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1 CASE REPORT ISSN , The Korean Journal of Helicobacter and Upper Gastrointestinal Research, 2015;15(3): 내시경점막하박리술을시행한환자에서발견된충돌성조기위암과거대 B 세포림프종 1 예 김상선, 김병관, 조아영, 이성희, 신홍식, 윤소희, 조진웅, 주명진 1 예수병원소화기내과, 병리과 1 A Collision Tumor Comprising Early Gastric Adenocarcinoma and Diffuse Large B-cell Lymphoma after Endoscopic Gastric Submucosal Dissection Sang Sun Kim, Byeong Gwan Kim, A Young Cho, Seong Hee Lee, Hong Shik Shin, So Hee Yun, Jin Woong Cho, Myoung Jin Ju 1 Division of Gastroenterology, Department of Internal Medicine, Department of Pathology 1, Presbyterian Medical Center, Jeonju, Korea Concurrence of primary gastric adenocarcinoma and lymphoma have been described very rarely in the literature; its incidence is estimated at 0.08%. To our knowledge, there are no reports about a collision tumor comprising early gastric cancer and diffuse large B-cell lymphoma from the same lesion. The term collision tumor refers to the coexistence of two or more histologically distinct tumors within the same mass with no histologic admixture. A 76-year-old man complained of a 5-month-history of dyspepsia, and underwent esophagogastroduodenoscopy. Endoscopic findings showed a nodular, round, flat mass lesion in the upper body, therefore we performed endoscopic submucosal dissection (ESD). Pathologic findings revealed a well-differentiated adenocarcinoma accompanied by diffuse large B-cell lymphoma without evidence of Helicobacter pylori infection. Conventional CT and PET-CT scans revealed metastatic lymph nodes in the parotid gland, submandibular gland, maxillary gland and the inguinal regions. The pathogenesis of a collision tumor comprising two different cancers is not well understood. In addition, there are no established treatment guidelines in this series. In the current case, the patient underwent ESD for the removal of adenocarcinoma concomitantly with chemotherapy for the management of metastatic lymphoma. (Korean J Helicobacter Up Gastrointest Res 2015;15: ) Key Words: Gastric adenocarcinoma; Lymphoma, large B-Cell, diffuse; Collision; Stomach neoplasms 서 론 위의악성종양중에서선암 (adenocarcinoma) 이 95% 이상을차지하며림프종은 5% 미만이다. 위의림프종은 90% 이상이 B세포림프종이며, 점막연관림프조직림프종 (mucosa-associated lymphoid tissue lymphoma, MALT) 과미만성거대 B세포림프종 (diffuse large B cell lymphoma) 이대부분을차지한다. 위장관에서중복암은흔하지않을뿐아니라위의선암과원발성악성림프종이동시에병발하는경우는 0.08% 로매우드물다. 1 중복암에서조직학적으로다른종양이한장기안에서로독립적으로공존하며조직학적혼합이나이행이나타나지않는것을충돌종양 (collision tumor) 이라하며, 이전에위의각각다른부위에림프종과선암이함께발견된동시성종양 Received: January 20, 2015 Accepted: August 6, 2015 Corresponding author: Jin Woong Cho Department of Internal Medicine, Presbyterian Medical Center, 365 Seowon-ro, Wansan-gu, Jeonju 54987, Korea Tel: , Fax: , jeja-1004@daum.net (synchronous tumor) 의증례는있었으나충돌종양의보고는전세계적으로없었다. 저자들은내시경점막하박리술 (endoscopic submucosal dissection) 로얻어진하나의조직내에선암과미만성거대 B세포림프종의두가지종양이나란히위치한 1예를경험하여문헌고찰과함께보고한다. 증례 76세남자가 5개월전부터소화불량이있었고 3개월전에척추수술을시행한후식욕저하가발생하여타병원에서시행한상부위장관내시경검사에서위체부에종괴가있어본원으로전원되었다. 환자는 25년전담낭결석을동반한담낭염으로담낭절제술을받았고 6년전에심방사이막결손폐쇄술 (atrial septal defect device closure) 을시행한기왕력이있으며복용중인약물은없었다. 활력징후는정상이었고신체검진및가족력에서특이사항은발견되지않았다. 일반혈액검사에서혈색소 12.5 g/dl, 백혈구 4,900/mm 3, 혈소판 190,000/mm 3 이고혈청생화학검사에서 AST 35 IU/L, ALT 21 IU/L, ALP 313 Copyright 2015 Korean College of Helicobacter and Upper Gastrointestinal Research The Korean Journal of Helicobacter and Upper Gastrointestinal Research is an Open-Access Journal. All articles are distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Sang Sun Kim, et al: A Collision Tumor Comprising Early Gastric Adenocarcinoma and DLBCL IU/L, 아밀라아제 131 U/L, 리파아제 77 U/L, 총단백 7.5 g/dl, 알부민 4.

