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1 대한내분비학회지 : 제 22 권제 6 호 2007 증례 골반내후복막에서기원한유상피혈관내피종양에의한저혈당 1 예 부산대학교의학전문대학원내과, 병리과 1, 대동병원내과 2 김지량 전윤경 박기태 강양호 손석만 김인주 김용기 최경운 1 이광재 2 A Case of Epithelioid Hemangioendothelioma of the Pelvic Retroperitoneum with Hypoglycemia Ji Ryang Kim, Yun Kyung Jeun, Kee Tae Park, Yang Ho Kang, Seok Man Son, In Ju Kim, Yong Ki Kim, Kyung Un Choi 1, Kwang Jae Lee 2 Department of Internal Medicine and Pathology 1, School of Medicine, Pusan National University; and Department of Internal Medicine 2, Dae-Dong Hospital ABSTRACT Hypoglycemia caused by a non-islet cell tumor (NICT) is a rare condition. The mechanism of NICT-induced hypoglycemia is still unclear, but insulin-like growth factor-ii (IGF-II) has been thought to play a major role in its development. NICT is usually of mesenchymal or epithelial cell origin, but reports on NICT of an endothelial cell origin, which causes hypoglycemia, have yet to surface. Here, we report on a case of a 63-year-old female patient who was diagnosed with epithelioid hemangioendothelioma-induced hypoglycemia. Epithelioid hemangioendothelioma is a borderline malignant vascular tumor that is of endothelial cell origin and usually occurs in soft tissue, skin, lung, and liver. It was observed that serum insulin, C-peptide, and IGF-I were reduced, but the IGF-II level was elevated in hypoglycemia. The PET-CT showed no abnormal glucose metabolism in the tumor. Dextrose fluid was administered to the patient to control hypoglycemia until the operation. For treatment and diagnosis, surgical resection of the tumor and total hysterectomy were performed. The specimen was noted to have epithelioid hemangioendothelioma. Hypoglycemia-related symptoms disappeared after surgical resection was performed. (J Kor Endocr Soc 22:440~445, 2007) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: epithelioid hemangioendothelioma, hypoglycemia, insulin-like growth factor-ii 서론 1) 저혈당을야기하는종양은크게세가지로나눌수있는데, 인슐린종, 네시디오블라스토시스 (Nesidioblastosis) 같은고인슐린혈증을동반하는췌장도세포종양, 혈청인슐린이낮은비도세포종양으로나뉜다. 비도세포종양은간엽조직기원인혈관주위세포종, 섬유육종, 중피종, 신경섬유종과간세포암 [1], 부신수질종양등이있다. 이런종양에의한저혈당의기전은종양조직에서저혈당을일으키는물질의생성접수일자 : 2007년 7월 2일통과일자 : 2007년 8월 23일책임저자 : 김인주, 부산대학교의학전문대학원내과 과종양조직의당이용에의한것으로생각되며, 저혈당을일으키는물질로는인슐린양성장인자 (Insulin-like growth factor, IGF) 가제시되고있다 [2]. 유상피혈관내피종은혈관내피에서기원한종양으로주로연부조직, 피부, 폐, 간에서발생하고비장, 두경부, 유방, 심장, 위장관, 종격동, 흉막에서도발생한다고알려져있다 [3,4]. 국내및국외에서유상피혈관내피종의보고는있지만저혈당을일으킨경우는아직까지보고된바가없다. 저자들은의식소실과저혈당을주소로내원한환자에서골반내의거대종괴를발견하였고, 혈장 IGF-I 농도는정상이나 IGF-II 농도의증가가있었던유상피혈관내피종 1예를경험하였기에보고하는바이다

- 김지량외 8 인 : 골반내후복막에서기원한유상피혈관내피종양에의한저혈당 1 예 - 증례환자 : 63세여자환자주소 : 의식소실현병력 : 특이병력없던분으로의식소실및저혈당증상으로 2차병원방문후골반내거대종양있어본원으로전원되어왔다. 2차병원내원시반혼수상태였으며혈당은 37 mg/dl였고 20% 포도당정주후의식은회복되었다.

검사실소견 : 내원시말초혈액검사에서백혈구 5,530 /ul, 혈색소 12.0 g/dl, 혈소판 305,000 /ul, AST 39 IU/L (10-40), ALT 50 IU/L (6-40), ALP 280 IU/L (95-280), total bilirubin 0.28 mg/dl (0.3-1.

