Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea

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1 대한응급의학회지제 27 권제 1 호 Volume 27, Number 1, February, 2016 Medical Etiology of Pleural Effusions in Cancer Patients 원 저 Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea Min Jee Lee, M.D., Yoon-Seon Lee, M.D., Youn Jung Kim, M.D., Shin Ahn, M.D., Chang Hwan Sohn, M.D., Dong Woo Seo, M.D., Jae Ho Lee, M.D., Won Young Kim, M.D., Kyung Soo Lim, M.D. Purpose: The purpose of this study is to examine the causes of Pleural effusion (PE) in cancer patients and to compare the clinical characteristics between malignant PE (MPE) and non-mpe. Methods: All consecutive cancer patients with PE who underwent diagnostic thoracentesis from January 1, 2008 to March 31, 2011 were analyzed retrospectively. Results: A total of 719 patients were included; mean age was 58.4±13.6 years and 44.5% were female. The most common cause of PE was MPE (57.7%), followed by parapneumonic or empyema in 16.3%. However, the etiology was significantly different according to primary tumor origin and subtypes of lung cancer. While MPE was most common in lung, breast, and gynecologic cancer, hepatic hydrothorax was the main cause in Hepatocellular carcinoma (HCC). MPE accounted for 85.2% in adenocarcinoma, and 30.2% and 58.8% in squamous cell and small cell carcinomas, respectively. Patients with MPE were younger (57.0 vs years) and female-dominant (55.4% vs. 29.6%) compared to those with non-mpe. MPE had the large size (53.5% vs. 34.9%) and left location of PE (31.3% vs. 19.4%) more frequently than non-mpe, and fewer neutrophils (15.4% vs. 30.6%) and more lymphocytes (32.2% vs. 28.2%), higher levels of ph (7.33 vs. 7.29), and lower levels of glucose (111.5 vs mg/dl) than non-mpe (p<0.001 for all). Conclusion: Overall, MPE was the most common cause of PE in cancer patients. However the etiology of PE was significantly different according to primary tumor origin and subtypes of lung cancer. A difference in age, gender, size 책임저자 : 이윤선서울특별시송파구올림픽로 43길 88 서울아산병원응급의학과 Tel: 02) , Fax: 02) ysdoc@amc.seoul.kr 접수일 : 2015년 10월 2일, 1차교정일 : 2015년 10월 3일게재승인일 : 2015년 10월 8일 and location of PE, cell count, ph, and glucose was observed between MPE and non-mpe. Key Words: Neoplasms, Causality, Pleural effusion Article Summary What is already known in the previous study With lack of interest in etiologies of PE in cancer patients, Malignant PE (MPE) accounts for 22% of all pleural effusions with more than one million diagnosed annually worldwide. PEs develop in cancer patients through several mechanisms including tumor metastasis to pleural surfaces, obstruction of the lymphatics leading to the accumulation of pleural fluid, obstruction of a bronchus leading to atelectasis and a PE from the decreased pleural pressure, a pneumonia distal to a partially obstructed bronchus leading to a parapneumonic effusion, and disruption of the thoracic duct by tumor leading to a chylothorax. MPE is known to represent an advanced malignancy disease with high morbidity and mortality. What is new in the current study MPE was the major cause of PE in cancer patients. However, the etiology of PE was different according to the origin and subtype of primary tumor. Introduction Pleural effusion (PE) is a common complication and frequently encountered by physicians caring for cancer patients. PEs develop in cancer patients through several mechanisms including tumor metastasis to pleural surfaces, obstruction of the lymphatics leading to the accumulation of pleural fluid, obstruction of a bronchus leading to atelectasis and a PE from the decreased pleural pressure, a pneumonia distal to a partially obstructed bronchus leading to a 15

