B-II. Intestinal Neuroendocrine Tumors: A to Z Room B 대장신경내분비종양의위험도평가와전략적인접근 국립암센터 Risk Stratification and Strategic Approach for Colorectal Neuroendocrine Tumor Byung Chang Kim National Cancer Center, Goyang, Korea 서론 카르시노이드종양은 1904년에독일의병리학자 Oberndorfer 에의해서일반적인샘암종에비해서비교적저등급의악성임상결과를보이는종양이라는의미로 karzinoid (carcinomalike) 라고처음소개되었다. 그후 1906년에 Giaccio 는카르시노이드종양이내분비관련종양임을처음기술하였고, Gosset 과 Masson 등이내분비관련종양임을확인하였으며, 1963년에 Williams와 Sandler 는발생기원에따라서앞창자 ( 폐, 위, 상부공장, 췌장 ), 중간창자 ( 하부공장, 회장, 충수돌기, 맹장 ), 뒤창자 ( 대장, 직장 ) 카르시노이드종양으로분류하였다. 1,2 이러한발생기원에따른분류는동일한장기에서발생하더라도다양한임상양상을보일수있다는한계점이있다. 그래서, 1971년 Soga와 Yakuwa는세포모양에따른분류를시도하였지만분화도가아닌단순한세포모양만으로여러장기에서발생하는카시노이드종양의임상양상을완전히설명하지는못했다. 3 카르시노이드종양은장크롬친화성세포, 가스트린세포, 그리고기타세포등에서기원한세포가분비하는호르몬이다양할수있고, 더불어다양한임상양상을보일수있으나, 과거에는비교적드문질환이고병에대한정확한이해가부족하여명확하게분류되지못했다. 1980년세계보건기구 (World Health Organization, WHO) 는췌장과갑상샘의내분비종양, 부신경절종, 폐의소세포암, 피부의 Merkel 세포종양을제외한대부분의내분비종양을카르시노이드종양으로분류하였는데, 이와같은분류는다양한임상양상을보이는이종양에 적용하기에부족한면이있었다. 그래서, 호르몬분비와임상양상에관계없이분화가좋은신경내분비종양에대해서 카르시노이드종양 이라는용어가사용되고있으며, 종양의발생빈도, 발생부위별분포, 악성도에따라서분류및진단기준측면에변화가있었다. 4-6 최근국내외연구보고에서신경내분비종양의발생빈도가증가하고있으며, 유럽과북미에서는중간창자에서발생한종양의빈도가거의절반을차지하고앞창자, 뒤창자순서로발생한다고보고하였다. 7 그러나, 일본의보고에서는뒤창자에서발생하는빈도가거의 60% 였으며, 국내보고에서도일본과비슷한발생빈도를보여지역간부위별발생빈도의차이가있다. 8,9 이는내시경을포함한진단기술의발전과검진목적으로검사를시행하여우연히발견되는것과연관이있을것으로생각된다. 그리고, 대부분의직장신경내분비종양 (82%) 이진단당시전이가없는상태에서진단되어다른장기의종양에비해서 5년생존율이거의 90% 이상이다. 그러나, 결장의신경내분비종양은직장에비해서좀더악성화의경향을보인다. 최근대장내시경시행빈도가증가하면서직장신경내분비종양 ( 카시노이드종양 ) 의발생빈도가증가하면서치료를결정하는데있어서적절한위험도평가와치료를위한전략적인접근이필요하다. 본론 1. 신경내분비종양분류 2000 년 WHO 분류에서는고분화신경내분비종양 (well dif- 제 4 회 EndoFest Korea 103
Table 1. Transition Scheme for the New Classification (WHO 2010) Including Previous Definitions for Neuroendocrine Neoplasms of the Digestive System (WHO 1980 and 2010) WHO 1980 WHO 2000 WHO 2010 1. Carcinoid 1. Well-differentiated endocrine tumour (WDET)* 1. NET G1 (carcinoid) 2. Well-differentiated endocrine carcinoma (WDEC) 2. NET G2 3. Poorly differentiated endocrine/small cell carcinoma (PDEC) 3. NEC (large cell or small cell type), 2. Mucocarcinoid 4. Mixed exocrine-endocrine carcinoma (MEEC) 4. Mixed adenoneuroendocrine carcinoma (MANEC) 3. Mixed forms carcinoid- adenocarcinoma 4. Pseudotumour lesions 5. Tumour-like lesions (TLL) 5. Hyperplastic and preneoplastic lesions G, grade (for definition, see text); NEC, neuroendocrine carcinoma; NET, neuroendocrine