CASE REPORTS THE KOREAN JOURNAL OF PANCREAS AND BILIARY TRACT 백인엽 1, 정윤진 1, 박민규 1, 정동형 1, 신동우 1, 권종규 1, 류현욱 1, 박종훈 2 대구파티마병원 1 내과, 2 외과 A Case of Mixed Adenoneuroendocrine Carcinoma in Common Bile Duct In Yub Baek 1, Yun Jin Chung 1, Min Kyu Park 1, Dong Hyong Jeong 1, Dong Woo Shin 1, Jong Kyu Kwon 1, Hyon Uk Ryu 1, Jong Hoon Park 2 Department of 1 Internal Medicine and 2 Surgery, Daegu Fatima Hospital, Daegu, Korea Mixed adenoneuroendocrine carcinoma occurs rarely in the biliary tract. We report a case of mixed adenoneuroendocrine carcinoma of common bile duct, based on the World Health Organization 2010 classification. A 79-year-old woman complained of right abdominal pain for 2 weeks. ERCP and MRCP revealed a narrow common bile duct with upstream dilatation and biopsy of common bile duct suggested only adenocarcinoma. Pancreaticoduodenectomy was performed, and a tumor was composed of both neuroendocrine carcinoma and adenocarcinoma. Immunohistochemically, neuroendocrine components were reactive for cytokeratin and synaptophysin. The neuroendocrine and exocrine components occurred in separate areas of the same lesion. Liver metastasis was developed at 16 months after surgery. The optimal strategy of management of mixed adenoneuroendocrine carcinoma involving the biliary tract is unknown because it is very unusual. However, more cases will be helpful to demonstrate clinical course and make a decision about management plans. key words: common bile duct, mixed adenoneuroendocrine carcinoma 서론 1) 담관은위장관과유사한내배엽기원의신경내분비세포 를가지고있으나, 담관에서발생하는악성종양은대부분 선암 (adenocarcnoma) 이며, 신경내분비암의발생은흔치 않다. 1,2 신경내분비암이원발성으로담관에서생기는경우 는전체의 1% 미만으로보고된다. 3 특히담도계에서선암 과신경내분비암이혼재하는경우는더욱드물고, 지금까 지보고된예들중에서도담관이아닌담낭이나바터팽 대부에서발생한경우가대부분이다. 3-6 Corresponding author. 정윤진대구파티마병원소화기내과 701-600 대구광역시동구신암동 576-31 Tel: 053-940-7191 Fax: 053-954-7417 E-mail: gooddr@hotmail.co.kr 저자들은우상복부통증과황달을주소로내원한 79세여자환자에서담관에발생한혼합신경내분비선암 (mixed adenoneuroendocrine carcinoma) 1예를경험하였기에 WHO 2010 분류에기초하여문헌고찰과함께보고한다. 증례 79세여자가 14일전부터발생한우상복부통증과황달을주소로내원하였다. 신체검사에서환자는만성병색이었으나의식은명료하였다. 혈압 130/80mmHg, 맥박 80 회 / 분, 체온 36.8도로정상이었다. 공막에황달이관찰되었으며복부진찰에서우상복부압통이있었다. 말초혈액검사에서백혈구 9,630 cells/ul, 혈색소 13.2 g/dl, 혈소판 383,000 cells/ul 이었고, 생화학검사에서 AST 192 IU/L, ALT 112 IU/L, ALP 349 IU/L, r-gtp 1160 IU/L, Total bilirubin 3.29 mg/dl, Direct bilirubin 2.87 56
57 Fig. 1. Abdomen CT showed a narrow common bile duct with upstream dilatation. A marked enhancement (arrow) of distal common bile duct was seen. mg/dl 로측정되어담즙정체가의심되었으며, 암표지자검사는 CA 19-9 75.92 U/mL 로상승되어있었다. 복부컴퓨터단층촬영에서간내담관과간외담관이늘어나있었고, 담관내에뚜렷한종괴는보이지않았지만총담관원위부로담관벽의조영이증강되어있었다 (Fig. 1). MRI에서총담관원위부는 T1 강조영상에서약간저신호강도, T2 강조영상에서는고신호강도로보이고동맥기, 문맥기에서간실질보다조영이증가되어보였다. 자기공명담췌관조영술에서는총담관이늘어나있으면서원위부가국소적으로좁아져있었다 (Fig. 2A). 내시경역행성담췌관조영술에서도동일병변이관찰되었다. 겸자를이용하여좁아진원위부담관을조직검사한결과고분화도의선암이진단되었다 (Fig. 2B). 양전자방출단층촬영 (PET) 검사에서는총담관원위부에 FDG 섭취가관찰되었으며다른부위로의전이소견은없었다 (Fig. 3). Fig. 2. (A) Magnetic resonance cholangiopancreatography showed abruptly narrow distal common bile duct with upstream dilatation. (B) Endoscopic retrograde cholangiopancreatography revealed abruptly narrow distal common bile duct with upstream dilatation. Endoscopic naso-biliary drainage tube was inserted. Fig. 3. Mild FDG uptake of distal common bile duct without metastasis on positron emission tomography.
