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1 대한내과학회지 : 제 81 권제 2 호 2011 특집 (Special Review) - Pleural effusion 악성흉수의진단과치료 인하대학교의학전문대학원내과학교실 남해성 류정선 Diagnosis and Management of Malignant Pleural Effusion Hae-Seong Nam and Jeong-Seon Ryu Department of Internal Medicine, School of Medicine, Inha University, Incheon, Korea Malignant pleural effusions (MPEs) are an important clinical problem in patients with neoplastic disease. They can occur as the initial presentation of cancer, a delayed complication in patients with previously diagnosed malignancies, or the first manifestation of cancer recurrence after therapy. Common cancer types causing MPEs include lymphomas, mesotheliomas, and carcinomas of the breast, lung, and ovaries. However, almost all tumor types have been reported to cause MPEs. Regardless of the etiology, the median survival from clinical recognition is 4 months. New imaging modalities assist the evaluation of patients with a suspected MPE. However cytologic or tissue confirmation of malignant cells is necessary to establish a diagnosis. Management of an MPE remains palliative. Managements are directed toward removing pleural fluids and when appropriate, performing pleurodesis or initiating long-term drainage to prevent fluid reaccumulation. Talc pleurodesis is still the choice of treatment although concerns about its safety remain. Several factors such as performance status, expected survival, lung re-expansion following pleural fluid drainage and co-morbidities should be considered before the treatment. (Korean J Med 2011;81: ) Keywords: Diagnosis; Malignancy; Pleural effusion; Treatment 서론악성흉수는흉수에서악성세포가발견되는것으로악성종양환자에서이환율의중요한원인이다. 악성흉수는악성종양의초기에발현될수있으며, 악성종양의합병증또는치료후재발의징후로발현될수있다. 악성흉수의발생률에관한연구는미비하나, 한사후부검연구에서는악성종양으로사망한환자의 15% 에서악성흉수가발견되었다 [1]. 악성종양환자에서흉수는다양한원인에의하여발생된 다 (Table 1) [2]. 일부연구에서는종양에의한혈관신생으로혈관내피성장인자에의한혈관투과성증가와액체의혈관누출에의하여흉수가생성됨을설명하고있다 [2,3]. 거의모든악성종양이악성흉수의원인이될수있으나, 75% 이상의악성흉수는폐암, 유방암, 난소암, 림프종등에의하여발생되며, 10% 내외에서는원인종양이확인되지않는경우도있다 [2,4]. 악성흉수환자의예후는불량하여원인종양질환과무관하게중앙생존기간은 4개월로알려져있으며 [5], 이와같은이유로새로개정된폐암 TNM병기에서도악 Correspondence to Jeong-Seon Ryu, M.D., Ph.D. Department of Internal Medicine, School of Medicine, Inha University, Sinheung-dong 3-ga, Jung-gu, Incheon , Korea Tel: , Fax: , jsryu@inha.ac.kr

