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1 대한두경부종양학회지제 24 권제 1 호 2008 online ML Comm 신장이식후발생한유두상갑상선암 아주대학교의과대학외과학교실, * 연세대학교의과대학외과학교실 ** 이잔디 * 홍협 * 정종주 ** 남기현 ** 정웅윤 ** 소의영 * 박정수 ** = Abstract = Papillary Thyroid Carcinoma in Renal Allograft Recipients Jandee Lee, M.D.,* Hyeop Hong,* Jong Ju Jeong, M.D.,** Kee-Hyun Nam, M.D.,** Woong Youn Chung, M.D.,** Euy-Young Soh, M.D.,* Cheong Soo Park, M.D.** Department of Surgery,* Ajou University College of Medicine, Suwon, Korea Department of Surgery,** Yonsei University College of Medicine, Seoul, Korea Purpose:The chronic use of immunosuppressive therapy in transplant recipients can increase the long-term risk of carcinoma. The aim of this study was to determine the incidence, biological behaviors, and treatment outcomes in PTC(papillary thyroid carcinoma) in renal allograft recipients. Material and Methods:The present study examined the incidence and biological behavior of PTCs in RA recipients. A total of 1,739 RA patients treated between January 1986 and December 1999 were followed-up for a median 137(84-238) months. During the follow-up period, 129(7.4%) recipients were identified as having posttransplant malignancies. Of those, 12(0.7%) had PTCs, and these comprised six male and six female patients with a median age of 41(23-57) years. Results:Nine cases(incidentalomas) were diagnosed based on ultrasonography(us) screening. Eight of those nine were TNM stage I, and two of the three clinical carcinomas were TNM stage IVa. During a median follow-up of 94(18-159) months, two(16.7%) PTC patients developed loco-regional recurrence, but no patients showed distant metastasis. Posttransplant PTC showed no gender bias, and was often associated with aggressive lymphatic metastasis. However, most incidentalomas showed a favorable treatment outcome. Conclusion:In conclusion, routine surveillance of the thyroid gland using US screening is recommended to ensure early detection, treatment and favorable prognosis in RA patients with PTC. KEY WORDS:Posttransplant malignancy PTC(papillary thyroid carcinoma) Renal allograft. 서 장기이식을받은환자의경우일반인구집단에비해서악성종양의발생빈도가높다고알려져있으며, 신이식의경우이식후악성종양의발생률이약 6~11% 정도로보고되고있다 1-3). 이식환자에서악성종양의발생이빈번한이유는이식장기의거부반응을예방하기위한장기간의면 론 교신저자 : 박정수, 서울서대문구신촌동 134 연세대학교의과대학외과학교실전화 :(02) 전송 :(02) jandee@ajou.ac.kr 역억제제의사용과관계가있으며, 이를뒷받침하는다양한가설들이보고되고있다 1-4). 하지만, 이식후악성종양의발생은암종의종류, 이식장기및면역억제정도등의임상특징과인종및지역적요인등에따라빈도에차이를보이고있다 1)2). 장기이식후흔히발생하는악성종양인피부암및악성림프종등은일반인구집단에비해이식환자에서발생하였을때치료에잘반응하지않고, 경과가불량하다고알려져있다 1-5). 하지만, 위암, 대장암, 유방암, 간암및갑상선암등의다양한고형암 (solid organs malignancy) 의경우에는일반인구집단과비교하였을때이식환자에서임상경과및예후에차이를보이는지에대해서는아직도논란이

