Neutrophil-to-lymphocyte ratio as an adjunct to CA-125 for the diagnosis of endometriosis

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1 ENDOMETRIOSIS Neutrophil-to-lymphocyte ratio as an adjunct to CA-125 for the diagnosis of endometriosis SiHyun Cho, M.D., a Hanbyoul Cho, M.D., a Anna Nam, M.D., a Hye Yeon Kim, M.D., b Young Sik Choi, M.D., b Ki Hyun Park, M.D., b Dong Je Cho, M.D., b and Byung Seok Lee, M.D. a a Department of Obstetrics and Gynecology, Yongdong Severance Hospital and b Department of Obstetrics and Gynecology, Severance Hospital, Yonsei University, College of Medicine, Seoul, South Korea Objective: To investigate the clinical value of differential white blood cell counts and neutrophil-to-lymphocyte ratio (NLR), by themselves or as adjunct to CA-125, in the diagnosis of endometriosis. Design: Retrospective study. Setting: University Medical Center. Patient(s): Two hundred thirty-one patients with endometriosis, 145 patients with benign ovarian tumors, and 384 healthy controls participated in this study. Intervention(s): None. Main Outcome Measure(s): Sensitivities and specificities of differential white blood cell (WBC) counts, NLR, serum CA-125, and the combined marker (NLR and serum CA-125) were evaluated by receiver-operating characteristic (ROC) analysis. Result(s): The mean NLR and the combined marker in patients with endometriosis were significantly higher than those in patients without endometriosis. The NLR was able to discriminate patients with endometriosis from those with benign ovarian tumors and from healthy controls, and 25 of the 38 endometriosis patients (65.8%) with minimal-to-mild disease exceeded the cutoff value. The combined marker had a sensitivity of 69.3% and specificity of 83.9% with a cutoff value of 55.7, showing 13.5% increase in sensitivity but 8.9% decrease in specificity when compared with serum CA-125 at a cutoff level of 35 IU/mL. The elevated combined marker detected 16 patients with endometriosis (42.1%) with minimal-to-mild disease, whereas only 10 patients (26.3%) had their serum CA-125 levels at more than 35 IU/mL. Conclusion(s): Measurement of NLR and the combined marker may be used as simple and easily obtained diagnostic markers for endometriosis. (Fertil Steril Ò 2008;90: Ó2008 by American Society for Reproductive Medicine.) Key Words: Endometriosis, diagnosis, CA-125, lymphocytes, neutrophils Endometriosis, defined as the proliferation of endometrial tissue outside the uterine cavity, is one of the most common benign gynecologic disorders. This disease is present in about 10% of all reproductive-aged women, and its prevalence increases to 20% 50% in infertile women (1). At present, the definitive diagnosis of endometriosis requires surgery with direct visualization of the lesions and histologic confirmation because imaging techniques, such as ultrasound and magnetic resonance imaging (MRI), have been shown to be unreliable in the diagnosis or staging of this disease. Although Received March 6, 2008; revised March 21, 2008; accepted March 25, SH.C. has nothing to disclose. H.C. has nothing to disclose. A.N. has nothing to disclose. H.Y.K. has nothing to disclose. Y.S.C. has nothing to disclose. K.H.P. has nothing to disclose. D.J.C. has nothing to disclose. B.S.L. has nothing to disclose. Reprint requests: Byung Seok Lee, M.D., Department of Obstetrics and Gynecology, YongDong Severance Hospital, Yonsei University College of Medicine, Dogok-dong, KangNam-gu, Seoul , South Korea (FAX: ; dr222@yuhs.ac). laparoscopy is a minimally invasive procedure, it requires general anesthesia and surgical skills, and it involves potential complications as well as procedural costs. Current evidence suggests that endometriosis likely induces local and systemic inflammatory processes. Numerous studies have focused on markers of inflammation in an effort to find less invasive methods for diagnosing endometriosis (2 5). Several cytokines have been shown to differ between women with endometriosis compared with controls, such as interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-a) (2, 4, 5). However, the most extensively studied marker is CA-125. Elevated CA-125 levels have been observed in serum, menstrual effluent, and the peritoneal fluid (PF) of women with endometriosis (6 11). Although CA- 125 is often elevated in advanced endometriosis, the low sensitivity of this assay limits its usefulness for detecting minimal and mild disease. A meta-analysis based on 23 articles showed limited diagnostic performance of serum CA-125 for detecting endometriosis (12) /08/$34.00 Fertility and Sterility â Vol. 90, No. 6, December doi: /j.fertnstert Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.

