Korean Journal of HBP Surgery Vol. 10, No 4, December 증 례 원발성위신경내분비종의간전이 2 예 경희대학교의과대학외과학교실 권택수, 김호연, 최재영, 이상목, 홍성화 Primary Gastric Neuroendocrine Tumor with Hepatic Metastasis Taek Soo Kwon, M.D., Ho Yuon Kim, M.D., Jae Young Choi, M.D., Sang Mok Lee, M.D., Sung Wha Hong, M.D. Department of Sugery, Kyunghee University College of Medicine, Seoul, Korea Gastric neuroendocrine tumor is an uncommon entity, and it constitutes less than 1% of all neuroendocrine tumors and less than 2% of all gastric neoplasms. Regardless of its origin, approximately 75% of the patients with neuroendocrine tumors will develop liver metastasis. We report here on two cases of primary neuroendocrine tumor with hepatic metastasis. A 37-year-old-man presented with chronic and intermittent abdominal pain in the epigastric area. He was diagnosed with gastric neuroendocrine tumor together with hepatic metastasis, based on the imaging studies and the octreotide scan. Subtotal gastrectomy and right hemihepatectomy was done and the patient was discharged on the postoperative 15th day without any complication. Another 41-year-old man presented with abdominal discomfort and a RUQ palpable mass. He was diagnosed with hepatocellular carcinoma based on the abdominal computerized tomography (CT). However, we incidentally found a gastric mass in the operating field and subtotal gastrectomy was then done. The pathologic report was large cell neuroendocrine carcinoma. The patient was discharged on the postoperative 19th day without any complication. Key word: Gastric neuroendocrine tumor, Carcinoid, Hepatic metastasis 중심단어 : 위유암종, 신경내분비종, 간전이 서 위신경내분비종은 1923년 Askanazy 1 에의해처음보고되었으며, 전체신경내분비종의 1% 미만, 전체위신생물 책임저자 : 론 홍성화서울시동대문구회기동 1 번지 130-702, 경희대학교의과대학외과학교실 Tel: 02-958-8264, Fax: 02-966-9366 E-mail: swhong@khmc.or.kr 중 2% 미만을차지하는드문질환이다. 2 신경내분비종은위장관의신경호르몬세포에서발생하며, 전체신경내분비종환자중간전이는 75% 정도발생한다고보고되고있다. 3-5 최근위신경내분비종에대한많은연구가이루어져다양한진단방법과치료기술이보고되고있으며, 특히간전이가있다하더라도종양의 90% 이상제거시치료적절제가가능하다는보고가있다. 6 저자들은최근원발성위신경내분비종의간전이 2예를치험하였기에이를문헌고찰과함께보고하는바이다. 증례 1 37세남자환자로한달전부터시작된간헐적상복부동통을주소로외부병원에방문하여시행한위내시경, 복부전산화단층촬영및초음파유도하간생검에서신경내분비종의심하에수술적치료위해본원에입원하였다. 과거력이나, 가족력에특이사항은없었다. 신체검사에서내원당시활력징후는안정적이었으며, 안면홍조, 황달, 경부림프절종대등의이상소견은없었고, 흉부청진소견은정상이었다. 복부는부드럽고편평했고, 청진상장음은정상적으로들렸다. 상복부압통이있었으며, 반발통은없었고촉지되는복부종괴는없었다. 생화학검사에서간효소수치중 ALT가 146 U/L로상승되어있었다. 위내시경에서위전정부와십이지장구에걸친부위가점막하병변에의해압박되어, 변형된모습을보이고있었으며, 점막부위조직검사결과만성염증소견만을나타냈다 (Fig. 1). 복부전산화단층촬영에서위전정부에점막하종양과, 간제 VIII분절에종양이관찰되었고 (Fig. 2), 내분비검사와 octreotide scan을시행하였다. 내분비검사는정상소견을보였으며, octreotide scan에서간제 VIII분절에소마토스타틴수용체흡수가증가되어 (Fig. 3) 원발성위신경내분비종의간전이로진단하고, 위아전절제술과위공장문합술, 간우엽절제술을시행하였다. 절제된검체를육안으로살펴보았을때위전정부에 4x3 cm 크기의종괴가관찰되 24
