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1 272 대한소화기내시경학회지 2007;35: 다발성점막하종양형태로발현된원발성직장 MALT 림프종 1 예 연세대학교의과대학내과학교실, * 병리학교실, 수원연세내과의원 문희선ㆍ박효진ㆍ이기병ㆍ정인수ㆍ양우익 * ㆍ홍순원 * ㆍ김정환 A Case of Primary Rectal MALT Lymphoma Presented as Multiple Submucosal Tumors Hee Sun Mun, M.D., Hyo Jin Park, M.D., Ki Byung Lee, M.D., In Su Jung, M.D., Woo Ick Yang, M.D.*, Soon Won Hong, M.D.* and Jung Hwan Kim, M.D. Departments of Internal Medicine and *Pathology, Yonsei University College of Medicine, Seoul, Suwon Yonsei Clinic of Internal Medicine, Suwon, Korea 위장관림프종중에서 MALT (mucosa-associated lymphoid tissue) 림프종이가장많다. 위장관 MALT 림프종은위에서가장호발하고위이외의부위에서는드물게발생하는데그빈도는소장, 회맹판, 대장, 식도순으로서대장에생기는 MALT 림프종은드물다. 수술을통해서조직학적인진단이이루어지는경우가많았으나최근에는육안적인소견이많이알려져서내시경검사로진단되는경우가많다. 61 세여자환자가건강검진을목적으로시행한대장내시경검사에서직장에다발성용종이발견되어본원으로전원되었고다발성점막하종양이의심되어내시경용종절제술및조직검사를시행하였다. 병리소견에서전반적인중심세포양세포 (centrocyte-like cell), 림프상피성병변 (lymphoepithelial lesion) 이관찰되었으며면역조직학적검사에서저등급 B 세포 MALT 림프종으로진단되었다. 병기를알아보기위하여시행한복부및흉부전산화단층촬영에서이상소견은보이지않았다. 저자등은다발성점막하종양의형태로발현된원발성직장 MALT 림프종 1 예를치험하였기에보고하는바이다. 색인단어 : 림프종, Mucosa-associated lymphoid tissue, 직장 서 MALT (mucosa-associated lymphoid tissue) 림프종은 1983년 Isaacson과 Wright에의해처음위장관에서기술된 1 이후폐, 갑상선, 유방, 침샘등의위장관이외의장기에도발생할수있다고알려져있다. 2-5 종양세포를면역학적소견과분자생물학적소견으로분류하면변 론 접수 :2007 년 6 월 7 일, 승인 :2007 년 10 월 1 일연락처 : 박효진, 서울시강남구도곡동 우편번호 : 연세대학교영동세브란스병원내과 Tel: , Fax: HJPARK21@yumc.yonsei.ac.kr 연구역 B세포 (marginal zone B cell) 림프종에해당한다. 6 MALT 림프종은위장관에서가장호발하고위장관중에서는대부분이위에서발생하며이외의부위에서는드물게발생한다. 2-5 대장에발생하는원발성악성림프종은전체대장악성종양의 % 로드문질환이며 7,8 이중에서는 MALT 림프종이가장흔하여한보고에의하면약 60% 를차지한다고한다. 9 대장과직장에생긴 MALT 림프종은대개단일성종괴의형태로발생한다. 10 저자등은다발성점막하종양의형태로발현되어대장내시경용종절제술로치료한원발성직장 MALT 림프종 1예를경험하였기에문헌고찰과함께보고하는바이다. 272

