Case report http://dx.doi.org/10.22470/pemj.2016.3.2.59 pissn: 2383-4897 / eissn: 2508-5506 양측고관절및복부의통증으로방문하여신경모세포종으로진단된 3 세남자환자 권재현 김중헌 1 송인혜 2 류정민 1 울산대학교의과대학소아청소년과학교실, 1 응급의학교실, 2 병리학교실 Neuroblastoma in a 3-year-old boy presenting with pain in the bilateral hip and abdomen Jae Hyun Kwon, Jung Heon Kim 1, In Hye Song 2, Jeong-Min Ryu 1 Departments of Pediatrics, 1 Emergency Medicine, and 2 Pathology, University of Ulsan College of Medicine, Seoul, Korea A 3-year-old boy presented to our emergency department with a 3-week history of pain in the bilateral hip and abdomen that had persisted through antibiotic therapy based on diagnosis of acute osteomyelitis. At presentation, he had fever, anemia, and increased concentration of lactate dehydrogenase. After the identification of a left adrenal mass indicating neuroblastoma on computed tomography scan, he was admitted to the hospital by a pediatric oncologist. Subsequently, positron emission tomography and bone scintigraphy showed disseminated metastasis to the bone and bone marrow, and neuroblastoma was pathologically confirmed. This case highlights the importance of differential diagnosis of non-traumatic hip pain in toddlers considering the protean manifestations of neuroblastoma. Key words: Child; Diagnosis, Differential; Emergencies; Hip; Neuroblastoma; Pain 서 론 신경모세포종은원시신경능선세포에서기원한악성종양으로서, 조직학적으로신경분화도에따라신경모세포종, 신경절신경모세포종, 신경절신경종으로분류된다 1). 이종양은소아고형암중뇌종양에이어두번째로흔하며, 5세미만소아에서부신종괴로발현하는경우가가장흔 Received: Nov 14, 2016 Revised: Nov 28, 2016 Accepted: Nov 30, 2016 Corresponding author Jeong-Min Ryu Department of Emergency Medicine, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-3350 Fax: +82-2-3010-3360 E-mail: qweynaver@naver.com 하다 2). 하지만, 원발및전이부위의다양한증상으로인해진단이어려운경우가많으므로, 신경모세포종을시사하는다양한임상증상에대하여감별진단할수있어야한다. 본저자는 3주간지속한양측고관절및복부의통증으로본원응급실에방문하여, 파종성뼈및골수전이를동반한신경모세포종으로진단된 3세남자환자의증례를보고하고자한다. 또한, 신경모세포종의임상증상및유아기비외상성고관절통증의감별진단을중심으로간략하게고찰하고자한다. 증례 3세남자환자가 3주간지속된양측고관절및복부의통증을주소로본원응급실을방문했다. 환자는본원방문 59
Pediatr Emerg Med J 2016;3(2):59-64 3주전, 우측고관절및복부통증이발생하여외부병원에입원했다. 당시복부컴퓨터단층촬영판독결과특이소견이없었지만, 골반자기공명영상에서양측골반및대퇴골근위부의다발성골병소를근거로급성골수염으로진단되었다. 이후항생제치료에도불구하고좌측고관절의통증과발열이동반하며증상이악화했다. 외부병원에서다시시행한자기공명영상에서우측고관절의활액 (synovial fluid) 증가및활막의조영증강소견을보였으며, 해당병원의료진은급성골수염에화농관절염이동반한것으로진단했다. 환자의부모는악화하는증상에대한추가적인진료를위해본원을방문했다. 본원방문당시의식은명료했고, 활력징후는혈압 109/74 mmhg, 호흡수 40회 / 분, 심장박동수 149회 / 분, 체온 38.1 C, 산소포화도 100% 였다. 외부병원입원당시보다고관절통증은비슷한정도였지만복통은악화된상태였다. 신체검사에서복부압통및간비장비대는없었지만, 우측넓적다리압통과양측고관절의운동범위제한이관찰되었으며체중부하는불가능했다. 발적, 부종, 멍은동반하지않았으며, 호흡곤란및국소신경학적결손은없었다. 혈액검사에서백혈구 7,300/μL, 혈색소 7.9 g/dl, 혈소판 310,000/μL, 적혈구침강속도 47 mm/h ( 참고치 : 0-9 mm/h) 프로트롬빈시간 13.4초 ( 참고치 : 10-13초 ) 였으며, 아스파르테이트아미노전달효소 44 IU/L, 알라닌아미노전달효소 24 IU/L, 크레아틴인산화효소 69 IU/L ( 참고치 : 50-250 IU/L), 젖산탈수소효소 690 IU/L ( 참고치 : 120-250 IU/L), C-반응단백질 18.3 mg/dl ( 참고치 : 0-0.6 mg/dl) 였다. 