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1 32 소아외과 : 제 12 권제 1 호 2006 년 Vol. 12, No. 1, June 2006 소아에서의췌장의고형유두상상피성종양 경북대학교의과대학외과학교실 윤혁진 박진영 서 론 대상및방법 췌장의고형유두상상피성종양 (Solid and papillary epithelial neoplasm of the pancreas:spen) 은췌장의유두상낭성종양 (Papillary and cystic tumor of the pancreas) 혹은 Frantz 종양이라고도알려져있는드문질환으로모든췌장암의 2-3 % 를차지한다 1. 주로 10대와 20대사이의젊은여성에서발생하며다른췌장에서발생하는종양과달리양성혹은상대적으로저등급악성종양이다 2. 대부분진단당시큰종괴를이루지만완전한절제를시행하면예후가좋다. 그러나 12-15% 에서는인접장기침범이나원격전이가동반된다 2,3. 저자들은경북대학병원소아외과에서 1995년부터 2005년까지술후췌장의고형유두상상피성종양으로진단받은 4예의임상양상, 수술및치료결과를분석하고문헌고찰을시행하였다. 이논문은 2005 년 10 월 27 일서울에서개최된제 57 회대한외과학회추계통합학술대회에서구연되었음. 접수일 : 05 / 12 / 1 게재승인일 : 06/3/22 교신저자 : 박진영, 대구광역시중구삼덕 2 가 50 경북대학병원일반외과 Tel : 053) , Fax : 053) kpnugs@yahoo.co.kr 1995년부터 2005년까지경북대학병원소아외과에서수술을받고병리조직검사상췌장의고형유두상상피성종양으로확진된 4예를대상으로성별, 나이, 증상, 진단방법, 수술방법, 수술소견및병리조직검사결과, 치료결과에대하여의무기록지를검토하여후향적조사를시행하였다. 결과본원에서술후췌장의고형유두상상피성종양으로확진된 4예환아의임상정보를요약하였다 ( 표 1). 수술당시환아의나이는 10세부터 13세까지로평균연령은 12세 7개월이었으며남아가 1예, 여아가 3예였다. 환아의주소는복통과복부종괴가 1예였고, 2 예에서는복부종괴없이복통혹은오심, 구토를호소하였다. 1예는복부둔상후에혈복강으로인한저혈압및복통을주소로본원응급실로전원되었다. 4예중 3예에서시행한종양표식자 (CEA, CA 19-9) 는정상범위내였다. 모든환아에서복부초음파검

mass Abdominal CT * SPEN; Solid and papillary epithelial neoplasm of the pancreas in children Table 2.

2 윤혁진외 : 소아에서의췌장의고형유두상상피성종양 33 Table 1. Demographics, Clinical Presentation and Diagnosis of Children with SPEN* Case No. Sex/age Presentation Diagnosis 1 F/13 Abdominal pain, mass Abdominal USG, CT 2 M/10 Nausea, vomiting Abdominal USG, CT 3 F/13 Abdominal pain, nausea, vomiting Abdominal CT, MRI 4 F/12 Abdominal pain, mass Abdominal CT * SPEN; Solid and papillary epithelial neoplasm of the pancreas in children Table 2. Location and Size, Surgical Procedure and Clinical Outcome of SPEN* Case Follow-up(months)/ Location Size(cm) Surgery No. Clinical status 1 Body 10 Distal pancreatectomy, splenectomy 121/NED 2 Body 8 Distal pancreatectomy 82/NED 3 Tail 10 Distal pancreatectomy, splenectomy 35/NED 4 Body & tail 15 Subtotal pancreatectomy, splenectomy 6/Metastasis * SPEN; Solid and papillary epithelial neoplasm of the pancreas in children NED; No evidence of disease Fig. 1. Abdominal CT scan, showing hemoperitoneum and a large pancreatic tumor, ruptured. 사혹은복부전산화단층촬영을시행하여췌장의종괴를발견하였으며술전에조직검사는시행하지않았다. 표 2는췌장종괴의위치및크기, 수술방법, 수술후경과를요약하였다 ( 표 2). 종괴는 2예에서췌장의체부, 1예에서체부및미부, 1예에서미부에발생하였으며주로췌장의체부및미부에위치하였다. 수술은 1예에서말단췌장절제술, 2예에서말단췌장절제술및비장 Fig. 2. Operative findings, demonstrating a ruptured huge mass through the transverse mesocolon. 절제술을시행하였다. 1예에서는복부둔상후복통및저혈압으로본원응급실로전원되었으며복부전산화단층촬영상 15 cm 크기의췌장종괴와혈복강소견을보여서 ( 그림 1) 응급개복술을시행하였다. 수술소견상췌장의종괴는횡행결장막하부를통하여파열되어혈복강이심했고, 15 cm 크기의종괴와상장간막동맥및정맥, 문맥과의구분이잘되지않아서 1차응급수술시에