tumour. * The difference between WDET and WDEC was defined according to staging features in the WHO 2000 classification. G2 NET does not necessarily translate into WDEC of the WHO 2000 classification. Definition in parentheses for the international Classification of Diseases for Oncology (ICD-O) coding. NET G3 has been used for this category but is not advised, since NETs are by definition well-differentiated. Table 2. Grade of Neuroendocrine Tumor (NET) Grade Mitotic count (10HPF)* Ki-67 index (%) G1 (low) <2 2 G2 (intermediate) 2-20 3-20 G3 (high grade) >20 >20 *10 HPF: high power field = 2 mm 2, at least 40 fields (at 40* magnification) evaluated in areas of highest mitotic density. MIB1 antibody; % of 2,000 tumor cells in areas of highest nuclear labeling. ferentiated neuroendocrine tumor, NET), 고분화신경내분비암종 (well differentiated neuroendocrine carcinoma), 그리고, 저분화신경내분비암종 (poorly differentiated neuroendocrine carcinoma) 으로구분하여악성도를예측하고자하였다. 그리고, 그동안사용되었던카시노이드종양이라는용어를더이상사용하지않도록하였다. 그러나, 2010년 WHO분류에서는세포증식정도 (Ki-지수, 유사분열수 ) 에따라서악성정도를추가하여신경내분비종양을 G1( 등급1), G2( 등급2), 신경내분비암종 (neuroendocinre carcinoma, NEC) G3( 등급3) 로분류하여임상양상을예측하고자하였다 (Table 1). 2,10 또한, 2010년도 WHO 분류에서는 2004년과, 2007년유럽내분비종양학회 (European Neuroendocrine Tumor Society, ENETS) 에서제시한등급분류와발생장기에따른병기체계를근거로 1) 발생부위에따라서종양의차이가있는이질성과, 2) 종양세포의분화도에따른차이, 3) 오랜경과관찰에서신경내분비종양이결국악성종양이라는개념을도입하였다. 등급 (grading) 은형태학적인기준과유럽내분비종양학회에서제안한세포증식정도 (Ki-지수, 유사분열수 ) 를기반으로분류하였다 (Table 2). 그러나, 이등급체계가위, 십이지장, 췌장의신경내분비종양에는유용하지만, 대장 ( 특히, 직장 ) 에서발생하는신경내분비종양도유효한지에대해서는아직근거가부족하다. 10 결장에 서발생하는신경내분비종양은매우드물게발생하지만, 대부분조직병리학적으로미분화신경내분비암종이며이미진단당시전이된경우가많아나쁜예후를갖는다. 11 면역조직화학염색에서는시냅토피신양성과, 소마토스타틴양성소견을보인다. 2 직장내에발생하는신경내분비종양은결장에서발생하는종양과비교하여발생빈도는높지만대부분분화도가좋아예후는더좋다. 10 대부분의직장신경내분비종양은내시경도중에우연히발견되며, 크기는 1 cm 미만이고, 점막하층에국한되어있다. 그러나, 고유근층을침범하거나, 크기가 2 cm 이상인경우는전이위험성이증가된다. 그래서, 유럽내분비종양학회와 2004년 WHO 에서는 2000년분류에기초하여순수한신경내분비종양만을대상으로조직병리학적으로위험요소 ( 분화도, 림프관또는혈관침범, 크기, 고유근층침범, 증식정도, 기능성등 ) 에따라서 1) 고분화신경내분비종양 ((a) 양성또는 (b) 경계성 -양성또는악성이불확실한 ), 2) 고분화신경내분비종양 ( 저등급악성 ), 3) 미분화신경내분비종양 ( 고등급악성 ) 으로나누었다 (Table 3). 2 대장 ( 결장과직장 ) 의신경내분비종양은발생학적인세포형태에따라서장크롬화친화성세포 (enterochromaffin cells; EC 세포 ) 과엔테로글루카곤세포 (enteroglucagon cell, or L 세포 ) 종양으로분류될수있다. 그리고, 특히직장신경내분비종양의 80% 가까이글루카곤유사펩타이드 (glucagon-like peptide) 및 PP/PYY- 를생성하는것으로보여 L-세포형태 (trabecular/ gyriform pattern; Soga type B) 를보인다고보고되어있다. 결장에서발생하는신경내분비종양은주로 EC 세포형태를보인다. EC 세포신경내분비종양은 L 세포신경내분비종양과달리크로모그라닌 A, 시냅토피신, 세로토닌등 EC 세포에서생성하는단백질에양성소견을보인다. L-세포신경내분비종양이 EC- 세포신경내분비종양과달리세로토닌생성보다는글루카곤유 104 The Korean Society of Gastrointestinal Endoscopy