전해질, 혈당, 크레아티닌, 요검사는정상이었다. 흉부, 복부및고관절 X선검사에서정상소견을보였다. 외부병원자기공명영상에서제기된화농관절염소견을평가하고자고관절관절천자를시행했고, 이를통해채취한활액분석검사결과, 백혈구 450/μL ( 중성구 53%) 였다. 영상의학과의사가외부병원자기공명영상및컴퓨터단층촬영을다시판독한결과, 전자에서확인된다발성골병소가급성골수염보다골수전이암또는혈액암을시사한다는소견이, 후자에서는외부병원판독에서확인되지않은좌측부신및대종맥주위림프절과융합된종괴가각각확인되었다. 의료진은조절되지않는다발성통증과빈혈, A B C D Fig. 1. The results of computed tomography scan performed at our emergency department (A and C) and at another hospital (B and D), showing a mass indicating neuroblastoma. A contrast-enhanced mass in the left para-aortic area, approximately 20 30 mm in size, is marked by the black arrows, and the size and location are comparable between the results from the two institutions. This mass abuts the left adrenal gland indicated by the black arrowheads in A and B. 60 Pediatric Emergency Medicine Journal
신경모세포종 젖산탈수소효소증가, 비감염성질환을시사하는활액분석검사결과, 외부병원영상검사재판독결과를근거로, 신경모세포종또는백혈병의가능성을의심했다. 이에신경모세포종가능성을평가하고자복부컴퓨터단층촬영을 시행한결과, 좌측부신및대동맥주위림프절과융합된종괴가재확인되었다 (Fig. 1). 의료진은이종괴가신경모세포종일가능성이높다고보고, 소아청소년종양혈액과입원치료를결정했다. A B C D Fig. 2. Positron emission tomography (A), positron emission tomography/computed tomography (B), and bone scintigraphy (C: early; D: delayed) showing disseminated metastasis to the bone and bone marrow. Multifocal increased uptake is shown in the early images of the skull, and this finding is most apparent in the left parietal bone (arrows, A and B). Bone scintigraphy shows increased uptake in the bilateral pelvic bones and proximal femora. A B Fig. 3. (A) Gross and (B) microscopic findings of the excised tumor after neoadjuvant chemotherapy. The gross specimen shows a well-demarcated, 19 18 16 mm-sized, round solid mass with whitish yellow cut surface and focal necrosis (asterisk, A). This mass abuts the left adrenal gland (white arrow, A). Most of the tumor is composed of Schwann cells. Foci of mature (red arrows, B) and maturing (blue arrows, B) ganglion cells are occasionally observed. There is no definite residual malignant component. Considering the neoadjuvant chemotherapy, overall findings suggest the diagnosis of neuroblastoma with extensive differentiation (H&E, 200). Pediatric Emergency Medicine Journal 61
Pediatr Emerg Med J 2016;3(2):59-64 입원후, 24시간소변검사에서 homovanilic acid (HVA) 및 vanillylmandelic acid (VMA) 는각각 28.4 mg/d ( 참고치 : 8.8 mg/d), 6.2 mg/d ( 참고치 : 8.0 mg/d) 로확인되었고, 혈액검사에서페리틴 757.3 ng/ml ( 참고치 : 20-320 ng/ml), 뉴런특이에놀라아제 (neuron-specific enolase) 98.5 ng/ml ( 참고치 : 4.7-14.7 ng/ml) 였으며, 응급실에서시행한혈액및활액배양검사에서동정된세균은없었다. 양측장골능선에서시행한골수생검에서, 신경모세포종이진단되었다. 3,4-dihydroxy-6-18F-fluoro-phenylalanine을이용한양전자방출단층촬영과 99 mtc-methylene diphosphonate을이용한골스캔에서신경모세포종에동반한파종성뼈및골수전이소견을보였다 (Fig. 2). 환자는 International Neuroblastoma Staging System에따른 4기, Children s Oncology Group Neuroblastoma Risk Stratification에따른고위험군으로분류되었다. 이후신보강화학요법에이어서복강경부신절제술 ( 좌측 ) 을시행했고, 생검을통해고분화도를보이는신경모세포종으로확진되었다 (Fig. 3). 