Cell Mol Med Res
Cellular and Molecular Medicine Research, ISSN 0000-0000 print, 0000-0000 online, Open Access
Article copyright, the authors; Journal compilation copyright, Cell Mol Med Res and Elmer Press Inc
Journal website www.thecmmr.org

Original Article

Volume 1, Number 1, June 2017, pages 11-14


Serum Tumor Markers for Preoperative Discrimination of Benign and Malignant Adnexal Masses

Besim Haluk Bacanakgila, Fehmi Unala, Sevinj Aliyevaa, b, Isa Shukru Oza, Roya Karimovaa

aIstanbul Education and Research Hospital, Gynecology and Obstetrics Clinic, Turkey
bCorresponding Author: Sevinj Aliyeva, Istanbul Education and Research Hospital, Gynecology and Obstetrics Clinic, Turkey

Manuscript submitted April 12, 2017, accepted May 19, 2017
Short title: Tumor Markers and Ovarian Cancer
doi: https://doi.org/10.14740/cmmr8e

Abstract▴Top 

Background: We aimed to determine the diagnostic values of individual tumor marker or combined in preoperative discrimination between benign and malignant ovarian tumors.

Methods: Medical data of 322 patients operated because of adnexal masses during 2009 - 2014 in Istanbul Research and Traning Hospital (a tertiary center) were retrospectively analyzed. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy (ACC) were determined for each individual tumor marker or markers combined.

Results: Median age of patients was 43 years. Of all patients, 68.3% were premenopausal and 31.7% were postmenopausal. CA125 levels in 29.8% patients, CA19-9 in 16.3% and CA15-3 in 6.1% were found higher than the cutoff value. The postmenopausal group had significantly higher levels of CA 125 and CA15-3 (P = 0.021 and P = 0.002, respectively) compared with the premenopausal group. In malignant cases, CA125 and CA15-3 were significantly higher (P < 0.001). Sensitivity, specificity, PPV, NPV and ACC of CA125 were 70.5%, 76.6%, 32.3%, 94.2% and 75.8%, respectively. Sensitivity, specificity, PPV, NPV and ACC of CA15-3 were 34.1%, 98.2%, 73.7%, 90.8% and 89.8%, respectively. There was no significant difference in CA19-9 levels between the benign and malignant groups. The ACC of combined CA125 + CA15-3 was 90.7%.

Conclusion: The elevated levels of CA125 or CA15-3 individually have a high diagnostic value for preoperative discrimination of benign/malignant adnexal masses. Combination of CA125 and CA15-3 does not present addtive effect. CA19-9 is not an appropriate marker for discrimination of benign/malignant adnexal masses.

Introduction▴Top 

According to the 2015 Guidelines of Centers For Disease Control and Prevention and National Cancer Institute, about 20,000 new cases of ovarian cancer are diagnosed in the United States each year [1]. The ovarian cancer is the eighth most common malignant tumor and the fifth most common cause of cancer death in females in the United States. It is the most fatal cancer of the female reproductive system. Over 14,000 women died of ovarian cancer in the Unites States in 2012 and the 5-year survival rate is a dismal 45% [1].

Preoperative differential diagnosis of ovarian cancers is very important, which facilitates the optimal treatment and helps prognosis prediction. As the ovarian cancers do not have spesific diagnostic symptoms, 65% cases when diagnosed are at stages 3 and 4 [2]. Blood cancer antigen 125 (CA125) is the most used tumor marker for ovarian cancer diagnosis. Using the cutoff value of 35 U/mL, CA125 has 80% sensitivity and 75% specificity for ovarian tumor diagnosis [3].

Preoperative benign/malignant distinction of the adnexal masses is important for the management of patients, and hgh levels of CA125 can be detected in several benign cases that include endometriosis, pelvic inflammatory disease, pregnancy, menstrual cycle, etc., resulting in false positive reports [2, 4]. In this study, we aimed to use preoperative serum CA125, CA19-9 and CA15-3 levels individually or combined to discriminate malignant and benign adnexal masses.