권택수외 : 원발성위신경내분비종의간전이 2 예 었고, 간제 VIII분절에약 3X3 cm의전이성병변이관찰되었다 (Fig. 4). 조직검사상종양의세포는 H&E 염색에서비교적단일하고둥근핵과호산구성의세포질로이루어져있었고, 특수염색에서 NSE와 synaptophysin에양성소견을보여위신경내분비암종과간제 VIII분절에전이성병변으로진단되었다 (Fig. 5). 환자는별다른합병증없이수술후 15일째퇴원하였으며, 외래에서항암치료와추적관찰중이다. Fig. 1. Gastroscopy shows the lesion which is compressed or invaded by submucosal or extrinsic mass in duodenum. Fig. 4. Gross specimen shows pyloric mass and hepatic metastatic lesion. H & E (high power field) Fig. 2. Abdominal CT shows submucosal tumor at pylorus and hepatic mass suggested hepatic adenoma. NSE(+) (low power field) (c) Synaptophysin(+) (low power field) Fig. 3. Octreotide scan shows somatostatin receptor positive tumor at the segment VIII of Rt. lobe of liver. Fig. 5. The tumor have moderate eosinophilic cytoplasm and tumor cell are positive for synaptophysin and NSE(c) 25
한국간담췌외과학회지 : 제 10 권제 4 호 2006 증례 2 41세남자환자로작년겨울부터복부불편감과 6개월간 6 kg의체중감소가있었으나별다른치료없이지내던중, 내원 3주전부터우상복부에촉지되는덩어리가있어개인병원에서실시한컴퓨터단층촬영소견에서간출혈성괴사, 혈종의심하에정밀검사를위해입원하였다. 환자과거력이나가족력상특이사항없었으며, 신체검사에서내원당시활력징후는안정적이었으며, 안면홍조, 황달, 경부임파절종대등의이상소견은없었고, 흉부청진음은정상. 복부는부드럽고팽창되어있었으며, 청진상장음은정상적으로들렸다. 우상복부에는단단하며고정된압통이없는종괴가촉지되었다. 생화학검사에서 AST 45 U/L, GGT 150 U/L로증가되었고종양표시자검사에서 AFP가 7949 ng/ml로매우증가되어있었다. 복부컴퓨터단층촬영에서중앙궤사가있으며우엽대부분을차지하는큰결절성종괴가관찰되었다 (Fig. 6). 간세포암진단하에간우엽절제술계획하고수술을하였다. 개복후복강내검사중위유문부에딱딱한종괴를발견하고, 동결절편시행결과암종이나왔으며, 위아전절제술및위십이지장문합술을시행후, 간우엽절제술을시행하였다 (Fig. 7). 조직검사결과세포는 H&E 염색에서기관양, 둥지상, 섬유주, 로제트같은그리고울타리양상을보이며, 특수염색에서 cytokeratin 와 CD 56 양성인위유문부에서 2x1 cm 의큰세포신경내분비종및간우엽에 22x11 cm 전이성큰세포신경내분비종이나왔다 (Fig. 8,9). 환자는별다른합병증없이수술후 19일째퇴원하였으며, 항암치료시행하였으나, 수술 6개월후복부전산화단층촬영에서재발소견보여, 현재항암치료중이다 (Fig. 10). Fig. 7. Preoperative picture and postoperative picture of Rt lobectomy and subtotal gastrectomy with Billroth-I anastomosis. Fig. 8. Gross specimen picture : stomach pylorus and Rt. lobe of liver. Fig. 6. Huge nodular HCC with central necrosis and capsular disruption, right lobe R/O cholangiohepatocellular carcinoma. 26
권택수외 : 원발성위신경내분비종의간전이 2 예 고 찰 (c) Fig. 9. A malignant neoplasm composed of large cells having organoid, nesting, trabecular, rosette-like and palisading patterns that suggest endocrine differentiation, and immunohistochemistry shows Cytokeratin - positive, CD56 - positive(c) 100여년전 Lubarsch 7 에의해말단회장부에발생된신경내분비종이처음으로보고된이후로신경내분비종에대한많은관찰과연구가이루어졌고, 1923년 Askanazy 1 에의해처음으로위신경내분비종이보고되었다. 신경내분비종은위장관에서주로발생하며, 간에전이를잘하는것으로보고되고있으며, gastrin증가에따라활발해진 enterochromaffin cell에의해발생한다. 