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1 진성적혈구증다증환자에서발현한 Erdheim-Chester Disease 1 예 가톨릭대학교의과대학내과학교실 김지은, 이현정, 이진국, 윤형규, 송정섭 A Case of Erdheim-Chester Disease Who Has Policythemia Vera Ji Eun Kim, M.D., Hyun Jeong Lee, M.D., Chin Kook Rhee, M.D., Hyung Kyu Yoon, M.D., Jeong Sup Song, M.D. Division of Pulmonary Medicine, St. Mary's Hospital, Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea Erdheim-Chester disease (ECD) is a rare disease that is characterized by multi-organ involvement of foamy histiocytes. It causes systemic inflammation, and also demonstrates various clinical manifestations and has a poor prognosis. We encountered a case of ECD in a patient that had been treated for underlying polycythemia vera. As far as we know, this is the first reported case worldwide where ECD developed in association with polycythemia vera. A 59-year-old man visited our hospital due to pleuric pain at the right side of the chest. Pleural tissue that was obtained following a thoracoscopic biopsy showed non-langerhan's cell histiocytosis, suggesting the presence of ECD. The histiocytes stained positively for CD68, but were negative for S-100 and CD1a. The patient also complained of pain at both hips and the right shoulder area. An X-ray and magnetic resonance image demonstrated that the lesion showed sclerosis and osteolysis in both the proximal femur and right humerus. Treatment was started with predinisolone, and subsequently cyclophosphamide was added. ECD is a very rare multi-systemic disease, and its cause and therapeutic options have not yet been defined. ECD has a poor prognosis. Therefore, we believe that additional case studies are needed prior to the determination of a novel therapy for ECD. (Tuberc Respir Dis 2008;64: ) Key Words: Erdheim-Chester disease, Polycythemia vera, Bone pain 서 Erdheim-Chester disease (ECD) 는 1930년미국병리학자 Edheim과 Chester에의해처음보고되었으며, 1972년 Jaffe 에의해 Erdheim-Chester disease 라는용어로사용된질환으로뼈, 심장, 폐, 후복강, 피부, 중추신경계및기타조직에황색육아종의침범을보이는전신질환이다. 과거에는악성조직구증에포함하여분류해왔으나장골에서의특징적인대칭적병변소견과랑게르한스과립및 S-100 항체가조직구에없음을들어독립적인원발성포식세포장애로정의한다 1. 현재까지외국에서는약 180 사례가보고되었고 2 국내에서는안구, 골격계, 피부, 후복막강을침 Address for correspondence: Jeong Sup Song, M.D. Division of Pulmonary Medicine, St. Mary's Hospital, 62 Yeouido-dong, Yeongdeungpo-gu, Seoul , Korea Phone: , Fax: jssong@catholic.ac.kr Received: Dec. 3, 2007 Accepted: Feb. 11, 2008 론 범한사례들이 7예가보고된 3-6 매우드문전신질환이며침범장기에따라무증상에서치명적인경우까지다양한임상발현을보인다 7. 이에저자들은국내에서처음으로진성적혈구증다증환자에서발현한 ECD 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 김, 남자 59세주소 : 내원 2일전부터지속되는오른쪽흉통현병력 : 내원 2일전부터오른쪽옆구리통증이지속되어응급실내원하였으며흉부방사선소견상오른쪽흉수소견보여이에대한검사와치료를위해입원하였다. 과거력 : 1998년 9월타대학병원에서전립선암으로전립선제거술과방사선치료병행 (5040 cgy/28fx) 하였고, 2003년에서 2004년까지내분비적절제치료시술을시행하였다. 이후 2005년 5월본원에서진성적혈구증다증을진단받고 hydroxyurea 복용중으로혈액내과추적관찰 224

Tuberculosis and Respiratory Diseases Vol. 64. No. 3, Mar. 2008 중이었다. 가족력 : 특이소견없었다. 약물복용력 : Hydroxyurea 500 1,500 mg (2005.9.14 2007.7.31) 과 2005년부터고혈압으로 amlodipine 복용중이었다.