2 문희선외 : 다발성점막하종양형태로발현된원발성직장 MALT 림프종 1 예 273 증 61세여자가별다른증상없이외부병원에서건강검진을목적으로대장내시경검사를시행한결과직장에다발성용종이발견되어본원에내원하였다. 과거력에서 4년전에고혈압을진단받고투약치료중이었으며가족력은특이사항이없었다. 내원당시전신쇠약감, 식욕부진, 체중감소, 발열, 오한, 복부통증및배변습관의변화, 배변시출혈등을포함한특이증상은없었다. 활력징후는혈압 120/70 mmhg, 맥박분당 78회, 호흡수분당 20회, 체온 36.6 C 이었으며의식은명료하였고두경부및액와부, 서혜부에림프절종대는없었다. 흉부진찰에서특이소견은없었고복부진찰에서장음은정상이었고압통은없었으며간이나비장은만져지지않았다. 말초혈액검사에서백혈구 6,710/mm 3 ( 호중구 54.9%, 림프구 36.2%, 단핵구 5.7%, 호산구 0.6%), 혈색소 13.1 g/dl, 혈소판 195,000/mm 3 이었으며혈청전해질검사에서 Na 141 meq/l, K 4.1 meq/l, Cl 106 meq/l, 혈청생화학검사에서 BUN 14.3 mg/dl, creatinine 0.8 mg/dl, AST 27 IU/L, ALT 26 IU/L, 총빌리루빈 0.9 mg/dl, alkaline phosphatase 65 IU/L, 총단백 8.1 g/dl, 알부민 5.4 g/dl이었다. 단순흉부촬영에서정상이었고복부및골반강전산화단층촬영및흉부전산화단층촬영에서림프절종대는없었고다른장기에도이상소견은없었다. 대장내시경검사에서직장에다양한크기의다발성점막하종양이진단되어 2회에걸쳐내시경적용종절제술 ( 총 18개 ) 을시행하였다 (Fig. 1). 병리학적소견에서점막하층과점막층에중심세포양세포 (centrocyte-like cell) 가침윤된림프소절 (lymphoid follicle), 점막층에림프상피성병변 (lymphoepithelial lesion) 이관찰되었으며면역조직화학염색에서 CD20, bcl-2는양성이었고 CD3, CD10, cyclin D1은음성이었다 (Fig. 2). 이러한소견을종합하여저등급의 B세포 MALT 림프종으로진단하였다. 환자는내시경용종절제술시행후 7개월째재발의증거없이외래에서추적관찰중이다. 고 MALT 림프종은 1983년 Isaacson과 Wright에의해처음그개념이제시되었고 1 면역학적소견과분자생물학적소견은변연구역림프구로부터유래된비호지킨 례 찰 림프종 (non-hodgkin's lymphoma) 의한종류이며 6 개정된 European-American Lymphoma (REAL)/World Health Organization (WHO) 분류에따라 MALT 형태의림프절외변연구역 B 세포림프종으로분류한다. 11 MALT 림프종이가장호발하는부위는위장관이고 66% 정도로발견되며그외에폐, 방광, 신장, 담낭, 갑상선, 타액선, 흉선, 결막, 유방및피부에생기는 MALT 림프종이보고되었다. 2-5 위장관내에서는위에서가장호발하며위이외의부위에서는드물게발생하고그빈도는소장, 회맹판, 대장, 식도순이다. 12 대장에발생하는원발성악성림프종은전체대장악성종양의 % 로드문질환이며 7,8 이중 MALT 림프종이가장흔하여한보고에의하면약 60% 를차지한다고한다. 9 대장과직장에생긴 MALT 림프종은대개단일성종괴의형태로발생하며본증례에서와같이다발성으로발현하는경우는드물다. 10 장관림프종에서는복부통증, 혈변, 배변습관의변화, 열및체중감소등의증상이있을수있으며장중첩증과복부종괴등의소견이보일수있고상기증상은수일에서수년간나타날수있다. 4,7 그러나 MALT 림프종에서만나타나는특징적인증상은없으며본증례에서도특이증상없이건강검진으로대장내시경검사를시행하여발견하였다. 정확한진단은수술또는내시경검사를통한조직검사로이루어진다. 대장내시경검사는주된진단적도구로서 13 MALT 림프종이점막하조직에만국한되어있는경우도있으므로내시경을이용한조직생검에서는점막하조직을채취하여야한다. 그외말초혈액검사, 단순흉부촬영, 대장조영술, 흉부와복부전산화단층촬영, 골수조직검사및복강경검사등을사용하기도한다. 대부분의대장 MALT 림프종은무경의돌출양또는궤양성병변으로나타나며육안적소견을국한형과범발형두가지형태로나누기도한다. 4,7,10 한연구에따르면상행결장또는맹장에서가장호발하였으며육안소견으로는점막하종양의형태또는용종양병변이많았다고보고하였다. 14 MALT 림프종에서림프상피성병변과중심세포양세포가관찰되며면역조직화학염색에서 CD5, CD10, CD23, cyclin D1은음성으로나타나고 CD19, CD20, CD21, CD35 항원이나타나며 bcl-2 단백질은저등급 MALT 림프종에서양성, 고등급에서는주로음성으로나타난다. 2,6,15 본증례에서는 CD20, bcl-2는양성이었고 CD3, CD10, cyclin D1은음성으로이러한소견을종합하여저등급의 B세포 MALT 림프종으로진단하였다.

