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1 pissn eissn J Korean Assoc Pediatr Surg Vol. 20, No. 2, December Original Article 신생아기신경모세포종의임상적고찰 : 산전진단군과산후진단군의비교 박훤함 1, 김수홍 4, 정성은 1, 이성철 1, 박귀원 1, 이지원 2, 강형진 2, 신희영 2, 백해운 3, 김현영 1 1 서울대학교어린이병원소아외과, 2 서울대학교의과대학소아청소년과학교실, 암연구소, 3 서울대학교어린이병원병리과, 4 부산대학교어린이병원소아외과 Clinical Feature of Neonatal Neuroblastoma: Comparison of Outcome between Diagnosed Prenatally and at Postpartum Group Hwon Ham Park 1, Soo-Hong Kim 4, Sung-Eun Jung 1, Seong-Cheol Lee 1, Kwi-Won Park 1, Ji Won Lee 2, Hyoung Jin Kang 2, Hee Young Shin 2, Hae Woon Baek 3, Hyun-Young Kim 1 1 Department of Pediatric Surgery, Seoul National University Children s Hospital, Seoul, 2 Department of Pediatrics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, 3 Department of Pathology, Seoul National University Children s Hospital, Seoul, 4 Department of Pediatric Surgery, Pusan National University Children s Hospital, Yangsan, Korea Purpose: Neonatal neuroblastoma (NBL) is the most common malignant tumor in neonates, but there have been few studies about it. The purpose of this study was to investigate the clinical features of NBL and to compare prenatal and postnatal diagnosed groups. Methods: Nineteen patients who were diagnosed with NBL prenatally or within 28 days after birth from February 1986 to February 2013 in Seoul National University Hospital were enrolled in the study. The patients were categorized according to the International Neuroblastoma Staging System (INSS) and Children s Oncology Group (COG). Retrospective medical-record reviews were performed on these patients. The operative date, complication, pathological stage, and overall survival of the prenatally diagnosed group and the postpartum diagnosed group were compared. Results: Tumor was detected via prenatal ultrasonography in 8 patients (42.1%), and 11 patients (57.9%) were diagnosed within 28 days after birth. Based on INSS, the patients were divided into the stage I (n=8), stage II (n=1), stage III (n=3), stage IV (n=4), and stage IVs (n=3) groups, respectively. Based on COG, on the other hand, the patients were divided into the low-risk (n=8), intermediate-risk (n=8), and high-risk (n=3) groups. The postoperative complication rate was 29%. One patient died from complications from chemotherapy. The other 18 patients mean follow-up period was 77.7 months. The differences between the postoperative complication rate, proportion