대한내과학회지 : 제 87 권제 4 호 2014 http://dx.doi.org/10.3904/kjm.2014.87.4.415 종설 (Review) 직장신경내분비종양의진단과치료 단국대학교의과대학내과학교실 신현덕 Diagnosis and Treatment of Rectal Neuroendocrine Tumor Hyun Deok Shin Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea Rectal neuroendocrine tumors (NETs) are not uncommon. Recently, the incidence of rectal NETs has increased markedly due to the widespread use of screening colonoscopy. Most rectal NETs detected incidentally are asymptomatic and at an early stage at diagnosis. Typical NETs < 10 mm in size and confined to the submucosal layer can be resected completely using various endoscopic treatments. These NETs have a good prognosis. However, not all NETs necessarily have good prognoses; those > 10 mm in size, with ulceration or depression, muscularis invasion seen on endoscopic ultrasonography (EUS), lymphovascular invasion, or a high mitotic index histologically are associated with metastasis. Generally, NETs < 10 mm can be treated endoscopically, while those > 20 mm should be resected surgically. The treatment of NETs between 10 and 20 mm is controversial. For these, it is necessary to choose an effective, safe primary resection method to ensure complete resection and to perform a careful histological examination of the resected tissue. (Korean J Med 2014;87:415-423) Keywords: Rectum; Neuroendocrine tumor; Endoscopic treatment; Prognosis 서론직장신경내분비종양 (rectal neuroendocrine tumors, NETs) 은흔히카르시노이드종양 (carcinoid tumor) 이란명칭으로알려져있다. 1867년에처음보고되었으며 [1], 1888년 Lubarsh 에의해서회장에존재하는다발성카르시노이드종양의병리학적현미경소견이기술된이후 [2], 간전이가있는회장의카르시노이드종양환자에서발생한카르시노이드증후군 (carcinoid syndrome) 이보고되었다. 1907년 Oberndorfer 에의해서보통의선암보다는양성의임상경과를갖는의미 로 karzinoid (carcinoma-like) 라는명칭이처음붙여졌다 [3]. 1914년, Gosset과 Masson 은카르시노이드종양이내분비계종양임을발견하였으며 [4], 2000년세계보건기구 (World Health Organization, WHO) 에서는카르시노이드종양대신신경내분비종양을사용할것을제안하였으며 [5] 근래에개정된가이드라인들에서는이를신경내분비종양으로명명하도록제안하였다 [6-8]. 직장 NETs는최근에는 Table 1과같이분류된다 [8]. 그러나여전히카르시노이드종양이란명칭은임상에서흔히사용되고있다. 대부분의직장 NETs는크기가 10 mm 미만으로쉽게내 Correspondence to Hyun Deok Shin, M.D., Ph.D. Department of Internal Medicine, Dankook University College of Medicine, 119 Dandae-ro, Dongnam-gu, Cheonan 330-714, Korea Tel: +82-41-550-3828, Fax: +82-41-556-3256, E-mail: emedicals@hanmail.net Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 415 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 87, No. 4, 2014 - Table 1. Nomenclature for NETs of the hindgut [8] Grade Traditional ENETS/WHO Low grade Carcinoid tumor Neuroendocrine tumor, grade 1 (G1) Intermediate grade Carcinoid tumor Neuroendocrine tumor, grade 2 (G2) High grade Small-cell carcinoma Large-cell neuroendocrine carcinoma Neuroendocrine carcinoma, grade 3 (G3), small-cell carcinoma Neuroendocrine carcinoma, grade 3 (G3), large-cell carcinoma NETs, rectal neuroendocrine tumors; ENETS, European Neuroendocrine Tumor Society; WHO, World Health Organization. 