육안적소견에서점막에한정된종양으로판단하여내시경초음파는시행하지않았으며조직검사로인한섬유화로발생할수있는일괄절제의어려움을생각하여사전에조직검사는시행하지않았고 IT-II Knife (Olympus, Tokyo, Japan) 를이용하여내시경점막하박리술로일괄절제하였다 (Fig. 1).

조직검사에서김자염색 (Giemsa stain) 은음성이었고 Epstein Barr virus (EBV) in situ hybridization 검사도음성이었다. 전산화단층촬영및양전자전산화단층촬영검사에서양쪽귀밑샘, 양쪽턱밑샘, 양쪽겨드랑이샘, 서혜부등에림프절이커져있고 FDG 섭취가증가되어림프종의침습이의심되었으며 (Fig.

2 Sang Sun Kim, et al: A Collision Tumor Comprising Early Gastric Adenocarcinoma and DLBCL IU/L, 아밀라아제 131 U/L, 리파아제 77 U/L, 총단백 7.5 g/dl, 알부민 4.2 g/dl 였고대변에서헬리코박터파일로리항원검사 (Helicobacter pylori Ag) 는음성이었다. 상부위장관내시경검사에서위상체부대만에약 3 cm 크기의궤양을동반하지않은결절성의둥글고편평한융기를가진종괴가발견되었다. 육안적소견에서점막에한정된종양으로판단하여내시경초음파는시행하지않았으며조직검사로인한섬유화로발생할수있는일괄절제의어려움을생각하여사전에조직검사는시행하지않았고 IT-II Knife (Olympus, Tokyo, Japan) 를이용하여내시경점막하박리술로일괄절제하였다 (Fig. 1). 병리조직검사에서절제조직의전체크기는 mm였고, mm 크기의분화도가좋은관상선암과함께나란한위치에서로맞닿아 8 6 mm 크기의미만성거대 B세포림프종이함께발견되었으며수직침범깊이는점막고유층까지였고절제변연에잔류병변과림프및혈관침윤은없었다 (Fig. 2). 조직검사에서김자염색 (Giemsa stain) 은음성이었고 Epstein Barr virus (EBV) in situ hybridization 검사도음성이었다. 전산화단층촬영및양전자전산화단층촬영검사에서양쪽귀밑샘, 양쪽턱밑샘, 양쪽겨드랑이샘, 서혜부등에림프절이커져있고 FDG 섭취가증가되어림프종의침습이의심되었으며 (Fig. 3), 왼쪽서혜부림프절에서시행한조직검사에서미만성거대 B세포림프종으로진단되었고추정병기는 Ann Arbor stage IIIA였다. 보호자가원하여타병원으로전원하였으며미만성거대 B 세포림프종의치료를위해 ritiximab,cyclophosphamide, hydroxydaunorubicin, oncovin, prednisolone 항암치료를 6주기까지시행하고완전관해에도달하여경과관찰및추적검사중이다. 고 찰 지난 20년간대부분의선진국에서위암발생률은감소하고있으나여전히암관련사망에있어높은비율을차지하고있다. 이중위점막을구성하는세포에서기원하는선암이 95% 이상을차지하고있으며, 림프종은 5% 미만을차지하고있다. 2 동시성으로위선암과위림프종을가진환자들에서위림프종의 69.6% 는 MALT 림프종으로보고되었으며, 미만성거대 B세포림프종과조기위암이동시에관찰되는예는매우드물어국내외에서 7예가보고되었다. 3-6 조직병리학적으로충돌종양은혼합종양 (composite tumor) 과구분되는데혼합종양은조직학적기원이다른두종양이서로무작위로섞여있는경우이며본증례에서와같이절제조직에서선암과미만성거대 B세포림프종의조직학적으로서로다른두종양이나란히위치하거나한종양위에다른종양이얹혀있는형태로나타나는경우를충돌종양이라하며, 본증례의환자와같이내시경점막하박리술로얻어진위의하나의절제조직에서선암과미만성거대B 세포림프종이동시에충돌성으로발견된경우는세계적으로보고된예가없었다. 선암과미만성거대 B세포림프종과같이조직학적으로관련성이없는종양병변이충돌성으로발생하는것에관한병인은명확히밝혀지지않았으나, Tihan 와 Filippa 7 는신생물이발생하기쉬운유전학적소인을가지고있는것과면역메커니즘이유사하게작용하는종양에서가능하다고하였다. 5 첫번째가설은면역기능의변화를동반하는미만성거대 B 세포림프종은골수, 비장, 흉선등전체림프계통 (lymphatic system) 에침범할수있어서, 악성화에대한면역감시를무력화시킬수있으며, 이는비혈액성악성종양이동시에발생할수있는가능성을증대시킬수있다는것이다. 8,9 일본의한연구는 Fig. 1. Endoscopic findings. (A) It shows nodular round flat elevation in upper body grater curvature. (B) It shows close-up of the lesion after spraying of indigocarmine. (C) Endoscopic submucosal dissection was performed. The specimen size was cm. 183