2 The systemic inflammatory response involves changes in the relative levels of circulating white blood cells (WBC); neutrophilia is accompanied by a relative lymphocytopenia (13, 14). Recent studies have proposed the use of WBC subtypes and the neutrophil-to-lymphocyte ratio (NLR) as simple indices of systemic inflammatory response in critically ill patients and as prognostic indicators for various diseases (15 18). We, therefore, hypothesized that changes in the relative levels of circulating WBCs are also found in patients with endometriosis. In this study, we evaluated differential WBC counts and NLR in patients with endometriosis and investigated whether these markers, either alone or in conjunction with CA-125, can be used as diagnostic markers for endometriosis. For all study subjects, differential WBC counts and CA-125 levels in serum obtained before operation were recorded. The NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count. For patients with endometriosis, the extent of disease was determined using the American Society of Reproductive Medicine (ASRM) revised classification (19) and the severity of the disease were classified as minimal-to-mild disease (stages I and II) or moderate-to-severe disease (stages III and IV). The presence of dysmenorrhea before surgery was also recorded. Healthy controls did not undergo surgery, and their NLR was calculated from their complete blood count performed as part of their routine health examinations. The time of the menstrual cycle was recorded for each patient: proliferative phase, beginning of menses until 14 days before the next menses, and secretory phase, 1 13 days before the next menses. Differential WBC counts and serum CA-125 levels of each group were expressed as a mean (95% confidence interval [CI]). The differences in means between groups were compared using one-way analysis of variance, post hoc tests or Student s t-test where appropriate, and an analysis of the percentage of patients with abnormally elevated values was performed using the c 2 test. Sensitivity and specificity for each marker were assessed by using receiver operating characteristic (ROC) curves (20). The area under the ROC curve (AUC) was calculated as a measure of the ability of each potential marker to discriminate between endometriosis cases and controls (benign tumor group and healthy control group). An AUC of 0.5 indicates classifications assigned by chance. The correlations between or within groups were evaluated with the use of Pearson s correlation coefficient or the Spearman rank correlation coefficient, where appropriate. The SPSS 12.0 package (SPSS Inc., Chicago, IL) was used for statistical analysis and P<.05 was considered to be statistically significant. MATERIALS AND METHODS We performed a retrospective review of 376 premenopausal women who underwent elective surgery with subsequent pathological evaluation at the Department of Obstetrics and Gynecology, Yongdong Severance Hospital from January 2004 to December Two hundred thirty-one women had pathologically confirmed endometriosis at the time of surgery. One hundred forty-five patients were diagnosed with benign ovarian tumors, including 58 cases of dermoid cysts, 38 cases of serous cystadenomas, 37 cases of mucinous cystadenomas, and 12 cases of other benign conditions. Patients with pathological confirmation or clinical suspicion of leiomyoma or adenomyosis were excluded from this study. The healthy control group (n ¼ 384) comprised premenopausal health check patients from Yongdong Severance Hospital who had no previous history of cancer or gynecologic disease or abnormalities on laboratory examination. This study was approved by the ethics committee of Yongdong Severance Hospital and Institutional Review Board (IRB) approval was obtained. RESULTS The overall mean age of the participants was years, and the mean ages of patients in the endometriosis group, the benign ovarian tumor group, and the healthy control group were years, years, and years, respectively. No significant