Abstract To date, the cellular composition of malignant pericardial effusion (MPE) and its association with the clinical course of carcinomatous pericarditis remain unclear. We aimed to determine the MPE cellular composition and its association with carcinomatous pericarditis. Forty-four cases indicated for pericardial drainage due to symptomatic carcinomatous pericarditis were retrospectively reviewed; the blood cell count and composition of MPE were examined. The most dominant cells in MPE were neutrophils. The appearance ratio of an atypical cell in cytologically positive MPE was 95.5%. Low neutrophil and high lymphocyte counts were significantly associated with good effusion failure-free survival at 1 month. The survival after pericardial drainage was significantly shorter when the neutrophil/lymphocyte ratio was 3.5 or more (P = 0.041). Patients whose performance status improved due to drainage had significantly high leukocyte counts in MPE (P = 0.02). Prediction of the course of drainage through basic examination of MPE cellular composition might be beneficial in clinical practice. malignant pericardial effusion, pericarditis, cell composition, cardio-oncology, supportive care in cancer Introduction Malignant pericardial effusion (MPE), which is confirmed via necropsy, accounts for 2.7% of all cancer-related deaths (1). MPE caused by carcinomatous pericarditis is often associated with lung cancer, breast cancer, esophageal cancer, malignant melanoma, leukemia and lymphoma (2). The most common cause of carcinomatous pericarditis is lung cancer, and the prognosis of carcinomatous pericarditis due to lung cancer is less than 3 months after diagnosis (3). Carcinomatous pericarditis leads to cardiac dysfunction, which causes circulatory insufficiency and thus requires pericardial drainage (4, 5). Since the cellular composition of malignant pleural effusion was discovered, examination of blood cell counts or cellular compositions in pleural effusion has been used in medical practice (6). However, the cellular composition of MPE remains unclear, and no reports regarding the association between cellular composition of MPE and the clinical course of carcinomatous pericarditis have been published. This study aimed to determine the cellular composition of MPE and its association with carcinomatous pericarditis. Patients and methods We retrospectively reviewed the data of patients with cancer indicated for pericardial drainage due to symptomatic carcinomatous pericarditis between January 2013 and March 2017 in our hospital. The patient characteristics at the time of pericardial drainage are as follows: median age, 61.5 years; men, 27; women, 17; median performance status (PS), 2 (range: 1–4); and patients with a history of chest radiotherapy, 16. The types of cancer were lung cancer (n = 38), esophageal cancer (n = 2), breast cancer (n = 1), gastric cancer (n = 1), malignant mesothelioma (n = 1) and cecal cancer (n = 1). The pericardial fluid was classified as positive if cytodiagnosis was class V. Only patients with positive cytology and whose pericardial fluid was drained during the day shift when cell counts and cell fractions can be examined were included in the study. Patients whose fluids were drained during the night shift or on holidays were excluded. Finally, 44 patients met these criteria and their data were examined retrospectively. The puncture site was confirmed via echocardiography. Pericardial puncture was conducted percutaneously, and a 6-Fr or 16-G catheter was used. The pericardial effusion was diagnosed via echocardiography. Drainage was performed when symptoms were observed and when it was deemed clinically necessary and was terminated when the amount of effusion reached ≤20 ml per day or when it reached a constant amount per day (7). The blood cell count and the cellular composition of MPE were then examined through an automatic measuring instrument and via Giemsa staining, respectively. The blood cell count was examined for the quantity of leukocytes, erythrocytes, platelets and hemoglobin. Meanwhile, the cellular composition was examined for the quantity of neutrophils, lymphocytes, histiocytes, eosinophils, basophils, mesothelial cells and atypical cells. Patient information was collected from electronic medical records. Data were collected on age, sex, PS, histological type, type of carcinoma, history of chemotherapy and radiation treatment, initial pericardial effusion drainage amount, final drainage amount per day, drainage period, bacterial culture of MPE, presence or absence of pericardial adhesion, PS a week after