Chest X-ray shows right-sided pleural effusion. 부이학적검사에서오른쪽폐하부의호흡음감소되었으며수포음및흉막마찰음은청진되지않았다. 복부진찰소견상특이소견은없었고양상지와하지에압박통은없었다. 신경학적검사상특이소견은없었다. 검사실결과 : 말초혈액검사에서백혈구 9,060/mm 3 ( 중성구 76%, 림프구 14%, 단핵구 6.

51 mg/dl, 나트륨 139 meq/l, 칼륨 3.7 meq/l, LDH 536 IU/L, CPK 64 IU/L로이상소견없었으며, 동맥혈가스검사에서 ph 7.4, PaCO 2 23.7 mmhg, PaO 2 92.

2 Tuberculosis and Respiratory Diseases Vol. 64. No. 3, Mar 중이었다. 가족력 : 특이소견없었다. 약물복용력 : Hydroxyurea 500 1,500 mg ( ) 과 2005년부터고혈압으로 amlodipine 복용중이었다. 계통학적문진 : 오른쪽흉통호소하였고, 전신피로감과함께어깨, 다리의통증을호소하였다. 신체진찰결과 : 내원당시환자의활력징후는혈압 130/90 mmhg, 맥박수 100회 / 분, 호흡수 28회 / 분. 체온 36.6 o C이었다. 급성병색소견띄었으나의식및지남력은정상이었고두경부진찰소견상이상소견은없었다. 흉 Figure 1. Chest X-ray shows right-sided pleural effusion. 부이학적검사에서오른쪽폐하부의호흡음감소되었으며수포음및흉막마찰음은청진되지않았다. 복부진찰소견상특이소견은없었고양상지와하지에압박통은없었다. 신경학적검사상특이소견은없었다. 검사실결과 : 말초혈액검사에서백혈구 9,060/mm 3 ( 중성구 76%, 림프구 14%, 단핵구 6.3% 호산구 3.5%) 혈색소 16.9 g/dl, 혈소판 531,000/mm 3 이었고, 생화학검사상 AST/ALT 21/13I U/L, BUN/Cr 8.9/0.97 mg/dl 총단백 7.11 g/dl, 알부민 3.72 g/dl, 총빌리루빈 0.9 mg/dl, 직접빌리루빈 0.12 mg/dl, 칼슘 8.8 mg/dl, 인 3.51 mg/dl, 나트륨 139 meq/l, 칼륨 3.7 meq/l, LDH 536 IU/L, CPK 64 IU/L로이상소견없었으며, 동맥혈가스검사에서 ph 7.4, PaCO mmhg, PaO mmhg, HCO 3 17 mmol/l, O 2 saturation 99% 로정상소견이었고, 적혈구침강속도 23 mm/h, C-반응성단백질은 43 mg/dl 로상승되었다. 지질검사결과총콜레스테롤 / 트리글리세라이드 / 고밀도리포단백질 / 저밀도리포단백질 155/153/28/94 mg/dl 로고밀도리포단백질의저하소견보였다. 우측늑막액천자시행했으며검사결과투명한노란색으로 ph 8, 백혈구 648/mm 3 ( 중성구 3%, 림프구 24%, 호산구 10%, 대식세포및단핵구 63%) 적혈구 12,758/ mm 3 로, 늑막액 / 혈장단백질비는 3.8/7.1 (0.53), 늑막액 / 혈장 LDH 비는 310/536 (0.57) 로삼출액소견을보였다. ADA는 10, TB PCR 음성이었다. 방사선결과 : 흉부 X-선사진에서우측흉수관찰되었으며 (Figure 1), 흉부전산화단층촬영에서소량의심막유출액과대동맥궁과복부대동맥의동맥염, 양측신장염 Figure 2. Chest CT shows large amount of right pleural effusion and surrounding pleural thickenings. Small amount of pericardial effusion are also noted (A). Focal wall thickening and enhancement is seen at lateral wall of aorta and bilateral perirenal fat infiltrations combined with bilateral pelvic dilatations are noted which represent bilateral nephritis and mild hydronephritis (B). 225

JE Kim et al: Erdheim-Chester disease Figure 3.