5), amylase 76 IU/L (36-128), lipase 34 IU/L (22-51), T3 119 ng/dl (80-170), free T4 1.31 ng/dl (0.8-2.1), TSH 0.32 miu/ml (0.3-5.0), B형간염바이러스표지자음성, C형간염바이러스표지자음성이였다. 환자는 Fig.

2 - 김지량외 8 인 : 골반내후복막에서기원한유상피혈관내피종양에의한저혈당 1 예 - 증례환자 : 63세여자환자주소 : 의식소실현병력 : 특이병력없던분으로의식소실및저혈당증상으로 2차병원방문후골반내거대종양있어본원으로전원되어왔다. 2차병원내원시반혼수상태였으며혈당은 37 mg/dl였고 20% 포도당정주후의식은회복되었다. 과거력 : 10년전갑상선결절로갑상선아전절제술을받았으며, 4년전충수돌기절제술을받았다. 가족력 : 특이사항은없었다. 사회력 : 특이사항은없었다. 이학적검사 : 생체징후는안정적이었으며, 두경부및흉부에는이상소견없었으며, 복부소견상하복부에압통이있었으나촉지되는덩어리는없었다. 검사실소견 : 내원시말초혈액검사에서백혈구 5,530 /ul, 혈색소 12.0 g/dl, 혈소판 305,000 /ul, AST 39 IU/L (10-40), ALT 50 IU/L (6-40), ALP 280 IU/L (95-280), total bilirubin 0.28 mg/dl ( ), direct bilirubin 0.11 mg/dl ( ), BUN 8 mg/dl (6-26), creatinine 0.8 mg/dl ( ), amylase 76 IU/L (36-128), lipase 34 IU/L (22-51), T3 119 ng/dl (80-170), free T ng/dl ( ), TSH 0.32 miu/ml ( ), B형간염바이러스표지자음성, C형간염바이러스표지자음성이였다. 환자는 Fig. 1. MRI. Huge tumor was well enhancing mass and was composed of necrotic and hemorrhagic portion in it. It showed engorged vessels around tumor. Fig. 2. Whole body PET-CT. There was no abnormal glucose metabolism. FDG uptake in tumor cell was slightly increased (SUV 1.7), but it was meaningless

대한내분비학회지 : 제 22 권제 6 호 2007 4시간공복후저혈당이생겼고, 이때측정한 plasma glucose 36 mg/dl, insulin 9.93 pmol/l (0-208), C-peptide 0.18 ng/ml (0.

7) 로정상보다약간낮은수치를보였고, IGFBP-3 (Insulin-like growth factor binding protein-3) 3924.

방사선학적검사 : 흉부 X-선소견상특이소견은없었고복부컴퓨터단층촬영과자기공명영상에서후복막에서기원한혈관이풍부하고내부에출혈을동반한약 16 cm 크기의종양이발견되었다. 종양은자궁과방광등주위구조물을누르는양상이나다른장기의침범소견은없었다 (Fig. 1).

임상경과 : 10% 포도당용액을점적하면서혈당은 142 mg/dl로유지되었다. 저혈당때문에환자에게지속적으로포도당을점적하였고, 내원 11일째산부인과에서후복막종양의절제및자궁아전절제술, 양측난소절제술을시행하였다. 자궁과대장사이에위치한종양은주위조직및장기 Fig. 3.

The largest one measured 6x6x5 cm in dimensions. The cut surface was pinkish and showed multiple small hemorrhagic foci.

3 대한내분비학회지 : 제 22 권제 6 호 시간공복후저혈당이생겼고, 이때측정한 plasma glucose 36 mg/dl, insulin 9.93 pmol/l (0-208), C-peptide 0.18 ng/ml (0.4-4), growth hormone 1.15 ng/ml (0-2), cortisol 11.1 ug/ml (5-25), ACTH 10.5 pg/ml (10-60) 였다. IGF-I은 9.10 nmol/l ( ) 로정상보다약간낮은수치를보였고, IGFBP-3 (Insulin-like growth factor binding protein-3) ng/ml ( ) 으로연령평균범위에서높은정상범위였고, IGF-II 1312 ng/ml ( ) 는연령평균보다상승되어있었다. 방사선학적검사 : 흉부 X-선소견상특이소견은없었고복부컴퓨터단층촬영과자기공명영상에서후복막에서기원한혈관이풍부하고내부에출혈을동반한약 16 cm 크기의종양이발견되었다. 종양은자궁과방광등주위구조물을누르는양상이나다른장기의침범소견은없었다 (Fig. 1). 저자들은종양의포도당이용정도와악성도판별에도움을얻기위하여양전자방출단층촬영술을시행하였다. 결과는전체적으로정상적인당대사를보였으며골반내종양에경도의 FDG 섭취증가 (SUV 1.7) 가있었으나의미는없었다 (Fig. 2). 임상경과 : 10% 포도당용액을점적하면서혈당은 142 mg/dl로유지되었다. 저혈당때문에환자에게지속적으로포도당을점적하였고, 내원 11일째산부인과에서후복막종양의절제및자궁아전절제술, 양측난소절제술을시행하였다. 자궁과대장사이에위치한종양은주위조직및장기 Fig. 3. Gross histology of the tumor. The tumor mass was composed of pinkish brown fragments and flesh soft tissue, measuring 630 gm in its weight. The largest one measured 6x6x5 cm in dimensions. The cut surface was pinkish and showed multiple small hemorrhagic foci. A B C D Fig. 4. Microscopic findings of the tumor. A. The tumor mass was composed of solid nests of rounded to slightly spindled endothelial cells (H&E stain, 200). B. The tumor cells formed small intracellular lumens, which was seen as vacuoles (H&E stain, 400). C, D. The tumor cells expressed CD34 and FVIII related antigen ( 400)