274 대한소화기내시경학회지 2007;35:272-276 Figure 1. Colonoscopy.

(B) The tumors are being removed by a snare polypectomy

(A) Massive mucosal and submucosal lymphocytic replacement

(B) In high power view, a few of neoplastic lymphocytes are

lymphoepithelial lesion) (H&E stain, 400).

lymphocytes show immunoreactive for CD20 (black arrow: same

(D) Immunohistochemical stains reveal that neoplastic

3 274 대한소화기내시경학회지 2007;35: Figure 1. Colonoscopy. (A) It shows multiple submucosal tumors in the rectum. (B) The tumors are being removed by a snare polypectomy fashion. Figure 2. Pathologic findings. (A) Massive mucosal and submucosal lymphocytic replacement is seen in lower power view (H&E stain, 40). (B) In high power view, a few of neoplastic lymphocytes are seen within the glandular epithelium (white arrow: lymphoepithelial lesion) (H&E stain, 400). (C) Immunohistochemical stains reveal that neoplastic lymphocytes show immunoreactive for CD20 (black arrow: same lesion of white arrow in Fig. 2B) (CD20, 400). (D) Immunohistochemical stains reveal that neoplastic lymphocytes do not show immunoreactive for CD3 (CD3, 400). (E) Immunohistochemical stains reveal that neoplastic lymphocytes do not show immunoreactive for CD10 (CD10, 400).

4 문희선외 : 다발성점막하종양형태로발현된원발성직장 MALT 림프종 1 예 275 저등급 MALT 림프종은천천히자라며대부분병이말기에이르기전까지는주로국소적인경우가많으며파종도느리게진행되고치료후재발하기까지오랜기간이걸리는것으로알려져있다. 16 따라서국소적 MALT 림프종의치료는근치적절제로완치가가능하며현재수술단독요법이가장많이사용되며, 본증례와같이내시경용종절제술이사용되기도한다. 고등급또는파종성 MALT 림프종의경우수술, 항암화학요법및방사선요법등이사용되지만확실히정해진방법은없다. 2-4,10 위 MALT 림프종에서는 Helicobacter pylori에대해항생제를포함한제균치료를시행한후림프종의관해를이루었다는보고들이많이있다. 2,15,17 직장 MALT 림프종에대한치료법에관해서도몇건의보고가있지만현시점에서표준적치료법은확립되어있지않다. 수술요법의대부분은직장절제술이필요하여환자의삶의질을현저하게떨어뜨리는결점이있어최근에는비수술적인치료를시행하고있다. 방사선요법에관해서유효하다는보고가있고 18 항암화학요법에관해서는 CHOP (cyclophosphamide, hydroxydaunomycin, oncovin, prednisolone) 요법외에 rituximab이나 leustatin 등의새로운약제에대한유효성이확인되었다. 19 또한 H. pylori 양성인직장 MALT 림프종에대하여 H. pylori 제균요법을시행하여개선된증례가있었다. 20 본증례에서는 H. pylori 음성으로제균요법은시행하지않았으며내시경용종절제술을시행하여완치되었고현재까지재발하지않아방사선요법또는화학요법은시행하지않았다. 5년생존율은위 MALT 림프종에서저등급 71%, 고등급 42% 이고장관 MALT 림프종에서는저등급 37%, 고등급 20% 이며병기 (stage), 침습의깊이, 조직학적등급과절제가능성등이중요한예후인자로보고되고있다. 3,4 용종양 MALT 림프종은초기국한형으로있을때발견하면근치적절제로완치가가능하며예후가좋으므로조기진단이중요하겠으며향후조기진단및내시경용종절제술을이용한치료등에내시경술의역할이중요할것으로생각한다. 본증례는다발성점막하종양의형태로발현된원발성직장 MALT 림프종으로서향후추가증례를수집하여치료지침의수립이필요할것으로생각한다. ABSTRACT MALT (mucosa-associated lymphoid tissue) lymphomas are the most common primary gastrointestinal (GI) lymphomas. MALT lymphomas of the GI tract tend to occur most commonly in the stomach, followed by the small intestine, ileocecal area, colon and the esophagus. However, MALT lymphomas of the large intestine are rare. Previously, a diagnosis was commonly established by the surgical specimens but endoscopic biopsy specimens are currently used to make a diagnosis. A 61-year-old woman was found to have multiple submucosal tumors of the rectum during a screening colonoscopy. The tumors were removed by a polypectomy. The histology revealed the diffuse infiltration of centrocyte-like cells and a lymphoepithelial lesion. Immunohistochemical staining confirmed the diagnosis of a low grade B cell lymphoma of the MALT type. No other site of involvement was identified on the CT of the chest, abdomen and pelvis. (Korean J Gastrointest Endosc 2007;35: ) Key Words: Lymphoma, Mucosa-associated lymphoid tissue, Rectum 참고문헌 1. Isaacson P, Wright DH. Malignant lymphoma of mucosaassociated lymphoid tissue. A distinctive type of B-cell lymphoma. Cancer 1983;52: Thieblemont C, Berger F, Coiffier B. Mucosa-associated lymphoid tissue lymphomas. Curr Opin Oncol 1995;7: Cogliatti SB, Schmid U, Schumacher U, et al. Primary B-cell gastric lymphoma: a clinicopathological study of 145 patients. Gastroenterology 1991;101: Radaszkiewicz T, Dragosics B, Bauer P. Gastrointestinal malignant lymphomas of the mucosa-associated lymphoid tissue: factors relevant to prognosis. Gastroenterology 1992; 102: d'amore F, Brincker H, Gronbaek K, et al. Non-hodgkin's lymphoma of the gastrointestinal tract: a population-based analysis of incidence, geographic distribution, clinicopathologic presentation features, and prognosis. Danish Lymphoma Study Group. J Clin Oncol 1994;12: Harris NL, Jaffe ES, Stein H, et al. A revised European- American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: Shepherd NA, Hall PA, Coates PJ. Primary malignant lymphoma of the colon and rectum. A histopathological and immunohistochemical analysis of 45 cases with clinicopathological correlations. Histopathology 1988;12: Jinnai D, Iwasa Z, Watanuki T. Malignant lymphoma of the