현재, 환자는화학요법후자가조혈모세포이식예정이다. 고찰 신경모세포종은 5세미만 ( 중앙값 23개월 ) 에서호발하고, 원발및전이부위 ( 뼈, 골수, 림프절, 간, 피부 ) 의다양한임상증상을나타낸다 2). 부신종괴로발현하는경우가가장흔하지만 (50%), 교감신경절을따라어느부위에도발생할수있다 1). 종괴위치에따라, 호흡곤란, 상대정맥증후군, 사지마비, 호너증후군이유발될수있다. 특히, 골수에전이된경우빈혈및혈소판감소증이나타난다 3). 발열, 고혈압, 설사를동반하는경우에는근골격감염, 심혈관또는위장관질환과의감별이어렵다. 드물지만안구간대경련-근간대경련증후군 (opsoclonus-myoclonus syndrome) 이발생하기도한다 4). 5세미만환자가설명되지않는다양한부위의통증, 신경학적증상, 호흡곤란, 발열및고혈압을보일경우, 감별진단에신경모세포종을포함해야한다. 본증례와같이비외상성고관절통증을보이는유아기환자에서는, 다양한감별진단을고려해야한다 (Table 1). 일과성고관절활막염은 3-8세환자에서호발하고대개발열없이 3주이내에호전되므로 5), 본증례와맞지않는다. 레그-칼베-페르테스병 (Legg-Calvé-Perthes disease) 은 4-9세환자에서고관절통증이 3주이상지 속하고약 10% 에서양측성으로나타날수있지만 6), 발열및다발성통증을동반하진않는다. 골수염이나화농관절염은단일부위를침범하는경우가흔하며 (>80%) 7), 활액백혈구가 50,000/μL 이상인경우가대부분이다 8,9). 본증례에서는체중부하가불가능하였고빠른적혈구침강속도 (47 mm/h) 및높은 C-반응단백질 (18.3 mg/dl) 을보였는데, 이는 Caird 등 9) 의기준에따르면화농관절염가능성이약 83% 에해당하는상황이었다. 이에관절천자를시행하였지만, 활액백혈구는 450/μL ( 중성구 53%) 였다. 검사결과해석에검사전항생제투여사실을고려해야하겠지만, 결과적으로활액배양검사에서세균은동정되지않았다. 게다가, 복통악화는근골격감염으로설명하기어렵다. 소아기특발관절염 (juvenile idiopathic Table 1. Differential diagnosis of non-traumatic limp pain in children Disease Characteristic Infection-related Septic arthritis Fever Osteomyelitis Elevated ESR, CRP Reactive arthritis Microbiology Acute rheumatic fever - Lyme disease - Toxic (transient) synovitis - Neoplastic Leukemia CBC, blood cell morphology Neuroblastoma Organomegaly Primary bone tumor Imaging tests Hematologic Hemophilia (hemarthrosis) History Sickle cell anemia - Rheumatologic Juvenile idiopathic arthritis Typical nature of pain Systemic lupus erythematosus Patterns of systemic involvement Henoch-Schönlein purpura - Orthopedic Slipped capital femoral epiphysis Prevalent age, history Legg-Calvé-Perthes disease Imaging tests Miscellaneous Growing pain Diagnosis of exclusion Fibromyalgia - Reflex sympathetic dystrophy - Conversion disorder - ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, CBC: complete blood count. Modified from Lee JA. Korean J Pediatr 2008;51:792-6 3). 62 Pediatric Emergency Medicine Journal
신경모세포종 arthritis) 은대개통증의강도가약하고 6주이상에걸쳐서서히발생하는경우가많다 10). 이중소수관절형은 2-4 세환자에서 4개이하의관절을침범 ( 주로무릎및발목 ) 하고아침경직을동반하는데 11), 고관절단독으로발생하거나체중부하가불가능한경우는드물다 10). 설명되지않는다양한부위의통증에빈혈및젖산탈수소효소증가가동반한경우, 신경모세포종및백혈병과같은종양을고려해야한다 3). 골육종과같은원발골종양도고려해야하지만, 사춘기에호발하므로 3), 가능성이떨어진다. 신경모세포종의진단기법은소변검사, 영상검사, 생검 ( 원발종양, 골수 ) 으로나뉜다. 소변을통하여카테콜아민대사산물인 HVA 및 VMA를검사할수있다. 컴퓨터단층촬영및자기공명영상을통하여, 원발종양과흉강및복강내전이를확인할수있다. 종괴는복부중앙선을넘거나내부에괴사및출혈을동반하는경우가흔하다. 부신외또는전이성종괴가의심되는경우, 123 I-metaiodobenzylguanidine을이용한섬광조영술또는양전자방출단층촬영과같은기능적영상검사를통하여교감신경활성도를확인하는것이중요하다 12). 골수검체에서 small round blue cell이로제트 (rosette) 를형성하는것이관찰되고소변에서 HVA 및 VMA 농도가증가한경우에는진단이가능하다 2). 하지만, 확진, 예후예측및치료계획결정에있어서원발종양의생검은필수적이다. 전암유전자 MYCN의증폭은높은병기및불량한예후와연관되므로, 유전자검사를통하여이를확인해야한다 1). 본증례에서진단이지연된이유를다음과같이요약할수있다. 첫째, 외부병원입원당시고관절통증이복통보다심했기때문에, 악성종양을고려하지못한상태에서복부컴퓨터단층촬영을시행했다는점이다. 