8 위신경내분비종은전체신경내분비종의 1% 미만, 전체위신생물중 2% 미만을차지하는드문질환이지만, 2 최근보고에의하면위신경내분비종의발생율이높아지고있는것으로보고되고있는데, 이는내시경에의한조기진단의증가와위산억제제의발달로인한가스트린증가가그원인으로생각된다. 9 위신경내분비종의임상적진단은증상의비특이성으로인하여어렵고늦어지기도한다. 상복부통증과함께위장관출혈이가장주증상이며, 안면홍조등의카르시노이드증후군을나타내기도한다. 종종무증상의환자에게서내시경을통해우연히발견되기도한다. 본증례 2예에서환자는간헐적인상복부통증이나불편감만을나타내었고카르시노이드증후군의증상은없었기때문에임상적소견만으로위신경내분비종을진단하기에는어려웠다. 위신경내분비종은크게세가지아형으로분류될수있다. 10 첫번째아형은위신경내분비종의 70-80% 를차지하며보통 2cm 미만, 다발성으로발생한다. 11,12 두번째아형은 5-10% 를차지한다. 세번째아형은 15-20% 를차지하며보통단일병소로크기는 2 cm이상이며, 평균 55세에진단된다. 남자에서발생율이높고가스트린수치는정상, 산발적으로발생한다. 전이가능성은 50% 이상이다. 이분류에의하면본증례 2예는세번째아형에합당하다 (Table 1). Table 1. Characteristics of gastric carcinoid subtypes Type I Type II Type III Fig. 10. Liver reveals new small nonenhancing nodule at left medial segment but no ductectasia and peripyloric node is enlarged to 2.3cm. Percentage of gastric 70-80% 5-10% 15-20% carcinoid tumors Tumor characteristics Usually multicentric Usually multicentric Usually solitary <2cm <2cm >2cm Age of diagnosis 63 50 55 Gender Females>males Male=females Males>females Associated conditions Chronic atrophic Zollinger-Ellison sporadic gatritis type A syndrome, multiple endocrine neoplasia-1 Gastrin levels Increased Increased Normal Metastatic potential <5% 7-12% >50% 위신경내분비종을진단하는방법에는여러가지가있다. 위내시경및생검은진단의정확도를향상시켜주며, 내시경초음파및초음파유도하조직검사는수술전병변의깊 27
한국간담췌외과학회지 : 제 10 권제 4 호 2006 이, 위치에대한정보를제시할수있다. 13 또한 chromaffin A 측정은진단및추적관찰에유용히사용될수있다. 복부전산화단층촬영은국소및원위부전이의평가에사용할수있으며, somatostatin labeled scintigraphy로 somatostatin 수용체를가진종양의원위부전이를발견할수있다. 최근에는 single photon emission computed tomography (SPECT) 가위신경내분비종환자의진단및전이판단에유용히사용되고있다. 14 위신경내분비종의치료법은제 1, 2 아형의경우크기가 1 cm 미만이고, 점막하에국한되었다면내시경적점막절제술 (EMR: Endoscopic mucosal resection) 이추천되며그외에는크기나위치에따라쐐기절제술, 위 ( 아 ) 전절제술을시행한다. 제 3 아형의경우에는국소및원격전이가능성이높으므로위 ( 아 ) 전절제술과림프절절제술을함께시행한다. 15 최근에는 LAR-octreotide를사용한치료법이사용되고있으며이는위신경내분비종첫번째아형으로다발성이며수술위험성이높은경우에사용된다. 전이성신경내분비종의치료법으로는 somatostatin analogue, 항암요법, 수술적절제술등이있다 (Table 2). 위신경내분비종의전체 5년생존율은 63% 이고국소적질환에서는 69.1%, 원격전이질환에서는 21.2% 이다. 16 아형에따른 5년생존율은제 1 아형은 78%, 제 2아형은 62-75%, 제 3 아형은 50% 미만이다. 17-19 우리가경험한증례 2예는제 3 아형으로수술적치료및술후항암요법을사용하였다. 이처럼신경내분비종치료에있어아형의분류및전이여부를정확히판별해야하며, 이에따른치료방법의개별화가이루어져야할것으로생각된다. Table 2. Type I, II Type III size <1cm, submucosal EMR* (Sub)total gastrectomy with LND** size >1cm Wedge resection - (Sub)total gastrectomy (Sub)total gastrectomy with LND 기타치료법 LAR***-octreotide, somatostatin analogue, chemotherapy * Endoscopic mucosal resection, ** Lymph node dissection *** Long-acting formulation 참고문헌 1. Askanazy M: Zur Pathogenese der Magen-krebse und uber inhren gelegentlichen Ursprung aus angeboren epithelialen Keimen in der Magenwand. Dtsch Med Wochenschr 1923, 49:49-51. 