age differences were noted between the groups (P¼.104). When the correlation between serum CA-125 and differential WBC counts were evaluated, serum CA-125 was positively correlated with WBC counts and neutrophil counts (r ¼ 0.250, P, and r ¼ 0.292, P, respectively). A positive correlation was also noted between serum CA-125 and NLR (r ¼ 0.246, P). To compare the usefulness of CA-125, NLR, and differential WBC counts in diagnosing endometriosis, we examined the ROC curve (Table 1). Only WBC subtypes with AUC of more than 0.5 were further evaluated for sensitivity, specificity, and cutoff value. The diagnostic performance of CA-125 alone was assessed at a cutoff point of 35 IU/mL, which is the value usually reported in the literature. The AUC for CA-125 was (95% CI ) with sensitivity of 55.8% and specificity of 92.8%. For NLR, the AUC was (95% CI ) and the cutoff value was 2.01 with 59.7% sensitivity and 60.1% specificity. Neutrophil counts, with AUC of (95% CI ) and a cutoff value of showed the highest sensitivity of 68.4%, but also demonstrated fairly low specificity (45.4%). The combination of CA-125 and NLR, the marker with the highest AUC, was also evaluated. The combined values were obtained by multiplying CA-125 levels by NLR, and ROC curve was constructed (Fig. 1). The AUC for the combined marker was (95% CI ) and the optimal cutoff value was 55.7 with sensitivity of 69.3% and specificity of 83.9% (Table 1). Mean counts of WBC subtypes, NLR, serum CA-125 levels. and the combined marker levels with 95% CI are shown in Table 2. Mean values for serum CA-125 levels, NLR, neutrophil counts, and WBC counts were increased in the endometriosis group, whereas lymphocyte counts, eosinophil counts, and basophil counts were significantly decreased in these patients. Bonferroni s test was used to 2074 Cho et al. Diagnosis of endometriosis using NLR Vol. 90, No. 6, December 2008

3 TABLE 1 Diagnostic sensitivity and specificity of the neutrophil-to-lymphocyte ratio and WBC subtypes in endometriosis patients. AUC (95% CI) Sensitivity (%) Specificity (%) Cutoff value P value WBC ( ) Neutrophil ( ) Monocyte ( ) NLR ( ) CA-125 (IU/mL) a ( ) Combined b ( ) Note: AUC ¼ area under the curve; CI ¼ confidence interval; NLR ¼ neutrophil-to-lymphocyte ratio; WBC ¼ white blood cells. a Cutoff level was set to 35 IU/mL. b Serum CA-125 levels multiplied by NLR. discriminate between the differences observed. Mean serum CA-125 levels were significantly higher in the endometriosis group than the benign tumor group (P) and the control group (P), but no significant differences was noted between the benign tumor group and the control group (Fig. 2). The NLR was significantly increased in the endometriosis group in comparison to the benign tumor group (P¼.037) and the control group (P), and was able to discriminate between the benign tumor group and the control group with statistical significance (P¼.044). For other WBC counts, such as neutrophil, lymphocyte, eosinophil, and basophil counts, significant differences were noted only between the endometriosis group and the control group. The mean value of the combined marker was (95% CI FIGURE 1 Receiver operating characteristic curves of CA-125, neutrophil-lymphocyte ratio (NLR), and the combined marker for the differential diagnosis between patients with endometriosis and controls ) and was significantly higher in the endometriosis group than the benign tumor group (P¼.002) and the healthy controls (P). No significant differences were observed between the benign tumor group and the control group (Table 2, Fig. 2). The endometriosis group was also evaluated according to the severity of the disease. There were no significant differences in comparisons of age, parity, and body mass index (BMI) between patients with minimal-to-moderate disease (stages I and II) and moderate-to-severe disease (stages III and IV). A comparison of CA-125 and differential WBC counts based on disease severity showed no significant differences except for NLR, which was