2 많은실정이다 1-4). 최근에고해상초음파등의영상학적진단기술의발달로우리나라를비롯한전세계적으로갑상선암, 특히유두상갑상선암이급격히증가하는추세이다 5-7). 하지만, 유두상갑상선암의임상양상및예후에대해서는수많은연구들이발표되고있으나, 이식후발생한유두상갑상선암의특징및치료경과에대해서는아직잘보고된자료가드물다. 이에저자들은단일기관에서약 14년간의경험을통해신장이식후발생한유두상갑상선암의임상양상및치료결과에대해알아보고자하였다. 대상및방법 1. 대상군 1986년 1월부터 1999년 12월까지신촌세브란스병원에서만성신부전으로신장이식을시행한환자는 1,739 예였으며, 신이식후추적관찰기간은평균 137(84~238) 개월이었다. 대상군은신장이식후적어도 6개월이상이식신의기능이유지되어이식전후면역억제제를포함한기본적인처치가이루어진경우만을포함하였다 년 12월 31일을기준으로신이식후발생한종양에대한데이터베이스를통해종양발생빈도를조사한결과, 악성종양이발병한경우는 129예 (129/1,739, 7.4%) 였으며, 이중유두상갑상선암은 12예 (0.7%) 였다. 일반인구집단에대한암발생률에대한자료는국립암센터및국민보험공단자료를참고하였다 8). 대상군의임상병리적특징, 이식신의종류, 면역억제제의종류및기간, 치료방법및치료결과등에대해의무기록및환자면담을통한후향적방법으로진행하였다. 갑상선암의진행정도는제 6판 TNM Cancer Staging Manual 을기본으로하여표기하였다 9). 2. 면역억제제대부분의경우싸이클로스포린및스테로이드병용요법을시행하였으며, 일부에서는타크롤리무스, 셀셒트, 시뮬렉트, 제나팍스등과같은추가적인면역억제제를사용하였다. 갑상선암의진단및수술후에주면역억제제의감량은없었으나항대사제제인임뮤란이나셀셒트등은감량하거나중단하였다. 3. 추적관찰및예후유두상갑상선암의수술범위및방사성요오드치료 ( 131 radioactive iodine therapy) 여부는임상병리적특징, 질병의병기 (TNM staging system), 위험요인 (risk factors) 등에따라결정하였다. 수술후에는 3, 6, 12개월간격으로 이학적검사, 티로글로불린 (thyroglobulin), 항티로글로불린항체 (anti-thyroglobulin antibody), 경부초음파검사를포함한영상학적검사, 및방사성요오드스캔 ( 131 radioactive iodine scan) 등을통해암종의재발여부를판단하였다. 무병생존 (disease-free survival) 은갑상선호르몬제제중단후혈청갑상선자극호르몬 (thyroid stimulating hormone) 이증가된상태에서혈청티로글로불린이 2ng/mL 미만 [ 티로글로불린항체 (-)] 이하로측정되며, 방사성요오드스캔및다른영상학적검사에서재발을의심할만한병변이없는경우로정의하였으며, 혈청티로글로불린이 2 ng/ml 이상이거나영상학적검사상이상병변이있는경우는유병생존 (disesase-realted survival) 로정의하였다. 결 1. 빈도 1,739 예의신이식환자중추적관찰기간동안 129예 (7.4%) 에서암종이발생하였다. 암종의발생빈도는피부암, 자궁경부암, 카포시육종 (Kaposi s sarcoma) 등의순서였으며, 특히피부암의경우는전체신이식환자의 1.8% 의높은빈도로발생하였다. 갑상선암의경우 12예에서발생하였으며, 0.7% 의빈도를보였으며, 일반인구집단의발생률 (0.02%) 와비교하여월등히높은빈도를보였다 (Table 1). 2. 임상병리적특징추적관찰기간동안갑상선암이발생한 12예의환자중 5 예는혈연간생체이식이었으며, 7예는비혈연간혹은뇌사자이식이었다. 남자가 6예여자가 6예로남녀비율에차이가없었으며, 갑상선암진단당시평균연령은 41(23~57) Table 1. Prevalence of malignancy in renal allograft recipients at the Severance Hospital( ) Type of malignancy Number Prevalence(%) Skin carcinoma Cervix carcinoma Kaposi s sarcoma Thyroid carcinoma Stomach carcinoma Colorectal carcinoma Urinary tract carcinoma Malignant lymphoma Breast carcinoma Hepatoma Ovary, uterus carcinoma Lung carcinoma Parotid gland carcinoma Total 과

3 세였다. 대상군중이식후급성거부반응을보인경우는 1예였다. 신이식후유두상갑상선암이진단된시기까지인잠복기 (induction period) 는평균 97(28~217) 개월이었다. 대상군중이식후주기적인검진과정에서경부초음파검사를통해서우연히발견된우연암 (incidental carcinoma) 의경우가 9예 (75%) 였으며, 임상증상의발현으로진단된임상암 (clinical carcinoma) 이 3예 (25%) 였다. 12예모두순수유두상갑상선암종 (pure papillary carcinoma) 였으며, 유두상갑상선암의아형이나미분화형태를보인경우는없었다. 암종의크기는평균 10.5(2~35) mm였으며, 다발성이 3예, 양측성 2예, 피막침습 6예를보였으며, 측경부림프절전이는 5예 (41.7%) 로비교적높은빈도를보였으며, 상위종격동림프절전이를보인경우도 1예있었지만, 원격전이를보인경우는없었다. 각각의병기를살펴보면 stage I이 10예, stage IVa 가 2예를보였다. 3. 치료및예후수술범위는 6예에서는갑상선아전절제술이시행되어졌고, 나머지 6예에서는갑상선전절제술이시행되어졌다. 