2. Godwin JD: Carcinoid tumors-analysis of 2837 cases. Cancer 1975,36:560-569. 3. Moertel CG. Karnofsky Memorial Lecture: An odyssey in the land of small tumors. J Clin Oncol 1987;5:1502-1522. 4. Shebani KO, Souba WW, Finkelstein DM, Stark PC, Elgadi KM, Tanabe KK, Ott MJ.: Prognosis and survival in patients with gastrointestinal tract carcinoid tumors. Ann Surg 1999;229:815-823. 5. Norheim I, Oberg K, Theodorsson-Norheim E, Lindgren PG, Lundqvist G, Magnusson A, Wide L, Wilander E.: Malignant carcinoid tumors. Ann Surg 1987;206:115-125. 6. J Gastrointest Surg. 2004 Sep-Oct;8(6):653-659. 7. Lubarsch O: Ueber den primaren Krebs des Ileum, nebst Bemerkungen uber das gleichzeitige Vorkommenvon Krebs und Tuberkolose. Virchows Arch 1888, 111:280-317. 8. Gough DB, Thompson GB, Crotty TB, et al.: Diverse clinical and pathological features of gastric carcinoid and the relevance of hypergastrinemia. World J Surg 1994, 18:473-480. 9. Abby Mulkeen and Charles Cha: Gastric carcinoid. Curr Opin Oncol 17:1-6. 10. Rindi G, Luinetti O, Cornaggia M, et al.: 3 Subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma-a clinicopathological study. Gastroenterology 1993, 104:994-1006. 11. Bordi C, D'Adda T, Azzoni C, Ferraro G: Pathogenesis of ECL cell tumors in humans. Yale J Biol Med 1998, 71:273-284. 12. Carney JA, Go VLW, Fairbanks VF, et al.: The syndrome of gastric argyrophil carcinoid-tumors and nonantral gastric atrophy. Ann Intern Med 1983,99:761-766. 13. Bordi C, Azzoni C, Ferraro G, et al.: Sampling strategies for analysis of enterochromaffin-like cell changes in Zollinger- Ellison syndrome. Am J Clin Pathol 2000, 114:419-425. 14. Schillaci O, Spanu A, Scopinaro F, et al.: Somatostatin receptor scintigraphy in liver metastasis detection from gastroenteropancreatic neuroendocrine tumors. J Nucl Med 2003, 44:359-368. 15. Gilligan CJ, Lawton GP, Tang LH, et al.: Gastric carcinoidtumors-the biology and therapy of an enigmatic and controversial lesion. Am J Gastroenterol 1995, 90:338-352. 16. Modlin IM, Lye KD, Kidd M: A 50-year analysis of 562 gastric carcinoids: small tumor or larger problem? Am J Gastroenterol 2004, 99:23-32. 17. Rappel S, Altendorfhofmann A, Stolte M: Prognosis of gastric carcinoid- tumors. Digestion 1995, 56:455-462. 18. Meko JB, Norton JA: Management of patients with Zollinger- Ellison syndrome. Annu Rev Med 1995, 46:395-411. 19. Modlin IM, Kidd M, Lye KD: Biology and management of gastric carcinoid tumours: a review. Eur J Surg 2002, 168:669-683. 28