2 16 / 대한응급의학회지 : 제 27 권제 1 호 2016 parapneumonic effusion, and disruption of the thoracic duct by tumor leading to a chylothorax 1). In addition to the mechanisms associated with tumor, PEs may result from other benign conditions such as congestive heart failure, cirrhosis, or pulmonary embolism. With lack of interest in etiologies of PE in cancer patients, Malignant PE (MPE) accounts for 22% of all pleural effusions with more than one million diagnosed annually worldwide 1,2). MPE is known to represent an advanced malignancy disease with high morbidity and mortality 3). The diagnosis of MPE is established by confirmation of malignant cells in the pleural fluid or in the pleural biopsy. However, the yield of pleural fluid cytology is approximately only 60% and depends on many factors including the volume of specimens, the tumor type, and experience of the cytologist 4). However, it is crucial to differentiate MPE from non-mpe in cancer patients with PE to determine the treatment plans and predict the prognosis. In this study, we investigated the causes of PE in cancer patients. Additionally, we compared the clinical and laboratory characteristics between MPE and non-mpe. 1. Patients Materials and Methods This is a observational study, with review of clinical records of patients admitted to hospitals or ED visits. We consecutively included patients who had a cancer and underwent a diagnostic thoracentesis for a newly developed PE from January 1, 2008 to March 31, 2011 in a tertiary referral hospital in Seoul, Korea. The study was approved by the Institutional Ethical Review Board. 2. Method All the patients were evaluated on the basis of British Thoracic Society pleural disease guideline ). Pleural fluid was analyzed biochemically, cytologically, and microbiologically. Pleural biopsy or thoracoscopy was considered when cytology was negative and MPE was still suspected. Data were obtained by reviewing the medical records. Demographic and clinical characteristics included age, gender, primary tumor origin, and characteristics of PE in a plain chest x-ray such as size and location. Both laboratory findings and effusion biochemistry included total and differential cell count, protein, glucose, and lactate dehydrogenase (LDH). According to Light s criteria, PE was classified into exudate and transudate 6). Classifications of amount of PE were chosen at <20%, 20% to 40%, and >40% of the hemithorax for small, moderate, and large effusions, respectively 7). A definitive diagnosis of MPE was made if pleural fluid cytology or pleural biopsy showed malignant cells. A clinical diagnosis of MPE by oncologists was also accepted when patients had advanced malignancy and cytology-negative PE and other potential causes had been ruled out 8). Parapneumonic effusion was diagnosed when associated with pneumonia, bronchiectasis, or pulmonary abscess and responsive to antibiotic treatment. Empyema was designated when pleural fluid had macroscopic pus, a positive Gram stain or culture, or a ph under 7.2. Tuberculous pleurisy was diagnosed when acid-fast bacillus was found in pleural fluid or pleural biopsy, or granuloma in a pleural biopsy specimen, or ADA >35 U/L with resolution after antituberculous therapy. Hepatic hydrothorax was considered in cirrhosis patients without other potential causes of PEs. Post-operation and post-radiation were defined when the PE was associated with surgery and radiation, respectively, and other etiologies had been ruled out. Chylothorax was diagnosed with a high triglyceride level and demonstration of chylomicrons. 3. Statistical analysis Categorical variables were presented as number (percent) and continuous variables as mean±standard deviation (SD). Difference between categorical variables was tested using the Chi-square test and difference between continuous variables was analyzed using the Student t test or Mann-Whitney U test. Statistical significance was established with a p<0.05. All calculations were performed using SPSS version 18.0 (Chicago, IL, USA). Results 1. Baseline characteristics A total of 719 cancer patients with PE were included in this study. As shown in Table 1, the mean age was

3 Min Jee Lee et al.: Etiology of Pleural Effusions in Cancer Patients / ±13.6 years and female was 44.5%. The most common origin of primary tumor was lung in 29.8%: adenocarcinoma 19.7%, squamous cell carcinoma 6%, and small cell lung cancer 2.4%, followed by gastrointestinal in 24.8%, hepatocellular carcinoma (HCC) in 14%, breast in 7.8%, hematologic in 7.1% respectively. The size of PE was small in 38.9%, moderate in 15.6%, and Table 1. Baseline characteristics of all study subjects. Total (n=719) Age (year), mean±sd 58.4±13.6 Female gender, n (%) 320 (44.5) Lung, n (%) 214 (29.8) Adenocarcinoma 142 (19.7) Squamous cell carcinoma 043 (06.0) Small cell