대상군모두중앙구획림프절청소술 (central compartment node dissection;ccnd) 이시행되어졌으며, 측경부림프절전이를보이는 6예에서는변형측경부광범위림프절청소술 (modified radical neck dissection:mrnd) 이시행되어졌고, 이중종격동까지림프절전이를보이는 1예에서는종격동절개를통한광범위종격동림프절청소술 (mediastinal lymph node dissection) 이시행되어졌다. 갑상선전절제술을시행한 6예모두수술후방사성요오드치료가 추가되었다. 갑상선수술후추적관찰기간은평균 94(18~159) 개월이었다. 추적기간중사망및원격전이는없었으나국소재발이 2예에서관찰되었다. 각각환자의임상병리적특징및치료결과에대해서는 Table 2에정리하였다. 고찰 이식후발생하는악성종양의빈도및임상양상은이식후추적관찰과정에서여전히주요한논쟁의하나가되고있다. 생체장기이식후장기간면역억제상태의유지가암종의발생을야기한다는이론에대한많은구체적인가설들이제기되고있다. 첫째, 장기간면역억제제의사용으로자가면역능이소실되어체세포돌연변이 (somatic mutation) 및바이러스감염을통해악성세포가증식할수있다 10). 둘째, 이식장기즉, 외부동종항원의존재로림프세망조직 (lymphoreticular system) 이만성적인자극을받아암형성을유발한다 11). 셋째, 면역능이억제된숙주의경우종양발생성바이러스에대한감수성이증가한다 12). 넷째, 면역억제제자체가직접적으로돌연변이를일으켜발암과정을유도할수있다 13). 다섯째, 만성적인요독상태 (uremic state) 가체액성 (humoral) 혹은세포매개성 (cell-mediated) 면역체계의불안정상태가지속되어암발생을야기할수있다 14). 장기이식후발생하는악성종양의빈도는다양하게보고되고있으며, 신이식후발생하는악성종양의경우 6~11% 정도로보고되고있다 1-3). 이러한암종의발생은이식후지 Table 2. Clinicopathologic characteristics, treatment methods and treatment outcomes in renal allograft recipients with papillary thyroid carcinoma No. Gender Induction Immunosuppressive /Age(yr) period(months) agents Rejection episode Clinical/Incidental (size, mm) Lymph node metastasis(c, L, M) TNM/Stage 01 M/ AZA+CS+PRN No Clinical (28) C(4/4), L(3/17) T4aN1bM0/ IVa LR Prognosis 02 F/ CS+ATZ+PRN Yes Clinical (16) C(5/6), L(4/19) T3N1bM0/I DFS 03 M/ CS+ATZ+PRN Yes Incidental (2) C(0/3) T1N0M0/I DFS 04 M/ CS+ATZ+PRN No Incidental (3) C(0/4) T1N0M0/I DFS 05 F/ AZA+CS+PRN No Incidental (8) C(0/2) T1N0M0/I DFS 06 F/ AZA+CS+PRN No Incidental (5) C(0/2) T1N0M0/I DFS 07 M/ MDF+CS+PRN No Incidental (6) C(1/7), L(1/23) T1N1bM0/IVa DFS 08 F/ AZA+CS+PRN No Incidental (5) C(0/3) T1N0M0/I DFS 09 M/ CS+ATZ+PRN No Clinical (35) C(16/23), L(8/25), T4aN1bM0/ I LR M(10/15) 10 F/ AZA+CS+PRN No Incidental (5) C(1/1), L(1/16) T1N1bM0/I DFS 11 F/ AZA+CS+PRN No Incidental (6) C(0/1) T1N0M0/I DFS 12 M/ MDF+CS+PRN Yes Incidental (7) C(2/2) T1N1aM0/I DFS AZA:azathioprine, CS:cyclosporine, PRN:prednisolone, ATZ:antithymocyte globulin, Clinical:clinical carcinoma detected by clinical symptoms, Incidental:Incidentaloma detected by screening ultrasonography, C:central compartment lymph node (metastatic lymph node(n) / total resected lymph node(n)), L:lateral cervical lymph node(metastatic lymph node(n) / total resected lymph node(n)), M:mediastinal lymph node(metastatic lymph node(n) / total resected lymph node(n)), LR:local recurrence, DFS:disease-free survival