백인엽외 7 인 58 행한복부컴퓨터단층촬영에서간전이가진단되었다. 고찰 Fig. 4. Gross finding showed a narrow distal common bile duct and thickening of the ductal wall (arrow). AJCC 병기 1A 로담관암에준하여유문보존췌십이지장절 제술을시행하였다. 수술후적출된담관을육안적으로관 찰했을때담관에종괴를형성하는부위는없었으며담관 벽이두꺼워져있고내강이좁아져있는것을확인할수 있었다. 담관주위에는림프절이커져있었고 4 개가절제 되었다 (Fig. 4). 광학현미경검사에서는신경내분비암종 과선암, 두종류의세포가관찰되는고등도악성 (high grade malignant) 혼합신경내분비선암으로진단되었다. 두가지구성요소는각각전체암의 30% 이상을차지하고 있었으며서로섞이지않고명확한경계를이루고있었다. 암세포의일부는췌장을침범하고있었다 (Fig. 5). 면역조 직화학검사에서는신경내분비표지자인 synaptophysin 염색에양성반응을보였다 (Fig. 5). 절제된 4 개의담관주 위림프절중 2 개에서전이소견이있었다. 수술후복합항 암치료가필요하다고판단되었다. 그러나환자는전신상태 가불량하고고령인이유로더이상의적극적인치료를원 하지않아외래에서경과관찰하였다. 수술후 16 개월째시 담관에서발생하는종양은대부분선암으로이부위에서발생하는종양의 90% 이상을차지하고있다. 반면, 간외담관에서발생하는신경내분비종양은극히드물며전체신경내분비종양의 0.4% 이하에불과하다. 1 2000 년세계보건기구 (WHO) 에서는소화기관의신경내분비종양의분류를양성고분화- 신경내분비종양 (well-differentiated neuroendocrine tumor), 고분화-신경내분비암종 (well-differentiated neuroendocrine carcinoma), 저분화- 신경내분비암종 (poorly-differentiated neuroendocrine carcnoma), 혼합외분비 -내분비암 (mixed exocrine-endocrine carcinoma) 으로분류하였다. 그러나 2010년개정된 WHO 분류에따르면유사분열의수 (mitotic count) 와 Ki-67 지수를기준으로신경내분비종양 G1 (neuroendocrine tumor grade 1, mitotic count of 2 per 10 high power field(hpf) and/or <2% Ki67 index), 신경내분비종양 G2 (neuroendocrine tumor grade 2, mitotic count 2-20 per 10HPF and/or 3-20% Ki67 index), 신경내분비암종 (neuroendocrine carcinoma, mitotic count of >20 per 10HPF and/or >20% Ki67 index), 혼합신경내분비선암 (mixed adenoneuroendocrine carcinoma) 으로분류하고있다. 3,6,7,8 2010년 WHO 신경내분비종양의분류에따르면 2000년기준으로분류되었던고분화-신경내분비암종과저분화- 신경내분비암종은각각신경내분비암종과신경내분비종양 G1, G2 로분류된다. 혼합신경내분비선암의경우선암과신경내분비종양의각각의구성비가전체의 30% 이상되어야정의할수있는것이 Fig. 5. Microscopic finding : (A) The neuroendocrine and exocrine components occurred in separate areas of the same lesion. Neuroendocrine carcinoma in right side and adenocarcinoma in left side were seen (H&E stain 200). (B) Immunohistochemical staining for synaptophysin was positive in neuroendocrine carcinoma cells. Some synaptophysin-positive cells (arrows) were scattered on the adenocarcinoma cells (synaptophysin 200).
59 특징이라하겠다. 본증례의경우는선암과신경내분비암종이각각전체종양의 30% 이상을차지하고서로다른두종류의세포가명확한경계를가지는충돌종양 (collision neoplasm) 의특징을가진혼합신경내분비선암으로진단할수있다. 7 그리고혼합신경내분비선암에서는신경내분비종양의분화도에따라악성도를나누는데본증례의경우는고등도악성으로분류할수있겠다. 이처럼서로다른두종류의암이발생하게되면발생기전에따라두종류의종양세포가서로섞여서한개의종양을형성하는혼합종양 (composite neoplasm) 과두개의종양이근접하여한장기에동시에발생하는충돌종양 (collision neoplasm) 으로나눌수있다. 혼합종양은동일한전구세포에서기원하였으나분화되면서두가지형태로변한것으로현미경으로관찰하면변환구역 (transitional zone) 이있는것이특징이고충돌종양은각각독립적으로생긴종양이바로옆에위치하기는하지만서로섞이지않고명확한경계가보이는특징을가진다. 1 본증례의현미경사진에서는 H&E 염색을하였을때선암과신경내분비암종이명확한경계를가지고있어충돌종양으로생각되나, 선암으로있는부위에도 synaptophysin 양성세포가하나씩관찰되어동일한전구세포에서기원했을가능성도배제할수없겠다 (Fig. 5). 담관의혼합신경내분비선암은신경내분비세포의분화도가예후및생존율과연관성이있을것으로여겨진다. 한연구에서는분화도가좋은신경내분비종양의경우 5년생존율이 84% 인반면분화도가나쁜신경내분비암종은 5년생존율이 0% 로보고하였다. 9 담낭및바터팽대부를포함하는담도계의혼합신경내분비선암으로진단된 7예에서재발률이 100%, 평균생존기간이 12.2개월이었고, 3 담관에발생한혼합신경내분비선암으로보고된여러증례의임상경과를살펴보면, 각각의병기에따라수술및항암치료, 방사선치료를하였지만평균생존기간은 2년을넘지못하였다. 1,2,10,11 이처럼혼합신경내분비선암의예후가불량한것은주변장기로의침윤가능성이높기때문인것으로생각된다. 