The Korean Journal of Gastrointestinal Endoscopy Case Report 대장샘암종과동시에발생한위장의위장관간질종양 이준섭ㆍ정우철ㆍ이강문ㆍ백창렬ㆍ김형진 * ㆍ전경화 * ㆍ조현민 * ㆍ진형민 * 가톨릭대학교의과대학내과학교실, * 외과학교실 Synchronous Incidental Occurrence of Gastric Gastrointestinal Stromal Tumor and Colon Adenocarcinoma Joune Seup Lee, M.D., Woo Chul Chung, M.D., Kang Moon Lee, M.D., Chang Nyol Paik, M.D., Hyung Jin Kim, M.D.*, Kyong-Hwa Jun, M.D.*, Hyeon-Min Cho, M.D.* and Hyung Min Chin, M.D.* Departments of Internal Medicine and *Surgery, The Catholic University of Korea College of Medicine, Seoul, Korea A few cases of gastrointestinal stromal tumor (GIST) synchronous cancers with other malignancies have been reported, such as gastric cancer, pancreatic cancer, renal cell carcinoma, colon cancer, and carcinoid tumor. However, little is known about their coincidence with other tumors with a different histogenesis. A 62-year-old man visited our hospital with generalized weakness and intermittent hematochezia. A colonoscopic examination showed an ulcerating mass in the ascending colon, and a biopsy specimen revealed adenocarcinoma. A lobulated submucosal mass in the gastric fundus was found incidentally during the preoperative staging procedures, including computed tomography (CT) and positron emission tomography-ct. The colon cancer and gastric tumor were removed simultaneously (laparoscopy assisted right hemicolectomy and total gastrectomy). Immunohistochemical studies on the gastric tumor surgical specimen showed that it was CD117 (+) and CD34 (+), and the final diagnosis was a GIST of the stomach. Herein, we report a case of the synchronous occurrence of colon adenocarcinoma and gastric GIST. (Korean J Gastrointest Endosc 2010;41:350-354) Key Words: Gastrointestinal stromal tumor, Colon adenocarcinoma, Synchronous cancer 교신저자. 정우철가톨릭대학교의과대학성빈센트병원내과학교실 (442-723), 경기수원시팔달구지동 93-6 전화 : 031-249-7137 팩스 : 031-253-8898 이메일 : jwchulkr@yahoo.co.kr 접수. 2010 년 8 월 12 일승인. 2010 년 10 월 21 일 서론 위장관간질종양 (gastrointestinal stromal tumor, GIST) 은간엽에서기원하며전체위장관종양의 1% 를차지하는드문종양이다. 조직학적으로세포의구성이불규칙한방추형으로보이기때문에과거에는평활근종혹은평활근육종등으로명명되어왔으나최근카할세포 (interstitial cells of Cajal) 또는그와연관된선조줄기세포 (primitive stem cell) 에서기원하는새로운영역의종양으로알려졌다. 1,2 면역조직화학염색에서는특징적으로 KIT 단백에서 95% 양성이며, CD34 (60 80%), smooth muscle actin (30 40%), S-100 protein (5%), desmin (1 2%) 에서양성을보인다. 3,4 최근문헌에따르면 GIST와위장관의상피성샘암종의동시성혹은이시성발생을보고하고있어그발생의연관관계에 대해주목하고있다. 위샘암종과공존은상대적으로많이있었지만, 5,6 원발성대장샘암종과의공존은매우드물게보고하고있다. 7 특히국내에서는현재까지대장샘암종과동시성혹은이시성발생에대한보고는없었다. 저자들은빈혈과간헐적인혈변으로입원한 62세남자에서우측대장의진행성대장샘암종으로진단하였고, 수술전복부전산화단층촬영에서위의점막하종양을동시에관찰하였다. 이후복강경을이용하여대장암에대한우측결장절제술과복강경보조의전위절제술과림프절절제술을시행하였다. 수술후조직검사와면역조직화학염색에서 CD117과 CD34 양성인위장의위장관간질종양으로진단하여, 동시에발생한대장샘암종과위장관간질종양에대해문헌고찰과함께보고한다. 350 The Korean Journal of Gastrointestinal Endoscopy
