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1 4 기신경모세포종에서시행한자가제대혈조혈모세포이식 1 례 연세대학교의과대학소아과학교실 채정현ㆍ김효선ㆍ권승연ㆍ원성철ㆍ김범식ㆍ최성열ㆍ유철주 A Case of Autologous Cord Blood Stem Cell Transplantation in Stage IV Neuroblastoma Jung Hyun Chae, M.D., Hyo Sun Kim, M.D., Seung Yeon Kwon, M.D., Sung Chul Won, M.D., Bum Sik Kim, M.D., Seong Yeol Choi, M.D. and Chuhl Joo Lyu, M.D. Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea Since High dose chemotherapy (HDCT) with autologous hematopoietic stem cell (HSC) rescue has been reported to be the most effective current treatment modality in advanced and refractory neuroblastoma, various types of multiple tandem transplantation has been tried to improve survival of these patients. Autologous peripheral blood stem cell (PBSC) is the most commonly used hematopoietic stem cell source for HDCT in solid tumors owing to its availability and rapid engraftment. However, in case of insufficient stem cell harvest, it is difficult to go on multiple transplantations requiring alternative source of HSC. Umbilical cord blood stem cell (UCBSC) is one of the promising sources of HSC nowadays; however, its autologous use in HSC transplantation is a very rare procedure with only few of previous reports. Here we present a case of 2-year-old boy with stage IV neuroblastoma who underwent 3 cycles of sequential HDCT followed by HSCT using autologous PBSC and UCBSC, which we think as the first case report of autologus UCBSC transplantation in pediatric solid tumor performed in Korea. Since the banking of UCB for autologous usage is still very controversial issue, we discuss the safety and feasibility of this procedure as well as some of the uncertainties surrounding autologous cord blood collection and usage. (Clin Pediatr Hematol Oncol 2009;16:21 26) Key Words: Autologous, Cord blood, Hematopoietic stem cell transplantation, Neuroblastoma 신경모세포종은소아에있어두개외고형암중가장흔한질환으로 1) 진단당시에반이상에서전이소견을보이고있어 2) 그예후가매우불량한것으로알려져있다. 그러나신경모세포종의고위험군의환자에서고용량항암화학요법과자 책임저자 : 유철주, 서울시서대문구신촌동 134 번지연세대학교의과대학소아과학교실, Tel: , Fax: cj@yuhs.ac 가조혈모세포이식의시행으로치료성적이향상되었으며 3) 생존율을높이기위해최근에는두차례혹은세차례이상의고용량항암화학요법후조혈모세포이식을연속적으로시행하고있다 4). 고형종양에서의고용량항암화학요법에따른조혈모세포이식에는수득이용이하고생착이빠르며면역억제의부담이없는자가말초혈조혈모세포가가장많이사용되어왔다 5,6). 특히최근말초혈액에서의조혈모세포의수득및보관법과 임상소아혈액종양제 16 권제 1 호