Korean J Helicobacter Up Gastrointest Res: Vol 15, No

(A) It shows gastric adenocarcinoma arisen from

(B) It shows well differentiated adenocarcinoma with

3 Korean J Helicobacter Up Gastrointest Res: Vol 15, No 3, September 2015 Fig. 2. Pathologic findings. (A) It shows gastric adenocarcinoma arisen from tubular adenoma (H&E, 40). (B) It shows well differentiated adenocarcinoma with hyperchromatic nuclei and increased nucleus-to-cytoplasm ratio (H&E, 400). (C) It shows gastric lymphoma, replacing much of the gastric epithelium (H&E, 20). (D) It shows large neoplastic lymphocytes with prominent nucleoli (H&E, 400). (E) In the immunohistochemical stain, lymphoid cells were positive for CD20 ( 200). (F) Diagram shows gastric lymphoma (arrow) and gastric adenocarcinoma with tubular adenoma (black). 184

4 Sang Sun Kim, et al: A Collision Tumor Comprising Early Gastric Adenocarcinoma and DLBCL Fig. 3. PET-CT shows hypermetabolic lesions in multiple lymph nodes (both parotid, both cervical, both axillae, bilateral mediastinal, portocaval, left gluteal, left external iliac, both inguinal lymph nodes). 림프종과위선암이동시에발생한대부분의환자에서림프종은진행성이고위선암은대부분조기위암이었음을보고하였다. 10 본증례에서도림프종은림프절전이를가진진행성이었고선암은점막에국한된조기위암이었다. 미만성거대 B세포림프종은환자의면역억제상태를유도하고, 이로인해선암과같은추가적인악성종양의발생에중요한역할을했을것으로추정된다. 위에서두암종이동시에발생할수있는두번째가설은공통된병원체에의한정상세포의암성변화가능성이다. 5 동시성으로발생한원발성림프종과위선암에서 H. pylori 감염이확인된경우는동양과서양에서각각 86% 와 72% 를나타내었으며, 이수치는위선암이나 MALT 림프종혹은다른위의원발성비호지킨림프종단독환자감염에서의 H. pylori 감염률과비슷하거나높았다. 3,11 H. pylori 는위선암과 MALT 림프종발생에중요한역할을하며, MALT 림프종은유전자전위및유전자손상이발생하여미만성거대 B세포림프종으로발전하는것으로알려져있다. 12 따라서 H. pylori 는위선암과미만성거대 B세포림프종모두의간접적인공통원인균이될수있다. EBV 또한미만성거대 B세포림프종, 위암, 비인두암등몇몇암과연관성이있는것으로보고되었다. 13 본증례에서는정상조직에서위축성위염과장상피화생의소견이있고조직검사에서선암이확인되었지만 H. pylori 및 EBV 감염의증거는없었다. 동시성으로발견된원발성림프종과선암의치료에대하여확립된치료방법은없다. 최근내시경치료의발전으로림프절 전이가없는조기위암은내시경점막하박리술에의해활발히치료되고있으며 Isomoto 등 14 은조기위암을내시경점막하박리술로치료한환자에서 5년생존율은 97.1% 였으며, 기존위암의표준치료인위절제술과동등한치료성적을보고하였다. 위에서발생한미만성거대 B세포림프종은 MALT 림프종의경우와달리 H. pylori 제균치료만으로완전관해에도달하는경우는많지않아화학요법을표준치료로제시하고있다. 15 본증례는내시경육안소견에서선종이나점막에한정된선암으로생각하고추가적인검사나조직검사없이내시경점막하박리술을이용하여종양을제거하였다. 조직검사에서선암과거대 B세포림프종이발견되고검사를통해림프종의림프절전이가확인되어항암화학요법을시행하였고재발의증거없이완전관해상태에서추적관찰중이다. 위에서선암과림프종이동시에발견되는경우는매우드물며, 특히충돌성으로발견된경우는보고된바가없다. 