증례 62세남자가전신무력감과간헐적인혈변을주소로내원하였다. 최근수개월간 15 kg의체중감소가있었다고하며과거력및가족력에서특이사항없었다. 주 3회소주한병씩 40년간의음주력과하루한갑 40년간의흡연력이있었다. 신체검사에서혈압은 110/60 mmhg, 맥박 80회 / 분, 호흡수 16회 / 분, 체온 36.6 o C이었다. 경부림프절은촉진되지않았고, 흉부청진에서폐, 심음은모두정상이었으며, 우하복부에경한압통이있었으나반발통은없었다. 일반혈액검사에서백혈구 7,900/ mm 3, 혈색소 6.2 g/dl, 헤마토크리트 25.7%, 혈소판 309,000/ mm 3 이었고, 빈혈의형태는평균직혈구의용적과혈색소의농 도가모두감소되어 microcytic hypochomic anemia였다. 혈청생화학검사에서총단백 6.0 g/dl, 알부민 3.6 g/dl, 총빌리루빈 1.0 mg/dl, AST 12 IU/L, ALT 7 IU/L였다. 알칼리인산분해효소와 γ-gtp는각각 217 IU/L와 45 IU/L이었고, 그외 FBS 92 mg/dl, 혈중요소질소 11.5 mg/dl, 크레아티닌 0.7 mg/dl, Na 138 meq/l, K 4.4 meq/l였다. 소변검사는정상이었다. 대장내시경을시행하였고, 우측상행결장에서궤양성종괴가관찰되어진행성대장샘암종이의심되었다. 복부전산화단층촬영에서는결장벽의비후와주변의림프절종대가보였고, 원격전이는관찰되지않았다 (Fig. 1). 조직검사를하였고, 결과는중등도의분화를보인샘암종이었다 (Fig. 2). 대장암의병기를결정하는복부전산화단층촬영에서우연히 4 cm 크기의점 Figure 1. Images of colon cancer in ascending colon. (A) Colonoscopic finding. It reveals a circumferential ulcerating mass lesion in proximal portion of ascending colon. (B) Abdominal CT finding. It shows irregular colonic wall thickening and lymph node enlargement. Figure 2. Microscopic findings of colon biopsy specimen. (A) It shows atypical glandular forming epithelial cells and marked stromal reaction (H&E stain, 100). (B) At high power field, tumor cells exhibit elongated, irregular shaped and nucleus contain coarse hyperchomatin (H&E stain, 400). Vol. 41, No. 6 December, 2010 (350-354) 351
Figure 3. Images of gastric submucosal tumor. (A) Endoscopic finding. It shows a round elevated lesion with smooth surface at gastric fundus. (B) Abdominal CT finding. It shows a 4 cm sized submucosal gastric mass (arrow) containing central necrosis. 하종양은 H&E 염색에서방추세포가관찰되었고 50 HPF (high power field) 당 4개의유사분열이관찰되었다. 면역조직화학염색에서 c-kit, CD34, vimentin에양성이었으며 smooth muscle actin (SMA) 및 S-100은음성이었다 (Fig. 5). 크기와유사분열의정도로저위험도 (low risk) 의위장관간질종양으로진단하였다. 환자는이후 4년간재발없이외래에서추적관찰중이다. 고찰 Figure 4. PET-CT finding. Two focal areas of increased FDG are seen at right colon and gastric fundus. 막하종괴가위의분문부에서관찰되었고, 이후상부위장관내시경을실시하였다. 주위점막과동일한점막으로덮여있고표면은비교적평활한융기성병변으로나타나며, 병변의주변에가교추벽 (bridging fold) 이관찰되어점막하종양의전형적인형태이었다 (Fig. 3). 점막병변은관찰되지않아조직검사는하지않았고수술적절제를결정하였다. 수술전양전자방출촬영 ( 18 F-fluorodeoxyglucose (FDG) positron emission tomography, PET-CT) 을시행하였고, 우측상행결장과위장분문부의종괴에서동시에 FDG가강하게섭취되는 (hot uptake) 양성반응을보였다 (Fig. 4). 수술은복강경보조의우측결장절제술 (right hemicolectomy) 과전위절제술및림프절곽청술을실시하여원인병소를동시에제거하였다. 수술후에조직검사소견에서우측결장의대장샘암종은장막하층 (subserosa) 의침습과주변림프절의전이가관찰되어 Duke C2이고 TNM 분류로는 3기의대장샘암종으로진단하였다. 그리고위장의점막 위장관간질종양은 CD117 antigen으로검출되는 KIT가양성인경우로분류하는데, KIT는 proto-oncogene인 c-kit의단백산물로서세포막에존재하는수용체이다. Tyrosine kinase 활성을가지고있고, KIT의발현은 c-kit 유전자의변이에의해배위자의결합이이루어지지않은상태에서발생한다. 주로종양이형성되는초기에 KIT 수용체의구조적인활성화가일어나면서카할세포는증식하고세포자멸사 (apoptosis) 가억제되어위장관간질종양이발생한다. 8 종양발생에중추적인역할을하는 c-kit 유전자는 chromosome 4q11-21에위치하고, 유전자의변이는 exon 11의거의모든 codon 안에서발생하며, 위장의위장관간질종양의경우에서이유전자의변이가발견되면상대적으로예후는좋은것으로알려져있다. 