2 - The Korean Journal of Medicine: Vol. 81, No. 2, Table 1. Mechanisms by which malignant disease leads to pleural effusions [2] Direct Result Pleural metastases with increased permeability Pleural metastases with obstruction of pleural lymphatic vessels Mediastinal lymph node involvement with decreased pleural lymphatic drainage Thoracic duct interruption (chylothorax) Bronchial obstruction (decreased pleural pressure) Pericardial involvement Indirect Result Hypoproteinemia Postobstructive pneumonitis Pulmonary embolism Postradiation therapy 성흉수는 M1a로재분류되었다 [6]. 악성흉수의원인질환에따른예후를보면폐암환자가가장짧은생존기간을보였고난소암환자의경우생존기간이길었으며, 원인이불명확한경우중간정도의생존기간을보였다 [7,8]. 또한 Karnofsky performance scale 점수가낮을수록, ph 7.20 미만, glucose 60 mg/dl 미만을보일경우예후가불량한것으로알려져있다 [5]. 본특집에서는최근문헌고찰을통하여악성흉수환자의진단및치료에대하여정리하고자한다. 임상양상 악성흉수의진단 악성흉수환자의 50% 이상의환자에서발생하는흔한증상은호흡곤란이다. 그외에도기저악성종양에의한체중감소, 식욕부진, 권태감과기침등을호소할수있으나, 증상이없이우연히영상의학적검사에서발견되는경우도있다 [2,9]. 악성중피종의경우는 60% 환자에서지속적인둔한또는간헐적인국소흉막통을호소하며육종환자에서발생한악성흉수에서는기흉이동반되는경우도있다 [9]. 영상의학적검사 대부분의환자에서흉부방사선사진상중등도이상의흉수양 (500-2,000 ml) 을보이며, 한쪽흉부전체를차지하는대량흉수의원인질환은대부분악성종양인경우가흔하다 [10]. 대량의흉수는 흉벽측면에흉수의흔적이있는반달모양 (meniscus) 징후, 반대측으로종격동이동, 횡격막의역위 등의소견이흉부방사선사진에서관찰될수있다 [11]. 흉부초음파검사는적은양의흉수 (5 ml) 를발견할수있어흉강천자와흉관삽입을위한가장좋은위치를아는데도움을준다 [12]. 악성흉수를시사하는초음파소견으로는 고체형의흉막밀도, 불규칙하거나명확치않은경계를지닌저에코의흉막비후, 종양이흉막에서이웃장기로침범 등이있다 [9]. 흉부전산화단층촬영은악성흉수가진단혹은의심되는환자에서원발종양을발견하는데에유용한정보를제공하여준다 [11]. 악성흉수를시사하는소견으로는 환상 (circumferential) 흉막비후, 결절성흉막비후, 1 cm 이상의벽쪽흉막비후, 원발종양의종격동흉막침범 등이있다 [13]. 흉부자기공명영상은악성종양의흉벽또는횡격막의침범여부를확인하는데전산화단층촬영보다더좋은영상을제공하고, 소량의흉수를발견하는데높은민감도를보이나, 폐실질에대한영상은흉부전산화단층촬영보다효과적이지못하여이용이제한적이다 [9]. 양전자방출단층촬영 (PET) 을이용한악성흉수진단의민감도는 %, 음성예상치 %, 양성예상치 63-94% 로알려져있으며 [14], 이는흉수세포학적검사가음성일때양전자방출단층촬영의음성결과는악성흉수를배제하는데유용하다고한다. 흉수분석흉부영상의학기술의발전에도불구하고, 악성흉수를확진하기위해서는흉수에서세포학적혹은조직학적검사에서암세포를확인하는것이필수적이다. 원인감별을위해흉수천자가필요하며진단적흉수검사에서는세포수와백분율산정 (total cell count with differential), 화학검사 (total protein, lactate dehydrogenase, ph, glucose, albumin 등 ), 세포학적검사등이필요하다. 대부분의악성흉수는삼출액이지만 3-10% 에서는저알부민증, 간경화, 또는만성심부전등과같은동반된질환이있는경우에여출액으로나타날수도있다 [15,16]. 악성흉수를시사하는특징을표 2에정리하였다. 흉수에서암표지자 (carcinoembryonic antigen, carbohydrate antigens 15-3, 19-9, 549, neuron-specific enolase, squamous cell carcinoma antigen, cytokeratin 19 fragments 등 ) 의유용성에대한연구들에서암표지자의평균치가악성흉수에서높았지만양성과악성을구분하는임계수준전후에서중복되는경향이있어서확진을위해서는침습적인검사가필요할것이다 [2,17,18]. 흉수에서세포학적검사는악성흉수를진단하는가장쉬운방법이나, 진단율은원인종양의자연경과, 병변분포에