4 - 김지량외 8 인 : 골반내후복막에서기원한유상피혈관내피종양에의한저혈당 1 예 - 와유착이심하였고, 출혈에대한지혈술을시행하면서유착을박리하여종양을제거하였다. 수술후포도당주사없이 8시간이상의금식시에도저혈당은유발되지않았고, 특별한불편감없어술후 9일째퇴원하였다. 이후검사한 IGF- II는 ng/ml으로감소되었으며, 외래에서경과관찰중에더이상의저혈당증상없이정상적인생활을하고있다. 병리학적소견 : 절제된조직은여러개의조각으로구성된갈색의종괴였고, 가장큰조각의크기는 cm 이었다. 균일한절단면은분홍빛을띠고있었으며여러개의작은출혈성병소가관찰되었으나괴사는뚜렷하지않았다 (Fig. 3). 현미경소견상종양세포는주로미만성성장양상을보이면서원시혈관을형성하고있었고대부분의둥글거나난원형인종양세포는일부에서세포질내에공포를형성하였다. 이들세포는 CD34, CD31, Factor VIII 관련항원과 vimentin에양성반응을보여혈관내피세포분화를보인다는것을확인할수있었다. 유사분열은 10 high power field에서 1개미만으로관찰되었다 (Fig. 4). 고찰저혈당을일으키는비도세포종양은임상증상만으로는인슐린종에의한저혈당과구별이되지않는다. 비도세포종양은모든연령에서발생할수있지만 40~70세에주로보고되고있으며, 간엽혹은상피세포기원의종양들이다. 유상피혈관내피종 (Epithelioid hemangioendothelioma) 은혈관내피세포에서기원한중등도의악성도를가진종양으로중간혹은큰정맥주위에서발생한다 [5] 년 Dail과 Liebow 가혈관내기관지폐포종양 (intravascular bronchioloalveolar tumor) 이라고보고하였고 [6], 이후전자현미경과면역조직화학검사법이도입되면서혈관내피세포기원의혈관종임을알게되었다 [7]. 현미경상종양은국소적으로경계가명확한혈관상을보이지만두드러지지는않으며, 종양세포는세포질이비교적풍부하고원형과타원형의핵을가지고기질내에미만형, 둥지혹은끈모양으로성장하고있다. 조직소견으로예후를판단할수있는데, 종양세포의이형성과유사분열의정도가심하고조직괴사의범위가넓을수록예후는좋지않다. 종양세포가면역조직화학염색에서 factor VIII 관련항원, CD34, CD31과간엽조직에대한특이항원인 vimentin에대하여양성을나타내면이질환을진단할수있다 [8]. 비도세포종양의저혈당발생기전은명확하지않지만, 종양자체의당이용의증가, 저혈당에대한대상성호르몬반응의저하와종양에의한인슐린양물질의분비등이저혈당발생의기전으로제시되고있다 [2]. 이중종양에의한 IGF-II의분비와이의인슐린양작용이저혈당발생의주기전으로생각되고있는데, 1988년 Daughaday 등이이들종 양은 IGF-II mrna를표현하며혈청 IGF-II치가증가되어있으며혈청 IGF-II가높지않더라도고분자량의 IGF-II ( big-igf-ii') 의비율이증가되어있다고보고하였다 [9]. 그리고 Hizuka와 Fukuda 등은비도세포종양은 IGF-II농도의상승과 IGF-I농도의저하를유발하며, 비도세포종양에서는 IGF-II와 IGF-I의비가 20 이상이며, 반대로정상에서는 10 이하라고보고하였다 [10,11]. IGF-II는일차적으로간에서합성되고다른국소조직에서도합성되어자가분비호르몬 (autocrine hormone) 혹은이웃분비호르몬 (paracrine hormone) 으로서여러조직에작용한다. 분자량은 7.5 kda이며 single-chain polypeptide로 6개의 IGF-binding protein 중하나에결합하고있다. IGF는신체대부분장기의성장에관여하고종양의성장에도관여한다고알려져있다 [12,13]. 일부종양에서는전구호르몬형태인 big-igf-ii를분비하게되는데, 이는종양의포도당섭취를증가시켜종양의성장에영향을준다 [9]. Big-IGF-II는간의포도당생성감소, 췌장의인슐린분비억제, 근육이나지방의포도당섭취증가, 뇌하수체의성장호르몬분비를억제하여 IGF-I과 IGFBP-3의감소를일으킨다 [14]. 이는저혈당을일으킬수있는물질로생각되는데, 그이유는종양세포내에서 IGF-II mrna발현과 big-igf-ii분비증가를보이고혈청내의 IGF- II 혹은 big-igf-ii 의증가를볼수있기때문이다 [1,9,14~16]. IGF-II는 big-igf-ii의 O-glycosylation과정에의하여만들어진다. IGF-II는 70~80% 가 150 kda의 IGF, IGFBP-3, acidlabile subunit의삼원복합체로혈청에존재하며, 나머지는 IGFBP-2 등의다른단백질과결합하여 50 kda보다작은형태로존재한다. 150 kda의삼원복합체는혈관내에서만순환하게되고작은분자량의 50 kda의복합체는모세혈관을통과하여표적장기에효과를나타낸다 [9,17]. 따라서종양에의한저혈당은 IGF-II의인슐린양작용과성장호르몬의감소로인한간의당신생을억제할뿐아니라 pro-igf- II와 IGFBP-3의결합억제로작은분자량의복합체가혈중에증가되어발생하는것으로생각할수있다. 저혈당을동반한비도세포종양의치료는수술적절제가우선시되어야하며, 수술이불가능한경우항암화학요법및방사선치료를해볼수있으나효과적이라는보고는없다. 간에전이된경우는간동맥화학색전술을시도해볼수있다. 수술적치료를하기전까지대증요법으로포도당점적, 성장호르몬, diazoxide, glucagon, steroid, somatostatin 투여를해볼수있다 [18]. 국내에서도수술을못하는비소도세포종양환자에서대증적요법으로당질코르티코이드치료로호전시킨증례가보고되었다 [19]. 유상피혈관내피종에서 carboplatin과 etoposide로관해를얻은보고와 interferon alfa-2a로부분관해를얻은보고가있지만 [20], 다른연구에서는종양이서서히자라는특징을가지고있어항암화