9,10 그외에도 exon 9, 13, 17에서도유전자의변이가관찰된다. 11 대부분의위장관간질종양은산발적으로발생하지만, 드문경우에서유전적결함에의해발생한다. 그중에서가족성위장관간질종양증후군 (familial gastrointestinal stromal tumor syndrome) 은매우희귀한유전병으로 c-kit의유전자의변이가일어난다. 보통어린나이에발생하고다발로발생하는경향을보인다. 산발적으로발생하는위장관간질종양은종양세포에서만유전자의변이가보이는반면에이유전병에서는종양뿐만아니라몸전체에서 c-kit 유전자의변이를동반하게된다. 12,13 C-kit 유전자이외에도 PDGFRA (platelet-derived growth factor receptor-alpha) 유전자의변이도이증후군을발생하게 352 The Korean Journal of Gastrointestinal Endoscopy
Figure 5. Microscopic findings of the surgical resected gastric specimen. (A) The tumor is cellular and consists of interlacing sheets, whorls and fascicles of uniform spindle cells with elongated nuclei and eosinophilic cytoplasm (H&E stain, 200). (B) The tumor cells have positive reaction for CD117 (immunohistochemical stain, 200). 한다. 14 그외에 Type 1 Neurofibromatosis (von Recklinghausen s disease) 에서는 NF-1 유전자의변이가발생하는데, 고위험군의위장관간질종양과다른상피성종양의발생을증가시킨다. 15 최근들어위장관간질종양과다른악성종양과동시성발생에대해지속적인보고를하고있고, 정확하게알수는없지만수술로확인된위장관간질종양에서다른악성종양과같이발생하는빈도는 14 17% 정도로알려져있다. 16,17 위장관간질종양과함께동시성혹은이시성으로발생하는악성종양으로는위샘암종, 대장샘암종, 악성림프종혹은백혈병, 부인과종양, 전립선암, 유방암, 췌장암혹은췌장의인슐린종, 폐암, 신장암과유암종이다. 또한연부조직에서기원하는육종이동반된경우도있어주목하고있다. 17 이번증례는위장관간질종양과대장암이동반된경우로국내에서는아직보고가없을뿐아니라세계적으로도아직제한된증례보고만있는실정이다. 이렇게동시에발생하는경우에서생각해볼수있는것은아직밝혀지지않은어떤유전자의변이에의해공통적으로일어나는현상으로볼수있지만, 지금까지밝혀진발암기전만으로는두종양사이의연결고리를추측하기가어렵다. 두번째는어떤발암물질이점막과간질에동시에작용하여발암과정을일으켰다는가설이다. 18 이가설은동물실험을통해입증된바있지만, 발생한기관이각각위와대장이라이것또한쉽게받아들이기는어렵다. 진단에있어서도이렇게동반하는악성종양을고려한다면지금까지위장관간질종양진단에중추적인역할을한전산화단층촬영으로는부족할가능성이있다. 따라서양전자방출촬영 이나다른진단적술기를활용해야할것이고, 특히 PET 혹은 PET-CT의사용은이후필수적일수있다. 현재까지 FDG를이용한 PET의위장관간질종양에서의역할에대한대단위의체계적인연구는아직많지않으나, 진단및병기결정에서종양의기능적정보를얻기위해 PET이필요하다는보고들이있다. FDG 음성인위장관간질종양은크기가작고, 균질한밀도를보이는경우가많으며, 전이를동반하는경우가드물어 FDG PET에서 FDG 섭취의여부가악성과양성을예측하는데도움을줄수있다고보고하고있다. 19 또한이번증례와같이동시성혹은이시성으로발생하는다발성원발암을찾는데도움을줄것으로기대한다. 그러나 PET-CT에도한계가있어상부소화기의초기병변일경우에는발견하지못하는수도있다. 국내의연구에서도조기위암에대해발견율이 25.9% 라고보고하였다. 20 따라서위장관종양의발생가능성을고려하면 PET- CT와더불어반드시내시경을시행하여위장관을평가해야할것이다. 이는치료방침을정하고예후를결정하는데중요한역할을할것이다. 앞으로위장관간질종양과다른악성종양에대한관계를명확하게해야하고, 이에따라위장관간질종양의진단에있어서동시성혹은이시성악성종양의선별검사에대한정확한가이드라인이필요할것이다. 요약위장관간질종양과함께동시에위암, 대장암, 췌장암, 신장암과유암종같은악성종양이발생하는것으로보고하고있지 Vol. 41, No. 6 December, 2010 (350-354) 353
만, 현재까지는제한된증례보고이고관련된기전이나원인에대해서는거의알려진것이없다. 이번증례는 62세남자가전신무력감과간헐적인혈변을주소로내원하여대장내시경을실시하였고, 우측상행결장에서궤양성종괴가관찰되었다. 조직검사에서샘암종으로진단되어병기결정을위한복부전산화단층촬영과양전자방출촬영을실시였고, 우연히위장의분문부에 4 cm 크기에점막하종괴가관찰되었다. 복강경을이용한우측결장절제술을실시하였고, 동시에복강경보조의전위절제술과림프절곽청술을실시하였다. 수술후조직검사에서 CD117와 CD34가양성인위장관간질종양으로진단되어대장샘암종과동시에발생한위장관간질종양에대해문헌고찰과함께보고한다. 색인단어 : 위장관간질종양, 대장샘암종, 동시암 참고문헌 1. Sircar K, Hewlett BR, Huizinga JD, Chorneyko K, Berezin I, Riddell RH. Interstitial cells of Cajal as precursors of gastrointestinal stromal tumors. Am J Surg Pathol 1999;23:377-389. 2. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: a consensus approach. Int J Surg Pathol 2002;10:81-89. 3. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 1998;11:728-734. 