drainage, effusion failure-free survival, effusion failure-free survival at 1 month and survival duration after drainage. Effusion failure-free survival was defined as patient survival without reoccurrence of MPE. The Kaplan–Meier method was used for the survival curve, and the log-rank test was used to compare the two groups. For comparison between the two groups in terms of patient characteristics or results, the Wilcoxon’s rank sum test or Fisher’s exact test was used. Scatter plots were prepared, and correlation coefficients were determined. Logistic regression analysis and multiple logistic regression analysis were performed to investigate factors affecting effusion failure-free survival at 1 month. P < 0.05 was considered to indicate statistical significance. Data were analyzed using JMP 9 (SAS, Institute Inc., Cary, NC, USA). Results The median initial drainage volume of the pericardial effusion was 710 ml (range, 250–1700 ml), and the final drainage volume was 10 ml/day (range, 0–500 ml/day). The median drainage period was 7 days (range, 2–36 days). Pericardial adhesions with bleomycin were performed in 10 patients; however, adhesion did not affect survival or effusion failure-free survival. There were no complications of pericardial drainage. There were no cases of positive MPE bacterial cultures. Pericardial drainage improved the PS of 23 patients after a week, whereas the PS of 21 patients remained unchanged. No patient had a declined PS. Effusion failure-free survival at 1 month was 79.5%, and median effusion failure-free survival was 2.7 months. The median survival duration after pericardial drainage was 4.0 months. The blood cell counts of the pericardial fluid (±2 SE) revealed the following: leukocytes, 4793 (577) cells/μl; erythrocytes, 129 (16) × 104 cells/μl; hemoglobin, 4 (0.5) g/dl; and platelets, 2.5 (0.6) × 104 cells/μl. The cellular composition of the pericardial fluid was as follows: neutrophils, 30.7 (4.1)%; lymphocytes, 21 (3.2)%; histiocytes, 22.8 (3.3)%; eosinophils, 1.4 (0.6)%; basophils, 0.2 (0.1)%; mesothelial cells, 1.3(0.5)%; and atypical cells, 22.6 (4.2)%. Atypical cells were found in the cellular compositions of the effusion in 42 of 44 (95.5%) patients. Neutrophils, lymphocytes and neutrophil-to-lymphocyte ratios in MPE were significantly associated with effusion failure-free survival at 1 month. The cut-off value for neutrophil-to-lymphocyte ratio based on the receiver-operator characteristic curve was 3.5. When the patients were grouped according to a neutrophil-to-lymphocyte ratio of ≥3.5 and <3.5, multivariate analysis showed a significant influence on effusion failure-free survival after 1 month (Fig. 1). The survival duration after pericardial drainage was significantly shorter when the neutrophil-to-lymphocyte ratio was ≥3.5 (P = 0.041; Fig. 2). Figure 1. View largeDownload slide Factors predicting effusion failure-free survival at 1 month. (A) Crude odds ratio. (B) Adjusted odds ratio. Figure 1. View largeDownload slide Factors predicting effusion failure-free survival at 1 month. (A) Crude odds ratio. (B) Adjusted odds ratio. Figure 2. View largeDownload slide Survival after pericardial drainage. In the group with a neutrophil-to-lymphocyte ratio of ≥3.5, the median survival duration after drainage was 1.3 months, while in the group with <3.5, the median survival period after drainage was 5.2 months. Figure 2. View largeDownload slide Survival after pericardial drainage. In the group with a neutrophil-to-lymphocyte ratio of ≥3.5, the median survival duration after drainage was 1.3 months, while in the group with <3.5, the median survival period after drainage was 5.2 months. Patients whose PS was significantly improved through drainage had significantly high leukocyte counts in the pericardial effusion (P = 0.02), and the cut-off value of leukocyte counts based on the receiver-operator characteristic curve was 3270 cells/μl. A moderate but significant correlation existed between the proportion of atypical cells in the MPE and the final volume of daily drainage (correlation coefficient: 0.44; P < 0.01). Discussion Several reports regarding the cellular composition of malignant pleural effusion have been published, and the cellular composition of malignant pleural effusion is considered to be lymphocyte dominant (8). In addition, the proportion of lymphocytes in malignant pleural effusion increases when the clinical condition is good, and the number of macrophages increase if the condition is critical (9). Meanwhile, studies regarding the cellular composition of MPE are limited. The leukocyte count (95% confidence