significantly increased in patients with moderate-to-severe disease (2.29 vs. 2.73, P¼.026). Table 3 provides the means levels of NLR, CA-125, and the combined marker, and the percentage of the patients with abnormally elevated values in various stages of endometriosis. The highest mean values were found in patients at stage IV for all three markers. In terms of the number and the percentage of patients with elevated serum markers, NLR was greater than the cutoff value of 2.01 in 14 of the 18 patients (77.8%) with stage I disease, whereas only 5 patients (27.8%) were found to have serum CA-125 levels greater than the cutoff levels. For the patients with stage IV disease, the combined marker was above the cutoff level in 101 of the 121 patients (83.5%), whereas the percentage of the patients above the cutoff levels for CA-125 and NLR were 74.4% (90/121) and 60.3% (73/121), respectively. The results were similar when the endometriosis patients were grouped as minimal-to-mild disease (stages I and II) and moderate-to-severe disease (stages III and IV). Twenty-five of the 38 patients (65.8%) with minimal-to-mild disease were found to have NLR above 2.01, whereas 16 patients (42.1%) had combined marker levels above the cutoff, and only 10 patients (26.3%) were above cutoff levels for CA-125. The differences in percentages were statistically significant between NLR and serum CA-125 (P), and Fertility and Sterility â 2075

4 TABLE 2 Mean counts of white blood cell subtypes, neutrophil-to-lymphocyte ratio, and serum CA-125 levels in study subjects. Endometriosis (n [ 231) Benign tumors (n [ 145) Healthy controls (n [ 384) P value WBC 6, (6, ,074.62) Neutrophil 4, (4, ,689.18) Lymphocyte 1, (1, ,888.34) Monocyte ( ) Eosinophil ( ) Basophil ( ) NLR 2.66 ( ) CA ( ) Combined a ( ) 6, (6, ,053.45) 4, (3, ,481.82) 1, (1, ,060.13) ( ) ( ) ( ) 2.31 ( ) ( ) ( ) 6, (5, ,290.84) 3, (3, ,729.72) 1, (1, ,005.33) ( ) ( ) ( ) 1.99 ( ) ( ) ( ) Note: Values are expressed as mean (95% confidence interval). Analysis of variance, post hoc test was used. NLR ¼ neutrophil-to-lymphocyte ratio; WBC ¼ white blood cells. a Serum CA-125 levels multiplied by NLR between NLR and the combined marker (P¼.038). For the patients with moderate-to-severe disease, 144 of the 193 patients (74.6%) had combined marker levels above the cutoff level of 55.7, followed by 119 patients (61.6%) with elevated CA-125 levels and 113 patients (58.5%) with elevated NLR levels. The percentage of patients in this group with an elevated combined marker value was significantly higher than those with elevated serum CA-125 and NLR levels (P¼.006 and P). In patients across all stages of endometriosis, more had an elevated combined marker than any other marker tested. One hundred sixty of the 231 patients (69.3%) had combined marker levels above the cutoff values. The percentage of patients with an elevated combined marker was significantly higher than those with elevated serum CA- 125 or NLR (P¼.003 and P¼.032, respectively). When correlations between the stage of the disease and the levels of serum CA-125, NLR, and the combined marker were evaluated, significant correlations were noted between the stage of the disease and serum CA-125 (r ¼ 0.396, P) and also between the stage of the disease and the combined marker (r ¼ 0.355, P); no significant correlation was found between the stage of the disease and NLR. When the mean NLR, serum CA-125 levels, and combined marker levels were compared in all study participants according to their phase within the menstrual cycle, the NLR and the combined marker failed to show significant differences, whereas the mean serum CA-125 levels of patients in the proliferative phase (78.26 IU/mL; 95% CI ) were significantly higher than those in the secretory phase (46.56 IU/mL; (95% CI ), with P¼.046. In patients with endometriosis, mean NLR, serum CA-125 levels, and combined marker levels were increased in the proliferative phase, but no statistical significance was noted (2.80 vs with P¼.189 for NLR, vs with P¼.073 