Table 3. Criteria for Assessing the Prognosis of Neuroendocrine Tumours of the Gastrointestinal Tract Biological behavior Metastases Invasion of Histological Tumor size Ki-67 index Hormonal Angioinvasion muscularis propria differentiation (cm) (%) syndrome - Benign negative negative Well-differentiated <1 negative <2 negative - Benign or low-grade malignant negative negative Well-differentiated 1-2 negative/positive <2 negative - Low-grade malignant positive positive Well-differentiated >2 positive >2 positive - High-grade malignant positive positive Poorly-differentiated any positive >20 negative Table 4. Proposal for TNM Classification and Stages for Endocrine Tumors of Colon and Rectum TNM Stages AJCC T N M T-primary tumor I T1 N0 M0 TX Primary tumor cannot be assessed IIA T2 N0 M0 T0 No evidence of primary tumor IIB T3 N0 M0 T1 Tumor invades mucosa or submucosa IIIA T4 N0 M0 T1a size <1 cm IIIB Any T N1 M0 T1b size 1-2 cm IV Any T Any N M1 T2 Tumor invades muscularis propria or size >2 cm T3 Tumor invades subserosa/pericolic/perirectal fat T4 Tumor directly invades other organs/structures and/or perforates visceral peritoneum For any T add (m) for multiple tumors N-regional lymph nodes NX Regional lymph node status cannot be assessed N0 Regional lymph node status cannot be assessed N1 Regional lymph node metastasis M-distant metastases (subspecification as in small bowel) MX Distant metastasis cannot be assessed M0 No distant metastases M1* Distant metastasis *M1 specific sites defined according to Sobin LH and Wittekind Ch 사펩타이드및 PP/PYY- (pancreatic polypeptide/peptide tyrosine tyrosine-) 를생성하고, 핵의형태가비교적균일하고, 유사분열수가 10 고배율 (high power field;hpf) 당대부분 2개미만인경우가많아 ICD-O3 분류에서는경계성종양 (Uncertain behavior) 으로분류하기도한다. 2 2. 치료전위험성평가 증상이없는상태에서우연히발견된직장신경내분비종양은항문피부선으로부터 4~10 cm 상부에위치하며, 내시경상에서정상점막소견을보이면서약간은노란색을띤점막하종양모양을나타내는것이전형적인특징이다. 12,13 그러나, 크기가크고, 종양의중심부에함몰이나궤양소견, 붉은색의충혈 (hyperemia) 이있는경우에전이가능성이높다고알려져있다. 13-16 직장신경내분비종양의크기에따른전이위험도는연구마다약간의차이가존재한다. 대부분의연구에서는 2 cm 이상직장신경내분비종양인경우림프절및원격전이위험성이 45%~74% 로매우높다. 1-2 cm 크기의직장신경내분비종양인경우전이확률은 7-27.6% 이며, 점막하층에국한된경우에도 18.6% 까지보고되고있다. 그러나, 1 cm 이하의직장신경내분비종양의경우전이위험성은 0-9.7% 까지매우다양하게보고되었다. 