interval) was 3.3 cells/μl (range, 0.1–6.5 cells/μl), and the lymphocyte proportion was 45% (range, 22–68%) in the MPE (10). Another report stated that MPE typically contains 484 446 erythrocytes/ml, 9280 leukocytes/ml, 26% neutrophils, and 74% monocytes (11). However, analysis of the cellular composition of pericardial effusion considering neutrophils, lymphocytes, histiocytes, mesothelial cells, eosinophils, basophils and atypical cells has not been reported. In this study, neutrophils were the dominant cellular composition, followed by histiocytes, atypical cells and lymphocytes. Unlike malignant pleural effusion, MPE may not be lymphocyte dominant. Moreover, as is the case with malignant pleural effusion, when the number of lymphocytes in the MPE was large, the prognosis was good. Since the next cycle of chemotherapy after drainage was thought to affect recurrence and survival, the effusion failure-free survival after 1 month was examined. In this study, 22 patients received chemotherapy after pericardial drainage, and chemotherapy was started 24 days (median) after drainage. When the proportion of neutrophils was high or the proportion of lymphocytes was low, the effusion failure-free survival at 1 month was poor. For this reason, it was assumed that both factors together could be a new better factor representing the clinical course. Indeed, the neutrophil-to-lymphocyte ratio was associated with effusion failure-free survival at 1 month. When we divided patients into two groups with a neutrophil-to-lymphocyte ratio cut-off value of 3.5, the prognosis was poor in the group with values ≥3.5. The relationship between cancer and inflammation is becoming evident, as it has been reported that inflammation helps cancer cells survive and proliferate, thereby promoting angiogenesis and metastasis. Leukocytes infiltrate the tumor; chemokines and cytokines in the tumor microenvironment interact with tumor cells; and leukocytes promote cancer cell proliferation, survival, and metastasis (12). Interleukin-8, chemokine ligand (CXCL) 1, and chemokine receptor (CXCR) 2 promote cancer cell proliferation, survival, and angiogenesis, and at the same time, recruit neutrophils on immune cells (13). However, CXCL12-CXCR4 simultaneously promotes tumor metastasis and lymphocyte recruitment on immune cells (13). It has been hypothesized that when there were numerous neutrophils in the MPE, proliferation and survival of epicardial cancer cells are increased. Moreover, when there are numerous lymphocytes in MPE, metastasis might be promoted in epicardial cancer cells. Therefore, there is a possibility that patient prognosis will be poor when there are numerous neutrophils in MPE, and the prognosis will be relatively good if there are numerous lymphocytes. For this reason, the neutrophil-to-lymphocyte ratio may be related to prognosis after drainage. In this study, patients with improved PS had significantly higher leukocyte counts in the pericardial effusion. The leukocytes observed in the pericardial effusion drainage are high in bacterial, rheumatic, malignant, and viral components and low in hypothyroid, uremic, and radiation factors (11). Diseases that involve a high leukocyte count appear to have an acute phase and a high pericarditis activity status. If the leukocyte count is high in the MPE, inflammation or the activity of malignant pericarditis may be high. Therefore, drainage may be highly effective in improving patient PS. The proportion of atypical cells in MPE was significantly correlated with the final volume of daily drainage. When the proportion of atypical cells was high, the final amount of MPE was also high. The incidence of a positive cytological diagnosis of pericardial fluid in cancer patients is 47% (14). In cancer patients, cytologically negative pericardial effusion may not be related to the cancer; however, positive fluid cytology in cancer patients was reported to be associated with poorer prognosis than that with negative cytology (15). If the proportion of atypical cells is high, then the size of the tumor in the epicardial space is possibly large or the pericarditis may be fatal. As such, controlling the volume of pericardial effusion can be difficult in patients who have high proportions of atypical cells. In the prospective study about pericardial drainage, the median effusion failure-free survival was 30 days (without pericardial adhesion) or 57 days (with pericardial adhesion), and the median survival duration after drainage is reported as 79 days or 119 days. In our study, the median effusion failure-free survival was 81 days, and the