for serum CA-125, and vs with P¼.078 for the combined marker). DISCUSSION In the present study we showed that the NLR is elevated in patients with endometriosis, and it demonstrated high sensitivity in detecting endometriosis when used in combination with CA-125. The overall sensitivity and specificity of the combination marker was 69.3% and 83.9% when using a cutcut off value of Endometriosis is an inflammatory process associated with altered function of immune-related cells in the peritoneum and may be viewed as a local disease with systemic, subclinical inflammation (21). C-reactive protein, an indirect marker of inflammatory processes, has been found to be increased in 2076 Cho et al. Diagnosis of endometriosis using NLR Vol. 90, No. 6, December 2008

5 FIGURE 2 FIGURE 2 Continued Serum CA-125 levels, neurophil-to-lymphocyte ratio (NLR), and combined maker levels in patients with endometriosis, benign ovarian tumor, and healthy controls. (A, C) Comparison of mean (95% confidence interval [CI]) serum CA-125 values and combined marker values between study groups showed that these were significantly increased in patients with endometriosis in comparison with those with benign tumors and healthy controls. No significant differences were noted between patients with benign tumors and healthy controls. (B) The mean (95% CI) NLR values were increased significantly in patients with endometriosis compared with other study groups, and the NLR of patients with benign tumors were significantly increased in comparison with healthy controls. Note: Open circles indicate mean and the whiskers indicate 95% CI. Analysis of variance (ANOVA), post hoc test was used. the patients with endometriosis. Decreased proliferation of peripheral blood lymphocytes in response to recognition of endometrial cells and antigens has also been reported (22 24). Because changes in the relative levels of circulating WBCs are associated with the systemic inflammatory response, it can be assumed that changes in WBC counts may also occur in patients with endometriosis. In this study, neutrophil counts were increased and lymphocyte, eosinophil, and basophil counts were decreased in patients with endometriosis. Neutrophilia, accompanied by a relative lymphocytopenia, yielded an increased NLR in patients with endometriosis. When compared with differential WBC counts, NLR showed the highest AUC with a sensitivity and specificity of 59.7% and 60.1%, respectively, at a cutoff level of Although CA-125 is often elevated in advanced endometriosis, the low sensitivity of this assay limits its usefulness for detecting minimal and mild disease. The sensitivity and specificity of CA-125 with a cutoff level of 35 IU/mL in this study was 55.8% and 92.8% and were similar to the results of a meta-analysis of 23 studies involving 2,866 patients (12). As expected, the sensitivity dropped to 26.3% for minimal-to-mild endometriosis patients, with only 10 of 38 patients showing serum CA-125 levels more than 35 IU/mL. In contrast, the mean NLR was more effective in detecting patients with endometriosis with minimalto-mild disease, with 25 of 38 patients (65.8%) exceeding the cutoff value. The mean NLR was also able to discriminate between patients with endometriosis and those with benign tumors, and those with benign tumors from healthy controls. The mean NLR was highest in the endometriosis group, followed by the benign tumor group and the healthy controls. As shown in this study, none of the differential WBC counts have better sensitivities or specificities for predicting endometriosis than CA-125 alone. We therefore evaluated the diagnostic utility of the combined marker, NLR, and serum CA-125. The overall sensitivity increased significantly from 55.8% with serum CA-125 alone to 69.3%, although Fertility and Sterility â 2077

