Investigating the performance and cost-effectiveness of the simple ultrasound-based rules compared to the risk of malignancy index in the diagnosis of ovarian cancer (SUBSONiC-study): protocol of a prospective multicenter cohort study in the Netherlands

Ovarian cancer is the second most common gynecologic malignancy [1]. In 2008 it was the seventh leading cause of cancer deaths in women worldwide [1, 2]. Estimating the risk of malignancy is essential in the management of adnexal masses. Patients with a malignancy should undergo an appropriate staging procedure or debulking surgery carried out in specialized surgical centers. This is associated with a better median survival [3]. Vice versa, patients with a benign lesion may be managed conservatively or with minimal invasive surgery in non-specialized hospitals. This will limit morbidity and avoid unnecessary costs: laparoscopic surgery is associated with less blood loss, shorter hospital stay, and fewer postoperative complications with an improved quality of life and faster return to preoperative functioning [4].

There are several methods to distinguish benign from malignant adnexal masses. The commonly most used method in clinical practice is the Risk of Malignancy Index (RMI) [5‐7]. The RMI is an easy to use scoring system that is recommended by many national guidelines in the differential diagnosis of ovarian masses. The RMI combines ultrasound variables, menopausal status and serum CA125 into a score used to predict the risk of ovarian cancer before surgery (Fig. 1). The reported sensitivity and specificity of RMI at a cut-off value of 200 are 75–80 % and 85–90 %, respectively [8]. This results in an incorrect diagnosis (false positive or false negative) in one out of five women with an adnexal mass. These patients therefore receive inappropriate treatment, potentially leading to increased morbidity and/or mortality.

The ‘simple ultrasound-based rules’ (simple rules) is another method to differentiate between benignity and malignancy. This method uses different morphological ultrasound features of adnexal masses (without including menopausal status or serum CA125 measurement). It includes 10 rules (Table 1); five rules to predict malignancy (M-rules) and five rules to predict a benign tumor (B-rules). If both or none of the M- and B-rules are met the test is inconclusive [9,10]. Simple rules are applicable in approximately 80 % of patients with an ovarian mass and in these cases a sensitivity of 95 % and a specificity of 91 % is achieved in previous studies [11].

In adnexal masses for which the simple rules yield an inconclusive result (unclassifiable masses), subjective assessment by Gray-scale and color Doppler ultrasound imaging by an experienced ultrasound examiner can be used as a second stage test to achieve an optimal diagnostic performance. This subjective assessment is also called ‘pattern recognition’ [12]. The downside of subjective assessment is that it is experience dependent. Nevertheless, subjective assessment by an expert sonographer seems to be superior to any scoring system or mathematical model when classifying adnexal masses [10, 13, 14]. However, it is neither feasible nor efficient that every patient would have to undergo an expert ultrasonography. Therefore, this method is very well suited as a second stage test. In cases where the simple rules were inconclusive (i.e., masses that are difficult to diagnose) subjective assessment was used successfully with a sensitivity of 91 % and a specificity of 93 % [10]. Several individual reports have confirmed that this two-step triage test is superior to the RMI, especially in terms of sensitivity [15‐17].

Magnetic Resonance Imaging (MRI) with diffusion weighted sequences is another option for second stage testing of unclassifiable masses. The use of MRI – when interpret by specialized radiologists - also seems to be superior to RMI in the preoperative identification of adnexal masses. A meta-analysis performed by Dodge et al. resulted in an overall sensitivity of 92 % and a specificity of 88 % [18]. The test holds as an advantage that an MRI can not only distinguish a benign from a malignant mass, but can also detect possible metastases in case of a malignancy. Furthermore, MRI can help to select patients who might be more appropriately managed by neoadjuvant chemotherapy [19].