(B) Right humerus AP X-ray also shows diffuse sclerosis in proximal humeral shaft. Figure 4.

signal changes (arrow) involving the L4-5 body and other multiple lesions in pelvic bone.

상하지 X-선사진에서양측대퇴부근위부, 좌측장골, 우측상완골에경화성병변과골융해성병변이함께관찰되었으며병적골절이나골막반응은동반되지않았으며관절액증가는없었다 (Figure 3).

3 JE Kim et al: Erdheim-Chester disease Figure 3. (A) Pelvis X-ray shows ill-defined sclerosis and osteolysis in both pubic bone and proximal femur metadiaphysis. (B) Right humerus AP X-ray also shows diffuse sclerosis in proximal humeral shaft. Figure 4. Coronal (A) and axial (B) T-1 wieghted pelvic bone MRI shows numerous variable sized (less than 1 cm to 7 cm) round oval to ill-defined patchy marrow signal changes (arrow) involving the L4-5 body and other multiple lesions in pelvic bone. Lesions appear relatively dark signal intensity on T1-wighted image. 과약간의수신증소견이관찰되었다 (Figure 2). 상하지 X-선사진에서양측대퇴부근위부, 좌측장골, 우측상완골에경화성병변과골융해성병변이함께관찰되었으며병적골절이나골막반응은동반되지않았으며관절액증가는없었다 (Figure 3). 대퇴골자기공명영상에서양측대퇴골근위부의골간단 (metaphysis) 과골간부 (diaphysis) 에서 T1영상에서골수의신호강도가미만성으로감소되었으며 T2 강조영상에서골수의저신호및고신호강도의병변이혼재되어있었으며조영제주입후에골수에강한조영증가소견이보였다 (Figure 4). 이러한병변은골단 (epiphysis) 에서는관찰되지않았고, 대퇴골이외에요추 4, 5, 장골, 좌골, 치골에서도관찰되었으며, 우측 상완골자기공명영상에서도상완골과견갑골에동일한소견이관찰되었다. 골스캔검사에서도병변의흡수율증가를관찰할수있었다 (Figure 5). 병리결과 : 흉수세포진검사상결핵이나악성세포발견되지않았으며, 확진위해비디오보조하흉곽수술시행, 흉막생검과종격동의조직검사시행하였다. 조직검사결과지질을함유한대식세포가미만성으로침윤된황색육아종소견을보였다. 면역조직화학염색에서 S- 100 항체음성, CD68 염색양성, CD1a 음성소견 (Figure 6) 을보이고있어 ECD에합당한결과를보였다. 치료및경과 : prednisolone 65 mg/day 경구투여시작하였고, 약 3주후심초음파시행했으며, 그결과심수축 226

Tuberculosis and Respiratory Diseases Vol. 64. No. 3, Mar. 2008 구혈률은 60%, 심낭유출액이전벽 0.5 cm, 후벽 0.9 cm으로측정되었으며이외다른심벽운동의이상소견은보이지않았다. 약 1주후호흡곤란과사지동통으로재입원했다.

추적관찰한흉부전산화단층촬영결과이전과비교해보았을때흉막의비후와양측폐실질의말초에미세결절이새로증가되었다. 한편당뇨발현되어, prednisolone 30 mg로감량후 cyclophosphamide 100 mg/day 추가하였고현재추적관찰중이다. 고 찰 Figure 5.

left 5th posterior rib. A focal hot uptake in right humeral head, and right 7th axillary rib is again seen.

진단은특징적인골병변과함께전신장기에황색육아종의침범으로, 침범된장기의조직검사와면역조직염색을통해확진된다. 본증례의경우폐막의조직검사에서황색육아종이관찰되었고, 특수염색결과 S-100 음성, CD68 양성, CD1a 음성으로 ECD를확진할수있었다 8,9.

Pleural biopsy, (A) there are diffuse lipid-laden histiocyte infiltration, and Touton-type multinucleated eosinophilic giant cell (arrow) (H&E stain, 200).