6 TABLE 3 The mean values of NLR, CA-125, and the combined marker, and the percentage of patients with abnormally elevated values at various stages of endometriosis. NLR NLR >2.01 CA-125 CA-125 >35 IU/mL Combined a Combined a >55.7 Stage I (n ¼ 18) 2.69 ( ) 14 (77.8%) ( ) 5 (27.8%) ( ) 10 (55.6%) Stage II (n ¼ 20) 1.94 ( ) 11 (55.0%) ( ) 5 (25.0%) ( ) 6 (30.0%) Stage III (n ¼ 72) 2.67 ( ) 40 (55.6%) ( ) 29 (40.3%) ( ) 43 (59.7%) Stage IV (n ¼ 121) 2.77 ( ) 73 (60.3%) ( ) 90 (74.4%) ( ) 101 (83.5%) Stage IþII (n ¼ 38) 2.29 ( ) 25 (65.8%) b,c ( ) 10 (26.3%) b ( ) 16 (42.1%) c Stage IIIþIV (n ¼ 193) 2.73 ( ) 113 (58.5%) d ( ) 119 (61.6%) e ( ) 144 (74.6%) d,e All stage (n ¼ 231) 2.68 ( ) 138 (59.7%) f ( ) 129 (55.8%) g ( ) 160 (69.3%) f,g Note: Data are expressed as mean (95% confidence interval) or number of patients with percentages in parentheses. NLR ¼ neutrophil-to-lymphocyte ratio. a Serum CA-125 levels multiplied by NLR. b,c,d,e,f,g P<.05 using c 2 test. the specificity decreased by 8.9%. When compared to serum CA-125 alone, the combined marker was elevated in a higher percentage of patients in various stages of endometriosis. These results indicate that the combined marker has better diagnostic value for patients in all stages of endometriosis and in those with moderate-to-severe disease than serum CA-125 or the NLR alone. Our results also confirmed previous reports that preoperative CA-125 levels increase with the stage of endometriosis (25, 26). The combined marker showed strong positive correlation with the stages, but the NLR did not. Although the mean NLR was highest in stage IV patients, the differences were very small in comparison with the values at stage I and there were no significant mean differences between stages of the disease. This may explain why NLR can detect more patients with minimal-to-moderate disease than other markers. The significant differences in mean NLR values between minimal-to-mild disease and moderate-to-severe disease seemed to be influenced by the relatively low NLR values in stage II patients. The weakness of the study is its retrospective design and our findings should be confirmed with prospective studies. There are some other limitations to our study. First, because changes in differential WBC counts and NLR are involved in the inflammatory process, all other acute inflammatory processes must be excluded before using them as a diagnostic tool for endometriosis. Second, the timing of blood collection for CA-125 in relation to the menstrual cycle is known to affect significantly this test (27). Although mean serum levels of CA-125 were increased in the proliferative phase, whereas NLR had no significant phase specific differences, the menstrual dates used in this study were obtained only by review of medical records; histologic confirmations were not made. In conclusion, the present study demonstrates that NLR and the combination of NLR and serum CA-125 are significantly higher in patients with endometriosis than in those without endometriosis. The NLR was more sensitive in predicting patients with minimal-to-mild endometriosis than serum CA-125, and was able to discriminate not only the patients with endometriosis from the patients with other benign ovarian tumors, but also those with benign ovarian tumors from healthy controls. The combined marker was found to have comparable overall sensitivity and specificity compared to serum CA-125 alone, although it was better able to detect endometriosis in patients with minimal-tomild disease. Although the additional increase in sensitivity and the accompanied decrease in specificity discourages the use of this marker as a novel screening tool for endometriosis, more accurate diagnosis of endometriosis, especially detecting women at risk of having early stages of the disease makes this approach clinically useful. The strongest advantage of using changes in differential WBC counts is that these counts can be easily obtained from nearly all patients by routine complete blood counts with no additional costs or testing. Confirmation in larger cohorts of patients should be 2078 Cho et al. Diagnosis of endometriosis using NLR Vol. 90, No. 6, December 2008

