Diagnostic performance of SHOX2 and RASSF1A gene methylation assays in malignant pleural effusion: A systematic review and meta-analysis

Background: Malignant pleural effusion (MPE) is a common complication of advanced malignancies, requiring differentiation from benign pleural effusion for appropriate management. Cytology and biopsy have limitations, necessitating more sensitive, less invasive diagnostic techniques. The objective of this study was to evaluate the diagnostic accuracy of methylated SHOX2 (short-stature homeobox 2) and RASSF1A (Ras association domain family member 1A) genes in detecting MPE. Methods: A systematic review and meta-analysis included studies that compared benign pleural effusion and MPE cohorts using methylation of SHOX2 and RASSF1A genes in pleural fluid as the index test and cytology/histopathology as the reference standard. A random-effects model was used to calculate sensitivity, specificity, predictive values, and diagnostic odds ratios. Subgroup analysis assessed performance in lung-predominant versus nonlung-predominant MPE. Results: Four studies with a total of 534 participants were included. The pooled sensitivity and specificity were 85% (95% confidence interval [CI], 53%–96%; heterogeneity [I²] = 0.00%) and 92% (95% CI, 88%–95%; I² = 24.8%), respectively. The positive and negative predictive values were 93% (95% CI, 85%–97%; I² = 61.5%) and 84% (95% CI, 53%–96%; I² = 0.00%), respectively. The diagnostic odds ratio was 22.78 (95% CI, 11.00–47.17; I² = 25.8%). Subgroup analysis showed a slight decrease in sensitivity (70%; 95% CI, 64%–76%; I² = 0.00%) and specificity (91%; 95% CI, 86%–94%; I² = 26.1%) when excluding the study with a lung cancer-predominant population. Conclusions: The combined analysis of SHOX2 and RASSF1A methylation demonstrated promising diagnostic accuracy for MPE detection, outperforming cytology. This less invasive method could reduce reliance on more invasive procedures, although further research is needed to confirm its efficacy across diverse populations and cancer types.