Methods▴Top 

Medical data of 322 patients operated because of adnexal masses between 2009 and 2014 were retrospectively analyzed. Cutoff values of blood CA125, CA19-9 and CA15-3 were set at 35, 35 and 31 U/mL, respectively. Tumor markers were evaluated individually and combined.

SPSS 15.0 for Windows program was used for statistical analysis. Descriptive statistics were expressed as average, standard deviation and median for quantitive variables. The comparison of the independent groups was performed via Mann-Whitney U analysis. In the independent groups, rate comparison was made using Chi-square analysis. The relationship between the quantitive variables was analized via Spearman Correlation test when parametric test conditions did not fit. Statistically, alpha significant rate was accepted as P < 0.05.

Results▴Top 

The average age of patients was 43.6 years, 68.3% of patients were premenopausal and 31.7% were postmenopausal. Of all patients, 29.8% had a higher than cutoff CA125 level, 16.3% had a higher than cutoff CA19-9 level and 6.1% had a higher than cutoff CA15-3 level. Average tumor size was 6.7 cm, 59.3% of tumoral masses were cystic, 86.3% were benign and 13.7% malignant (Table 1).

Table 1.
Click to view
Table 1. Features of Patients
 

According to the histopathological analysis, in the benign group the most common ovarian tumor found in our series was serous cystadenoma (21.7%), and in the malignant group serous adenocarsinoma was the most common one (5.9%) (Table 2).

Table 2.
Click to view
Table 2. Histopathological Results
 

CA125 and CA15-3 levels were significantlly higher in postmenopausal patients than in premenopausal patients (P = 0.021 and P = 0.002, respectively). There was no significant difference in CA19-9 levels between these 2 groups (Table 3). The malignancy rate was 7.3% in premenopausal group, and 27.4% in postmenopausal group. This difference was statistically significant (P < 0.001) (Table 3).

Table 3.
Click to view
Table 3. Preoperative Tumor Marker Levels and Menopausal Situations
 

CA125 and CA15-3 levels were significantly higher in malignant group than in benign group (P < 0.001) (Table 4). There was no significant difference in CA 19-9 levels between malignant and benign groups.

Table 4.
Click to view
Table 4. Preoperative Tumor Marker Levels
 

According to tumor markers’ cutoff values, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy (ACC) were determined (Table 5). The highest sensitivity and NPV values were seen for CA125 (70.5% and 94.2%, respectively), the highest specificity and PPV values were detected for CA15-3 (98.2% and 73.7%, respectively). CA15-3 reached the highest diagnostic accuracy rate (89.8%). When these markers were combined and calculated, the most significant combination was CA125 + CA15-3. Via this combination, specificity and diagnostic accuracy became 99.3% and 90.7%, respectively but sensitivity was compromised (Table 5).

Table 5.
Click to view
Table 5. Preoperative Tumor Marker Diagnostic Values
 
Discussion▴Top 

For preoperative benign/malignancy differentation of adnexal masses, an optimal tumor marker must have a high specificity. CA125 is the most commonly used surface epithelial sourced tumor marker. Blood CA 125 is detected to be elevated in 90% of advanced stage and 50% of early stage epithelial ovarian tumors [6, 7]. Medeiros et al have reported 80% sensitivity and 75% specificity for CA125 in the diagnosis of ovarian tumors [3]. Other investigations show similar results [8]. In our study, we identified 70.5% sensitivity and 76.6% specificity, and the diagnostic accuracy of 75.8% for CA125 in the discrimination of benign/malignant adnexal masses.

Diagnostic value of CA15-3 for benign/malignant adnexal masses is variable with sensitivity reported ranging 26-62%, specificity 84-96%, PPV 66-80%, and NPV 46-81% [9-12]. In our study, specificity was 34.1%, however sensitivity was 98.2%. The specificity and negative predictive values we found were some higher than those previously reported. In our patients, diagnostic accurracy rate of CA15-3 was 89.9%.