2 22 채정현ㆍ김효선ㆍ권승연등 그생물학적활동성을최적화하기위한다양한방법들이개발되면서좀더효과적인자가조혈모세포의수득이가능하여졌으나, 일부혈관확보가어렵거나기존의강력한치료로인해효과적인조혈모세포의수득에실패할경우에는연속이식 (tandem transplantation) 을진행하는데어려움을겪게될수있다. 제대혈조혈모세포는최근다양한질환에서중요한조혈모세포이식의대안으로사용되고있으며향후그활용가치가더욱기대되는조혈모세포의원천이지만, 신경모세포종에대한자가제대혈의치료적사용은현실적으로매우드물고보고된바도적다. 저자들은 3차례의순차적고용량항암화학요법및조혈모세포이식중최종 3차고용량항암화학요법에서자가제대혈을이용한조혈모세포이식을시행받고무질병생존하여추적관찰중인환자를경험하여보고하고자한다. 증례환아 : 이, 2년 2개월, 남아주소 : 일주일간의우측팔의통증현병력 : 환아는내원일주일전넘어지면서발생한우측팔의통증을주소로개인정형외과에서치료받았으나증상호전보이지않아외부종합병원내원하여시행한단순방사선검사상우측상완골의종괴가관찰되어본원정형외과로전원되었다. 과거력및가족력 : 특이사항없음. 이학적소견 : 내원당시활력징후는혈압 98/ 56 mmhg, 맥박 84회 / 분, 호흡수 22회 / 분, 체온 36.7도였다. 환아의두경부및흉부진찰상이상소견은관찰되지않았으며우측상완골부분의압통외특이소견관찰되지않았다. 복부진찰상에서도종괴촉지등의이상소견은없었다. 검사소견 : 우측팔의자기공명영상소견상상완골근위부에종괴소견과병적골절이보였으며상완골근위부부터원위부까지골수의변화가 관찰되었다 (Fig. 1). 우측상완골근위부조직검사상미만성침윤을동반한악성소원형세포 (small round cell tumor) 가관찰되었고, 시행한면역조직화학검사상 neuron specific enolase (NSE) 양성, chromogranin, synaptophysin CD99, CD3, CD20/CD79, PAS, DPAS, Tdt, CK 음성소견을보여신경모세포종으로진단받았다. 복부컴퓨터단층촬영상 cm 크기의타원형종괴가좌측후복강에서관찰되었으며, 18-FDG positron emisssion tomogram (PET) 전신스캔검사상좌측신장의상부와우측상완골근위부및액와림프절에 FDG 섭취가증가되어있었다 (Fig. 1). 혈청 ferritin ng/ml, LDH 1225 IU/L로상승되어있었다. 혈청 NSE는 ng/ ml, 24시간소변 vanillyl mandelic acid는 3.05 mg/d로정상이었다. 골수침범여부확인을위해시행한골수흡인및조직검사상우측골수에서는특이소견이없었으나좌측골수에서신경모세포종의전이소견이보였으며시행한 MYCN 유전자는 2.7배의증폭소견을보였다 (Fig. 2). 임상경과및치료 : 환아는 vincristine, doxorubicin, cyclophosphamide와 cisplatin, etoposide를포함하는 3차례의항암화학요법을시행받았으며, 이후시행한방사선검사상종괴감소소견을보여좌측종양및부신적출술을시행받았다. 수술후네번째항암화학요법완료후말초혈조혈모세포수득을하였으며각각 및 cells/kg의 CD 34+ 조혈모세포를수득하였다. 이후두차례항암화학요법을이어시행받았으며영상검사상완전관해소견을보였다. 이식전시행한골수흡인및조직검사에서정상소견을보였으며 tyrosine hydroxylase reverse transcriptase polymerase chain reaction (TH-RT PCR) 검사상음성소견을확인하였다. 수득한말초혈조혈모세포및보관되었던제대혈에서도 TH-RT PCR의음성소견을확인하였다. 환아는 cyclophosphamide, carboplatin, etoposide의고용량항암화학요법후앞서수득한자가말초혈조혈모세포이식 (autologous peripheral blood stem cell transplantation, auto-

(A) Contrast-enhanced abdominal CT image shows an oval

bulging mass (arrow) at right humerus and bone marrow

(C) FDG-PET scan image shows focal increased uptake

head) and right axillar area (black arrow).

follow-up CT after 30 months off therapy.

disappeared at follow-up MRI after 30 months off

3 4기 신경모세포종에서 시행한 자가 제대혈 조혈모세포 이식 1례 23 Fig. 1. (A) Contrast-enhanced abdominal CT image shows an oval shaped mass (arrow) at retroperitoneal space. Left kidney is compressed by the mass. (B) Contrast-enhanced T1-weighted MR image shows a bulging mass (arrow) at right humerus and bone marrow change. (C) FDG-PET scan image shows focal increased uptake above left renal pelvis (arrow), right humerus (arrow head) and right axillar area (black arrow). (D) There is no evidence of tumor recurrence at follow-up CT after 30 months off therapy. (E) Previously noted mass at right humerus is disappeared at follow-up MRI after 30 months off therapy. (F) FDG-PET scan shows no abnormal uptake after 30 months off therapy. Fig. 2. The bone marrow aspiration shows mutifocal aggregates of small to medium sized atypical cells most consistent with metastatic neuroblastoma (H&E stain, A: 100, B: 1,000).