12,17-24 1 cm 이하의직장신경내분비종양에서림프절전이는림프관또는혈관침윤, 높은유사분열수, 고유근층침윤같은위험요소를갖는경우전이위험성이있는경우로생각되었으나, 1 cm 이하종양에다른위험요소들이없음에도림프절전이가가능하다. 18 국내보고를보면 2가지의다기관연구가있다. 16,25 박등은 2 cm 미만의 402 증례의직장신경내분비종양을대상으로한연구에서전이와연관된인자로크기, 유사분열비율, 림프관및혈관침윤을보고하였고, 1 cm 이하에서는전이소견이없었으며, 크기는 14 mm 미만에다른전이위험인자가없다면전이위험성이거의없는것으로보고하였다. 16 또한다른다기관연구는크기에관계없이직장신경내분비종양을진단받은 제 4 회 EndoFest Korea 105
514 증례를대상으로하였고, 1 cm 이하인경우림프절전이율은 1.99% 가관찰되었으나, 추가적으로병리소견에따른전이위험성에대해서는분석하지못했다. 25 직장신경내분비종양의초음파내시경소견은경계가잘구분되는저에코성동질성의초음파음영을보이며, 초음파내시경으로종양의크기, 침윤깊이, 주변림프절의전이등을파악할수있어치료전병기설정에도움이되어치료방법설정에도움이된다. 24 그러나, 1 cm 미만의직장신경내분비종양에서는일반적으로고유근층을침범하는경우가거의없어초음파내시경검사가항상필수적인검사는아니다. 26 대장신경내분비종양진단에사용되는영상의학적인검사법으로는전산화단층촬영, 자기공명영상등으로원격전이및림프절전이유무를확인할수있다. 전산화단층촬영은장관및장간막의변화와간전이등을평가하는데도움이된다. 직장의신경내분비종양은약 85% 에서전이가없는상태에서진단되고, 전형적으로동맥기때에뚜렷이조영증강이되는 1 cm 미만의한과혈관성소결절로관찰되나, 전산화단층좔영에서는민감도가많이떨어진다. 27,28 자기공명영상은공간및측면해상력이전산화단층촬영에비해서열등하여위장관의작은병변을찾기에는많은도움이되지는않으나, 간전이병변의진단및평가에는유용한검사방법이다. 소마토스타틴수용체신티그래피 ( 옥트레오스캔 ) 는전이가있는경우유용하지만, 크기가작은국소병변인경우에병기결정을위해서사용하는것에대해서는민감도가낮아서논쟁의여지가있다. 12 이렇듯이, 영상의학검사들은신경내분비종양의일차평가및향후추적관찰에매우중요한검사법이다. 뒤창자 ( 특히, 직장 ) 에서발생하는신경내분비종양은매우적은빈도에서세로토닌및호르몬을분비하므로혈청내세로토닌및그대사물질인소변내 5-hydroxyindoleacetic acid (5-HIAA) 검사를항상권고하지는않는다. 혈청크로모그라닌 A (CgA) 는 2기이상의신경내분비종양환자에서진단당시및치료후감시방법으로유용한종양표지자로생각되나, 초기병변에대해서는명확하지않다. 그러나, 프로톤펌프억제제사용, 만성위염, 신부전, 만성염증성질환에서위양성소견을보일수있다. 12 3. 치료후전이위험성평가 직장신경내분비종양을국소절제술 ( 내시경적인절제술또는경항문절제술등 ) 로제거한후조직병리소견을바탕으로치료방침을결정할필요가있다. 앞서언급한것과같이신경내분비종양의분화도, 증식정도 ( 유사분열수, Ki-67 지수 ), 혈관및림프관침범유무, 등급 (grade), 고유근층침범유무등을 Fig. 1. Management strategy for rectal neuroendocrine tumors. 확인하여야한다. Konishi 등은림프관침범소견이없는 1 cm 이하의직장신경내분비종양은전이가능성이낮아국소절제술만으로도완전절제가가능할것으로주장하였다. 20 Konishi 등과 Shields 등은혈관및림프관침범소견이림프절전이및간전이의중요한위험인자임을주장하였다. 17,20 2010년에발표된미국암학회 (American Joint Cancer Commision, AJCC) 에서발표한병기에서는고유근층을침범하는경우는신경내분비종양 2 cm 크기와같이 T2 병기로최소한 2기상태로국소전이및원격전이, 재발위험이 1기상태보다월등히증가하게된다 (Table 4). 29,30 Fahy 등은유사분열수즉, 등급이증가할수록진단당시전이가능성이높아지고, 재발률도증가함을보여주었다. 31 국소절제 (EMR, ESD, TEM, 등 ) 를시행한경우에절단면양성인경우잔여병변이남거나, 국소재발및전이의위험인자로생각된다. Park 등은내시경적으로불완전절제로생각되는경우추가적인치료결과를보면대부분의환자에서잔여병변이남아있었고 (94.5%, 34/36), 내시경적으로완전절제로생각되는경우잔여병변이남아있는경우는약 3% (8/268) 정도였다. 16 그러므로, 내시경적으로불완전절제로생각되는경우는완전절제를위한추가적인치료법이필요하거나, 면밀한추적관찰이필요하다. 결론 최근직장신경내분비종양은진단대장내시경검사가증가하면서발생빈도가증가하고있다. 1 cm 이하의종양이더라 106 The Korean Society of Gastrointestinal Endoscopy