5 276 대한소화기내시경학회지 2007;35: large intestine: operative results in Japan. Jpn J Surg 1983; 13: Yatabe Y, Nakamura S, Nakamura T, et al. Multiple polypoid lesions of primary mucosa-associated lymphoid-tissue lymphoma of colon. Histopathology 1998;32: Schmid C, Vazquez JJ, Diss TC, Isaacson PG. Primary B-cell mucosa-associated lymphoid tissue lymphoma presenting as a solitary colorectal polyp. Histopathology 1994;24: Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-airlie House, Virginia, November J Clin Oncol 1999;17: Koch P, del Valle F, Berdel WE, et al. Primary gastrointestinal non-hodgkin's lymphoma: I. anatomic and histologic distribution, clinical features, and survival data of 371 patients registered in the German Multicenter Study GIT NHL 01/92. J Clin Oncol 2001;19: Myung SJ, Joo KR, Yang SK, et al. Clinicopathologic features of ileocolonic malignant lymphoma: analysis according to colonoscopic classification. Gastrointest Endosc 2003;57: Shoji H, Hisashi E, Tomohiro N, et al. Mucosa-associated lymphoid tissue lymphoma occurring in the transverse colon. Digestive Endoscopy 2003;15: Isaacson PG. Gastrointestinal lymphoma. Hum Pathol 1994;25: Chung CH, Kim HG, Park WS, et al. A case of mucosaassociated lymphoid tissue lymphoma of colon as multiple large polypoid lesions. Korean J Gastrointest Endosc 2004;23: Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosaassociated lymphoid tissue type after eradication of Helicobacter pylori. Lancet 1993;342: Tsang RW, Gospodarowicz MK, Pintilie M, et al. Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome. J Clin Oncol 2003;21: Jager G, Neumeiser P, Brezinschek R, et al. Treatment of extranodal marginal zone B-cell lymphoma of mucosaassociated lymphoid tissue type with cladribine: a phase II study. J Clin Oncol 2002;20: Matsumoto T, Iida M, Shimizu M. Regression of mucosaassociated lymphoid-tissue lymphoma of rectum after eradication of Helicobacter pylori. Lancet 1997;350:

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Jkbcs016(92-97).hwp Expression of bcl-2 and Apoptosis and Its Relationship to Clinicopathological Prognostic Factors in Breast Cancer - A Study with Long Term Follow-up correlated with the survival rate.(journal of Korean