술후 ifosfamide, etoposide, cisplatin 을이용하여 3차례의항암요법을시행하였으며복부전산화단층촬영상종양의크기가 7.5 cm로줄어들어서 ( 그림 3) 1차수술 3개월후다시 2차수술로췌장아전절제술및비장절제술을시행하였다.

3 34 소아외과제 12 권제 1 호 2006 년 Fig. 3. Follow-up abdominal CT scan after 3 cycles of chemotherapy. The pancreatic mass decreased in size. Fig. 4. Follow-up abdominal CT scan, showing metastatic nodule in the segment 7 and 8 of the liver. Radiofrequency ablation was performed. 는종양을절제해내지못하고지혈만시행하였으며술후조직검사상췌장의고형유두상상피성종양으로확진되었다 ( 그림 2). 술후 ifosfamide, etoposide, cisplatin 을이용하여 3차례의항암요법을시행하였으며복부전산화단층촬영상종양의크기가 7.5 cm로줄어들어서 ( 그림 3) 1차수술 3개월후다시 2차수술로췌장아전절제술및비장절제술을시행하였다. 2차수술 3개월후에시행한복부전산화단층촬영상문맥내종양혈전및간 7, 8번구역에전이성병변이발견되어 radiofrequency ablation을시행하고 ( 그림 4) 현재항암요법을계속시행하고있다. 수술후측정한종괴의최대직경은평균 10.8 cm (8-15 cm) 였다. 전예에서수술후합병증은없었으며수술후 6개월부터 121개월까지평균 61개월간의추적관찰에서 3예에서는재발및사망이없었으나 1예에서문맥내종양혈전및간전이로항암요법을계속시행하고있다. 고찰췌장의고형유두상상피성종양은과거에유두상낭성종양 (papillary cystic tumor), 고형유두상상피성종양 (solid and papillary epithelial neoplasm), 유두상상피성종양 (papillary epithelial neoplasm) 등으로혼동되어져불려지기도했다 4,5. 하지만 1959년 Frantz가처음으로과거에비기능성도세포암 (islet cell tumor) 으로잘못진단된 4예의췌장종양을모아서그녀의이름을인용한새로운질환 Frantz 종양을확립했다 6. 췌장의고형유두상상피성종양은드문일차성췌장종양으로모든췌장암의 2-3 % 를차지하며 1 다른췌장에서발생하는종양과달리양성혹은상대적으로저등급악성종양이다. 남녀비는 1:9.78로여성에서호발하며, 주로 10대와 20대사이의젊은여성에서호발하며평균나이는 21.97세이다 6,7. 최등 8 은성인과비교해서소아의경우여아에서

