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1 대한내과학회지 : 제 71 권제 3 호 2006 후신경모세포종에합병된이소성부신피질자극호르몬증후군 1예 서울대학교의과대학내과학교실 구보경 구윤희 김진택 김홍일 이유진 조영민 김성연 =Abstract= A case of ectopic adrenocorticotropic hormone syndrome with olfactory neuroblastoma Bo Kyung Koo, M.D., Yun Hyi Ku, M.D., Jin Taek Kim, M.D., Hong Il Kim, M.D., You Jin Lee, M.D., Young Min Cho, M.D. and Seong Yeon Kim, M.D. Department of Internal Medicine, College of Medicine Seoul National University, Seoul, Korea We here present the case of a 37-year-old woman who suffered from adrenocorticotrophic hormone (ACTH)-dependent Cushing's syndrome due to an olfactory neuroblastoma. The patient's clinical course was complicated by co-infection with cytomegalovirus and Pneumocystis jirovechi, which improved with appropriate antimicrobial therapy and suppression of endogenous steroidogenesis with ketoconazole and octreotide. Radiation to the mass in the nasal cavity resulted in reduction of tumor size and remission of the Cushing's syndrome. This is the first report of the ectopic ACTH syndrome resulting from olfactory neuroblastoma in Korea.(Korean J Med 71: , 2006) Key Words : Neuroblastoma, Olfactory, ACTH Syndrome, Ectopic 서론부신생물증후군 (paraneoplastic syndrome) 으로이소성부신피질자극호르몬 (ACTH) 증후군을동반하는종양으로는소세포폐암 (50%), 카시노이드분비종 (17%), 췌도종양 (10%) 등이있다 1, 2). 이외에도유방암 3), 결장암, 5), 전립선암 6) 에합병된보고들이있지만매우드물다. 본증례는후신경모세포종에의한이소성 ACTH 증후군증례로서조사한바에의하면후신경모세포종에합병된이소성 ACTH 증후군은 1987년부터현재까지네예가보고되었을뿐이다 7-10). 저자들은국내에서는최초로후신 경모세포종에의한이소성 ACTH 증후군 1예를경험하였기에보고하는바이다. 증례 37세여자환자가내원 1일전시작된발열과마른기침을주소로응급실을방문하였다. 환자는내원 2개월전비강과우측사골동, 접형동을침범하는후신경모세포종을진단받고 ( 그림 1A) 내원 3주전까지 2회의선행화학항암요법 (neoadjuvant chemotherapy; etoposide (100 mg/m 2 ), ifosphamide (1,500 mg/m 2 ), cisplatin (80 mg/m 2 )) 을시행받았다. 비강내종괴에서시행한생검은 Received : Accepted : Correspondence to : Young Min Cho, M.D., Department of Internal Medicine, Seoul National University College of Medicine, #28 Yongon-dong, Chongno-gu, Seoul 110-7, Korea ymchomd@snu.ac.kr

-The Korean Journal of Medicine : Vol. 71, No. 3, 2006 - A B Figure 1. Magnetic resonance image (MRI) of the paranasal sinus at the time of diagnosis.

2 -The Korean Journal of Medicine : Vol. 71, No. 3, A B Figure 1. Magnetic resonance image (MRI) of the paranasal sinus at the time of diagnosis. (A) The image shows the mass in the nasal cavity involving the ethmoidal and sphenoidal sinus. (B) The pituitary gland has high signal density in the T1-weighted images. There was no mass or abnormal signal density in the pituitary gland. Table 1. Dexamethasone suppression test plasma cortisol (μg/dl) plasma ACTH (pg/ml) 2hour urine cortisol (μg/dl) Basal level Low dose dexamethasone suppression test High dose dexamethasone suppression test 후신경모세포종에합당했으며면역형광염색상 neuron specific enolase 양성, 크로모그라닌양성, 사이토케라틴음성, 백혈구-공통항원 (leukocyte common antigen) 음성이었다. 두번째화학항암요법당시저포타슘혈증및당뇨병이발견되었고, 이의원인을찾기위해검사를진행하였다. 호르몬억제검사결과 ( 표 1) ACTH 의존성쿠싱증후군으로진단되었으며부신생물증후군의심하에생검조직에서추가로 ACTH에대해면역화학염색을시행하였다. 염색결과는음성이었으나임상적으로후신경모세포종에의한이소성 ACTH 증후군의가능성이높다고판단하였으며, 선행화학항암요법후조속한수술을위해추가적인검사는하지않고항암치료를진행하였다. 경구포타슘제제투여로저포타슘혈증을교정하였고코르티솔과잉상태에대해서는특별한치료를하지않았다. 환자는두번째항암치료직후부터기침, 후비루가있었 고, 응급실방문 1일전부터는 38 이상의발열과함께호흡곤란을경험하였다. 응급실방문당시체온 38.9, 호흡수분당 2회였고, 흉부단순촬영상양측상부폐야에반점형음영이있었다 ( 그림 2B). 코르티솔과잉에의한면역기능저하상태임을고려하여광범위항생제 (cefotaxime, amikacin, roxithromycin) 와 trimethoprim-sulfamethoxazole (TMP/SMX) 을투여하였으나저산소증이더악화되어제3병일에기계호흡을시작하였다. 당시의혈액검사결과는표 2 및표 3에표기한바와같다. 입원일에시행한전산화단층촬영에서양측부신은미만성증식소견을보였고, 종괴는관찰되지않았다 ( 그림 3). 제3병일부터코르티솔생성을억제하기위해 ketoconazole (800~1,200 mg/day) 과 octreotide (300 μ g/day SC) 를투여하였으며, 제병일에진단적기관지내시경, 제5병일에흉강경수술 (video-assisted thoraco