3 - Hae-Seong Nam, et al. Diagnosis and management of malignant pleural effusion - Table 2. Pleural fluid findings suggestive of malignant pleural effusion (MPE) [9] Cell Counts Lymphocytes More than 50% of MPEs have lymphocyte predominant effusions (lymphocytes = 50-70% of nucleated cells). Lymphocyte counts > 85% suggest tuberculous pleurisy, lymphoma, sarcoidosis, chronic rheumatoid pleurisy, yellow-nail syndrome or chylothorax. Erythrocytes Bloody effusions common with MPE but also found with benign asbestos pleurisy, postcardiac injury syndrome, trauma, and pulmonary infarction. Eosinophils From 12-24% of eosinophilic effusions (>10% eosinophils) are malignant in etiology. Chemical analysis Protein and LDH Most MPEs are exudates according to Light criteria; 3-10% are transudates. LDH > 1,000 IU/L narrows the differential diagnosis to MPE, empyema, rheumatoid pleurisy, and pleural paragonimiasis. Amylase 1-8% of pleural effusions are rich in amylase (> 100 IU/L) and so routine amylase measurement is not cost-effective unless pancreatic disease or ruptured esophagus is strongly suspected before the test. Higher pleural fluid concentrations are associated with shorter survival times among patients with MPE. ph Levels < 7.30 in 30% of MPE cases; decreasing pleural fluid ph correlates with decreasing survival and success rates with pleurodesis; however, in the absence of other clinical information, the correlation does not assist patient selection for pleurodesis. Glucose Levels < 60 mg/dl suggest MPE, rheumatoid pleurisy, complicated parapneumonic effusion, tuberculous pleurisy, lupus pleuritis, or esophageal rupture. 따라 50-90% 로다양하며 [19], 암세포의감별을위해유전자또는면역조직화학검사등이추가로필요할수있다. 최근진단율을높이기위하여유전자분석, DNA 메틸화, 염색체분석등을이용한연구가활발히진행되고있다 [2,9,20]. 흉막조직검사악성흉수가의심되지만세포학적검사가음성일때, 흉막조직검사가필요하다. 악성흉수를진단하는데있어세포학적검사가흉막조직검사보다더민감하며, 흉막조직검사의진단율은약 40-75% 이다 [20]. 영상유도하에시행되는흉막조직검사는합병증을줄일수있고악성흉수를진단함에있어서민감도 (76-86%) 와특이도 (100%) 를향상시킬수있으며, 5 mm의두께의적은흉막액에서도성공적으로조직검사를시행할수있는장점이있다 [21]. 경직성또는반경직성흉강경을이용한내과적흉강경검사와비디오흉강경수술을이용한조직검사에서는더많은조직을정확히얻을수있으며, 민감도를 % 로향상시킬수있다 [9,22]. 비디오흉강경수술의높은진단율에도불구하고, 비악성흉수에대한확진에있어서는덜효과적이며, 침습적이고전신마취가필요하다는단점이있다. 따라서삼출액흉수가있는환자에서임상적으로악성흉수가의심 되는경우또는한달이상지속된증상, 열이없는경우, 혈성흉수, 악성을암시하는흉부전산화단층촬영소견이있는경우비디오흉강경검사를고려하도록추천하고있다 [23]. 기관지내시경원인미상의흉수에서기관지내시경검사는진단율이낮아서기본검사로추천되지않는다. 객혈, 무기폐, 반대쪽으로종격동이동이없는대량흉수의경우처럼기관지내병변이의심되는경우에기관지내시경을시행한다 [20]. 악성흉수의치료악성흉수에대한보존적치료는암환자의생존율을향상시키지못하기때문에원인이되는종양에대한치료가중요하다. 흉수에의한호흡곤란과같은증상, 전반적인건강상태, 수행능력, 기대수명등을종합적으로고려하여악성흉수에대한고식적치료를결정한다. 치료의가장중요한목적은흉수제거와재축적방지를통하여호흡곤란등의증상을완화시키는것이다. 따라서무증상이면서원인이되는악성종양에대한치료가가능한환자에서는경과관찰을추천한다 (Table 3, Fig. 1) [4]