시경치료로제거되며선암에비해매우천천히자라고양성경과를보여예후가좋지만, 2010년 WHO와 AJCC (American Joint Cancer Commission) 에서는명백히악성종양으로분류하고있으며침습적으로진행하여다른장기로전이될수있음에유의하여야한다 [9,10]. 최근직장 NETs의발생빈도는다른장기에서보다크게증가하고있으며 [11,12], 이는검진대장내시경의증가, 내시경광학기술의발전에의한발견율의향상과임상적관심의증가에의한것으로생각된다 [13]. 이글에서는최근증가하고있는직장 NETs의진단과치료에대해서요약하고자한다. 역 학 NETs는서구의경우, 위장관에서가장흔히발견되며 (67%), 소장 (25%), 직장 (14%), 충수돌기 (12%) 의빈도로발견된다 [14]. 직장 NETs의연간발생률은 1973년 10만명당 0.2명에서 2004년에는 0.86명으로약 4배정도증가하였으며 [15], 모든위장관 NETs 의 27%, 모든 NETs의 16% 를직장 NETs가차지한다고보고하고있다 [8]. 직장 NETs는다른장기와는달리백인에비해흑인과아시아인에게서보다높은비율로발생한다 [16]. 서양과달리일본과우리나라에서는직장 NETs가가장흔한호발부위로약 50% 를차지한다 [17,18]. 국내연구에서직장 NETs 최근 10년사이에급격히증가하여 2000년에비해 2009년에는 9배이상발생하였고, 남녀비율은 1.1:1이며평균진단연령은 56세였다 [18]. 진단직장 NETs의약 50% 는증상이없는초기단계에서대장내시경검사도중우연히발견된다. 진행된상태에서는하복 Figure 1. This shows solitary, sessile and smooth subepithelial lesion with yellowish colored normal mucosa. 부불편감, 변비, 직장출혈, 배변습관의변화, 직장통증, 항문소양증과같은증상이나타날수있다. NETs는병리조직학적검사를통해서확진된다. 그러나내시경적으로전형적인소견이관찰되면병리검사없이도 90% 이상에서진단할수있다 [19]. 전형적인내시경소견은표면점막은대부분정상이고경계가매끄럽고약간융기된무경성의상피하병변으로노란색조변화가관찰된다 (Fig. 1). 대부분단독으로발견되는경우가대부분이나드물게다발성으로발생하는경우도있어주의깊은관찰이필요하다. 내시경검사에서전형적인소견이관찰되면조직검사는시행하지않는것이바람직하다. 조직검사는반흔을유발하며이로인해병변의경계가불분명해지고섬유화로인해내시경적완전절제가방해될수있다 [19,20]. 내시경적으로반유경성 (semipedunculated), 점막발적, 함요, 궤양과같은비전형적인소견이관찰될경우에는전형적인내시경소견에비해 - 416 -
- Hyun Deok Shin. Diagnosis and Treatment of Rectal NETs - 병변이보다크고림프절전이및타장기전이의위험이높을수있으므로보다세심한관찰및치료전검사가필요하다 [21,22]. 병리학적확진및감별진단을위해서는 chromogranin과 synaptophysin에대한면역화학염색이필요하다. serum chromogranin, serotonin, glucagon, gastrin, urinary 5-hydroxy-indoleacetic acid (5-HIAA), synaptophysin과같은생화학적검사는 1 cm 미만의작은직장 NETs의진단및치료에도움이되지않는다. 그러나진행성병변으로림프절전이나다른장기에전이가의심되거나발생한경우에는빈도는낮으나카르시노이드증후군여부를확인하기위해위와같은생화학적검사가필요할수있다. 직장 NETs가고유근층을침범한경우에는림프절침범및타장기전이의가능성이높고예후가나빠치료전에내시경초음파 (endoscopic ultrasonography, EUS) 를통한침윤도에대한평가가반드시필요하다 [23]. EUS 는직장 NETs의크기, 심달도및림프절전이여부를평가하는데유용하며정확도가높아병변의추후치료방침을결정하는데매우유용하다 [23-30]. 골반자기공명촬영 (pelvic MRI) 또는복부전산단층촬영 (abdominopelvic CT) 은병변의크기가 10 mm를넘을경우전이여부를확인하기위해시행하도록권고된다 [26]. 병변의크기가 20 mm를넘어서는병변의경우에는 octreotide scintigraphy 가시행되어야한다 [26]. 대장내시경을통해직장 NETs가발견된경우 EUS는치료전에시행하는것이치료방침의결정에크게도움이되며, 크기에따라 pelvic MRI, abdominopelvic CT 또는 octreotide scintigraphy 는상황에맞게시행되어야한다. 예후인자직장 NETs의병기 (TNM stage) 는가장중요한예후인자이다 [10,25,30]. 