Malignant pleural effusion is commonly seen in three conditions namely cancer, tuberculosis and parapneumonic effusion.

Biochemical tests routinely and universally performed in clinical practice for investigating pleural effusion are serum lactate dehydrogenase (LDH) and protein, pleural LDH, protein, differential cell count, pH, glucose, and adenosine deaminase (ADA) [1]

Tuberculosis pleural effusion (TPE), malignant pleural effusion (MPE), and parapneumonic pleural effusion are the most common aetiologies of an exudative pleural effusion in clinical practice [2]

In this context, among routinely performed pleural fluid analyses, neutrophilic predominance is indicative of a parapneumonic pleural effusion, and a raised ADA level is highly suggestive (specificity of 92%) for TB, but to date, no test is specific to “rule-in” MPE [3-4].

This inability presents itself both as a challenge, and an opportunity for improvement. In recent years, several more advanced assays have been developed to diagnose malignancy in a patient presenting with pleural effusion. Examples include measurement of tumour markers CEA, CA15-3, CA125, and cyfra 21-1 in pleural fluid and protein microarray technologies to differentiate malignant from TB effusion [5-6].

Among the routinely performed biochemical tests for investigating pleural effusion, serum lactate dehydrogenase (LDH), pleural ADA, and pleural lymphocyte count change in reciprocal manner in patients with MPE and TPE. Serum LDH is raised in MPE whereas pleural ADA and pleural fluid.

Lymphocyte count remain comparatively low. Conversely, serum LDH is low in TPE whereas pleural ADA and pleural fluid lymphocyte count are raised. This reciprocal change presents an opportunity to combine these test results developing a ratio with the diagnostic power to differentiate MPE from TPE in a cost effective, timely, generalizable, and universally applicable manner. Such a marker not only may provide an early signal toward malignant nature of pleural effusion, but can potentially serve as a “forewarning” for patients with negative cytology who are subsequently found to have MPE. Our previous report of a retrospective analysis demonstrated that a “cancer ratio” (serum LDH: pleural ADA ratio) yielded sensitivity and specificity of 0.98 and 0.94, respectively, at the cut-off level of >20 for identifying MPE [7].

Pleural effusion (PE) is a common sign in clinical practice, and its differential diagnosis is challenging for clinicians. It can be caused by various disorders, including tuberculosis, heart failure (HF), malignancy, and pneumonia [8]

However, the factors affecting the diagnostic accuracy of CR remain largely unknown. Previous studies have revealed that serum LDH increases with advancing age [9-10], and the diagnostic accuracy of pleural ADA for tuberculosis pleural effusion (TPE) is also affected by age [11]. Therefore, we hypothesized that age could affect the diagnostic accuracy of CR. Here, we performed a study to investigate the diagnostic accuracy of CR for MPE and the effect of age on its diagnostic accuracy. We reported our work following the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines [12-13].

In this study, our primary objective was to prospectively identifying the use of “cancer ratio” cancer ratio plus for its association with Malignant and assess its utility to differentiate MPE from TPE.

Objectives:  

1. Identifying the role of cancer Ratio and Cancer Ratio Plus differentiability of Tubercular PLET and Malignant pleural effusion
2. Compared the diagnostic potential of cancer ratio (CR, serum lactate dehydrogenase [LDH]/pleural fluid adenosine deaminize [pf. ADA]), cancer ratio plus (CR plus, cancer ratio/pleural lymphocyte percentage).

Methods: Data from 100 (36% female and 64% male) patients with malignant pleural effusion study participants. The study was conducted O.P.D. and I.P.D. in the P.G. department of Pulmonary, Hi-Tech Medical College and Hospital, Bhubaneswar.

Study design:  Hospital based Prospective cohort study

Study Period: May 2023 and Oct 2023

Study Population: Ready to participant to the study after consent form and fulfil the inclusive criteria.

Sample Size: 100.

Inclusion criteria: All Inpatients with exudative pleural effusion

Exclusion criteria:

• Transudative effusion
• Neutrophilic effusion
• Pyothorax
• Hemothorax

Ethical permission. This Study was approved by institutional ethical committee from Ethical Committee of Hitech Medical College and Hospital, Bhubaneswar.

Statistical Analysis.

SPSS for Windows version 22.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analysis. Data were presented, Mean, Standard deviation and percentage, and chi-square test was used for comparison between qualitative variables. The correlations between sex, age, and the best cut-off values and diagnostic performance were evaluated based on the receiver operating characteristic (ROC) curve. Differences in the areas under the ROC curve (AUCs),  P values below 0.05 were regarded as significan.

Table 1.0    Distribution of Demography Variables

Fig No. 1.0 Sex wise distribution of diagnosis

Fig2.0 Age wise distribution of study subjects

Fig 3.0 Distribution of Final diagnosis

From the above table1.0 and fig 1.0, fig 2.0 gives the age and sex wide distribution of the study subjects.  The mean and standard deviation of different diagnosis relation with  Malignant, age (55.31 ± 13.22), mean and standard deviation of diagnosis relation with  PPE, age (51.52 ± 11.50), and  mean and standard deviation of diagnosis relation with  TB PLEF, age (48.18 ± 17.49) with a range of 19-84. From the above table 1.0 we see the total number of male i.e.  64% and 36% female participants,  Sex wise age group of Male (51.52 ± 14.99, range 19-84) and Female (49.41 ± 15.85, range 20-78).