4 윤혁진외 : 소아에서의췌장의고형유두상상피성종양 35 호발하는경향이적다고보고하였으며, 저자들의경우에도비록증례수가적어서단순비교는어렵지만 25 % 가남아에서발생하여소아의경우여아에서호발하는경향이적었다. 발생부위는췌장의미부에 35.9 % 로가장호발하고다음이췌장의두부로 34 % 발생하였으며 7, 대부분의종양은췌장에서발생하지만결장간막, 후복막이나간의이소성췌장조직에서도발생한다고한다 2,4. 저자들의경우는 2예에서췌장의체부, 1예에서체부및미부, 1예에서미부에종양이발생하여주로체부와미부에종양이발생하였으며두부에는발생하지않았다. 아직까지병인은정확하게규명되지않았지만 Zamboni 등 9 과 Ladanyi 등 10 은에스트로겐수용체와프로게스테론수용체를발견하여고형유두상상피성종양의병인이호르몬과관련이있다고제안하였다. Morales 등 11 은임신중에종양의크기가증가하는것을보고성호르몬이종양의병인보다는종양의성장에중요한역할을한다고주장하였다. Kosmahl 등 12 도가임기초반에성호르몬이증가되어종양의성장을자극한다고했으며, 월경주기동안에프로게스트론수치의증가및감소에의해서광범위한출혈성괴사부위및고형부위가생긴다고설명하였다. Sclafani 등 13 은에스트로겐수용체가양성인환자에서 tamoxifen을성공적으로사용하였다고보고하였다. SPEN의생물학적및조직학적특징은잘알려져있지만아직까지기원세포및췌장에관한표현형 (phenotype) 은수수께끼로남아있다. 선방세포 (acinar cell), 소관세포 (ductal cell) 혹은내분비세포가기원세포라는가설이있는데 14 Stommer 등 15 과 Mao 등 4 은종양이내분비혹은외분비세포로분화될수있는 pluripotential 태아줄기세포에서유래한다고주장하였다. Kosmahl 등 12 은태아발생과정중에 genital ridge와 ovarian anlage related 세포에서종양이발생한다고주장하였다. 많은다른종양발생이 p53 mutation과연관이있어서 SPEN 에서도 p53 과표현에관한연구가진행되었으나연관성을찾는데는실패하였고다른악성낭성췌장종양과는달리 K-ras mutation 은발견되지않았으 며 9,16,17 염색체 13 번과 17 번사이의불균형 염색체전이가발견되었다 18,19. 면역조직학적으로이종양은 vimentin, alpha-1-antitrypsin, alpha-1-antichymotrypsin과 neuron specific enolase (NSE) 에양성을보인다 12. 신경내분비표식자로는 NSE, synaptophysin, chromogranin A와 tyrosine hydroxylase (TH) 가있는데 SPEN 의경우에 90 % 이상에서 NSE가양성으로나타나며 synaptophysin은 22 % 에서면역반응을보이지만, TH는단지몇몇종양에서나타나며 chromogranin A는발견이되지않는다. 이런신경내분비세포표식자에대한뚜렷하지않은반응은결국 SPEN이순수한신경내분비종양으로간주될수없다는것을나타낸다 12. 증상은상복부불쾌감이나종양의성장에의한통증과같은비특이적인위장관증상이주로동반되며종종복부종괴가촉지될수도있다 7. 종양은서서히자라기때문에종종종양이상당히커질때까지증상이없