-Bo Kyeong Koo, et al : A case of ectopic adrenocorticotropic hormone syndrome with olfactory neuroblastoma - A B Figure 2. Simple X-ray image of the chest.

compared to the image 1 month ago. Table 2. Changes of the hematological laboratory values during the hospitalization Variables 1 mo.

3 -Bo Kyeong Koo, et al : A case of ectopic adrenocorticotropic hormone syndrome with olfactory neuroblastoma - A B Figure 2. Simple X-ray image of the chest. (A) Simple X-ray image of the chest at one month before admission had no abnormal finding; (B) There was newly developed patchy consolidations at both upper lung fields on the day the admission compared to the image 1 month ago. Table 2. Changes of the hematological laboratory values during the hospitalization Variables 1 mo.ago * 1st day 3rd day th day 7th day 13th day 2th day 25th day 32th day WBC (/μl) Differential count (%) Neutrophils Lymphocytes Monocytes Hemoglobin (g/dl) Platelet (x10 3 /μl) Reticulocyte (%) * Laboratory findings one month before the admission tomic surgery) 을시행하여배양을위한검체를확보하였다. 제13병일에추적한 2시간소변코르티솔은 161 μg/ day로이전보다감소했다 ( 표 ). 이후점진적으로저산소증, 발열, 흉부방사선소견등임상상이호전되어기계호흡은중단하였고, levofloxacin과예방용량의 TMP/SMX만처방하였다. 당시까지각종배양검사및염색에서특이소견없었으며주폐포자충에대한직접면역염색및거대세포바이러스항원검사결과는모두음성이었다. 이후흉강경수술로얻었던조직배양에서 거대세포바이러스가동정됨이보고되어 gancyclovir 투여를시작했고항생제는모두중단하였다. 환자상태는지속적으로호전되었고, 비강내종괴에대해방사선치료를시작했다. 제25병일, 다시저산소증이발생하였고, 38 이상의고열이동반되었다. 흉부단순촬영상양측폐야의침윤이새로발생하였고당시 2시간소변코르티솔은 9.2 μg/day였다. 객담에서시행한주폐포자충에대한면역형광염색결과양성으로보고되어 TMP/SMX을치료

- 대한내과학회지 : 제 71 권제 3 호통권제 553 호 2006 - Table 3. Changes of blood chemistry values during the hospitalization Variables 1 mo.