4 24 채정현ㆍ김효선ㆍ권승연등 PBSCT) 을연속적으로 2회시행받았다. 이후최종적으로 carboplatin, etoposide, melphalan을사용한고용량항암화학요법후자가제대혈조혈모세포이식 ( 해동시 CD /kg) 을시행받았다. 이식 29일째부터중성구수치 /L 이상 3일간유지되었고혈소판수치는이식 48일째부터수혈없이 /L 이상유지되었다. 이식후감염이나주요장기출혈등의특별한중증의합병증관찰되지않았다. 본환아는제대혈조혈모세포이식 3개월후부터 interleukin-2와레티노익산으로 6주간유지치료를받았으며치료종료후 30개월에시행한영상검사상재발소견없는상태로현재치료종료후 32개월째외래추적관찰중이다 (Fig. 1). 고찰진행된신경모세포종에서조혈모세포이식을동반한고용량항암화학요법의시도가효과적인것으로보고된이후로다양한불응성소아고형종양에서고용량항암화학요법이시도되었으나많은수의환자들이궁극적으로는재발을경험하였다. 이에따라조혈모세포이식을동반한고용량항암화학요법을 2회이상시행하는연속이식이고위험군신경모세포종을비롯한불응성소아고형종양에서시도되고있으며최근의미있는생존율의향상이보고되고있다 7). 그러나이러한연속적인고용량항암화학요법의시도는심각한치료독성및합병증을동반할수있으므로이를최소화하기위해적절한조혈모세포의주입및충분한지지요법의보조가필수적이다. 자가말초혈조혈모세포는고형종양의고용량항암화학요법에사용되는가장흔한조혈모세포로서최근그수득, 보관및주입술의발달로현재는매우안전하고용이하게사용되고있으며여러소아고형종양에서생존률향상에크게기여하고있다. 그러나수득전장기간의항암화학요법또는방사선요법을시행받은경우나혈관확보가어려워수득이충분치못한경우에는대 안적인조혈모세포가필요하게된다. 또한수득된말초혈조혈모세포내의종양세포오염가능성에대한우려역시제기될수있으며이로인한종양재발에대한잠재성에대하여도논의가지속되고있다 8). 신경모세포종에서는자가조혈모세포내종양오염가능성을배제하기위해카테콜아민합성의첫번째효소이자속도제한단계효소인 tyrosine hydroxylase (TH) 를 reverse transcriptase PCR 방법으로확인하는 TH-RT PCR이여러연구자들에의해보고된바있다. 골수및주입조혈모세포의 TH가재발및최종생존에미치는영향에대하여는아직논란의여지가남아있으나상당수의연구에서 TH의높은발현이불량한예후와연관되어있음이보고되고있다 9,10). 따라서지금까지밝혀진미세잔존질병을확인할수있는가능성이가장높은표지자로생각할수있다. 제대혈조혈모세포이식은 1988년 Gluckman 등이판코니빈혈환자에서형제제대혈이식에처음성공한이후전세계적으로활발히시행되고있으며, 그수는매년증가하고있다 11). 여러연구에서제대혈의조혈모세포는골수나말초혈액의조혈모세포에비해이식후이식편대숙주질환의위험도가적고질환의재발률이낮다는결과가보고되고있으며 12), 조혈모세포가풍부하고, 상대적으로조혈모세포가더미성숙하기때문에면역장벽의장애가적어조혈모세포이식에보다유용하다고알려져있다 13,14). 뿐만아니라제대혈은쉽게얻을수있어유용하고, 골수및말초혈액과비교하여혈인성감염질환의전파의가능성이낮으며, 검체를기증하는과정에서공여자에대한위험성이없는이점이있어 15) 향후유용한조혈모세포이식의공급원으로서잠재적인가능성을지니고있다. 그러나이러한장점에도불구하고제대혈조혈모세포사용에있어소아백혈병의태아기원인에대한몇가지연구들이진행된바있고, 고형암에서도분자유전학적으로태아기원인에대한안정성을확증할수없기때문에제대혈에전암