도전이가능성이존재하기때문에항상치료전에내시경소견, 영상의학검사, 초음파내시경등을통하여위험도를평가하여적절한치료적인접근이필요하겠다. 그러나, 2 cm 이상의종양은전이가능성이매우높으므로원격전이가없는경우림프절절제를포함한근본적인절제술을시행하고, 1-2 cm 크기의종양은연구에따라서 7-27.6% 까지림프절전이위험성이존재하므로환자상태에따라서적절한치료법을적용하여하겠다. 치료후종양의분화도, 크기, 침범정도, 증식정도및등급, 혈관침범유무등의병리소견에대한평가가필요하며이를근거로추가적인치료및추적검사에대한접근이필요하다 (Fig. 1). 참고문헌 1. Van Eeden S, Quaedvlieg PF, Taal BG, et al. Classification of low-grade neuroendocrine tumors of midgut and unknown origin. Hum Pathol 2002;33:1126-1132. 2. Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 2004;1014:13-27. 3. Soga J. Carcinoids of the rectum: an evaluation of 1271 reported cases. Surg Today 1997;27:112-119. 4. Chetty R. An overview of practical issues in the diagnosis of gastroenteropancreatic neuroendocrine pathology. Arch Pathol Lab Med 2008;132:1285-1289. 5. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 2010;34:300-313. 6. Washington MK, Tang LH, Berlin J, et al. Protocol for the examination of specimens from patients with neuroendocrine tumors (carcinoid tumors) of the colon and rectum. Arch Pathol Lab Med 2010;134:176-180. 7. Yao JC, Hassan M, Phan A, et al. One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol 2008;26:3063-3072. 8. Ito T, Sasano H, Tanaka M, et al. Epidemiological study of gastroenteropancreatic neuroendocrine tumors in Japan. J Gastroenterol 2010;45:234-243. 9. M-J K. Data of multi-institutional survey of gastroenterohepatic neuroendocrine tumors. NET symposium, 2009. 10. Bosman F, Carneiro F, Hruban R, et al. WHO classification of tumours of the digestive system. WHO classification of tumours of the digestive system 2010. 11. Grabowski P, Schonfelder J, Ahnert-Hilger G, et al. Expression of neuroendocrine markers: a signature of human undifferentiated carcinoma of the colon and rectum. Virchows Arch 2002;441: 256-263. 12.Anthony LB, Strosberg JR, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors (nets): well-differentiated nets of the distal colon and rectum. Pancreas 2010; 39:767-774. 13. Shim KN, Yang SK, Myung SJ, et al. Atypical endoscopic features of rectal carcinoids. Endoscopy 2004;36:313-316. 14. Kim BN, Sohn DK, Hong CW, et al. Atypical endoscopic features can be associated with metastasis in rectal carcinoid tumors. Surg Endosc 2008;22:1992-1996. 15.Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005;128:1717-1751. 