4 - 대한내과학회지 : 제 71 권제 3 호통권제 553 호 Table 3. Changes of blood chemistry values during the hospitalization Variables 1 mo.ago * 1st day 3rd day th day 7th day 13th day 2th day 25th day 32th day Urea nitrogen (mg/dl) Creatinine (mg/dl) Glucose (mg/dl) Cholesterol (mg/dl) Total protein (g/dl) Albumin (g/dl) Total bilirubin (mg/dl) Direct bilirubin (mg/dl) Alkaline phosphatase (IU/L) AST (IU/L) ALT (IU/L) Gamma GT C-reactive protein (mg/dl) LDH (IU/L) * Laboratory findings one month before the admission 이상과대사병변은없었다. 이후종괴에대해수술을권유하였으나환자가거부하여 2년간특별한치료없이외래에서경과관찰중이다. 방사선치료종료 2년후시행한자기공명영상에서종양의크기는감소하였으며 ( 그림 B) ketoconazole, octreotide 등의처방없이혈중 ACTH 농도및 2시간소변코르티솔양모두정상범위로유지되고있다 ( 혈장 ACTH 32 pg/ml, 2시간소변코르티솔 27 μg/day) ( 그림 5). 고찰 Figure 3. Bilateral adrenal hypertrophy on CT on admission. No mass is visualized around either adrenal gland in the image. 용량으로증량하였으며이후환자상태는호전되었다. 방사선치료를완료하였고 ( 총조사량 5,00 cgy) ketoconazole, octreotide는유지하였다. 방사선치료종료직후시행한부비동자기공명영상상종양의크기는큰변화가없었으나 ( 그림 A) 개월후시행한전신양성자방출단층촬영 ([18F]-FDG PET) 결과두경부에서 본증례는후신경모세포종과함께쿠싱증후군을진단받고면역억제상태에서거대세포바이러스폐렴및주폐포자충폐렴에이환된예로서, 환자는 ketoconazole 및 octreotide 투여로코르티솔생성이억제되면서면역능이호전되어거대세포바이러스폐렴은호전되었지만, 급격한스테로이드의감소와 TMP/SMX의감량으로인해주폐포자충폐렴의급성악화를경험하였다. 본증례에서쿠싱증후군의원인은진단당시혈중 ACTH 농도가과도하게높았으며저용량및고용량덱사메타손에의해코르티솔이억제되지않은점으로미루어이소성 ACTH 증후군이라고생각된다. 환자의종양조직에서시행한 ACTH 면역화학염색은음성으로종양에서 ACTH의분비를직접증명하지는못했지만, 방사선치료후종양의크기가감소하면서쿠싱증후군

5 - 구보경외 6 인 : 후신경모세포종에합병된이소성부신피질자극호르몬증후군 1 예 - Table. Changes in the hormonal values Hormone 1 mo.ago 1st day 3rd day 9th day 13th day 17th day 19th day 25th day 32th day Plasma cortisol (5~25 μg/dl) Plasma ACTH (0~60 pg/ml) 2h-urine cortisol (39~200 μg/day) Ketoconazole (mg/day) * Octreotide (μg/day) * * Administration dose for suppression of endogenous steroidogenesis. Laboratory findings one month before the admission. Fever with hypoxia redeveloped on the 25th day after admission, which turned out to be associated with Pneumocystis infection. A B Figure. Subsequent MRI of the paranasal sinus. (A) The size of the tumor did not change immediately after completion of radiotherapy. (B) Image 2 years later shows that the mass in the nasal cavity decreased in size; the maxillary sinus is filled with soft tissue due to sinusitis. 도함께관해상태에도달한점은쿠싱증후군의원인이후신경모세포종임을시사한다하겠다. 이소성 ACTH 증후군의임상상을보이면서도조직에서 ACTH에대한면역형광염색이음성이었던원인으로종양에서 ACTH 가아닌, ACTH 분비자극호르몬 (corticotrophinreleasing hormone; CRH) 이분비되었을가능성 1), 종양에서 propiomelanocortin (POMC) 등 ACTH의전구물질이분비되었을가능성 11), 면역화학염색의위음성가능성등을고려해볼수있겠다. 종양에서 CRH를분비하는경우는매우적은것으로알려져있는데 1) CRH 분 비가증명된종양의일부는 ACTH를분비하지않음이보고되어있다 1, 12). 종양에서 POMC나 ACTH 전구체를분비하는경우에도이소성 ACTH 증후군과같은임상상을보일수있는데, 뇌하수체이외의종양에서분비된 POMC는정상적인 ACTH와크기가다른 ACTH 전구체로만들어지는경우가흔하며이들은 ACTH에비해생화학적활성이떨어지기는하지만, 이들전구체에의해서도이소성 ACTH 증후군의임상상이가능하다 11). 실제로이소성쿠싱증후군이동반된부신신경모세포종에서 ACTH의증가없이 POMC의발현이증가되었다

