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Malcolm V. Brock
Stephen C. Yang
David Mason
Marc Sussman
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Ann Thorac Surg 2005;80:1241-1247
© 2005 The Society of Thoracic Surgeons

Original article: General thoracic

Can We Improve the Cytologic Examination of Malignant Pleural Effusions Using Molecular Analysis?

Malcolm V. Brock, MD a , * , Craig M. Hooker, MPH b , Rex Yung, MD c , Mingzhou Guo, MD, PhD b , Yu Han, BS a , Stephen E. Ames, BS a , David Chang, PhD d , Stephen C. Yang, MD a , David Mason, MD e , Marc Sussman, MD a , Stephen B. Baylin, MD b , James G. Herman, MD b

a Department of Surgery, Division of Thoracic Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland
b Department of Medical Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland
c Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland
d Department of Surgery, Division of Surgical Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland
e Department of Thoracic Surgery, The Cleveland, Clinic, Cleveland, Ohio

Accepted for publication May 12, 2005.

* Address reprint requests to Dr Brock, 240 Blalock, 600 N Wolfe St, Baltimore, MD 21287 (Email: mabrock{at}jhmi.edu).

Presented at the Poster Session of the Forty-first Annual Meeting of The Society of Thoracic Surgeons, Tampa, FL, Jan 24–26, 2005.

BACKGROUND: Currently, 40% of patients remain undiagnosed after routine cytologic examination for malignant pleural effusions. Deoxyribonucleic acid (DNA) methylation is a robust strategy for detecting cancer early in tissue. We hypothesized that DNA methylation would be more sensitive in diagnosing patients with malignant pleural effusions than cytology.

METHODS: We conducted a prospective cohort study of 31 inpatients with pleural effusions (24 malignant pleural effusions metastatic from 10 different organs and 7 benign) over 18 months. Aspirated pleural fluid underwent cytologic examination and DNA extraction for nested methylation-specific polymerase chain reaction (PCR). We assayed for promoter hypermethylation in 8 genes known to be methylated in many cancers. Pleural fluid was considered positive if 2 or more genes were methylated by methylation-specific PCR.

RESULTS: Cytology alone confirmed malignant pleural effusions in 15 of 24 patients (sensitivity 63%), whereas methylation alone positively identified 16 of 24 patients (sensitivity 67%). Both tests had 100% specificity in predicting benign effusions. If cytology and methylation were considered together, they exhibited 88% sensitivity and 100% specificity in discriminating benign and malignant effusions. Combined, the two assays were more sensitive than either test alone. Although the positive predictive value of each test was 100%, the negative predictive value of cytology and methylation combined was 78%, better than 47% and 44% for methylation and cytology alone, respectively.

CONCLUSIONS: Epigenetic analysis of pleural fluid can detect malignant DNA from a variety of neoplasms, provide complementarity with cytology, and improve the diagnostic yield of the current standard examination of pleural fluid.






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