5년생존율은국소질환인 Ⅰ/Ⅱ/Ⅲa 기에는 94-100%, 림프절양성인 Ⅲb기에는 54-74%, 타장기전이가있는 Ⅳ기에서는 15-37% 정도이다 [27]. 미국과유럽의직장 NETs에대한병기는각각표 2와 3과같다 [31,32]. 전이위험인자는우선종양의크기가매우중요하며크기에따라전이위험이증가하여직경이 < 10 mm, 10-19 mm, 20 mm에따라각각 0-10%, 4-30%, 57-80% 이며, 형태학적으로는궤양이나함요, 발적같은비전형적인소견이관찰될 때, 환자가고령일경우 ( 60세 ), 병리학적으로고유근층침범, 림프혈관침범또는신경주위침범이있거나높은유사분열지수및 Ki-67 index를보일경우전이의위험이높다 [16,22,23,26,27,33-44]. 유사분열지수및 Ki-67 index 같은병리학적등급은표 4와같이분류한다 [8]. 전이위험인자가없는환자는림프절전이나다른장기로의전이가없으면 3년생존율이 100% 이다 [30]. 치료직장 NETs의치료는근치적절제이다. 대부분의직장 NETs는성장이느리고양성경과를따르지만국소전이및원격전이의위험이있고, 전이가발생하면생존율이감소하므로완전절제가필요하다 [26]. 대부분의직장 NETs는크기가작고 (< 10 mm), 점막하층에한정되어있는국소병변으로발견된다. 치료방침은직장 NETs의크기에의해결정되는데크기가작고 (< 1-2 cm) 점막하층이내에위치하는한정된병변인경우전이의가능성이낮아내시경적절제와같은국소절제치료의좋은적응증이된다. 이와같은 NETs의내시경적치료에는여러가지방법들이보고되고있으며전통적인용종절제술 (conventional polypectomy), 내시경적점막절제술 (endoscopic mucosal resection, EMR), cap을이용한내시경적점막절제술 (cap-assisted EMR, EMR-C or aspiration lumpectomy), ligating device 를이용한내시경적점막하절제술 (endoscopic submucosal resection with ligating device, ESMR-L), 내시경적점막하박리술 (endoscopic submucosal dissection, ESD), 경항문적내시경미세수술 (transanal endoscopic microsurgery, TEM) 과같은방법들이이에포함된다. 그러나전향적대조연구가부족하여이와같은작은직장 NETs의내시경적치료방법에있어지속적으로논쟁이되어왔으며이들중어느하나가표준화된치료로인정되고있지는않으나, 최근에이에대한많은데이터들이발표되고있다. 일반적으로직장 NETs는위장관어디에나존재하는장크롬친화성세포 (enterochromaffin cell, EC cell) 에서기원하며이들세포는상피층의가장깊은곳에위치하고있어점막고유판을쉽게뚫고점막하층으로침윤하기때문에일반적인대장용종에적용되는전통적인용종절제술 [20,45] 이나 EMR [28,45-47] 은충분한완전절제면을얻지못하며절제 - 417 -
- 대한내과학회지 : 제 87 권제 4 호통권제 650 호 2014 - 면에압착손상을받아적절한병리학적평가에어려움이있는경우들이있다. 따라서종종 NETs의불완전절제에의해추가적인수술적치료가필요한경우가발생한다. 보다완전한절제면을얻기위하여 EMR-C [20,46-50], ESMR-L [20,50-57] 또는 ESD [20,24,47,58-62] 를이용하여더깊은부분까지완전절제할수있게되었다. ESMR-L 과 ESD는가장효과적인방법으로각각의완전절제율은 94.8%, 89.6% 로완전절제율이 59.1% 와 72.4% 인전통적인용종절제술 /EMR 과 EMR-C 방법에비하여월등히높다. 그러나이들두가지방법은단지세개의연구에서만비교되었다 [57-59]. 또한, ESD는다른내시경치료법들에비해보다많은경험, 숙련된기술, 더많은시간이필요하며근본적으로보다높은천공의위험을가지고있음을유념하여야한다. 현재까지의연구들은 ESMR-L 과 ESD가전통적인용종절제술이나 EMR에비해더높은완전절제율을보고하고있다. 그러나 ESMR-L 이절제에걸리는시간이 ESD에비해짧으며, 치료기법이 Table 2. NANETS tumors and stage guidelines [31] TNM staging TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor invades lamina propria or submucosa and size 2 cm or less T1a Tumor size < 1 cm in greatest dimension T1b Tumor size 1-2 cm in greatest dimension T2 Tumor invades muscularis propria or size > 2 cm with invasion of lamina propria or submucosa T3 Tumor invades through the muscularis propria into the subserosa, or into non-peritonealized pericolic or perirectal tissues T4 Tumor invades peritoneum or other organs; for any T, add (m) for multiple tumors No No nodal involvement N1 Nodal involvement M0 No metastatic disease M1 Metastatic disease Tumor staging Stage T stage N stage M stage Ⅰ T1a or T1b N0 M0 ⅡA T2 N0 M0 ⅡB T3 N0 M0 ⅢA T4 N0 M0 ⅢB Any T N1 M0 Ⅳ Any T Any N M1 NANES, North American Neuroendocrine Tumor society. 