 From the above fig 3.0 gives the final diagnosis, maximum number of TB PLEF (48%) followed by the Malignant, 29% and PPE, 23% out of 100 study participants.

Table No. 2.0 Distribution of Pleural Fluid Parameters.

From the above Table no 2.0 gives the Distribution of Pleural Fluid Parameters along with the Final diagnosis of  Malignant Effusion , ADA with range (10-32), and  the mean and SD is (20.45±5.82), and  Sr LDH with range(130-952), the mean and SD of (332.48±176.39),and Plural Fluid _Lymphocyte with range (0.05-0.95), the mean and SD (0.59±0.31), Cancer Ratio with range(4.64-56), the mean and SD of (18.75±12.92), Cancer Ratio  plus with range (6.63-471.54), the mean and SD of (54.94±94.76).

Pleural Fluid Parameters along with the Final diagnosis of  PPE , ADA with range (20-32), and  the mean and SD is (24.34±3.99), and  Sr LDH with range(149-346), the mean and SD of (251.74±66.09),and Plural Fluid _Lymphocyte with range (0.03-0.95), the mean and SD (0.62±0.31), Cancer Ratio with range(5.47-16.48), the mean and SD of (10.74±3.71), Cancer Ratio  plus with range (33.86-342.42), the mean and SD of (159.40±99.57).

Pleural Fluid Parameters along with the Final diagnosis of  TB PLEF , ADA with range (39-76), and  the mean and SD is (8.15±1.17), and  Sr LDH with range(164-434), the mean and SD of (248.62±91.69),and Plural Fluid _Lymphocyte with range (0.03-0.95), the mean and SD (0.55±0.32), Cancer Ratio with range(2.90-9.86), the mean and SD of (5.03±2.06), Cancer Ratio  plus with range (3.37-131.17), the mean and SD of (8.98±18.22).

Along with the P value for all the above parameters (ADA, Sr. LDH, Plural Fluid _Lymphocyte, Cancer Ratio, Cancer Ratio Plus) which is statistically less than 0.05 i.e. (p=0.001), Significant. 

Table 3.0 Cancer Ratio

Table 4.0 Cancer Ratio Plus

In a ROC curve the true positive rate (Sensitivity) is plotted in function of the false positive rate (100-Specificity) for different cut-off points. Each point on the ROC plot represents a sensitivity/specificity pair corresponding to a particular decision threshold.

In this study we have the age and sex wide distribution of the study subjects.  The mean and standard deviation of different diagnosis relation with  Malignant, age (55.31 ± 13.22), mean and standard deviation of diagnosis relation with  PPE, age (51.52 ± 11.50), and  mean and standard deviation of diagnosis relation with  TB PLEF, age (48.18 ± 17.49) with a range of 19-84.

In a study, Age distribution the mean age at presentation is 47.5 years. Minimum being 17 and maximum of 84 years. Though malignancy is more common in the elderly, the possibility of malignancy like lymphomas, PNET etc in younger age group must be carefully ruled out, in which they had studied the exudative effusions [14]. In a study the mean age for tuberculosis effusion is 69 and for MPE is 56.[15].

In this study, we have the total number of male i.e.  64% and 36% female participants, Sex wise age group of Male (51.52 ± 14.99, range 19-84) and Female (49.41 ± 15.85, range 20-78).

We have the final diagnosis, maximum number of TB PLEF (48%) followed by the Malignant, 29% and PPE, 23% out of 100 study participants.

In a study, sex wise distribution 134(61%) of male and 85(39%) of study participants out of 219. And out of which 54.33% TPE cases and 45.66% of MPE cases.[16]

In this study, we study all the  above parameters (ADA, Sr. LDH, Sr. CRP, Cancer Ratio, Cancer Ratio Plus) which is statistically less than 0.05 i.e. (p=0.001), Significant. 

In this study, the Mean and SD  of Cancer Ratio of malignant with range(4.64-56), the mean and SD of (18.75±12.92), Cancer Ratio of PPE with range(5.47-16.48), the mean and SD of (10.74±3.71), Cancer Ratio of TB PLEF with range(2.90-9.86), the mean and SD of (5.03±2.06), with a p value of <0.001

In a study, the cancer ratio [7, 15] it is 65 and 11.5 respectively. In this study the sensitivity and specificity are 94.1 and 98 % respectively.

Cancer Ratio plus of malignant with range (6.63-471.54), the mean and SD of (54.94±94.76). Cancer Ratio plus PPE with range (33.86-342.42), the mean and SD of (159.40±99.57). Cancer Ratio plus TB PLEF with range (3.37-131.17), the mean and SD of (8.98±18.22), with a p value of <0.004.