of early-stage tumor, and overall survival of the prenatal and postnatal groups were not statistically significant (p=0.446, p=0.607, p=0.414). Conclusion: NBL showed favorable outcomes but relatively higher postoperative complications. There seem to be no significant statistical differences in the postoperative complications, proportion of early-stage tumor, and overall survival between the prenatally diagnosed group and the postpartum diagnosed group. Keywords: Neuroblastoma, Neonate, Prenatal diagnosis, Postpartum, Outcome 서론신경모세포종은소아기에관찰되는 1세미만에서가장흔한악성종양으로전체소아암의 7% 이상을차지하고있으며, 백혈병, 중추신경계종양, 림프종다음으로흔하다 [1]. 신경모세포종은진단시나이, 병기, N-myc 증폭여부, 염색체이상, 병리조직학적소견, DNA 배수성결과등에따라병기와위험군이나누어지며, 위험군에따라다른치료가적용되고예후에도차이가있다 [2-6]. 그러나같은병기에서도나이가어릴수록생존율이높음이보고되기도하였다 [7]. Received: October 16, 2014, Revised: November 3, 2014, Accepted: November 4, 2014 Correspondence: Hyun-Young Kim, Department of Pediatric Surgery, Seoul National University Children s Hospital, 101, Daehak-ro, Jongno-gu, Seoul , Korea. Tel: , Fax: , spkhy02@snu.ac.kr Copyright 2014 Korean Association of Pediatric Surgeons. All right reserved. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited Journal of the Korean Association of Pediatric Surgeons 53

2 J Korean Assoc Pediatr Surg 2014;20(2):53-57 발생부위에따라임상양상은다양하게나타나며, 복부종괴로만져지는경우가가장많다. 그외종격동에발생시호흡기계증상을유발하며, 척추주변이나신경절에발생시신경관련증상등이나타나는등원발부위에따라다른임상양상이나타난다 [1,8]. 신생아기신경모세포종은신생아기에가장많이발생하는악성종양으로신생아기악성종양의약 20% 를차지한다 [9]. 1983년 Fénart 등 [10] 이처음으로산전초음파로진단된신경모세포종을보고한후산전검사가발전함에따라신생아기신경모세포종의발생빈도는증가하고있다. 신생아기신경모세포종의전체생존율은약 90%-91% 정도로, 예후가좋은것으로알려져있으며 [8,11], 산전진단된경우예후를높일수있다는연구 [12] 와산전진단이생존율에미치는영향이없다는보고 [13] 도있어산전진단의유용성에대해서는논란이있다. 국내에서신생아기신경모세포종에대한연구는드문실정으로본연구에서는신생아기신경모세포종의임상양상을조사하고산전진단된군과산후진단된군을비교분석하고자하였다. 대상및방법 1986년 2월부터 2013년 2월까지서울대학교어린이병원에서산전또는생후 28일이내초음파에서신경모세포종이의심되었던환자중조직검사로확진된환자를대상으로하였다. 추적관찰기간은 2014년 2월을기준으로하였고치료종료된환자는종료된시점을기준으로하였다. 조직검사는수술후조직검사와세침흡인조직검사로시행되었다. 대상환자의연령, 성별, 재태기간, 동반기형유무, 임상증상, 징후, 영상의학적진단, 종양의크기, 병리소견, 치료및예후대해의무기록검토를통하여후향적으로분석하였다. 또한 N-myc 유전자의증폭을형광동소보합법 (flurorescent in situ hybridization) 을통해평가하였으며, 12 명의환자는기존의병리결과에서확인되었으나 5명의환자는기존병리결과에있지않아보관되어있던병리검체를이용하여추가검사를시행하였다. 종양의병기는 International Neuroblastoma Staging System (INSS) 에따라분류하였으며위험도는 Children s Oncology Group (COG) [14] 에따라분류하였다. 치료는 INSS 병기와위험도, 원발부위종괴의크기를고려하여진행하였다. INSS 제I 병기, 제II 병기의경우수술적치료를시행한후조직검사결과에따라항암치료를추가하였으며, 제III 병기의경우원발부위종괴의크기가매우큰경우는항암치료후수술을시행하고수술후항암치료를추가하였고, 절제가 가능할정도의크기인경우는수술적절제를먼저시행하고수술후항암치료를하였다. 