Evaluation of Risk of Malignancy Index 5—A New Indicator in Differentiating Benign and Malignant Ovarian Masses

INTRODUCTION

Ovarian malignancies represent a great challenge as over two-thirds of the patients have advanced disease at diagnosis.¹ Ovarian cancer patients operated by gynec-oncologists are more likely to undergo accurate staging and optimal cytoreductive surgery as compared to patients who are operated by general gynecologists.² The preoperative diagnosis of whether a mass is benign or malignant cannot always be made out by CA125 and ultrasound features. Minimal invasive surgery or minilaparotomy can be planned if an ovarian neoplasm is known to be benign preoperatively. The risk of malignancy index (RMI) is a simple scoring method based on menopausal status (M), ultrasound score (U), and serum CA125 levels developed by Jacobs et al.³ Risk of malignancy index has been modified by Tingulstad^4,5 to obtain RMI2 and RMI3. Yamamoto et al. developed RMI4 by including the size of tumor into the calculation.⁶ We developed risk of malignancy index 5 (RMI5) to circumvent the drawbacks of the older malignancy indices. Risk of malignancy index 5 is calculated using the following formula:

where M, menopausal status; U, ultrasound score.

In premenopausal woman, tumor size (S, single greatest diameter) is of %3C;7 cm, S = 1 and ≥7 cm, S = 2.

In postmenopausal women, tumor size is of <5 cm, S = 1 and ≥5 cm, S = 2.

CA125 <35 U/mL: C = 1.

35–100 U/mL: C = 2.

%3E;100 U/mL: C = 3.

The RMI5 indicator developed is believed to be a more efficacious parameter to differentiate benign and malignant ovarian tumors. Thus, we wanted to test the efficacy of RMI5 as against RMI1, RMI2, RMI3, RMI4, and the individual parameters in differentiating benign or malignant ovarian tumors.

MATERIALS AND METHODS

This is a retrospective study of 200 women admitted to gynec-ward at RajaRajeswari Medical College and Hospital between 2010 and 2015 with ovarian masses. The Ethical Committee approval was obtained from the Institutional Ethics Committee of RajaRajeswari Medical College and Hospital, Bengaluru. The data of the women were taken from the records, and preoperative serum CA125 levels, ultrasound findings, and menopausal status were noted. RMI1, RMI2, RMI3, RMI4, and RMI5 were calculated. Serum CA125 levels were measured using chemiluminescence assay (Roche Diagnostics, Tokyo, Japan) and ultrasound was performed transabdominally with 7 MHz transducer. Ultrasound features of malignancy like the presence of multilocular cystic lesion, solid areas, bilateral lesions, ascites, and intra-abdominal metastasis were given one score each. A total ultrasound score (U) for each patient was calculated. Tumor size (S) was measured.

RESULTS

The distribution of benign and malignant cases by age, menopausal status, ultrasound score, and tumor size are in Table 1. Amongst the 200 patients, 35 (17.5%) had malignant and 165 (82.5%) had benign tumors as determined by histopathological examination. The mean age of the patients with malignancy was 36.92 ± 14 and 34.06 ± 12 in those with benign ovarian tumors.

Distribution of diagnosis in premenopausal and postmenopausal women is shown in Table 2.

The performance of the individual parameters is shown in Table 3. CA125 has a good sensitivity of 80% than others among the individual parameters. The risk of malignancy was more with increased CA125 and in postmenopausal women with significant p value %3C; 0.001.

The performance of RMI1–5 is presented in Table 4.

Direct comparison of the five indices shows that there is statistically significant difference in the performance of RMI2 and RMI5 with a McNemar’s test value of 0.047 and 0.034, respectively, as shown in Table 5. Here, McNemar’s test compared the indices with the histopathology which is the gold standard.

Seventeen (8.5%) patients had infertility and found to have ovarian cysts while evaluating.

Laparoscopy was done in 105 (52.5%), and laparotomy in 60 (30%) patients with benign masses.