5 대한내분비학회지 : 제 22 권제 6 호 2007 학요법이효과가없는것으로보고하고있다. 본증례에서는공복시저혈당증상이있는환자에서골반내의거대종양을발견하였고저혈당시에인슐린과 C-peptide의수치가낮은것으로보아종양에의한저혈당을의심하였다. 저혈당시 counter-regulatory hormone 수치는정상이었고저혈당을유발시키는물질로알려진 IGF-I은조금감소되어있었지만 IGF-II는환자연령대의정상수치보다증가되었고 IGF-II/IGF-I비는 20 이상으로높았다. IGF-II 수치가높아 big-igf-ii의비율을확인하기위한 IGF-II immunoblot은시행하지않았다. 저자들은종양의크기가커서종양내포도당대사가활발하여저혈당이생길가능성을생각하여전자방출단층촬영술검사를하였으나뚜렷한포도당대사의증가는발견할수없었다. 환자는종양절제수술후보존적치료없이도저혈당은일어나지않았다. 따라서환자는종양에서분비한 IGF-II에의한인슐린양효과에의하여저혈당이유발되었으며, 원인인종양제거후저혈당에서회복된것으로생각된다. 절제한조직은 CD34, CD31, Factor VIII 관련항원과 vimentin에양성반응을보여혈관내피에서분화한다는것을알았으나제한점으로는본원에서 IGF-II에대한염색이불가능하여시행하지못했다. 요약유상피혈관내피종이골반내후복막에서발생하는경우는드물며, 이종양에서분비한 IGF-II에의해저혈당을동반한증례는보고된적이없다. 저자들은저혈당을동반한골반내의유상피혈관내피종이 IGF-II를분비하고이것의인슐린양작용으로저혈당이유발되었을것으로생각되는 1예를경험하였기에문헌고찰과함께보고하는바이다. 참고문헌 1. Lee MH, Kang SS, Lee J, Ihm SH, Yoo JM, Choi MG, Yoo HJ, Park SW: A Case of Non-Islet Cell Tumor Hypoglycemia. J Kor Soc Endocrinol 10:65-69, Daughaday WH, Deuel TF: Tumor secretion of growth factors. Endocrinol Metab Clin North Am 20: , Celikel C, Yumuk PF, Basaran G, Yildizeli B, Kodalli N, Ahiskali R: Epithelioid hemangioendothelioma with multiple organ involvement. APMIS 115: , Crotty EJ, McAdams HP, Erasmus JJ, Sporn TA, Roggli VL: Epithelioid hemangioendothelioma of the pleura: clinical and radiologic features. AJR Am J Roentgenol. 175: , Bölke E, Gripp S, Peiper M, Budach W, Schwarz A, Orth K, Reinecke P, van de Nes JA: Multifocal epithelioid hemangioendothelioma: case report of a clinical chamaeleon. Eur J Med Res. 11: , Dail DH, Liebow AA: Intravascular bronchioloalveolar tumor. Am J Pathol 78:6-7, Corrin B, Manners B, Millard M, Weaver L: Histogenesis of the so-called "intravascular bronchioloalveolar tumor". J Pathol 128: , Einsfelder B, Kuhnen C: Epithelioid hemangioendothelioma of the lung (IVBAT)-clinicopathological and immunohistochemical analysis of 11 cases. Pathologe 27: , Daughaday WH, Emanuele MA, Brooks MH, Barbato AL, Kapadia M, Rotwein P: Synthesis and secretion of insulin-like growth factor II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med 319: , Fukuda I, Hizuka N, Takano K, Asakawa-Yasumoto K, Shizume K, Demura H: Characterization of insulin-like growth factor II (IGF-II) and IGF binding proteins in patients with non-islet-cell tumor hypoglycemia. Endocr J 40: , Hizuka N, Fukuda I, Takano K, Okubo Y, Asakawa- Yasumoto K, Demura H: Serum insulin-like growth factor II in 44 patients with non-islet cell tumor hypoglycemia. Endocr J 45:S61-S65, Baxter RC: Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab. 278: E , Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE: Molecular interactions of the IGF system. Cytokine Growth Factor Rev 16: , Hamidou M, Bani-Sadr F, Kenzi A, Sagan C, Grolleau JY: Hypoglycemia associated with pleural fibromas. Study of insulin-like growth factors (IGF) and pathogenic considerations. Rev Med Interne 23: , Fukuda I, Hizuka N, Ishikawa Y, Yasumoto K, Murakami Y, Sata A, Morita J, Kurimoto M, Okubo Y, Takano K: Clinical features of insulin-like growth factor-ii producing non-islet-cell tumor hypoglycemia