carcinoma 012 (01.7) Others 017 (02.4) Gastrointestinal a, n (%) 178 (24.8) Hepatocellular carcinoma, n (%) 101 (14.0) Breast, n (%) 056 (07.8) Hematologic b, n (%) 051 (07.1) Gynecologic c, n (%) 033 (04.6) Genitourinary d, n (%) 027 (03.8) Others e, n (%) 059 (08.2) SD: standard deviation a Includes esophagus, stomach, colorectal, bile duct, pancreas, gall bladder, gastrointestinal stromal tumor. b Includes lymphoma, leukemia, and multiple myeloma. c Includes uterus, ovary, cervix, vagina, and tubal cancer d Includes bladder, kidney, prostate, ureter, testis cancer e Includes head and neck, thymoma, melanoma, sarcoma, adrenal gland, thyroid cancer large in 45.5% and the location was unilateral in 70.4%: 44.1% on the right side and 26.3% on the left.according to Light s criteria, 86.1% was exudates, 9.3% transudates, and 4.6% undetermined (Table 2). 2. Etiology of pleural effusion Table 3 shows the etiology of PE. The most common etiology was MPE in 57.7%, followed by parapneumonic effusion and empyema in 16.3%. As the patients with HCC were included in 14% of the total patients, hepatic hydrothorax associated with cirrhosis comprised 9.6%. These were followed, in order of frequency, by postoperation (3.8%), heart failure (2.1%), post-radiation (1.4%), volume overload (1.1%), tuberculous pleurisy (0.8%), and chylothorax (0.7%). Among the total 415 cases with MPE, 76.6% was confirmed on the cytologic analysis and the other 23.4% was clinically diagnosed. 3. Comparison of characteristics between MPE and non-mpe As shown in Table 4, patients with MPE were younger (57.0 vs years, p=0.002) and female-dominant (55.4% vs. 29.6%, p<0.001) compared to those with non-mpe. There was also difference in primary tumor origin between MPE and non-mpe. Lung cancer was the most common in 37% among patients with MPE, whereas gastrointestinal cancer and HCC were the most frequent in 28.0% and 27.6%, respectively among those Table 2. Characteristics of pleural effusion in the overall cancer patients. (n=719) No. (%) Amount Small 280 (38.9) Moderate 112 (15.6) Large 327 (45.5) Location Right 317 (44.1) Left 189 (26.3) Bilateral 213 (29.6) Light s criteria 6) Exudate 619 (86.1) Transudate 067 (09.3) Undetermined 033 (04.6) Table 3. Etiology of pleural effusion in the overall cancer patients. (n=719) No. (%) Malignant 415 (57.7) Infection 117 (16.3) Parapneumonic 107 (14.9) Empyema 010 (01.4) Hepatic hydrothorax 069 (09.6) Post-operation 027 (03.8) Heart failure 015 (02.1) Post-radiation 010 (01.4) Volume overload 008 (01.1) Tuberculous pleurisy 006 (00.8) Chylothorax 005 (00.7) Others 003 (00.4) Undetermined 043 (06.0)

4 18 / 대한응급의학회지 : 제 27 권제 1 호 2016 with non-mpe. In addition, there was significant difference in the size and the location of pleural fluid between MPE and non-mpe. The large size of PE was more frequent in MPE than in non-mpe (53.5% vs. 34.9%, p<0.001). For the cases with unilateral PEs, MPE was located more frequently on the left than non-mpe (31.3% vs. 19.4%, p=0.001). Most of MPEs were exudates in 94.9% and only 5.1% were transudates. On pleural fluid analysis, MPE had less neutrophil (15.4% vs. 30.6%) but more lymphocyte (32.2% vs. 28.2%) than non-mpe. MPE was neutrophil-dominant in only 11.2%, whereas non-mpe was neutrophil-dominant in 33.7% (p <0.001). In addition, MPE had higher level of ph (7.33 vs. 7.29, p<0.001) and lower level of glucose (111.5 vs mg/dl, p<0.001) than non-mpe. 4. Etiology of PE according to primary tumor origin In Fig. 1, there was significant difference in the etiology of PE according to primary tumor origin. For the PEs in patients with breast cancer, more than 90% had MPE (91.1%). Next, MPE comprised of a large part of PE also in gynecologic (81.8%) and lung cancer (71.5%). On the other hand, the PE in HCC patients was largely composed of hepatic thorax in 63.4%, while MPE was only 16.8% in those patients. Similarly, non-mpe in HCC was most frequent in genitourinary cancer (55.6%). Interestingly, the etiology of PE was substantially different according to the subtypes of lung cancer. MPE accounted for 85.2% in adenocarcinoma, while MPE comprised 30.2% and 58.8% in squamous cell and small cell carcinomas, respectively. Table 4. Comparison of characteristics between patients with MPE and non-mpe. MPE (n=415) Non-MPE (n=304) p value Age (year), mean±sd 57.0± ±12.5 <0.002 Female gender, n (%) 230 (55.4) 090 (29.6) <0.001 Primary tumor, n (%) <0.001 Lung 153 (37.0) 061 (20.1) Adenocarcinoma, n (%) Squamous cell ca., n (%) Small Cell ca., n (%) Gastrointestinal 093 (22. 