5 36 소아외과제 12 권제 1 호 2006 년 이지내다가다른질환혹은복부둔상후에복부초음파나복부전산화단층촬영을시행하는중에우연히발견되기도한다. SPEN에서합병증이발생하는경우는드물지만 Mao 등 4 은복강내출혈을동반한 SPEN을보고하였으며저자들의경우에도복부둔상후에종양파열로인한혈복강으로진단이된경우가있었다. 임상병리검사상에서췌장기능부족이동반되는경우는없으며, 간기능검사와혈중췌장효소혹은췌장내분비검사는정상이며, 종양표식자검사도보통정상범위내이다 20. 저자들의경우에도전예에서간기능검사, 혈중췌장효소및췌장내분비검사는정상범위내였으며, 4예중 3예에서시행한종양표식자 (CEA, CA 19-9) 검사도정상범위내였다. 간혹드물지만종양의파열로인한혈복강으로빈혈이발생하는경우가있는데 21,22 저자들도 1예에서복부둔상후종양파열로인한혈복강으로저혈압및빈혈이발생한경우가있었다. 술전에췌장에발생한종괴를구분하기위해서복부초음파, 복부전산화단층촬영. MRI, 혈관촬영등을시행한다 하지만술전에방사선학적검사만으로췌장종양을정확하게감별진단하기가어렵기때문에복부초음파하세침흡입검사는수술전진단에중요하다 21,25. Crawford 등 25 은술전세침흡입검사로 SPEN의 70% 이상을진단해냈다고보고했지만세침흡입검사는상당히침습적이고종양전파의가능성때문에시행하지말자는의견도있다 26. SPEN은조직학적으로악성의양상을보이지만임상적으로는전형적인양성의경과 를보이고저등급의악성을나타낸다. 일부분에서국소적인침윤과간, 주위림프절, 장간막, 대망및복막으로드물게전이가되는경우가있지만이러한경우에도장기간생존하는것을경험하였다고한다 13, 소아에서는전이가동반되는경우가매우드물며, 40세이후의나이가많은환자나남성에서종양이발생하는경우에예후가나쁘다 31. 특히정맥침범, 핵의비정형의정도, 유사분열수, 큰괴사군집이있는경우악성의가능성이증가되며, 전이가동반되는경우에핵의 DNA- 배수성등급이홀배수체를나타내며악성의징후가없는환자에서는두배수체를나타낸다고한다 32. 종양의절제가불가능한경우나불완전절제시에아직까지치료에대한의견이분분하며, 항암치료및방사선치료에대한성적이정확하게알려지지않았으며단지몇몇증례만이보고되었다. Fried 등 33 은 SP- EN은 radiosensitive 하며 6주간에걸쳐서 4000 cgy방사선으로치료하였다고보고하였다. Strauss 등 34 은술중에발견된상장간막정맥을침범한 5 cm 크기의절제불가능한종양을 cis-platinum과 5-fluorouracil으로 6개월간치료하여 3.5 cm 크기의절제가가능한종양으로크기를줄인후에수술을시행했다고보고하였다. Rebhandl 등 21 은술후에다발성으로복막과간, 비장의표면에전이가발생한환자에서 ifosfamide, cisplatin, VP16을 2회사용하였다고보고하였다. Das 등 35 도위후벽침윤및대동맥주위림프절병증을동반한 11 cm크기의절제불가능한종양을 gemcitabine 과 cisplatin으로 6회치료한후에종양의크기를 50 % 까

6 윤혁진외 : 소아에서의췌장의고형유두상상피성종양 37 지감소시키고위후벽침윤과대동맥주위림프절병증도사라진후에수술을시행하였다. 저자들의경우에도췌장종괴파열로인한혈복강으로본원에전원된여아에서 1 차수술시종괴와상장간막동맥및정맥, 문맥과의경계가불분명하고절제가불가능하여지혈만시행하였으며, 술후 ifosfamide, etoposide, cisplatin을이용한항암요법을시행하여종양의크기를줄인후에 1 차수술 3개월후 2차수술에서췌장아전절제술및비장절제술을시행하였다. 이상으로볼때절제불가능한종양의경우에술전에항암치료를시도하여종양의크기를줄이거나주위조직으로침범된부위를치료하여안전한수술을시행할수가있다고사료된다. 하지만이러한환자의장기생존이항암치료및방사선치료에의한것인지아 니면 SPEN의자연적인병경과에의한것인지는정확히판단하기가어려워앞으로더많은연구가필요하다. 참고문헌 1. Morohoshi T, Held G, Kloppel G: Exocrine pancreatic tumours and their histological classification: A study based on 167 autopsy and 97 surgical cases. Histopathology 7: , Madan AK, Weldon CB, Long WP, Johnson D, Raafat A: Solid and papillary epithelial neoplasm of the pancreas. J Surg Oncol 85: , Gonzalez-Campora R, Rios Martin JJ, Villar Rodriguez JL, Otal Salaverri C, Hevia Vazquez A, Valladolid JM, Portillo M, Galera Davidson H: Papillary cystic neoplasm of the pancreas with liver metastasis coexisting with thyroid papillary carcinoma. Arch Pathol Lab Med 119: , Mao C, Guvendi M, Domenico DR, Kim K, Thomford NR, Howard JM: Papillary cystic and solid tumors of the pancreas : A pancreatic embryonic tumor? Studies of three cases and cumulative review of the world s literature. Surgery 118: , Lam KY, Lo CY, Fan ST: Pancreatic solid-cystic-papillary tumor: clinicopathologic features in eight patients from Hong Kong and review of the literature. World J Surg 23: , Frantz VK: Tumors of the pancreas Atlas of Tumor Pathology, section VII, fascicles 27 and 28. Washington, DC, US Armed Forces Institute of Pathology, 19-59, Pp Papavramidis T, Papavramidis S: Solid pseudopapillary tumors of the pancreas: Review of 718 patients reported in English literature. J Am Coll Surg 200: , 최석호, 김대연, 박귀원, 정성은, 이성철, 김우기, 장자준 : 소아에서의췌장의고형유두상상피성종양. 소아외과 4:55-60, Zamboni G, Bonetti F, Scarpa A, Pelosi G, Doglioni C, Iannucci A, Castelli P, Balercia G, Aldovini D, Bellomi A: Expression of progesterone receptors in solid- cystic tumour of the pancreas: a clinicopathological and immunohistochemical study of ten cases. Virchows Arch A Pathol Anat Histopathol 423: , Ladanyi M, Mulay S, Arseneau J, Bettez P: Estrogen and progesterone receptor determination in the papillary cystic neoplasm of the pancreas with immunohistoc-