In this study, we found CA19-9 had 30.2% sensitivity and 85.9% specificity for the discrimination of benign/malignant adnexal masses. CA19-9 levels were not significantly different between premenopausal and postmenopausal, also between benign and malignant patient groups. Therefore we felt CA19-9 was not a sensitive marker for preoperative discrimination of adnexal masses between benign and malignant tumors. Similar results were revealed by Bozkurt et al [12].

High CA125 levels in differentiation of benign and malignant masses are more important in postmenopausal patients [13-15]. Malkasian et al have reported high CA125 levels have diagnostic sensitivity of 60% and 80%, and specificity of 73% and 91% in premenopausal and postmenopausal patients, respectively [13]. Preoperative CA125 and CA15-3 levels were significantly higher in our postmenopausal patients compared with premenopausal individulas and the rate of malignancy in postmenopausal group was 26.7%. In postmenopausal patients, elevated CA125 and CA15-3 levels have been shown to be suggestive of possible malignant pathology [13, 16]. Our findings also support this consideration.

Although several studies have used combination of tumor markers for preoperative detection of benign/malignant tumors, the conclusion remains elusive. Therefore, no combination has been recommended yet. However, it is suggested some combinations might be beneficial [2-6, 9, 11]. In our study, combination of CA125 and CA15-3 minimally improved the diagnostic accuracy in discrimination of benign and malignant ovarian tumors. Similarly, Bozkurt et al. applied different combinations of CA125, CA19-9, CA15-3 and CEA, and concluded that these combinations didn't improve diagnostic accuracy significantly.

Conclusion

Elevated levels of CA125 have high sensitivity and specificity for discrimination of benign and malignant adnexal masses, however combination of CA125 and CA15-3 does not show additive effect on diagnostic accuracy. CA19-9 is not a suitable marker in this regard. Specific attention and careful analysis should be given if postmenopausal patients have high CA125 and CA15-3 levels.


References▴Top 
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.
    doi pubmed
  2. Jordan MS, Bristow ER. Ovarian cancer biomarkers as diagnostic triage tests. Current Bio-marker Findings. 2013;3:35-42.
  3. Medeiros LR, Rosa DD, da Rosa MI, Bozzetti MC. Accuracy of CA 125 in the diagnosis of ovarian tumors: a quantitative systematic review. Eur J Obstet Gynecol Reprod Biol. 2009;142(2):99-105.
    doi pubmed
  4. Freydanck MK, Laubender RP, Rack B, Schuhmacher L, Jeschke U, Scholz C. Two-marker combinations for preoperative discrimination of benign and malignant ovarian masses. Antican-cer Res. 2012;32(5):2003-2008.
    pubmed
  5. Nolen B, Velikokhatnaya L, Marrangoni A, De Geest K, Lomakin A, Bast RC Jr, Lokshin A. Serum biomarker panels for the discrimination of benign from malignant cases in patients with an adnexal mass. Gynecol Oncol. 2010;117(3):440-445.
    doi pubmed
  6. Moore RG, McMeekin DS, Brown AK, DiSilvestro P, Miller MC, Allard WJ, Gajewski W, et al. A novel multiple marker bioassay utilizing HE4 and CA125 for the prediction of ovarian cancer in patients with a pelvic mass. Gynecol Oncol. 2009;112(1):40-46.
    doi pubmed
  7. Tanyi JL, Scholler N. Oncology biomarkers for gynecologic malignancies. Front Biosci (Elite Ed). 2012;4:1097-1110.
    doi
  8. Jacobs I, Bast RC Jr. The CA125 tumor-associated antigen: a review of the literature. Hum Re-prod. 1989;4:1-12.
    doi pubmed
  9. Bian J, Li B, Kou XJ, Liu TZ, Ming L. Clinical significance of combined detection of serum tumor markers in diagnosis of patients with ovarian cancer. Asian Pac J Cancer Prev. 2013;14(11):6241-6243.
    doi pubmed
  10. Scambia G, Benedetti Panici P, Baiocchi G, Perrone L, Greggi S, Di Roberto P, Mancuso S. CA 15-3 serum levels in ovarian cancer. Oncology. 1988;45(3):263-267.
    doi pubmed
  11. Berek JS, Bast RC Jr. Ovarian cancer screening. The use of serial complementary tumor markers to improve sensitivity and specificity for early detection. Cancer. 1995;76(10 Suppl):2092-2096.
    doi
  12. Bozkurt M, Yumru AE, Aral I. Evaluation of the importance of the serum levels of CA-125, CA15-3, CA-19-9, carcinoembryonic antigen and alpha fetoprotein for distinguishing benign and malignant adnexal masses and contribution of different test combinations to diagnostic ac-curacy. Eur J Gynaecol Oncol. 2013;34(6):540-544.
    pubmed
  13. Malkasian GD Jr, Knapp RC, Lavin PT, Zurawski VR Jr, Podratz KC, Stanhope CR, Mortel R, et al. Preoperative evaluation of serum CA 125 levels in premenopausal and postmenopausal patients with pelvic masses: discrimination of benign from malignant disease. Am J Obstet Gynecol. 1988;159(2):341-346.
    doi
  14. Patsner B, Mann WJ. The value of preoperative serum CA 125 levels in patients with a pelvic mass. Am J Obstet Gynecol. 1988;159(4):873-876.
    doi
  15. Baron AT, Boardman CH, Lafky JM, Rademaker A, Liu D, Fishman DA, Podratz KC, et al. Soluble epidermal growth factor receptor (sEGFR) [corrected] and cancer antigen 125 (CA125) as screening and diagnostic tests for epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev. 2005;14(2):306-318.
    doi pubmed
  16. Van Calster B, Valentin L, Van Holsbeke C, Zhang J, Jurkovic D, Lissoni AA, Testa AC, et al. A novel approach to predict the likelihood of specific ovarian tumor pathology based on serum CA-125: a multicenter observational study. Cancer Epidemiol Biomarkers Prev. 2011;20(11):2420-2428.
    doi pubmed