4 Tuberculosis and Respiratory Diseases Vol. 64. No. 3, Mar 구혈률은 60%, 심낭유출액이전벽 0.5 cm, 후벽 0.9 cm으로측정되었으며이외다른심벽운동의이상소견은보이지않았다. 약 1주후호흡곤란과사지동통으로재입원했다. 동맥혈가스검사에서저산소증없었으며폐기능검사시행하였고, 그결과 1초간노력성호기량 2.5 L (86%), 노력성폐활량 3.3 L (91%) 비는 77%, 노력성호기중간유량 64% 로말초소기도폐쇄성질환소견보였으나폐확산능은 84% 로정상이었다. 추적관찰한흉부전산화단층촬영결과이전과비교해보았을때흉막의비후와양측폐실질의말초에미세결절이새로증가되었다. 한편당뇨발현되어, prednisolone 30 mg로감량후 cyclophosphamide 100 mg/day 추가하였고현재추적관찰중이다. 고 찰 Figure 5. Bone scan shows multifocal hot uptake in right humeral neck, right side of L5-S1 vertebrae, right 7th-9th costovertebral junction areas, left iliac bone, and left 5th posterior rib. A focal hot uptake in right humeral head, and right 7th axillary rib is again seen. Periarticular areas of bilateral hips show increased activity. ECD 는현재까지원발성포식세포장애라는것외에정확한병인론이밝혀지지않았으며, 악성조직구증과는독립된질환으로정의되고있다 1. 진단은특징적인골병변과함께전신장기에황색육아종의침범으로, 침범된장기의조직검사와면역조직염색을통해확진된다. 본증례의경우폐막의조직검사에서황색육아종이관찰되었고, 특수염색결과 S-100 음성, CD68 양성, CD1a 음성으로 ECD를확진할수있었다 8,9. 특징적인골병변은대부분의경우하지에서나타나며장골의골간단 (metaphysis) 및골간부 (diaphysis) 에서대칭적으로피질의경화성및융해성소견을보인다 10. 신경계, 안구, 피부, 폐, 심장, 후복막, 간, 비장, 췌장, 담관, Figure 6. Pleural biopsy, (A) there are diffuse lipid-laden histiocyte infiltration, and Touton-type multinucleated eosinophilic giant cell (arrow) (H&E stain, 200). (B) Immunohistochemical staining of S-100 protein reveals cytoplasmic staining only few macrophages (S-100, 200). (C) Immunohistochemical staining of CD68 demonstarates strong positive, expressed as brown color in most macrophages (CD-68, 200). (D) Immunohistochemical staining of CD1a reveals negative result (CD1a, 200). 227