혼합신경내분비선암은발견되는예가드물고치료경험이부족하여표준화된지침은없으나, 치료전에분화도에따라서어느구성요소가환자의예후에더큰영향을미칠것인지고려하는것이중요하다. 고분화-신경내분비세포가구성요소인혼합신경내분비선암은선암에준하여치료 하고, 저분화 - 신경내분비세포가구성요소인혼합신경내분 비선암은선암에대한치료와함께저분화 - 신경내분비암 종에준하여치료할것을권한다. 12 신경내분비암종은표 준치료방침이마련되지않은실정으로일반적으로소세포 폐암에준하는항암요법을하고있으며여러항암제사용 에대한연구가활발히이루어지고있다. 13 이처럼앞으로 신경내분비암종의표준화된치료지침에대한더많은연구 가진행되면, 이를바탕으로혼합신경내분비암의치료에도 진전이있을것이라생각된다. 결론적으로담도계의혼합신경내분비암은매우드물게 발생하는질환으로, 임상경과및예후뿐만아니라적절한 치료지침에대해서도향후체계적인연구가필요하다. 저 자들은우상복부통증과황달을주소로내원한 79 세여자 환자에서수술전담관암을의심하여유문보존췌십이지장 절제술을시행하였고, 조직학적고찰을통하여최종적으로 혼합신경내분비선암 (mixed adenoneuroendocrine carcinoma) 으로진단한 1 예를경험하였기에문헌고찰과함께 보고한다. 요약 총담관에서발생하는악성종양은대부분선암이고신 경내분비종양의발생은드물다. 특히선암과신경내분비종 양이동시에발생하는경우는매우드물다. 저자들은담관 에서발생한선암과신경내분비암의혼합종양 1 예를경험 하였으며, 2010 년개정된 WHO 분류에근거하여혼합신경 내분비선암 (mixed adenoneuroendocrine carcinoma) 으 로진단하였다. 색인단어 : 총담관, 혼합신경내분비선암. 참고문헌 1. K Sato, R Waseda, Y Tatsuzawa, et al. Composite large cell neuroendocrine carcinoma and adenocarcinoma of the common bile duct. J Clin Pathol 2006;59:105 107. 2. Kim SH, Park YN, Yoon DS, et al. Composite neuroendocrine and adenocarcinoma of the common bile duct associated with Clonorchis sinensis: a case report. Hepatogastroenterology. 2000;47:942-944. 3. Kim J, Lee WJ, Lee SH, et al. Clinical features of 20 patients
백인엽외 7 인 60 with curatively resected biliary neuroendocrine tumours. Dig Liver Dis. 2011;43:965-970. 4. JA Musialik, MJ Kohut, T Marek, et al. Composite neuroendocrine and adenomatous carcinoma of the papilla of Vater. World J Gastroenterol 2009;15:4199-4200 5. Yannakou N, Rizos S, Parissi-Mathiou P, et al. Mixed (composite) glandular-endocrine cell carcinoma of the gallbladder. HPB (Oxford). 2001;3:7-9. 6. Harada K, Sato Y, Ikeda H, et al. Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs. Virchows Arch. 2012;460(3):281-289. 7. S La Rosa, A Marando, F Sessa et al. Mixed adenoneuroendocrine carcinomas(manecs) of the gastrointestinal tract: An update. Cancers 2012;4:11-30 8. Hamilton SR, Aaltoren LA, WHO classification of tumours of digestive system. 3rd ed. Lyon : The International Agency for research on Cancer;2000. 9. Albores-Saavedra J, Batich K, Hossain S, et al. Carcinoid tumors and small cell carcinomas of the gallbladder and extrahepatic bile duct: a comparative study based on 221 cases from Surveillance, Epidemiology, and End Results Program. Ann Diagn Pathol 2009;13:378-383 10. Motojima K, Furui J, Terada M, et al. Small cell carcinoma of the pancreas and biliary tract. J Surg Oncol 1990;45:164 168. 11. Tanaka M, Shibui S, Nomura K, et al. Brain metastases from adenoendocrine carcinoma of the common bile duct: a case report. Jpn J Clin Oncol 1999;29:252 255. 12. Hervieu V, Scoazec JY. Mixed endocrine tumors. Ann Pathol. 2005;25:511-528. 13. Nakano K, Takahashi S, Yuasa T, et al. Feasibility and Efficacy of Combined Cisplatin and Irinotecan Chemotherapy for Poorly Differentiated Neuroendocrine Carcinomas. Jpn. J. Clin. Oncol. 2012;42:697-703