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8 윤혁진외 : 소아에서의췌장의고형유두상상피성종양 39 S, Oda K, Ichikawa M, Hayakawa S: Frantz s tumor(solid and cystic tumor of the pancreas) with liver metastasis: Successful treatment and long-term follow-up. J Ped Surg 30: , Hassan I, Celik I, Nies C, Zielke A, Gerdes B, Moll R, Ramaswamy A, Wagner HJ, Bartsch DK: Successful treatment of solid-pseudopapillary tumor of the pancreas with multiple liver metastases. Pancreatology 5: , 문상희, 김현영, 박귀원, 정성은, 이성철, 김우기 : 소아에서의간전이를동반한췌장의고형유두상상피성종양. 소아외과 11:40-45, Matsunou H, Konishi F: Papillary cystic neoplasm of the pancreas: A clinicopathologic study concerning the tumor aging and malignancy of nine cases. Cancer 65: , Nishihara K, Nagoshi M, Tsuneyoshi M, Yamaguchi K, Hayashi I: Papillary cystic tumors of the pancreas. Assessment of their malignant potential. Cancer 71:82-92, Fried P, Cooper J, Balthazar E, Fazzini E, Newall J: A role for radiotherapy in the treatment of solid and papillary neoplasms of the pancreas. Cancer 56: , Strauss JF, Hirsch VJ, Rubey CN, Pollock M: Resection of a solid and papillary epithelial neoplasm of the pancreas following treatment with cis-platinum and 5-fluorouracil: A case report. Med Pediatr Oncol 21: , Das G, Bhuyan C, Das BK, Sharma JD, Saikia BJ, Purkystha J: Spleen-preserving distal pancreatectomy following neoadjuvant chemotherapy for papillary solid and cystic neoplasm of pancreas. Indian J G astroenterol 23; , 2004

9 40 소아외과제 12 권제 1 호 2006 년 Solid and Papillary Epithelial Neoplasm of the Pancreas in Children Hyukjin Yoon, M.D., Jinyoung Park, M.D. Department of Surgery, School of Medicine, Kyungpook National University Taegu, Korea Four children with solid and papillary epithelial neoplasm of the pancreas are reported. Three were girls. Mean age at operation was 12 years and 7 months (10-13 years). Clinical presentation included nausea, vomiting, and apalpable mass. One had hemoperitoneum due to tumor rupture. In two cases, tumors were in the body of the pancreas, and one the body and tail, and in one,the tail. Mean diameter of the tumors was 10.8 cm (8-15cm). Surgical procedures were distal pancreatectomy and splenectomy in 2 cases, distal pancreatectomy in one, and subtotal pancreatectomy and splenectomy in one. Mean follow-up period was 61 months (6-121 months). Three patients are still alive without any recurrence. However, in the one case of ruptured tumor, portal vein thrombosis and liver metastasis developed after subtotal pancreatectomy and splenectomy during the course of postoperative adjuvant chemotherapy. (J Kor Assoc Pediatr Surg 12(1):32~40), Index Words:Solid and papillary epithelial neoplasm, Pancreas, Children, Chemotherapy Correspondence:Jinyoung Park, M.D., Department of Surgery, Kyungpook National University Hospital, 50 Samduk-2 Ga, Chung-gu, Taegu , Korea Tel : 053) , Fax : 053) kpnugs@yahoo.co.kr

김범수

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