7 obtained and, if confirmed, this simple measurement from the complete blood counts, in conjunction with serum CA-125, may lead to a more accurate diagnosis of endometriosis. REFERENCES 1. Taylor RN, Lebovic DI, Mueller MD. Angiogenic factors in endometriosis. Ann N Y Acad Sci 2002;955: Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 2002;17: Cho SH, Oh YJ, Nam A, Kim HY, Park JH, Kim JH, et al. Evaluation of serum and urinary angiogenic factors in patients with endometriosis. Am J Reprod Immunol 2007;58: Darai E, Detchev R, Hugol D, Quang NT. Serum and cyst fluid levels of interleukin (IL) -6, IL-8 and tumour necrosis factor-alpha in women with endometriomas and benign and malignant cystic ovarian tumours. Hum Reprod 2003;18: Ulukus M, Ulukus EC, Seval Y, Zheng W, Arici A. Expression of interleukin-8 receptors in endometriosis. Hum Reprod 2005;20: Barbieri RL, Niloff JM, Bast RC Jr, Scaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations of CA-125 in patients with advanced endometriosis. Fertil Steril 1986;45: Patton PE, Field CS, Harms RW, Coulam CB. CA-125 levels in endometriosis. Fertil Steril 1986;45: Pittaway DE, Fayez JA. The use of CA-125 in the diagnosis and management of endometriosis. Fertil Steril 1986;46: Koninckx PR, Riittinen L, Seppala M, Cornillie FJ. CA-125 and placental protein 14 concentrations in plasma and peritoneal fluid of women with deeply infiltrating pelvic endometriosis. Fertil Steril 1992;57: O Shaughnessy A, Check JH, Nowroozi K, Lurie D. CA 125 levels measured in different phases of the menstrual cycle in screening for endometriosis. Obstet Gynecol 1993;81: Hornstein MD, Harlow BL, Thomas PP, Check JH. Use of a new CA 125 assay in the diagnosis of endometriosis. Hum Reprod 1995;10: Mol BW, Bayram N, Lijmer JG, Wiegerinck MA, Bongers MY, van der Veen F, et al. The performance of CA-125 measurement in the detection of endometriosis: a meta-analysis. Fertil Steril 1998;70: Jilma B, Blann A, Pernerstorfer T, Stohlawetz P, Eichler HG, Vondrovec B, et al. Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin. Am J Respir Crit Care Med 1999;159: Dionigi R, Dominioni L, Benevento A, Giudice G, Cuffari S, Bordone N, et al. Effects of surgical trauma of laparoscopic vs. open cholecystectomy. Hepatogastroenterology 1994;41: Zahorec R. Ratio of neutrophil to lymphocyte counts rapid and simple parameter of systemic inflammation and stress in critically ill. Bratisl Lek Listy 2001;102: Bishara S, Griffin M, Cargill A, Bali A, Gore ME, Kaye SB, et al. Pretreatment white blood cell subtypes as prognostic indicators in ovarian cancer. Eur J Obstet Gynecol Reprod Biol. Published online 17 July 2007 [epub ahead of print; ]. 17. De Angulo G, Yuen C, Palla SL, Anderson PM, Zweidler-McKay PA. Absolute lymphocyte count is a novel prognostic indicator in ALL and AML: implications for risk stratification and future studies. Cancer 2008;112: Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol 2005;91: American Society for Reproductive Medicine. Revised American Society for Reproductive Medicine classification of endometriosis: Fertil Steril 1997;67: Hanley JA, McNeil BJ. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 1982;143: Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung D. Is endometriosis associated with systemic subclinical inflammation? Gynecol Obstet Invest 2006;62: Abrao MS, Podgaec S, Filho BM, Ramos LO, Pinotti JA, de Oliveira RM. The use of biochemical markers in the diagnosis of pelvic endometriosis. Hum Reprod 1997;12: Dmowski WP, Steele RW, Baker GF. Deficient cellular immunity in endometriosis. Am J Obstet Gynecol 1981;141: Steele RW, Dmowski WP, Marmer DJ. Immunologic aspects of human endometriosis. Am J Reprod Immunol 1984;6: Pittaway DE, Douglas JW. Serum CA-125 in women with endometriosis and chronic pelvic pain. Fertil Steril 1989;51: Cheng YM, Wang ST, Chou CY. Serum CA-125 in preoperative patients at high risk for endometriosis. Obstet Gynecol 2002;99: Spaczynski RZ, Duleba AJ. Diagnosis of endometriosis. Semin Reprod Med 2003;21: Fertility and Sterility â 2079