5) 085 (28.0) HCC 17 (04.1) 084 (27.6) Breast 051 (12.3) 005 (01.6) Hematologic 027 (06.5) 025 (8.2) Gynecologic 027 (08.5) 006 (2.0) Genitourinary 012 (06.5) 015 (4.9) Exudate, n (%) 393 (94.9) 226 (74.3) <0.001 Amount, n (%) <0.001 Small 124 (29.9) 155 (51.0) Moderate 069 (16.6) 043 (14.1) Large 222 (53.5) 106 (34.9) Location, n (%) <0.001 Right 162 (39.0) 155 (51.0) Left 130 (31.3) 059 (19.4) Bilateral 123 (29.6) 090 (29.6) RBC count, 10 9 cells/l 118.8± ±382.0 <0.379 Leukocyte, 10 9 cells/l 02.7± ±13.8 <0.058 Neutrophil, % 15.4± ±32.7 <0.001 Lymphocyte, % 32.2± ±25.9 <0.038 Neutrophil predominance, % <0.001 ph 7.33± ±0.22 <0.049 Glucose, mg/dl 111.5± ±69.20 <0.001 LDH, U/L ± ± <0.369 MPE: malignant pleural effusion, SD: standard deviation, HCC: hepatocellular carcinoma, RBC: red blood cell, LDH: lactic dehydrogenase

5 Min Jee Lee et al.: Etiology of Pleural Effusions in Cancer Patients / 19 Discussion To the best of our knowledge, this is the first study on the etiology of PE in cancer patients. Previously, there were several studies which investigated etiologies of PE in all adult patients who underwent diagnostic thoracentesis 8,9). In those studies, congestive heart failure, pneumonia, and cancer were common causes of PE. Among non-cancer patients, MPE was reported to account for 16% to 36.5% among PE series 10-12). In this study with cancer patients, MPE comprised more than half of PE (58%) in the overall study subjects. However, interestingly, the etiology of PE was highly different according to the underlying cancer. MPE was predominant in breast, gynecologic, and lung cancer in 91%, 82%, and 72%, respectively. On the contrary, MPE comprised only a small proportion of PE in HCC (17%). Moreover, there was also a substantial difference according to the subtypes of lung cancer. MPE comprised more than 80% of PE in adenocarcinoma but approximately only 30% in squamous cell carcinoma. Therefore, primary tumor origin and subtypes of lung cancer should be considered to establish the etiology of PE in cancer patients. MPE implies an advanced stage of malignancy and precludes the potential for curative treatment. Therefore, it is critical to differentiate MPE from non-mpe in cancer patients. In the current study, cytology was positive in 77% of the patients with MPE. The yield of the cytologic analysis in this study is comparable to 40% to 90% in many previous studies 4,13). The sensitivity of cytologic analysis depends on many factors including the primary tumor origin, the volume of the pleural fluid sample, the number of specimens, the experience of the examiner 1,4,14). MPE associated with mesothelioma, sarcoma, and lymphoma is commonly negative on cytologic examination 15). Repeated pleural taps and sufficient extraction of pleural fluid may improve the diagnostic yield 16). Although many attempts have been made to discriminate between MPE and non-mpe using biochemical, genetic, or radiological methods, it is still challenging 17-19). In this study, we compared clinical characteristics of PE between MPE and non-mpe. MPE was larger in size and located on the left side more frequently compared to non-mpe. This finding is partially consistent with a previous study where malignancy was found to be the lead- Fig. 1. The proportion of pleural effusion causes according to primary tumor origin. PE: pleural effusion, MPE: malignant pleural effusion, Tbc: tuberculous, ACC: adenocarcinoma, SCC: squamous cell carcinoma, SCLC: small cell lung cancer, GI: gastrointestinal, HCC: hepatocellular carcinoma, HEM: hematologic malignancy, GY: gynectologic cancer, GU: genitourinary cancer