4 - 대한내과학회지 : 제 81 권제 2 호통권제 612 호

5 - 남해성외 1 인. 악성흉수의진단과치료 - Figure 1. Algorithm for the management of malignant pleural effusion [2,4]. Table 4. Available and investigational sclerosing agents for pleurodesis [9] Agent Success rates (%) Mineral Talc Antibiotic Doxycycline Quinacrine Antiseptic Iodopovidone Silver nitrate Anticancer drug Bleomycin Mitoxantrone Cisplatin Bacterial product or component Corynebacterium parvum Staphylococcus aureus superantigen OK432 Cytokine Interferon alpha-2β 치료적흉강천자호흡곤란과같은증상이있는악성흉수환자에서흉수제거후호흡곤란의개선정도를평가해야한다. 많은양의흉강천자에도호흡곤란과같은증상의호전이없다면, 림프관성암종, 혈전증, 무기폐, 심장질환등호흡곤란을유발할수있는다른원인을생각해야한다 [9,19]. 일반적으로흉강천자후호흡곤란은호전될수있으나, % 의환자는 30일이내에흉수가재축적되어증상이재발하게된다. 이경우반복적인흉강천자를하면유착, 소방형성, 감염등의위험성이증가된다 [24]. 따라서치료목적의반복적흉강천자는흉수가서서히재축적되는경우, 전신적치료에악성종양이반응하는경우, 1-3개월미만의기대수명이예상되는경우, 흉막유착술과같은다른방법으로흉수를조절할수없는경우등에서고려해야한다 [9,20,22]. 화학흉막유착술화학흉막유착술은화학물질을이용하여흉막에염증, 섬유소침착에의한유착을초래하여흉수의재축적을방지하여호흡곤란을호전시키고자하는방법이다 [2,19]. 이런흉막유착술은흉수에의한호흡곤란등호흡기증상이있고, 2-3개월이상의기대수명, 전신항암치료에반응하지않는악성흉수, 치료적흉강천자후폐확장확인된환자에서시행 한다 [9]. 흉막유착술에사용되는약제인경화제는흉관카테터또는흉강경등을이용하여주입할수있으며, 경화제에따라서매우다양한치료효율을보인다 (Table 4) [9]. 경화제의안전성과효과에대한연구들이시행되었으나, 아직까지적절하게비교된데이터가부족하여가장이상적인약제의선택이라는측면에서논쟁의소지가있지만 talc가악성흉수를방지하는데가장효과적인약제로알려져있다 [25,26]. 일반적으로 talc 사용에따른부작용은호흡곤란, 열, 흉통, 폐렴, 부정맥, 무기폐, 급성호흡부전등이알려져있으며, 가장치명적인급성호흡부전의발생률은약 1-9% 로보고된다 [19,27]. 이런급성호흡부전의합병증은 talc 입자의크기가클수록드물게발생하는것으로알려져있다 [27]. 따라서, talc 흉막유착술에의한저산소증등의합병증을줄이기위해서입자의크기가큰것을사용하도록추천하고있다 [4]. 일부세균의생산물과사이토카인등의치료성적이보고되고있으나, 아직까지는널리사용되기에는제한적이다 (Table 4) [2,9,20]. 흉막유착술시행시영국흉부학회 (British Thoracic Society) 에서는다음과같은권고를하고있다 [4]. 첫째, 악성흉수를배액또는흉막유착술을위하여소구경 (10-14Fr) 카테터를사용한다. 둘째, 리도카인 (3 mg/kg; 최대용량 250 mg) 은경

6 - The Korean Journal of Medicine: Vol. 81, No. 2, 화제주입전에만사용한다. 셋째, 시술전투약은흉막유착술과관련된통증과불안을완화하기위해서고려한다. 넷째, 흉막유착술약제주입후환자를여러방향으로회전시킬필요는없다. 다섯째, 흉막유착술약제주입후 1시간동안카테터를잠근다. 여섯째, 흉막유착술약재주입후하루에 250 ml 이상의배액이없다면 24-48시간내에카테터를제거한다. 유치흉막카테터 (indwelling pleural catheter) 주 2-3회정도흉수가 1,000 ml까지배액되는환자에서고려될수있는방법으로 % 환자에서호흡곤란를기대할수있다 [28]. 유치흉막카테터를사용한환자들의약 40-58% 에서 2-6주후자연흉막유착술이발생할수있으며, 카테터를통하여경화제등을주입할수있는장점도있다 [28,29]. 흉복막간단락 (pleuroperitoneal shunt) 흉복막간단락은유치흉막카테터, 흉막유착술을시행할수없거나실패한환자들에서대안으로고려할수있는방법으로, 95% 의환자에서증상완화를기대할수있으며, 단락폐쇄와감염같은합병증은 15% 환자에서발생하는것으로알려져있다 [9,30]. 결론악성흉수는거의모든악성종양에서발생할수있는흔히접하는임상적문제이다. 새로운영상의학적기법의소개로진단의정확도가향상되었으나, 확진을위해서는악성세포를세포학적, 조직학적검사를통하여확인하는것이필요하다. 환자의전신상태와원인질환에대한평가후악성흉수에대한적절한치료방법을선택하는것이중요하겠다 (Table 3, Fig. 1). 