저자들은내시경점막하박리술후에얻어진조직에서조기선암과미만성거대 B세포림프종이나란히존재하여충돌종양으로진단하고문헌고찰과함께보고한다. REFERENCES 1. Noda T, Akashi H, Matsueda S, Katsuki N, Shirahashi K, Kojiro M. Collision of malignant lymphoma and multiple early adenocarcinomas of the stomach. Arch Pathol Lab Med 1989;113: Freeman C, Berg JW, Cutler SJ. Occurrence and prognosis of extranodal lymphomas. Cancer 1972;29: Hamaloglu E, Topaloglu S, Ozdemir A, Ozenc A. Synchronous and metachronous occurrence of gastric adenocarcinoma and gastric lymphoma: a review of the literature. World J Gastroenterol 2006;12: Park JH, Jang JY, Cho YD, et al. A case of synchronous early gastric cancer and diffuse large B cell lymphoma treated with endoscopic submucosal dissection and chemotherapy. Korean J Gastroenterol 2012;59: Park SY, Eun CS, Byun YS, et al. A case of synchronous double primary cancer of gastric adenocarcinoma and diffuse large B cell lymphoma. Korean J Gastroenterol 2011;57: Lee YJ, Kim YJ, Choi US, et al. A case of advanced gastric adenocarcinoma with synchronous gastric diffuse large B cell lymphoma. Korean J Gastrointest Endosc 2010;40: Tihan T, Filippa DA. Coexistence of renal cell carcinoma and malignant lymphoma. A causal relationship or coincidental occurrence? Cancer 1996;77: Hu XR, Hu YX, Fu HR, et al. Diffuse large B-cell lymphoma with concurrent gastric adenocarcinoma: case report and literature review. J Int Med Res 2011;39: Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks 185

5 Korean J Helicobacter Up Gastrointest Res: Vol 15, No 3, September 2015 after non-hodgkin's lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol 2010; 28: Ishihama T, Kondo H, Saito D, et al. Clinicopathological studies on coexisting gastric malignant lymphoma and gastric adenocarcinoma: report of four cases and review of the Japanese literature. Jpn J Clin Oncol 1997;27: Wotherspoon AC, Isaacson PG. Synchronous adenocarcinoma and low grade B-cell lymphoma of mucosa associated lymphoid tissue (MALT) of the stomach. Histopathology 1995;27: Iwano M, Watanabe N, Matsushima Y, et al. Rapid development of diffuse large B-Cell lymphoma after successful eradication of Helicobacter pylori for gastric MALT lymphoma. Am J Gastroenterol 2006;101: Long HM, Parsonage G, Fox CP, Lee SP. Immunotherapy for Epstein-Barr virus-associated malignancies. Drug News Perspect 2010;23: Isomoto H, Shikuwa S, Yamaguchi N, et al. Endoscopic submucosal dissection for early gastric cancer: a large-scale feasibility study. Gut 2009;58: Raderer M, Valencak J, Osterreicher C, et al. Chemotherapy for the treatment of patients with primary high grade gastric B-cell lymphoma of modified Ann Arbor Stages IE and IIE. Cancer 2000;88:

김범수

김범수 Analysis of Outcomes after Resection of Sarcomatous Hepatocellular Carcinoma Purpose: Sarcomatous hepatocellular carcinoma (HCC) is rare. Therefore, the clinicopathologic characteristics and prognosis