Diagnostic and prognostic significance of lysophosphatidic acid in malignant pleural effusions

Abstract

Background: Lysophosphatidic acid (LPA) is an important extracellular signal transmitter and intracellular second messenger in body fluids. It can be detected in the ascitic fluid of patients with ovarian cancer. Increasing evidence shows that LPA can stimulate cancer cell proliferation and promote tumor invasion and metastasis. Our study aimed to evaluate the diagnostic value of LPA in differentiating between malignant pleural effusions (MPEs) and benign pleural effusions (BPEs) and to evaluate the association between the level of LPA in MPE and the prognosis of lung cancer patients.

Patients and methods: The level of LPA in the pleural effusions (PEs) of 123 patients (94 MPE, 29 BPE) with lung cancer was evaluated using an enzyme-linked immunosorbent assay. The performance of LPA was analyzed by standard Receiver operator characteristic curve (ROC) analysis methods, using the area under the curve (AUC) as a measure of accuracy. Overall survival (OS) curves and progression-free survival (PFS) curves were based on the Kaplan-Meier method, and the survival differences between subgroups were analyzed using the log-rank or Breslow test (SPSS software). A multivariate Cox proportional hazards model was used to assess whether LPA independently predicted lung cancer survival.

Results: The levels of LPA differed significantly between MPE (22.08±8.72 µg/L) and BPE (14.61±5.12 µg/L) (P<0.05). Using a cutoff point of 18.93 µg/L, LPA had a sensitivity of 60% and a specificity of 83% to distinguish MPEs from BPEs with an AUC of 0.769±0.045 (SE) (P=0.000) (95% CI, 0.68-0.857). In the three pathological types of lung cancer patients with MPE, there were no significant associations between LPA levels and the length of PFS and OS (P=0.58 and 0.186, respectively). Interestingly, in the patients with MPE caused by lung adenocarcinoma there were significant associations between the LPA levels and the PFS and OS (P=0.018 and 0.026, respectively). Multivariate analysis showed that the LPA level was an independent prognostic factor for PFS in lung adenocarcinoma.

Conclusions: Our results indicate that LPA can be used as a new biomarker for the diagnosis of MPE caused by lung cancer and that higher levels of LPA are related to shorter PFS in adenocarcinoma of the lung.

Keywords: Lysopohsphatidic acid (LPA); diagnosis; lung cancer; malignant pleural effusions (MPEs); prognosis.

Figure 1

(A) Comparisons of LPA levels between MPE and BPE. The value between the MPE and BPE groups (22.08±8.72 versus 14.61±5.12) has significant difference. P=0.000. (B) Subgroups comparisons of LPA levels in MPE caused by adenocarcinoma, squamous cell carcinoma and small cell lung carcinoma. No significant differences were found among the three groups (P=0.603). LPA, lysophosphatidic acid; MPE, malignant pleural effusions; BPE, benign pleural effusions.

Figure 2

ROC of LPA for the diagnosis of MPE vs. BPE. The plot was constructed by computing the sensitivity vs. (1-specificity) for the different possible cutoff points of the LPA ELISA assay. ROC, receiver operator characteristic curve; LPA, lysophosphatidic acid; MPE, malignant pleural effusions; BPE, benign pleural effusions.

Figure 3

Kaplan-Meier analysis for OS and PFS according to the level of LPA in MPE. Data were dichotomized at the median value for each parameter. (A,B) LPA in MPE caused by the three types of lung cancer; (C,D) LPA in MPE caused by lung adenocarcinoma. For Figure 3C, when using Log-rank test, it didn’t reach a statistical significance (P=0.076), while using Breslow (Generalized Wilcoxon) test reach a statistical significance (P=0.018). The Figure 3 showed a P value using the latter test method. OS, overall survival; PFS, progression-free survival; LPA, lysophosphatidic acid; MPE, malignant pleural effusions.