더욱단순하며천공과같은합병증의빈도가 ESD에비해낮아 1 cm 미만의직장 NETs에대한치료로일반적으로선호되는방법이다. 경항문내시경미세수술은항문피부선에서 20 cm 상방까지대장벽전층의절제가가능한기법으로전통적인경항문절제술 (transanal excision, TAE) 에비해중부및상부직장에서병변의치료에보다유리하다 [63]. TEM 은 TAE에비해시야확보가용이하며완전절제율이높아재발률이낮다 [64]. TEM 은불완전용종절제술후남은직장 NETs에대한구제치료로매우높은완전절제율을보고하였다 [65,66]. 내시경적치료법에대하여정리하면일반적으로 1 cm 미만의점막하층이내에한정된림프절침범의위험이낮은직장 NETs에대하여적응되며전통적인용종절제술이나 EMR에비해 EMR-C, ESMR-L, ESD가완전절제율이높으며이들중특히 ESMR-L 과 ESD가매우우수한결과들을보이고있으며더짧은치료시간, 치료기술의간편성, 합병증의빈도가낮음을고려할때 ESMR-L 을보다고려할수있을것이다. Table 3. ENETS tumors and stage guidelines [32] TNM staging TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor invades mucosa or submucosa T1a Size < 1 cm T1b Size 1-2 cm T2 Tumor invades muscularis propria or size > 2 cm T3 Tumor invades subserosa/pericolic/pericolic fat T4 Tumor directly invades other organs/structures and/or perorated visceral peritoneum N0 No regional lymph node metastasis N1 Regional lymph node metastasis M0 No distant metastasis M1 Distant metastasis Tumor staging Stage T stage N stage M stage ⅠA T1a N0 M0 ⅠB T1b N0 M0 ⅡA T2 N0 M0 ⅡB T3 N0 M0 ⅢA T4 N0 M0 ⅢB Any T N1 M0 Ⅳ Any T Any N M1 ENETS, European Neuroendocrine Tumor Society. - 418 -
- 신현덕. 직장신경내분비종양의진단과치료 - 10-19 mm 크기의직장 NETs에대해서는적절한치료법에대한합의에도달한것이없다. 그러나 10 mm 미만의 NETs에비해더나쁜예후와더높은원격전이위험을보이고있다 [33,35,37,44]. 림프절침범의위험도는 26-40% 에이르며고유근층을침범한경우에는 54% 까지보고하고있다 [33,35,37,44]. 치료법으로는내시경적국소절제, TAE, TEM Table 4. ENETS/AJCC grading systems for neuroendocrine tumors [8] Grade Mitotic count (/10HPF) Ki-67 index (%) Low grade (G1) < 2 2 Intermediate grade (G2) 2-20 3-20 High grade (G3) 20 20 AJCC, American Joint Cancer Commission; ENETS, European Neuroendocrine Tumor Society; HPF, high power field. 또는근치적직장절제술을고려할수있다 [8,26]. 종양의크기가 15 mm 미만이고 EUS상에서고유근층의침범이없는경우에 10 mm 미만의종양에서와같이내시경적으로치료될수있다 [30,60,67,68]. 그러나병리학적검사에서림프혈관침범소견이있거나 G3와같은나쁜병리학적등급소견이보이는경우추가적인수술적치료가필요할수있다. 15 mm를넘는경우또는크기에관계없이 EUS상고유근층의침범이있는경우주변림프절을포함한근치적절제술이고려되어야하며 TEM을포함한경항문절제술도대안이될수있으나경항문절제술의경우주변림프절에대한치료에는제한이있다. 크기가 20 mm 이상인직장 NETs의경우전이가있거나추적관찰중전이가발생할위험이 57% 에서 80% 에이른다 [33,36,44]. 이들종양은일반적으로직장암과같은근치적절제및총직장간막절제술이이루어져야한다 [8,26]. Figure 2. Treatment algorithm for rectal NETs [26]. MRI, magnetic resonance imaging; CT, computed tomography; SRS, somatostatin-receptor scintigraphy; PET, positron emission tomography; TME, total mesorectal excision; PRRT, peptide-receptor radiotargeted radiotherapy. - 419 -