In a study, the cancer plus of the mean value of cancer ratio plus is 62.4 for MPE and 11.8 for non-malignant with a p value of <0.001. The sensitivity and specificity are 94.1 and 95.6 % respectively.

The best parameter for diagnosing malignant effusion was Cancer ratio and Cancer ratio plus was a good parameter for the differential diagnosis to find a fastest and reliable marker to identify the malignant pleural effusion.

Cancer ratio being simple, cost effective and easily available biochemical markers may help people with exudative lymphocytic but inconclusive pleural effusion.

Funding: No.

Declaration of competing interest: The authors declare that there is no conflict of interest regarding this article.

Acknowledgments: The authors would like to thanks to P.G. department of Pulmonary, Hi-Tech Medical College and Hospital, Bhubaneswar, for support.

1. J. M. Porcel and R. W. Light, “Diagnostic approach to pleural effusions in adults,” American Family Physician, vol. 73, pp. 1211– 1220, 2006.
2. R. W. Light, “Pleural effusion,” The New England Journal of Medicine, vol. 346, no. 25, pp. 1971–1977, 2002.
3. H. E. Davies, R. J. O. Davies, and C. W. H. Davies, “Management of pleural infection in adults: British Thoracic Society pleural disease guideline 2010,” Thorax, vol. 65, no. 2, pp. ii41–ii53, 2010.
4.  Q.-L. Liang, H.-Z. Shi, K. Wang, S.-M. Qin, and X.-J. Qin, “Diagnostic accuracy of adenosine deaminase in tuberculosis pleurisy: a meta-analysis,” Respiratory Medicine, vol. 102, no. 5, pp. 744–754, 2008.
5. L. Antonangelo, R. K. Sales, A. P. Cor´a, M. M. P. Acencio, L. R. Teixeira, and F. S. Vargas, “Pleural fluid tumour markers in malignant pleural effusion with inconclusive cytologic results,” Current Oncology, vol. 22, no. 5, pp. e336–e341, 2015.
6. J. M. Porcel, A. Esquerda, M. Mart´ınez-Alonso, S. Bielsa, and A. Salud, “Identifying thoracic malignancies through pleural fluid. Biomarkers: a predictive multivariate model,” Medicine, vol. 95, no. 10, Article ID e3044, 2016.
7. A. Verma, J. Abisheganaden, and R. W. Light, “Identifying malignant pleural effusion by a cancer ratio (serum LDH: pleural fluid ADA ratio),” Lung, vol. 194, no. 1, pp. 147–153, 2016.
8. Tian P, Qiu R, Wang M, Xu S, Cao L, Yang P, Li W. Prevalence, causes, and Health Care Burden of Pleural Effusions among hospitalized adults in China. JAMA Netw Open. 2021; 4(8):e2120306.
9. Bawua SA, Ichihara K, Keatley R, Arko-Mensah J, Ayeh-Kumi PF, Erasmus R, Fobil J. Derivation of sex and age-specific reference intervals for clinical chemistry analytes in healthy ghanaian adults. Clin Chem Lab Med. 2022; 60(9):1426–39.
10. Wang D, Ma C, Zou Y, Yu S, Li H, Cheng X, Qiu L, Xu T. Gender and age-specific reference intervals of common biochemical analytes in Chinese population: derivation using real laboratory data. J Med Biochem. 2020; 39(3):384–91.
11. Jiang CG, Wang W, Zhou Q, Wu XZ, Wang XJ, Wang Z, Zhai K, Shi HZ. Influence of age on the diagnostic accuracy of soluble biomarkers for tuberculosis pleural effusion: a post hoc analysis. BMC Pulm Med. 2020; 20(1):178.
12. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, Lijmer JG, Moher D, Rennie D, de Vet HC, et al. STARD 2015: an updated list of essential items for reporting diagnostic accuracy studies. Clin Chem. 2015; 61(12):1446–52.
13. Zheng FF, Shen WH, Gong F, Hu ZD, Lippi G, Šimundić AM, Bossuyt PMM, Plebani M, Zhang K. Adherence to the Standards for Reporting of Diagnostic Accuracy Studies (STARD): a survey of four journals in laboratory medicine. Ann Transl Med. 2021; 9(11):918.
14. Mehta AA, Gupta AS, Ahmed S, Rajesh V. Diagnostic utility of adenosine deaminase in exudative pleural effusions. Lung India: official organ of Indian Chest Society. 2014 Apr; 31(2):142.
15. Verma A, Dagaonkar RS, Marshall D, Abisheganaden J, Light RW. Differentiating malignant from tubercular pleural effusion by cancer ratio plus (cancer ratio: pleural lymphocyte count). Canadian respiratory journal. 2016;2016
16. Zenghua Ren, Ling Xu., Role of cancer ratio and other new parameters in the differential diagnosis of malignant pleural effusion., CLINICS 2021;76:e2515, DOI: 10.6061/clinics/2021/e2515.