즉, 충수염과같은급성복증의감별진단이촬영목적이었기때문에, 촬영후에도부신주위를확인하지못했을수있다. 둘째, 당시혈색소가 9.6-11.6 g/dl로본원검사결과에비해높았던것도, 악성종양을고려하지못한것에기여했을수있다. 셋째, 자기공명영상에서나타난다발성골병소를급성골수염으로단정했다는점이다. 골수염은대부분단일병소로발생하고환자가항생제치료에반응하지않았으므로, 악성종양의뼈및골수전이를의심했어야했다. 하지만, 골스캔과같은검사는추가로시행되지않았다. 본증례에서, 의료진은조절되지않는다발성통증과혈액학적이상소견, 비감염성질환을시사하는활액분석검사결과, 신경모세포종및파종성뼈및골수전이를시사하는외부병원영상검사재판독결과를근거로신경모세포종가능성을고려했다. 이후컴퓨터단층촬영, 소변 HVA 및 VMA 검사를통해신경모세포종으로잠정진단했고, 원발종양및골수의생검을통해진단을확인했다. 신경모세포종은다양한임상증상을나타낼수있다. 특히, 5세미만환자에서설명되지않는다양한부위의통증에빈혈및젖산탈수소효소증가가동반한경우, 신경모세포종을감별진단으로고려해야한다. References 01. Zage PE, Ater JL. Neuroblastoma. In: Kliegman RM, Stanton BF, St Geme JW III, Schor NF, editors. Nelson textbook of pediatrics. 20th ed. Philadelphia (PA): Elsevier; 2015. p. 2461-4. 02. Park JR, Eggert A, Caron H. Neuroblastoma: biology, prognosis, and treatment. Hematol Oncol Clin North Am 2010;24:65-86. 03. Lee JA. Malignancies in children who present with bone pain. Korean J Pediatr 2008;51:792-6. Korean. 04. Wu H, Mody AP. A toddler with uncontrollable shaking after a minor fall. Pediatr Emerg Care 2015 Oct 13 [Epub]. http://dx.doi.org/10.1097/pec.0000000000000580. 05. Sankar WN, Horn BD, Wells L, Dormans JP. Transient monoarticular synovitis (toxic synovitis). In: Kliegman RM, Stanton BF, St Geme JW III, Schor NF, editors. Nelson textbook of pediatrics. 20th ed. Philadelphia (PA): Elsevier; 2015. p. 3279. 06. Black KJ, Duffy C, Hopkins-Mann C, Ogunnaiki-Joseph D, Moro-Sutherland D. Musculoskeletal disorders in children. In: Tintinalli JE, Stapczynski JS, Ma OJ, Yealy DM, Meckler GD, Cline DM, editors. Tintinalli s emergency medicine: a comprehensive study guide. 8th ed. New York: McGraw-Hill Educations; 2016. p. 915-33. 07. Kaplan SL. Osteomyelitis. In: Kliegman RM, Stanton BF, St Geme JW III, Schor NF, editors. Nelson textbook of pediatrics. 20th ed. Philadelphia (PA): Elsevier; 2015. p. 3322-6. 08. Herman MJ, Martinek M. The limping child. Pediatr Rev 2015;36:184-95. 09. Caird MS, Flynn JM, Leung YL, Millman JE, D Italia JG, Dormans JP. Factors distinguishing septic arthritis from transient synovitis of the hip in children: a prospective study. J Bone Joint Surg Am 2006;88:1251-7. 10. Punaro M. Rheumatologic conditions in children who may present to the orthopaedic surgeon. J Am Acad Orthop Surg 2011;19:163-9. 11. Wu EY, Bryan AR, Rabinovich CE. Juvenile idiopathic arthritis. In: Kliegman RM, Stanton BF, St Geme JW III, Pediatric Emergency Medicine Journal 63
Pediatr Emerg Med J 2016;3(2):59-64 Schor NF, editors. Nelson textbook of pediatrics. 20th ed. Philadelphia (PA): Elsevier; 2015. p. 1160-70. 12. Lopci E, Piccardo A, Nanni C, Altrinetti V, Garaventa A, Pession A, et al. 18F-DOPA PET/CT in neuroblastoma: comparison of conventional imaging with CT/MR. Clin Nucl Med 2012;37:e73-8. 64 Pediatric Emergency Medicine Journal