제IV 병기의경우는항암치료를먼저시행후수술적치료를시행하고수술후항암치료를추가하였다. 제IVs 병기의경우원발부위를절제한후항암치료를하거나경과관찰만을하기도하였다. 전체환자를산전진단군과산후진단군으로나누어수술시기와수술후합병증, 병기및생존율을비교하였다. 통계는 IBM SPSS Statistics version 20.0 (IBM co., Armonk, NY, USA) 를이용하여 Fisher s exact test 로분석하였고, 생존율은 Kaplan-meier 방법으로산출하였으며 Log-rank test 로비교하였다. 결과총 19 명중남자가 12 명, 여자가 7명이었다. 35 주에태어난 1명의환자를제외하고모든환자는만삭아였으며 (Table 1), 체중은평균 3.5 kg이었다. 5명에서동반기형이있었으며 2 명은심실중격결손, 1명은방광요관역류, 1명은태아수종, 배아기기질부출혈, 유미흉, 1명은선천성사경을진단받았다. 8명 (42.1%) 은출생전진단되었고, 11명 (57.9%) 은출생후진단되었다. 수술없이세침흡인검사로확진된경우가 2명, 수술후조직검사로확진된경우가 17명이었다. 산후진단된 11 명중 6명은다른질환에대해검진중우연히발견되었으며, 4명은만져지는종괴, 다른한명은지속적인담즙성구토가주된증상이었다. 종괴로만져져진단되었던경우는경부에서 2명, 복부에서 1명, 경부, 복부, 두피에서다발성으로촉지되었던경우가 1명이었다. 전체 19 명의환자중 18명의환자는영상검사에서신경모세포종이의심되었으나나머지 1명은산전초음파에서부신출혈소견으로추적관찰중크기가감소되지않아수술시행후진단되었다. 종양은부신에서 15명, 종격동에서 2명, 요추의우측주위에서 1명, 우측경부에서 1명이발생하였다. 종양의크기는중앙값 3.7 cm ( 범위 cm) 로측정되었다. INSS 에따른분류에서제I 병기환자가 8명, 제II 병기환자가 1명, 제III 병기환자가 3명, 제IV 병기환자가 4명, 제 IVs 병기환자가 3명이었다. COG 에따른위험도분류결과저위험군은 8명, 중간위험군 8명, 고위험군 3명이었다. N-myc 유전자증폭은 1명에서만발견되었다. 제I 병기 8명은수술적절제만시행하였고, 제II 병기환자 1명은불완전절제가되었고중간위험군이어서수술후항암치료를추가하였다. 제III 병기의경우 2명은크기가 4 cm, 6 cm로절제가가능하여수술을먼저시행후항암치료를추가하였다. 제 III 병기중다른 1명은산전진단된경우로출생후종격동에약 12 cm 크기로대동맥을감싸고있는종괴가있었으며, 출 54 Journal of the Korean Association of Pediatric Surgeons

3 Park HH, et al: Comparison of Outcomes between Diagnosed Prenatally and at Postpartum Group Table 1. Patient Demographics Patients No. Sex Birth weight (kg) Age at diagnosis (day) Age at operation (day) Stagea) Risk b) N-myc amplification Tumor site/ size (cm) Pre/postop. chemotherapy Operation Postop. complications Follow-up period (mo) Present status 1 M 3.00 Prenatal 147 I Low Unilateral AG/3 / Complete resection Ileus, vesicoureteral reflux 142 Alive 2 M 4.08 Prenatal 296 III Intermediate Mediastinal/12 +/+ Incomplete resection - 95 Alive 3 F 3.17 Prenatal 30 III Intermediate Paravertebral/6 /+ Incomplete resection Surgical wound 71 Alive complication, Rt. hydronephrosis 4 M 4.58 Prenatal 22 I Low Unilateral AG/3.5 / Complete resection Alive 5 F 3.25 Prenatal 42 IVs Intermediate Unilateral AG/5 /+ Complete resection c) Alive 6 F 3.40 Prenatal 32 I Low Unilateral AG/2 / Complete resection - 70 Alive 7 M 3.80 Prenatal 52 I Low Unilateral AG/3 / Complete resection Abdominal 58 Alive abscess 8 M 3.80 Prenatal 93 I Low Unilateral AG/2.5 / Complete resection - 13 Alive 9 M IV Intermediate Unilateral AG/5.6 +/+ Incomplete resection - 14 Alive 10 M I Low Unilateral AG/4 / Complete resection - 