4 속되는면역억제기간혹은면역억제제의종류에따른작용기전과관계된다고알려져있으나, 상관관계를보이지않는다는주장도있다 3)15). 그외에도암종의종류, 빈도, 지정학적조건, 공여장기의특징, 거부반응여부등의특징들이이식후암발생빈도에영향을미치는지에대해서는다양하게보고되고있으며, 현재까지논란이되고있는부분이다 2)16) 피부암이나악성림프종등의경우일반인구집단에비해이식후발생빈도가월등히높다는점은이미잘알려져있다. 하지만, 위암, 대장암, 유방암, 갑상선암등의다양한고형암의발생빈도가일반인구집단과차이가있는지에대해서는여전히논란이되고있다 2-4)15)16). 저자들의경우신이식후전체암발생률은 7.4% 이며, 대상기간동안가장높은빈도를보인것은피부암으로다른연구보고들과차이가없었다. 하지만, 갑상선암 (0.7%) 및위암 (0.7%) 의경우다른연구결과에비해비교적높은빈도를보였다. 최근에고해상초음파의발달및세침흡인검사를통한진단병리검사결과의정확도가높아지면서갑상선암의빈도가전세계적으로점점증가하는추세이다 5-7). 하지만, 근래에급격히증가하는갑상선암에대해많은연구결과들이있지만, 신이식후발생하는갑상선암의빈도및임상특징에대해서는아직잘알려져있지않다. 지금까지전세계적으로보고된자료에따르면신이식후갑상선암의발생빈도는약 0.02~0.74% 로다양한결과를보였으며, 이는대부분일반인구집단과의비교자료가없어정확한정보를얻기는어렵다 (Table 3) 7)17-20). 가장최근의자료는미국의일반인구집단과의비교연구로, 장기이식환자의경우일반인구집단에비해내분비종양 (endocrine carcinoma) 이 5배이상의높은빈도로발견되었다. 또한, 이연구에서장기이식후 1, 2, 3년의시간이경과함에따라내분비종양의발생빈도가 0.09%, 0.17%, 0.21% 로점차적인증가를보임을제시하였다 3). 저자들의경우대상기간동안갑상선암은약 0.7% 로다른연구보고들에비해비교적높은발생빈도를보였다. 이러한발생빈도의차이는아마도지역적, 인종적요소와관계가있을것으로추정된다. 즉한국의일반인구집단은서구와비교하여위암의유병 률이월등히높으며, 갑상선암도최근에급격히증가하는추세이다 8). 즉, 본연구에서신이식환자들에서갑상선암및위암의발생률이다른보고들과상이하게높은것은우리나라의지역적요인으로질병자체의유병률이높기때문일것으로생각되며, 향후국가적인차원에서대규모의대상군을통해정확한질병발생률을비교할수있을것이다. 장기이식후발생하는악성종양은일반인구에서발생한경우에비해진행이빠르고공격성향을보여치료결과및예후가불량하다는보고들이있지만, 암종의종류에따라여전히논란이되고있다 1-5). 하지만, 신이식후발생한유두상갑상선암에대한치료결과및공격성에대해서는거의보고된바가없다. Pond 등 18) 이최초로신이식후발생한유두상갑상선암을일반인구집단과비교한결과, 신이식후발생한암종의경우남성에서도비교적빈번히발생하며림프절전이빈도가높은특징을보인다고주장하였지만, 치료결과에대한분석은언급되지않았다. 저자들의경우비록일반인구집단과의비교연구는불가능하였지만, 신이식후발생한암종의특징상남녀비가 1:1 로동일하였고, 측경부림프절전이역시 41.7% 의비교적높은빈도를보였다. 또한, 최초진단당시암종이진행된상태로발견된경우는 2예 (stage IVa) 였으며, 나머지경우는모두검진을통한선별경부초음파검사를통해발견된우연암이었다. 조기에발견된유두상갑상선암은신이식후장기간의면역억제제의사용에도불구하고모두양호한치료결과와예후를보였으며, 국소재발을보인경우는진단당시진행된병기로발견된임상암이었다. 즉, 신이식후발생한유두상갑상선암의경우에도조기발견시치료경과및예후가양호하므로, 신이식후주기적인선별경부초음파검사등의치료지침확립을통해암종의조기진단을위한노력이선행되어야겠다. 본연구에서는단일기관에서대규모신이식환자를대상으로추적기간동안발생한유두상갑상선암의임상병리적특징및치료결과를검토하였다. 그러나, 추적관찰기간이짧고, 대상군이적으며후향적인방법을선택한연구의제한점이있지만, 현재까지장기이식후발생하는갑상선암의 Table 3. Thyroid carcinoma in renal allograft recipients Author(year) Number Prevalence of thyroid Carcinoma in renal allograft recipients (%) Pathology Induction period:mean (months) Prevalence in general population (%) Wang et al. (2006) 17) Pond et al. (2005) 18) P 1 (13), M 2 (4), U 3 (5) Samhan et al P(4) 58 - (2005) 19) Hoshida et al (2004) 20) Veroux et al. (2004) 2) P(1) - - Nemes et al. (2000) 7) P(4) 38 - P 1 :papillary carcinoma, M 2 :medullary carcinoma, U 3 :undifferentiated thyroid carcinoma

5 빈도및치료결과에대한우리나라의보고가없으므로향후대규모연구의기초가될수있는예비보고라는점에서의미있는자료가될수있을것이다. 결 신이식후발생하는유두상갑상선암은일반인구집단에비해높은빈도로발생한다. 신이식후발생하는유두상갑상선암은남녀비에차이가없으며, 측경부림프절전이의빈도가높은특징을보였다. 신이식후선별초음파검사상주로발견되는갑상선우연암의경우장기적인면역억제치료에도불구하고초기에발견되며치료경과및예후가우수하다. 따라서신이식후주기적인경부초음파검사를통해서갑상선암의조기발견에대한치료지침이필요할것으로생각된다. 중심단어 : 이식후발생한악성종양 유두상갑상선암 신장이식. 론 References 1) London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP: Risk of neoplasia in renal transplant patients. Lancet. 