16. Park CH, Cheon JH, Kim JO, et al. Criteria for decision making after endoscopic resection of well-differentiated rectal carcinoids with regard to potential lymphatic spread. Endoscopy 2011. 17. Shields CJ, Tiret E, Winter DC. Carcinoid tumors of the rectum: a multi-institutional international collaboration. Ann Surg 2010;252:750-755. 18. Fujimoto Y, Oya M, Kuroyanagi H, et al. Lymph-node metastases in rectal carcinoids. Langenbecks Arch Surg 2010;395: 139-142. 19. Tsukamoto S, Fujita S, Yamaguchi T, et al. Clinicopathological characteristics and prognosis of rectal well-differentiated neuroendocrine tumors. Int J Colorectal Dis 2008;23:1109-1113. 20. Konishi T, Watanabe T, Kishimoto J, et al. Prognosis and risk factors of metastasis in colorectal carcinoids: results of a nationwide registry over 15 years. Gut 2007;56:863-868. 21. Lauffer JM, Zhang T, Modlin IM. Review article: current status of gastrointestinal carcinoids. Aliment Pharmacol Ther 1999; 13:271-287. 22. Naunheim KS, Zeitels J, Kaplan EL, et al. Rectal carcinoid tumors--treatment and prognosis. Surgery 1983;94:670-676. 23. Soga J. Early-stage carcinoids of the gastrointestinal tract: an analysis of 1914 reported cases. Cancer 2005;103:1587-1595. 24. Kobayashi K, Katsumata T, Yoshizawa S, et al. Indications of endoscopic polypectomy for rectal carcinoid tumors and clinical usefulness of endoscopic ultrasonography. Dis Colon Rectum 2005;48:285-291. 25. Coloproctology CSGoKSo. Clinical characteristics of colorectal carcinoid tumors. J Korean Soc Coloproctol 2011;27:17-20. 26.Scherubl H, Jensen RT, Cadiot G, et al. Management of early gastrointestinal neuroendocrine neoplasms. World J Gastrointest Endosc 2011;3:133-139. 27. Levy AD, Sobin LH. From the archives of the AFIP: Gastrointestinal carcinoids: imaging features with clinicopathologic comparison. Radiographics 2007;27:237-257. 28. Chang S, Choi D, Lee SJ, et al. Neuroendocrine neoplasms of the gastrointestinal tract: classification, pathologic basis, and imaging features. Radiographics 2007;27:1667-1679. 29. Rindi G, Kloppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 2007;451:757-762. 30.Edge SB. AJCC cancer staging manual. New York; London: Springer, 2009. 31. Fahy BN, Tang LH, Klimstra D, et al. Carcinoid of the rectum risk stratification (CaRRs): a strategy for preoperative outcome assessment. Ann Surg Oncol 2007;14:1735-1743. 제 4 회 EndoFest Korea 107