85 Alive 11 M I Low Unilateral AG/1.8 / Complete resection - 64 Alive 12 F IVs Intermediate Unilateral AG/3.2 /+ Complete resection c) - 69 Alive 13 M IV High Rt. AG/2.2 +/ Dead Lt. AG/2.3 (sepsis) 14 M II Intermediate Mediastinal/3.5 /+ Incomplete resection - 89 Alive 15 F IV High + Rt. AG/2 Lt. AG/2.5 +/+ Complete resection Adrenal insufficiency 48 Alive 16 M I Low Unilateral AG/5 / Complete resection - 89 Alive 17 F IV High Rt. neck/4.5 /+ Incomplete resection Vocal cord 51 Alive palsy 18 F IVs Intermediate Unilateral AG/5 / Alive 19 M III Intermediate Unilateral AG/4 /+ Incomplete resection Alive M, male; F, female; AG, adrenal gland; Pre/postop., pre/postoperative; Rt., right; Lt., left. a) b) Stage according to the International Neuroblastoma Staging System. Risk according to the Children's Oncology Group. c) Complete resection of primary site. Journal of the Korean Association of Pediatric Surgeons 55

4 J Korean Assoc Pediatr Surg 2014;20(2):53-57 생당시호흡곤란을보여양쪽흉관삽입후생후 22일에조직검사를시행하여진단이되었던환자로, 항암치료후수술을시행하였고다시수술후항암치료를진행하였다. 제IV 병기의경우경부종괴로호흡이어려웠던 1명에서수술로종괴를제거하고수술후항암치료를하였고, 다른 3명은항암치료를먼저시행하였다. 제IVs 병기의경우 2명은각각보호자거부및초기진단이부신출혈이어서수술을먼저시행한후항암치료를시행하였고, 나머지 1명은수술을시행하지않고경과관찰하였다. 이환자는 6개월후시행한초음파검사상원발부위인부신과간의다발성전이가소실된소견을보여자연관해가확인되었다. 19명중 10명에서항암치료가수술전혹은수술후에시행되었고 modified Children s Cancer study Group (CCG 321P2; cisplantinum, doxorubicin, etoposide) 이주로이용되었으며, 이중 1명은수술전항암치료시행중폐합병증으로인한패혈증으로사망하였다. 수술시평균나이는 2.6 개월이었으며, 22일에서 296 일사이에분포되어있었다. 수술후합병증은수술을시행한 17 명중 5명 (29.4%) 에서 7예발생하였으며신경인성방광, 우측수신증과같은비뇨기계합병증 2예, 장폐색 1예, 복강내감염 1예, 부신기능부전 1예, 성대마비 1예, 수술후창상부작용 1예가발생하였다. 합병증은제I 병기에서 3예, 제III 병기에서 2예, 제IV 병기에서 2예발생하였다. 저위험군 2명에서 3예, 중간위험군 1명에서 2예, 고위험군 2명에서 2예발생하였다. 총 19명의환자중항암화학치료후발생한패혈증으로사망한환자 1명을제외하고 18명의환자는재발이나불완전절제한종양의크기가더늘지않고생존해있다. 정중관찰기간은 77.7 개월 ( 범위 개월 ) 이었다. 산전진단군과산후진단군을비교하였을때산전진단군의수술시나이는평균 2.4 개월이었고, 산후진단군의수술시나이는평균 3.4 개월이었다. 산전진단군의 37.5%, 산후진단군의 22.3% 에서합병증이발생하였으나통계적유의성은없었다. 초기병기의비율및생존율에있어서도산전및산후진단군사이에유의한차이는보이지않았다 (Table 2). 고찰 Moppett 등 [11] 은신생아신경모세포종은소아악성종양중약 2% 정도로보고하였고, 미국출생아 10만명중 명의빈도로발생한다고하였다. 최근산전초음파의확대와주산기검사의발전으로인해신생아신경모세포종의빈도는점차증가하는추세이다 [12,13]. 신생아기신경모세포종의치료는일반적인신경모세포종의치료원칙에준하지만신생아라는특수성과신경모세포종이자연관해가가능한특성등을고려하여시행된다. Dhir 과 Wheeler[8] 는제IVs 병기환자의치료에대해증상과조직세포의양상을기준으로한다고보고하였다. 위장관, 호흡기, 또는신경학적증상이없고세포양상이좋은경우에는자연관해를기다려볼수있다고발표하였다. 다른연구 [13] 에서도증상이있지않은제IVs 병기환자에서는치료를시행하지않았고자연관해를기대하였다고하였다. 따라서본병원에서는신생아기에발생한신경모세포종에대해무증상의경우초음파등의영상검사로추적관찰을하다가종괴의크기가감소하지않을경우치료를결정하게된다. 