최근분자생물학의발전과조직학적진단기술의발전으로기존세포학적, 조직학적검사의진단율이향상되고있다. 향후신속하고, 효과적인진단방법과안전하고효율적인경화제의개발이필요할것이다. 악성흉수진단후에는보다적극적인치료적중재를통하여환자삶의질을향상시킬수있도록노력하여야하겠다. 중심단어 : 진단 ; 악성종양 ; 흉수 ; 치료 REFERENCES 1. Rodrîguez-Panadero F, Borderas Naranjo F, López Mejîas J. Pleural metastatic tumours and effusions: frequency and pathogenic mechanisms in a post-mortem series. Eur Respir J 1989;2: Light RW. Pleural Diseases. 5th ed. Philadelphia: Lippincott Williams & Wilkins, Kraft A, Weindel K, Ochs A, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer 1999;85: Roberts ME, Neville E, Berrisford RG, Antunes G, Ali NJ. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline Thorax 2010;65(Suppl 2):ii32-ii Heffner JE, Nietert PJ, Barbieri C. Pleural fluid ph as a predictor of survival for patients with malignant pleural effusions. Chest 2000;117: Goldstraw P, Crowley J, Chansky K, et al. The IASLC lung cancer staging project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2007;2: Abbruzzese JL, Abbruzzese MC, Hess KR, Raber MN, Lenzi R, Frost P. Unknown primary carcinoma: natural history and prognostic factors in 657 consecutive patients. J Clin Oncol 1994;12: van de Molengraft FJ, Vooijs GP. Survival of patients with malignancy-associated effusions. Acta Cytol 1989;33: Heffner JE, Klein JS. Recent advances in the diagnosis and management of malignant pleural effusions. Mayo Clin Proc 2008;83: Maher GG, Berger HW. Massive pleural effusion: malignant and nonmalignant causes in 46 patients. Am Rev Respir Dis 1972; 105: Qureshi NR, Gleeson FV. Imaging of pleural disease. Clin Chest Med 2006;27: Kocijancic I, Vidmar K, Ivanovi-Herceg Z. Chest sonography versus lateral decubitus radiography in the diagnosis of small pleural effusions. J Clin Ultrasound 2003;31: Yilmaz U, Polat G, Sahin N, Soy O, Gülay U. CT in differential diagnosis of benign and malignant pleural disease. Monaldi Arch Chest Dis 2005;63: Schaffler GJ, Wolf G, Schoellnast H, et al. Non-small cell lung cancer: evaluation of pleural abnormalities on CT scans with 18F FDG PET. Radiology 2004;231: Porcel JM, Alvarez M, Salud A, Vives M. Should a cytologic study be ordered in transudative pleural effusions? Chest 1999; 116: Ryu JS, Ryu ST, Kim YS, Cho JH, Lee HL. What is the clinical

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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