This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Cellular and Molecular Medicine Research is published by Elmer Press Inc.

 
Home     |     Log In     |      About     |      Search     |      Current     |      Archives     |      Submit      |     Subscribe


 

     

Aims and Scope

Current Issues

Conflict of Interest

About Publisher

Editorial Board

Archives

Copyright

Company Profile

Editorial Office

Misconduct and Retraction

Permissions

Company Registration

Contact Us

Abstracting and Indexing

ICMJE

Ownership

Instructions to Authors

Access

Declaration of Helsinki

Contact Publisher

Submission Checklist

Reprints

Terms of Use

Company Address

Submit a Manuscript

Open Access Policy

Privacy Policy

Browse Journals

Publishing Fee

Publishing Policy

Disclaimer

Recent Highlights

Peer-Review Process

Publishing Quality

Code of Ethics

Advertising Policy

Manuscript Tracking

Advanced Search

For Librarians

Careers

Publishing Process

Publication Frequency

For Reviewers

Propose a New Journal

       
       

Cellular and Molecular Medicine Research, quarterly, ISSN 0000-0000 (print), 0000-0000 (online), published by Elmer Press Inc.     
The content of this site is intended for health care professionals.
This is an open-access journal distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons Attribution license (Attribution-NonCommercial 4.0 International CC-BY-NC 4.0)


This journal follows the International Committee of Medical Journal Editors (ICMJE) recommendations for manuscripts submitted to biomedical journals,
the Committee on Publication Ethics (COPE) guidelines, and the Principles of Transparency and Best Practice in Scholarly Publishing.

website: www.thecmmr.org   editorial contact: editor@thecmmr.org
Address: 9225 Leslie Street, Suite 201, Richmond Hill, Ontario, L4B 3H6, Canada

© Elmer Press Inc. All Rights Reserved.

DECLARATION: THIS JOURNAL SITE OUTLOOK IS DESIGNED BY THE PUBLISHER AND COPYRIGHT PROTECTED. DO NOT COPY!