본연구의경우진단후수술시기가매우다양하게관찰되고있는바, 이는치료결정에있어종괴의성상및자연경과, 환자의전신상태, 다양한치료방법및보호자의동의여부등다양한요인이작용한결과라할수있으며, 후향적연구의한계로인해이에대한상세한분석이어려웠다. 신생아기의신경모세포종은대체로좋은예후를보인다. 기존의연구에서신생아기신경모세포종의전체생존율은 91% 로, 초기병기의비율이약 67% 에달했다. 이를 INSS 병기로분류하였을때 I, II, III, IVs 병기의생존율은 93%-100% 이고, IV 병기의생존율은 50% 였다 [11]. 약 92% 의좋은생존율을보인다고보고한신생아기신경모세포종에관한다른연구에서도초기병기의비율은약 73% 로높았다 [15]. 본연구결과전체생존율은 94.7% 로다른연구와유사하게양호하였고, 진단시초기병기에속하는 I, II, IVs 병기의환자가약 63% 로비율이높았으며, COG 에따른분류에서도저위험군환자의비율또한 42% 로높았다. 예후에영향을미치는 N-myc 증폭도전체환자중 1명에서만관 Table 2. Outcome of Prenatally Diagnosed Group and Diagnosed at Postpartum Group Prenatally diagnosed group Diagnosed at postpartum group p-value Number of patients 8 11 Mean age at operation (mo) Postoperative complication (%) Early stage (I, II, IVs) (%) Overall survival (%) Journal of the Korean Association of Pediatric Surgeons

5 Park HH, et al: Comparison of Outcomes between Diagnosed Prenatally and at Postpartum Group 찰되었다. 이는진단시초기병기가많은점과저위험군의빈도가높은것, N-myc 증폭이적게발생하는것등이좋은예후에영향을미친것임을알수있는결과라하겠다. 신생아기신경모세포종은좋은예후를보이나영아기에수술이진행되는경우가많아수술혹은항암치료등과연관된합병증을유의해야한다. Gigliotti 등 [13] 은신생아기신경모세포종의치료의부작용으로사망한환자가진행된병기에서는 45명중 11명 (24.4%) 이었으며, 초기병기에서도 88명중 5명 (5.4%) 에달한다고하였고, 그중수술과관련된합병증으로사망한경우가 3.4% 로보고한바있다. 영아기신경모세포종의연구에서도 17% 의환자가치료합병증으로사망하였다고발표하였고이중 12.1% 가감염으로사망하였다 [16]. 본저자들의경우약 29% 의환자에서치료와관련된합병증이발생하였고 1명은항암치료와관련된패혈증으로사망하여신생아기신경모세포종의치료에있어이른연령대임을고려하여합병증을줄이기위한노력이중요할것으로생각된다. 1983년최초로산전검사로진단된신경모세포종이보고된후 [10], 산전진단을통해신생아기신경모세포종의좋은예후를얻을수있을것으로알려졌다 [12,17]. Blackman 등 [17] 은산전초음파를통해중간위험도의척추에인접한신경모세포종의증을확인한뒤조기분만과조기항암치료로합병증방지및예후에도움을줄수있다고보고하였다. Granata 등 [12] 도산전진단된종양의양상에따라치료방침을조기에결정함으로써좋은예후를기대할수있다고하였다. 반면다른저자들은산전진단된경우전체생존율은 66.7%, 산후진단된경우는 75.1% 로보고하면서진단된시기와전체생존율에유의한의미가없다고하였다 [13]. 본연구에서도산전진단군과산후진단군과의합병증, 초기병기의빈도, 생존율간통계적으로유의한차이를발견하지못했다. 다만저자들의경우대상환자수가적어향후더많은환자를대상으로산전진단의유용성에대한연구가진행되어야할것으로생각된다. 신생아기신경모세포종은좋은예후를보이나치료와관련된합병증의빈도는비교적높아신생아기신경모세포종의치료에있어합병증예방이중요함을확인하였다. 또한산전진단군과산후진단군사이에합병증, 초기병기의빈도, 생존율은통계적으로유의한차이를발견할수없었으나향후많은환자를대상으로한연구가필요할것으로생각된다. CONFLICTS OF INTEREST No potential conflict of interest relevant to this article was reported. REFERENCES 1. Mullassery D, Dominici C, Jesudason EC, McDowell HP, Losty PD. Neuroblastoma: contemporary management. Arch Dis Child Educ Pract Ed 2009;94: Schwab M, Alitalo K, Klempnauer KH, Varmus HE, Bishop JM, Gilbert F, et al. Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour. Nature 1983;305: Coldman AJ, Fryer CJ, Elwood JM, Sonley MJ. Neuroblastoma: influence of age at diagnosis, stage, tumor site, and sex on prognosis. Cancer 1980;46: Schmidt ML, Lukens JN, Seeger RC, Brodeur GM, Shimada H, Gerbing RB, et al. Biologic factors determine prognosis in infants with stage IV neuroblastoma: a prospective Children's Cancer Group study. J Clin Oncol 2000;18: Evans AE, D'Angio GJ, Propert K, Anderson J, Hann HW. Prognostic factor in neuroblastoma. Cancer 1987;59: Joshi VV, Cantor AB, Brodeur GM, Look AT, Shuster JJ, Altshuler G, et al. Correlation between morphologic and other prognostic markers of neuroblastoma. A study of histologic grade, DNA index, N-myc gene copy number, and lactic dehydrogenase in patients in the Pediatric Oncology Group. Cancer 1993;71: London WB, Castleberry RP, Matthay KK, Look AT, Seeger RC, Shimada H, et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children's Oncology Group. J Clin Oncol 2005;23: Dhir S, Wheeler K. Neonatal neuroblastoma. Early Hum Dev 2010;86: Fisher JP, Tweddle DA. Neonatal neuroblastoma. Semin Fetal Neonatal Med 2012;17: Fénart D, Deville A, Donzeau M, Bruneton JN. Retroperitoneal neuroblastoma diagnosed in utero. Apropos of 1 case. J Radiol 1983;64: Moppett J, Haddadin I, Foot AB. Neonatal neuroblastoma. Arch Dis Child Fetal Neonatal Ed 1999;81:F Granata C, Fagnani AM, Gambini C, Boglino C, Bagnulo S, Cecchetto G, et al. Features and outcome of neuroblastoma detected before birth. J Pediatr Surg 2000;35: Gigliotti AR, Di Cataldo A, Sorrentino S, Parodi S, Rizzo A, Buffa P, et al. Neuroblastoma in the newborn. A study of the Italian Neuroblastoma Registry. Eur J Cancer 2009;45: Sposto R, London WB, Alonzo TA; Children's Oncology Group. Criteria for optimizing prognostic risk groups in pediatric cancer: analysis of data from the Children's Oncology Group. J Clin Oncol 2007;25: Michalowski MB, Rubie H, Michon J, Montamat S, Bergeron C, Coze C, et al; Groupe Neuroblastome de la Société Française d'oncologie Pédiatrique. Neonatal localized neuroblastoma: 52 cases treated from 1990 to Arch Pediatr 2004;11: Suh JM, Lee SG, Yoo KH, Sung KW, Koo HH, Kim JY, et al. Outcome of patients with neuroblastoma aged less than 1 year at diagnosis. Korean J Pediatr 2009;52: Blackman SC, Evenson AR, Voss SD, Barnewolt CE, Puder M. Prenatal diagnosis and subsequent treatment of an intermediate-risk paraspinal neuroblastoma: case report and review of the literature. Fetal Diagn Ther 2008;24: Journal of the Korean Association of Pediatric Surgeons 57

김범수

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