median survival duration after drainage was 123 days (7). In this study, chemotherapy was administered in 22 cases after pericardial drainage, and the prognosis was significantly better when chemotherapy was administered after drainage. The previous prospective trials have been performed from 1999 to 2006 (7). Our study was performed from 2013 to 2017. The prognosis of cancer has improved by the dramatic progress in chemotherapy, such as the appearance of molecular targeted drugs. This study was a retrospective exploratory study with a small number of patients. Investigating the incidence of MPE according to the type of cancer was impossible owing to the limited number of patients. Studying more cases is necessary in future research. Conclusions The neutrophil count, lymphocyte count and neutrophil-to-lymphocyte ratio were associated with survival after pericardial drainage. A high leukocyte count in the MPE may be an indicator of improved PS through pericardial drainage. Moreover, the proportion of atypical cells in MPE was correlated with the final daily drainage amount. Because patient prognosis after the onset of cancerous pericarditis is poor, predicting the course of drainage by measuring the cellular composition of MPE may be a useful tool in developing a treatment plan. Funding This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. Conflict of interest statement The authors declare no conflict of interest. References 1 Klatt EC, Heitz DR. Cardiac metastases. Cancer 1990; 65: 1456– 9. Google Scholar CrossRef Search ADS PubMed 2 Jeong T-D, Jang S, Park C-J, et al. . Prognostic relevance of pericardial effusion in patients with malignant diseases. Korean J Hematol 2012; 47: 237– 8. Google Scholar CrossRef Search ADS PubMed 3 Abraham KP, Reddy V, Gattuso P. Neoplasms metastatic to the heart: review of 3314 consecutive autopsies. Am J Cardiovasc Pathol 1990; 3: 195– 8. Google Scholar PubMed 4 Liu G, Crump M, Goss PE, et al. . Prospective comparison of the sclerosing agents doxycycline and bleomycin for the primary management of malignant pericardial effusion and cardiac tamponade. J Clin Oncol 1996; 14: 3141– 37. Google Scholar CrossRef Search ADS PubMed 5 Maruyama R, Yokoyama H, Seto T, et al. . Catheter drainage followed by the instillation of bleomycin to manage malignant pericardial effusion in non-small cell lung cancer: a multi-institutional phase II trial. J Thorac Oncol 2007; 2: 65– 8. Google Scholar CrossRef Search ADS PubMed 6 Dixit R, Agarwal KC, Gokhroo A, et al. . Diagnosis and management options in malignant pleural effusions. Lung India 2017; 34: 160– 6. Google Scholar CrossRef Search ADS PubMed 7 Kunitoh H, Tamura T, Shibata T, et al. . A randomised trial of intrapericardial bleomycin for malignant pericardial effusion with lung cancer (JCOG9811). Br J Cancer 2009; 100: 464– 9. Google Scholar CrossRef Search ADS PubMed 8 McGrath EE, Anderson PB. Diagnosis of pleural effusion: a systematic approach. Am J Crit Care 2011; 20: 119– 27. Google Scholar CrossRef Search ADS PubMed 9 Yamagishi K, Tajima M, Suzuki A, et al. . Relation between cell composition of pleural effusions in patients with pulmonary carcinomas and their clinical courses. Acta Cytol 1976; 20: 537– 41. Google Scholar PubMed 10 Ben-Horin S, Bank I, Shinfeld A, et al. . Diagnostic value of the biochemical composition of pericardial effusions in patients undergoing pericardiocentesis. Am J Cardiol 2007; 99: 1294– 7. Google Scholar CrossRef Search ADS PubMed 11 Meyers DG, Meyers RE, Prendergast TW. The usefulness of diagnostic tests on pericardial fluid. Chest 1997; 111: 1213– 21. Google Scholar CrossRef Search ADS PubMed 12 Mantovani A, Allavena P, Sica A, et al. . Cancer-related inflammation. Nature 2008; 454: 436– 44. Google Scholar CrossRef Search ADS PubMed 13 Atretkhany KN, Drutskaya MS, Nedospasov SA, et al. . Chemokines, cytokines and exosomes help tumors to shape inflammatory microenvironment. Pharmacol Ther 2016; 168: 98– 112. Google Scholar CrossRef Search ADS PubMed 14 Pawlak Cieślik A, Szturmowicz M, Fijałkowska A, et al. . Diagnosis of malignant pericarditis: a single centre experience. Kardiol Pol 2012; 70: 1147– 53. Google Scholar PubMed 15 Gornik HL, Gerhard-Herman M, Beckman JA. Abnormal cytology predicts poor prognosis in cancer patients with pericardial effusion. J Clin Oncol 2005; 23: 5211– 6. Google Scholar CrossRef Search ADS PubMed © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: email@example.com
Japanese Journal of Clinical Oncology – Oxford University Press
Published: Mar 1, 2018
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