6 - 김지량외 8 인 : 골반내후복막에서기원한유상피혈관내피종양에의한저혈당 1 예 - Growth Horm IGF Res 16: , Höög A, Sandberg Nordqvist AC, Hulting AL, Falkmer UG: High-molecular weight IGF-2 expression in a haemangiopericytoma associated with hypoglycaemia. APMIS 105: , Zapf J: Role of insulin-like growth factor II and IGF binding proteins in extrapancreatic tumor hypoglycemia. Horm Res 42:20-26, Teale JD, Wark G: The effectiveness of different treatment options for non-islet cell tumour hypoglycaemia. Clin Endocrinol(Oxf) 60: , Chae YT, Hwang IJ, Ryu KH, Ko EH, Rue JI, Kim SK, Park SW, Kim YR, Cho YW, Choi YK, Lee SJ: A Case of Non-Islet Cell Tumor Hypoglycemia. J Kor Soc Endocrinol 21:74-78, Roudier-Pujol C, Enjolras O, Lacronique J, Guillemette J, Herbreteau D, Leibowitch M, Escande JP: Multifocal epithelioid hemangioendothelioma with partial remission after interferon alfa-2a treatment. Ann Dermatol Venereol 121: ,

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Kjtcs324( ).hwp 과오종과유사한폐상피모양혈관내피종 -1 예보고 - Pulmonary Epithelioid Hemangioendothelioma Mimicking Hamartoma -A case report- Epithelioid hemangioendothelioma, originating from the vascular endothelium, is a very rare and