5 JE Kim et al: Erdheim-Chester disease 부신, 전신혈관등을침범함으로써다양한전신증상으로나타내게되는데, 연구된바에의하면가장흔한증상은하지의골통증이고, 심장막삼출, 신경학적증상, 요붕증, 수신증, 후복막섬유화, 간질성폐침윤, 안와후부종괴및안검의황색판종, 간이나비장의비대등거의모든장기에침윤에의한증상을보인다고한다 7,11. 본증례의경우침범부위의골통이있었으며단순방사선촬영과자기공명영상에서 ECD 의특징적인골병변을관찰할수있었다. 이외타장기의침범증상으로는시력저하와이명호소했으나시력검사, 청력검사상저하소견없었다. 흉수로인해처음진단적접근이이루어졌으나폐실질의침범은없었으며흉막의비후가관찰되었다. 그외침범된장기는심막, 대동맥궁과복부대동맥을침범한대동맥염의혈관염, 양측신장염과약간의수신증이있었다. 본환자의특이한점은진성적혈구증다증으로치료받던중에 ECD 가발현한것으로세계적으로첫번째증례인것이다. ECD의치료로아직까지확립된치료법이없으며고식적으로스테로이드를사용, 염증작용을완화시키고전신증상의완화를위해사용되고있으며 12 prednisolone을 1 mg/kg/day 또는 100 mg/day 로사용한경우등다양한치료가시도되었고 methylprednisolone 1 g/day를사용하기도했다. 경험적으로 cyclosphosphamide, vinblastine, adriamycin, azathioprine 등의항암제를스테로이드와병합하여사용한예가있으며 13 colchicine, 방사선치료도시도되었다. 고농도의 etoposide 와자가모세포이식이일부좋은성과를보이고있고 INF-a 를사용하여좋은치료성적을거둔예가있다 14,15. 본증례의경우스테로이드만으로전신증상과골통의호전보이지않았으며추적관찰한흉부전산화단층촬영에서진행된흉막비후와폐실질의미세결절을근거로병의진행으로판단하여스테로이드를감량 ( 프레드니졸론 30 mg/day) 하였고 cyclophosphamide를추가하였다. ECD 의예후는진단후평균생존기간 32개월로호흡곤란, 폐섬유화, 심부전, 신부전으로진행되며합병된이후에는 6개월이내 36%, 3년이내 50% 가사망할수있는치명적인질환이다 7. 본증례의경우장기침범에따른기능적손실이오기전에진단하고치료를시작했으며향후지속적인치료예정이다. 요약 ECD 는포말대식세포의전신침범으로염증반응을일 으키는드문질환으로다양한임상양상과불량한예후를보이는질환이다. 본증례는골동통과폐막침범이된자에서흉막생검을통한확진으로 ECD 가진단된경우이며기저질환으로진성적혈구증다증이있는자에서발현한예를경험하였기에이를문헌고찰과함께보고하는바이다. 참고문헌 1. Devouassoux G, Lantuejoul S, Chatelain P, Brambilla E, Brambilla C. Erdheim-Chester disease: a primary macrophage cell disorder. Am J Respir Crit Care Med 1998;157: Allen TC, Chevez-Barrios P, Shetlar DJ, Cagle PT. Pulmonary and ophthalmic involvement with Erdheim- Chester disease: a case report and review of the literature. Arch Pathol Lab Med 2004;128: Hwang HS, Ji BS, Lee CK, Kim JY, Choi BS, Yang CW, et al. A case of Erdheim-Chester disease that presented with chronic renal failure. Korean J Med 2007;73: Kim YJ, Kim YD. Erdheim-Chester disease: two cases of orbital involvement. J Korean Ophthalmol Soc 2002; 43: Park YK, Ryu KN, Huh B, Kim JD. Erdheim-Chester disease. J Korean Med Sci 1999;14: Hong JR, Lee HG, Ko YH, Ahn JM, Choi YH, Kim BT. A case of Erdheim-Chester disease with periodic fever and knee pain. Korean J Med 1999;56: Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, Wechsler J, Brun B, Remy M, et al. Erdheim-Chester disease. Clinical and radiologic characteristics of 59 cases. Medicine (Baltimore) 1996;75: Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW. Erdheim-Chester disease: case report with multisystemic manifestations including testis, thyroid, and lymph nodes, and a review of literature. J Clin Pathol 2004;57: Favara BE, Jaffe R. Pathology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1987; 1: Chung JH, Park MS, Shin DH, Choe KO, Kim SK, Chang J, et al. Pulmonary involvement in Erdheim- Chester disease. Respirology 2005;10: Athanasou NA, Barbatis C. Erdheim-chester disease with epiphyseal and systemic disease. J Clin Pathol 1993;46: Koziolek MJ, Kunze E, Muller A, Thiem V, Scheel AK, 228

6 Tuberculosis and Respiratory Diseases Vol. 64. No. 3, Mar Muller D, et al. Erdheim-Chester disease. Dtsch Med Wochenschr 2005;130: Bourke SC, Nicholson AG, Gibson GJ. Erdheim-Chester disease: pulmonary infiltration responding to cyclophosphamide and prednisolone. Thorax 2003;58: Boissel N, Wechsler B, Leblond V. Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation. Ann Intern Med 2001;135: Braiteh F, Boxrud C, Esmaeli B, Kurzrock R. Successful treatment of Erdheim-Chester disease, a non-langerhans-cell histiocytosis, with interferon-alpha. Blood 2005;106:

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<31352EC8B2C7F6BCAE2E687770> 대한내과학회지 : 제 73 권제 2 호 2007 만성신부전으로발현된 Erdheim-Chester disease 1 예 가톨릭대학교의과대학내과학교실 황현석 지병수 이진국 김진영 최범순 양철우 김용수 =Abstract= A case of Erdheim-Chester disease that presented with chronic renal failure Hyun