6 -The Korean Journal of Medicine : Vol. 71, No. 3, Figure 5. The 2-hour urine cortisol and concentration of plasma ACTH. The level of plasma ACTH was normalized and urine cortisol maintained within normal limits without ketoconazole or octreotide after radiotherapy. 는보고가있다 13). 이소성 ACTH를동반한후신경모세포종 개의증례 7-10) 중한예 10) 에서도 ACTH가음성이었는데, 혈중호르몬농도측정및억제검사를통해임상적으로이소성 ACTH 증후군을진단하였다. 이소성 ACTH 증후군은면역기능저하로인해감염에대한감수성이증가하기때문에환자의예후에악영향을준다. 실제로가장흔히이소성 ACTH 증후군을동반하는소세포폐암환자를대상으로시행한연구에따르면, 소세포폐암환자에서이소성 ACTH 증후군을동반한경우는그렇지않는경우보다화학항암치료중감염으로인한사망률이유의하게높았다 1). 고코르티솔혈증은내인성, 외인성에관계없이주로세포매개면역기능의장애를초래하는것으로알려져있으며 15) 이는쿠싱증후군환자가주폐포자충이나헤르페스, 칸디다등의병원체에대해취약한원인이다. 이소성 ACTH 증후군환자에서감염의중증도및빈도는혈중코르티솔농도와직접적인관련이있으며 16) 이들에서는칸디다, 크립토콕쿠스, 아스페르길루스, 노르카디아, 주폐포자충, 톡소플라스마, 헤르페스바이러스, 결핵등에의한기회감염의빈도가높다. 이소성 ACTH 증후군을동반하는종양의대부분이종양의완전제거가불가능하다는점을고려하면 1, 17) 종양의치료와별개로내인성코르티솔과잉상태의해결이필요하다하겠다 1). 코르티솔억제치료시에는본증례에서와같은급격한스테로이드감소에의한주폐포자충폐렴의발현가능성등을고려해야한다 18). 이증례의경우종양이부비동을침범하였지만원격전이나림프절침범이없었기때문에 Kadish 병기 19) B 에속하며방사선치료에반응이있었기때문에이전연 구결과 20) 를토대로판단했을때 5년생존율은 60~80 % 에이를것으로생각된다. 종양이재발할경우종양에동반되었던부신생물증후군도함께악화되는경우가많은것으로알려져있으므로 1, 10) 환자의예상생존기간을고려할때코르티솔의변화를추적관찰하는것은종양의진행상태를판단하는데유용할것이라고생각된다. 이소성 ACTH 증후군이재발했을경우원발종양의치료에앞서코르티솔의억제를위한치료를고려해야하겠다. 요약 요약하면본증례는후신경모세포종에병발한이소성 ACTH 증후군에대한보고로서국내에서는첫보고이다. 고코르티솔혈증에의한면역기능약화로주폐포자충폐렴및거대세포바이러스폐렴에이환되었으며부신의스테로이드합성억제및 TMP/SMX 투약후회복되었다. 이소성 ACTH 증후군에서원인질환의조속한치료와더불어내인성코르티솔과잉상태의해결이필요함을시사하는증례이다. 중심 단어 : 후신경모세포종, 이소성부신피질자극 호르몬증후군 REFERENCES 1) Strewler GJ. Williams textbook of endocrinology. 10th ed. p , Philadelphia, Saunders, ) DeLellis RA, Xia L. Paraneoplastic endocrine syndromes: a review. Endocr Pathol 1: , ) Poddar NK, Saha R, Hedau S, Ray A. Adrenocorticotropic hormone production in breast cancer. Indian J Exp Biol 3:35-39, 2005 ) Ordi J, Bosch JA, Pigrau C, Tornos J, Ruibal A, Saigi E. Ectopic ACTH secretion syndrome in a sigmoid neoplasia: an infrequent association. Rev Clin Esp 163: , ) Eggenberger C, Brandle M, Galeazzi RL, Spinas GA, Schmid C. Cushing syndrome due to ectopic ACTH secretion: an uncommon case presentation, diagnosis and therapy. Schweiz Med Wochenschr 129: , ) Rickman T, Garmany R, Doherty T, Benson D, Okusa MD. Hypokalemia, metabolic alkalosis, and hypertension: Cushing's syndrome in a patient with metastatic prostate adenocarcinoma. Am J Kidney Dis 37:838-86,

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<32342EC7D1C1A6C8A32E687770> 대한내과학회지 : 제 76 권부록 1 호 2009 갑상샘유두암과동반된이소성쿠싱증후군 1 예 가톨릭대학교의과대학 1 내과학교실, 2 병리학교실 김용철 1 정문경 1 송윤미 1 권혁상 1 정찬권 2 문성대 1 한제호 1 A case of ectopic Cushing s syndrome combined with papillary thyroid carcinoma Yong