6 20 / 대한응급의학회지 : 제 27 권제 1 호 2016 ing cause of large and massive effusions 20). In relation to the location of MPE, studies are lacking although a small study showed no difference in the location between MPE and non-mpe 18). Contrary to our expectations, MPE was associated with younger age. With regard to gender, patients with MPE were female-dominant compared to those with non-mpe. This finding is consistent in part with a previous study which showed less male proportion but older age in MPE compared to non-mpe 20). Due to the heterogeneity of patients, especially those with non-mpe, in terms of the various causes of PE or underlying cancer, it may be difficult to characterize them. However, if further studies are able to clarify the association of MPE with large amount of PE and female gender, it would help to differentiate MPE from non-mpe. Biochemical features of pleural fluid are useful to distinguish between MPE and non-mpe in some degree. More than 50% of MPE have lymphocyte predominant effusions and grossly bloody effusions suggest of MPE 6,21). In addition, most MPE are exudates according to Light s criteria with only 3~10% transudates. Consistent with the previous reports, MPE had less neutrophil predominance and more lymphocyte compared to non-mpe in this study. Also, this study showed that most MPE were exudates but only 5% transudates. On biochemical analysis, MPE was associated with higher ph and lower glucose than non-mpe. Chemical characteristics of PE can suggest the presence of MPE 22). The ph<7.3 is found in 30% of MPE cases and glucose <60 mg/dl suggest MPE and some benign conditions including complicated parapneumonic effusion, tuberculous pleurisy 22). In this study, MPE had higher ph and lower glucose than non-mpe. However, it may be difficult to expect high discrimination power with the value itself. Other clinical conditions should be considered to establish the cause of PE. Besides the diagnostic value, biochemical characteristics provide prognostic and therapeutic implications. A low ph below 7.2 in patients with MPE suggests that the patient s life expectancy is only about 30 days and that chemical pleurodesis is likely to be ineffective 6). In cases with parapneumonic effusion, a ph value below 7.2 indicates the need for drainage of the fluid 23). In relation to pleural fluid glucose level, a low glucose concentration (<60 mg/dl) indicates that the patient probably has a complicated parapneumonic or a malignant effusion 24). In this study, long-term observation is needed to evaluate the prognostic significance of chemical variables including ph and glucose as well as diagnostic value. This study has some limitations. First, the study included only the patients who underwent diagnostic thoracentesis. Therefore, certain minor groups of patients might be excluded. For example, ones might not undergo thoracentesis for some reasons such as definitive clinical diagnosis of cause of PE such as heart failure or cirrhosis, a scanty amount of pleural fluid, or terminal stage of malignancy without any further treatment plans. Second, this study was conducted in a single referral center, which might cause a selection bias or referral bias. In conclusion, MPE was the major cause of PE in cancer patients. However, the etiology of PE was different according to the origin and subtype of primary tumor. MPE comprised the most part of PE in lung, breast, and gynecologic cancers, whereas MPE comprised only small proportions of PE etiology in HCC and genitourinary cancer. Between MPE and non-mpe, there was significant difference in clinical, biochemical, and radiologic characteristics. MPE was larger in size and located more commonly on the left side compared to non-mpe. In addition, MPE had less neutrophil and more lymphocyte, higher level of ph, and lower level of glucose compared to non-mpe. REFERENCES 01. Light RW. Pleural effusions. Med Clin North Am. 2011; 95: American Thoracic S. Management of malignant pleural effusions. Am J Respir Crit Care Med. 2000;162: Nam HS. Malignant pleural effusion: medical approaches for diagnosis and management. Tuberc Respir Dis (Seoul). 2014;76: Porcel JM, Light RW. Pleural effusions. Dis Mon. 2013; 59: Hooper C, Lee YC, Maskell N; BTS Pleural Guideline Group. Investigation of a unilateral pleural effusion in adults: British Thoracic Society Pleural Disease Guideline Thorax. 2010;65 Suppl 2:ii Light RW. Pleural diseases. 4th ed. Philadelphia: Lippincott Williams & Wilkins; p Moy MP, Levsky JM, Berko NS, Godelman A, Jain VR, Haramati LB. A new, simple method for estimating pleur-

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