary mucinous neoplasms are at high risk of colorectal cancer development. Surgery 2006;139: Yoon WJ, Ryu JK, Lee JK, et al. Extrapancreatic malignancies in patients with intraductal papillary mucinous neoplasm of the pancreas: prevalence, associated factors, and comparison with patients with other pancreatic cystic neoplasms. Ann Surg Oncol 2008;15: Serikawa M, Sasaki T, Fujimoto Y, Kuwahara K, Chayama K. Management of intraductal papillary-mucinous neoplasm of the pancreas: treatment strategy based on morphologic classification. J Clin Gastroenterol 2006;40: Tanaka M, Chari S, Adsay V, et al; International Association of Pancreatology. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006; 6: Billroth T. Die allgemeine chirurgische pathologie und thera- 272 The Korean Journal of Gastrointestinal Endoscopy

6 pie in 51 Vorlesungen: ein handbuch fur Studirende und Arzte, 14 Aufl. Berlin, Germany: G. Reimer, International Association of Cancer Registries. Multiple primaries internal report No. 00/003. Lyon: IARC, Slaughter DP, Southwick HW, smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implication of multicentric origin. Cancer 1953;6: Wheeler JM, Warren BF, Mortenson NJ, et al. An insight into the genetic pathway of adenocarcinoma of the small intestine. Gut 2002;50: Abrahams NA, Halverson A, Fazio VW, Rybicki LA, Goldblum JR. Adenocarcinoma of the small bowel: a study of 37 cases with emphasis on histologic prognostic factors. Dis Colon Rectum 2002;45: Ahn YJ, Jang JY, Lee SE, et al. Germline genetic alterations in intraductal papillary neoplasms associated with extrapancreatic tumors. J Korean Surg Soc 2009;76: Vol. 42, No. 4 April, 2011 ( ) 273

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내시경 conference 부울경소화기내시경학회 6월집담회 고신대학교복음병원소화기내과전임의서광일 F/63 CASE C.C) epigastric pain for 2 wks P. I) 2014.04.16 EGD at LMC adm via OPD for further evaluation. P. Hx) CASE HTN/DM/Hepatitis/Tbc (+/+/-/-) S. Hx) N-S ROS)