1995;346: ) Veroux M, Puliatti C, Fiamingo P, et al: Early de novo malignancies after kidney transplantation. Transplant Proc. 2004;36: ) Kasiske BL, Snyder JJ, Gilbertson DT, Wang C: Cancer after kidney transplantation in the United States. Am J Transplant. 2004;4: ) Brunner FP, Landais P, Selwood NH: Malignancies after renal transplantation: the EDTA-ERA registry experience. European Dialysis and Transplantation Association-European Renal Association. Nephrol Dial Transplant. 1995;10: ) Fahey TJ 3rd, Reeve TS, Delbridge L: Increasing incidence and changing presentation of thyroid cancer over a 30-year period. Br J Surg. 1995;82: ) Franceschi S, La Vecchia C: Thyroid cancer. Cancer Surv. 1994; 19-20: ) Nemes B, Zalatnai A, Podder H, et al: Papillary microcarcinoma of the thyroid gland in renal transplant patients. Pathol Oncol Res. 2000;6: ) Korea Central Cancer Registry Working Group: Korea Cancer Statistics: 1996 Incidence. Seoul. GA: Department of Disease Control and Prevention Services. National Health Insurance Cooperation and Nation Cancer Institute, 2004.Korean cancer Survellence, 2007:1190 9) Shah JP: AJCC Cancer Staging Handbook. TNM classification of malignant tumors, 6 th ed. In: Greene FL(ed) Springer-Verlag, New York, 2002: ) Keast D: Immunosurveillance and cancer. Lancet. 1970;2: ) Schwartz RS: Immunoregulation, oncogenic viruses, and malignant lymphomas. Lancet. 1972;1: ) Suzuki T, Takano Y, Yamashita K, Sato K, Kakita A, Okudaira M: A possible role for Epstein-Barr virus in tumorigenesis after immunosuppression in cases of renal transplantation. J Cancer Res Clin Oncol. 1993:119: ) Penn I: Cancers following cyclosporine therapy. Transplantation. 1987;43: ) Penn I: Cancer is a complication of severe immunosuppression. Surg Gynecol Obstet. 1986;162: ) First MR, Peddi VR: Malignancies complicating organ transplantation. Transplant Proc. 1998;30: ) Nafar M, Einollahi B, Hemati K, Gholi FP, Firouzan A: Development of malignancy following living donor kidney transplantation. Transplant Proc. 2005;37: ) Wang CX, Liu LS, Chen LZ, et al: Characteristics of neoplasm occurrence and the therapeutic effect of Sirolimus in South Chinese kidney transplant recipients. Transplant Proc. 2006;38: ) Pond F, Serpell JW, Webster A: Thyroid cancer in the renal transplant population: epidemiological study. ANZ J Surg. 2005; 75: ) Samhan M, Al-Mousawi M, Donia F, Fathi T, Nasim J, Nampoory MR: Malignancy in renal recipients. Transplant Proc. 2005;37: ) Hoshida Y, Aozasa K: Malignancies in organ transplant recipients. Pathol Int. 2004;52:

김범수

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