- The Korean Journal of Medicine: Vol. 87, No. 4, 2014 - 내시경적절제후병리검사소견에서림프혈관침범, 불완전절제면, G3와같은나쁜병리학적등급소견들중하나라도발견되면수술을포함하는구제치료를고려해야만한다 [13]. 마지막으로최근발표된유럽가이드라인에따른치료는그림 2에제시되어있다 [26]. 치료후추적관찰직장 NETs는절제후수년이지난후에도재발할수있다. 그러나아직까지장기추적관찰의필요성에대한연구는드물다. 크기가 15 mm 미만, 림프혈관침범및고유근층의침범이없으며유사분열지수가낮고, 완전절제면을보이는직장 NETs는전이위험이거의없고, 재발가능성이낮아좋은예후를보이므로많은전문가들은이들환자에대한추적관찰을권고하지않고있다 [8,23,26,36,37,69,70]. 국소및원격재발의위험인자들을갖는경우에는첫 3년동안에는 6개월마다직장경및 EUS를반복하고이후로매년추적관찰할것을권고한다 [26,67]. 국소재발의조기발견을위해추적내시경검사중절제면에서대한조직검사는경우에따라필요할것으로보인다 [71]. 간전이유무를확인하기위해복부전산화단층촬영이나간자기공명촬영은 5년동안매년시행할것을권고하고있다. 매년 octreotide scintigraphy 검사를시행하는것에대한평가는없으나유럽가이드라인에서는권고하고있다 [7,26]. 추적관찰을언제까지해야하는가에대한데이터는현재까지는없으나 2 cm 이상의종양이나 G3와같은나쁜병리학적등급을보이는종양의경우는장기간의추적관찰이필요할것으로생각된다. 결론직장 NETs는검진대장내시경검사가급격히증가하면서발견빈도가증가하고있다. 내시경검사에서육안적으로전형적인모습을보이면직장 NETs를의심하고근치적절제를시행해야한다. 모든직장 NETs에서치료전적절한내시경초음파검사가선행되어야하며 15 mm 미만의크기에점막하층이내에국한된위험인자가없는작은직장 NETs 의경우내시경적으로완전절제를시행할수있다. 치료방 법에있어서는현재표준화되어있지는않으나전통적인용종절제술이나 EMR보다는 EMR-C, ESMR-L 또는 ESD 중하나를각병원의상황에맞게선택하는것이좋을것으로생각된다. 절제후에는세심한병리검사가반드시이루어져야하며결과에서전이나재발위험인자가발견되는경우에는구제치료시행을고려해야한다. 완전절제후에는전이에대한위험인자가없는작은직장 NETs에대해서는추적관찰이필요없으나크기가크거나위험인자를동반한경우에는내시경, EUS, CT나 MRI가상황에맞게시행되어야한다. 현재까지는내시경적치료방법에대한표준화, 크기가 10-19 mm인종양들에대한치료원칙, 절제후추적관찰에대한연구가부족한실정으로이에대한많은연구가필요할것으로생각된다. 중심단어 : 직장 ; 신경내분비종양 ; 내시경치료 ; 예후 REFERENCES 1. Langhans T. Ueber einen drusenpolyp im ileum. Virchows Arch Pathol Anat Physiol Klin Med 1876;38:559-560. 2. Lubarsch O. Uber den primaren Krebs des ileum nebst Bemerkungen uber das gleichzeitige Vorkommen von Krebs and Tuberkulose. Virchows Arch 1888;3:280-317 3. Oberndorfer S. Karzinoide Tumoren des Dunndarms. Frank Z Pathol 1907;1:426-429. 4. Gosset A, Masson P. Tumeurs endocrines de l'appendice. Presse Med 1914;22:237-240. 5. Solcia E, Kloppel G, Sobin LH, et al. Histologic Typing of Endocrine tumours. WHO International Histological Classification of Tumours. 2nd ed. Berlin: Springer, 2000. 6. Ramage JK, Goretzki PE, Manfredi R, et al. Consensus guidelines for the management of patients with digestive neuroendocrine tumors: well-differentiated colon and rectum tumors/carcinoma. Neuroendocrinology 2008;87:31-39. 7. Niederle MB, Hackl M, Kaserer K, Niederle B. Gastroenteropancreatic neuroendocrine tumors: the current incidence and staging based on the WHO and European Neuroendocrine Tumor Society classification: an analysis based on prospectively collected parameters. Endocr Relat Cancer 2010; 17:909-918. 8. 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 distal colon and rectum. Pancreas 2010;39: 767-774. - 420 -
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