5 4 기신경모세포종에서시행한자가제대혈조혈모세포이식 1 례 25 성클론이존재해서추후에암이발현될수있는가능성이제기되기도하였다 16). 최근제대혈에서 PCR 방법이나면역글로불린유전자재배열등의검사를통해향후백혈병의발병가능성에대한예측도가능해지고있으나 17), 이에대하여는아직도논의가지속되고있으며더욱심화된연구가필요한상태이다. 더욱이저장된제대혈을본인의치료에사용하는자가제대혈조혈모세포이식에대하여는더욱큰주의와고찰이필요하다. 그간보고된바에의하면국내에서는고형종양에서의자가제대혈조혈모세포이식이보고된예가없으며, 국외에서 Hayani 등 18) 이백혈병에서, Ferreira 등 19) 이신경모세포종에서, 그리고 Fruchtman 등 20) 이재생불량성빈혈에서시행하여보고된것이외에는많은연구가진행되지않은상태이다. 앞서인용한국외의몇몇보고에서도성공적인자가제대혈조혈모세포이식을보고하였으나제대혈내전암성클론의포함에대한우려와이로인한재발가능성을염두에둔위험대비효과를고려하여신중히자가제대혈조혈모세포이식을결정하도록논의하고있다. 또한연간소아암발생율및이중조혈모세포이식을필요로하는고위험군소아종양의발생빈도가매우낮은수준임을생각할때마치 생물학적보험 의개념으로개인적인재대혈을보관하는것에대한윤리적문제점을충분히고려하도록권유하고있다 18). 본증례의환아는뼈와골수에전이되어신경모세포종 4기로진단받고두차례의고용량항암화학요법및자가말초혈조혈모세포이식을시행받았으며, 최종 3차고용량항암화학요법후자가제대혈조혈모세포이식을시행받았다. 이식당시자가말초혈및제대혈에서시행한 TH-RT PCR 검사상음성소견을보여종양세포오염으로인한재발의위험성을가능한한배제하였으며, 이식후중증의합병증없이이식 29일째생착되었다. 이식 3개월후부터 6주간 interleukin-2 투여및레티노익산복용후치료종료하였고, 이식후 32개월까지질병없는상태로추적관찰중 이다. 요 본증례는국내에서시행된첫소아고형암환자에서의성공적으로시행된자가제대혈조혈모세포이식으로장기간의추적관찰동안아직후유증이없고, 병의재발이없는경우로보고하는바이다. 그러나앞서보고된바와같이자가제대혈조혈모세포이식은자가제대혈보관및사용의의학적, 윤리적문제점들을고려하여신중히결정되어야하며자가제대혈보관의무분별한홍보로이어지지않아야하는점을유의하여야하겠다. 약 참고문헌 1. Gurney JG, Davis S, Severson RK, Fang JY, Ross JA, Robison LL. Trends in cancer incidence among children in the U.S. Cancer 1996;78: De Bernardi B, Milanaccio C, Occhi M. Neuroblastoma. In: Sheaves R, editor. Clinical Endocrine oncology. Oxford, United Kingdom, Blackwell Science, 1997: Kim JY, Baek HJ, Han DK, Sung JS, Nam TK, Yoon MS, et al. Improved survival in neuroblastoma by autologous peripheral blood stem cell transplantation: a single institution experience. Clin Pediatr Hematol Oncol 2006;13: George RE, Li S, Medeiros-Nancarrow C, Neuberg D, Marcus K, Robert C, et al. High-risk neuroblastoma treated with tandem autologous peripheralblood stem cell-supported transplantation: long-term survival update. J Clin Oncol 2006;24: William IB, Paul JM, Barry S. Reginald C, Steven JF, Robert N, et al. Transplantation of bone marrow as compared with peripheral blood cells from HLAidentical relatives in patients with hematologic cancers. N Engl J Med 2001;344: Oliver H, Anne GC, Didier B, Jean M, Irene P, Francoise N, et al. Peripheral blood stem cell and bone marrow transplantation for solid tumors and lymphoma: hematologic recovery and cosets: a randomized, controlled trial. Ann Int Med 1997;126:

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김범수

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