4. Went PT, Dirnhofer S, Bundi M, et al. Prevalence of KIT expression in human tumors. J Clin Oncol 2004;22:4514-4522. 5. Uchiyama S, Nagano M, Takahashi N, et al. Synchronous adenocarcinoma and gastrointestinal stromal tumors of the stomach treated laparoscopically. Int J Clin Oncol 2007;12: 478-481. 6. Maiorana A, Fante R, Maria Casinaro A, Adriano Fano R. Synchronous occurrence of epithelial stromal tumors in the stomach: a report of 6 cases. Arch Pathol Lab Med 2000;124: 682-686. 7. Efstathios P, Athanasios P, Papaconstantinou I, et al. Coexistence of gastrointestinal stromal tumor (GIST) and colorectal adenocarcinoma: a case report. World J Surg Oncol 2007;5: 96. 8. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 1998;279:577-580. 9. Antonescu CR, Viale A, Sarran L, et al. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res 2004;10:3282-3290. 10. Lasota J, Dansonka-Mieszkowska A, Stachura T. Gastrointestinal stromal tumors with internal tandem duplications in 3' end of KIT juxtamembrane domain occur predominantly in stomach and generally seem to have a favorable course. Mod Pathol 2003;16:1257-1264. 11. Lux ML, Rubin BP, Biase TL, et al. KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. Am J Pathol 2000;16:791-795. 12. Hirota S, Nishida T, Isozaki K, et al. Familial gastrointestinal stromal tumors associated with dysphagia and novel type germline mutation of KIT gene. Gastroenterology 2002;122: 1493-1499. 13. Beghini A, Tibiletti MG, Roversi G, et al. Germline mutation in the juxtamembrane domain of the kit gene in a family with gastrointestinal stromal tumors and urticaria pigmentosa. Cancer 2001;92:657-662. 14. Hirota S, Ohashi A, Nishida T, et al. Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology 2003;125: 660-667. 15. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 2006;30:90-96. 16. Wronski M, Ziarkiewicz-Wroblewska B, Gornicka B, et al. Synchronous occurrence of gastrointestinal stromal tumors and other primary gastrointestinal neoplasms. World J Gastroenterol 2006;12:5360-5362. 17. Liu YJ, Yang Z, Hao LS, Xia L, Jia QB, Wu XT. Synchronous incidental gastrointestinal stromal and epithelial malignant tumors. World J Gastroenterol 2009;15:2027-2031. 18. Sugimura T, Fujimura S, Baba T. Tumor production in the glandular stomach and alimentary tract of the rat by N- methyl-n'-nitro-n-nitrosoguanidine. Cancer Res 1970;30:455-465. 19. Yamada M, Niwa Y, Matsuura T, et al. Gastric GIST malignancy evaluated by 18FDG-PET as compared with EUS-FNA and endoscopic biopsy. Scand J Gastroenterol 2007;42:633-641. 20. Cheon GJ, Kim BI, Lim SM. Role of PET scan in gastric cancer as a diagnostic tool. J Korean Gastric Cancer Assoc 2002;2:184-190. 354 The Korean Journal of Gastrointestinal Endoscopy