Three cases with suspected dermoid cysts underwent laparoscopic salpingo-ophorectomy were later diagnosed as malignant. Laparotomy with salpingo-ophorectomy was done in six cases of suspected benign serous cystadenomas turned malignant. Staging laparotomy was done in 26 patients.

Mature cystic teratomas or ovarian cysts dealt laparoscopically were removed by using bag without spillage. Laparoscopy was abandoned in two patients and converted to laparotomy as findings were more in favor of malignancy. Endometrial hyperplasia was found in 4 (2%) patients.

DISCUSSION

The mean value of CA125 levels in benign cases was 155.25 (4–1,770), and in malignant cases, it was 169.25 (4–5,342) with p < 0.001.

When individual parameters were compared, CA125 had better sensitivity than the ultrasound score, size, and menopausal status. The postmenopausal status had better specificity than CA125 but less sensitivity.

According to Ulusoy et al., the median value of preoperatively determined CA125 serum levels of the patients with benign cases was 31.42 (3–1,153), and in those with malignant cases, it was 152.75 (1–5,000). There was a significant difference between the two groups (p < 0.001).⁹

The determination of adnexal masses with use of RMI1 (for cutoff of 200; sensitivity and specificity were 85.4% and 96.9%, respectively) was better as compared to ultrasound and serum CA125 individually.³

RMI2 was better than RMI1 with McNemar’s test (p = 0.001).⁴ RMI3 had a sensitivity and specificity of 71% and 92%, respectively, at a cutoff level of 200.⁵

Yamamoto et al. confirmed high performance values of the RMI2 and RMI3 at a cutoff level of 200. The sensitivity and specificity of RMI2 were 90% and 80%, while that for RMI3 were 82.6% and 86.4%, respectively.⁶

In the present study, RMI2 had a sensitivity and specificity of 77.14% and 84.22%, respectively.

Yamamoto et al. in 2003 developed RMI4 to overcome the low PPV of other indices. He derived a sensitivity of 86.8%, a specificity of 91%, a PPV of 63.5%, and a NPV of 97.5% at a cutoff of 450.⁶

This is comparable with the performance of RMI4 in our study.

RMI4 uses tumor size but uses the cutoff of 7 cm both in pre- and postmenopausal women. The adnexal masses of %3E;8 cm and >5 cm in pre- and postmenopausal women, respectively, should be considered for intervention.¹⁰ Also, the older indices use CA125 directly.

CA125 levels are elevated in a variety of conditions like endometriosis, uterine fibroids, pancreatitis, pelvic inflammatory disease, and cirrhosis. Also malignancies of endometrium, lung, breast, pancreas, and gastrointestinal tract can have a raised CA125.¹¹

The specificity and sensitivity of CA125 are 78% and 75%, respectively, at a cutoff of 35 U/mL.⁸ More the CA125 more is the specificity.

In malignant ovarian tumors, CA125 is elevated to a greater extent. Hence, to incorporate the two aspects and improve the efficacy, RMI5 was developed.

Risk of malignancy index 5 has a specificity of 93.17%, better than any of the four indices. Univariate analysis of the five indices shows RMI5 to be a good index to indicate malignancy (p = 0.034). RMI2 has also proved to have p value = 0.047 (McNemar’s test).

This helps us to involve oncosurgeons or refer to better center where these surgeries can be performed more efficiently. This helps in deciding the surgery to be performed preoperatively than deciding intraoperatively. Also, benign tumors can be efficiently and cosmetically dealt laparoscopically. Furthermore, this can be done by general gynecologists and eliminates the involvement in gynec-oncologists while screening. This helps in earlier diagnosis and appropriate referrals.

CONCLUSION

Risk of malignancy index 5 has a specificity of 93.17% and a NPV of 90.91 at a cutoff of 25. Also, the ROC curve indicates that the RMI5 is better index with an area under curve of 0.950 with significant p values. Hence, RMI5 is simple score that can be used to differentiate benign and malignant ovarian masses. Amongst the individual parameters, CA125 is better parameter to detect malignancy.

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