Differentiation between borderline and benign ovarian tumors: combined analysis of MRI with tumor markers for large cystic masses (≥5 cm)

Abstract

Background

There is overlap in imaging features between borderline and benign ovarian tumors.

Purpose

To analyze diagnostic performance of magnetic resonance imaging (MRI) combined with tumor markers for differentiating borderline from benign ovarian tumor.

Material and Methods

Ninety-nine patient with MRI and surgically confirmed ovarian tumors 5 cm or larger (borderline, n = 37; benign, n = 62) were included. On MRI, tumor size, septal number (0; 1–4; 5 or more), and presence of solid portion such as papillary projection or septal thickening 0.5 cm or larger were investigated. Serum tumor markers (carbohydrate antigen 125 [CA 125] and CA 19-9) were recorded. Multivariate analysis was conducted for assessing whether combined MRI with tumor markers could differentiate borderline from benign tumor. The diagnostic performance was also analyzed.

Results

Incidence of solid portion was 67.6% (25/37) in borderline and 3.2% (2/62) in benign tumors (P < 0.05). In all patients, without combined analysis of MRI with tumor markers, multivariate analysis revealed solid portion (P < 0.001) and CA 125 (P = 0.039) were significant for predicting borderline tumors. When combined analysis of MRI with CA 125 ((i) the presence of solid portion or (ii) CA 125 > 44.1 U/mL with septal number ≥5 for borderline tumor) is incorporated to multivariate analysis, it was only significant (P = 0.001). The sensitivity, specificity, PPV, NPV, and accuracy of combined analysis of MRI with CA 125 were 89.1%, 91.9%, 86.8%, 93.4, and 90.9%, respectively.

Conclusion

Combined analysis of MRI with CA 125 may allow better differentiation between borderline and benign ovarian tumor compared with MRI alone.

Keywords

Borderline tumor ovary magnetic resonance imaging (MRI)tumor marker CA 125

Introduction

Borderline ovarian tumors account for 15–20% of ovarian epithelial tumors (1,2). They may involve the peritoneum or lymphatics, which may be the cause of tumor recurrence after incomplete resection (3,4). For benign ovarian tumors, laparoscopic tumor excision is the preferred surgical approach to preserve ovarian function (5). On the contrary, insufficient surgical resection such as laparoscopic cystectomy may lead to inaccurate tumor staging and a higher recurrence rate in borderline ovarian tumors (4,6 –8). Thus, a broader range of surgical resection and exploration including salgingo-ophorectomy, hysterectomy, or peritoneal washing or biopsy through laparotomy has been recommended to reduce the recurrence rate (3,9,10).

Radiologically, borderline ovarian tumors typically manifest as septated cystic masses with solid nodules or septal thickening (11,12). About 60–90% of the tumors have discrete solid portions, which may provide clues for differentiating borderline ovarian tumors from benign tumors (11,13,14). Conversely, some borderline tumors may appear as multiseptated cystic masses without a solid portion, which may complicate differentiation between benign and borderline tumors because many benign ovarian tumors also exhibit multiseptation (13,15). Hence, intraoperative frozen section analysis is sometimes additionally conducted to assess the histologic aggressiveness of ovarian tumors when they are preoperatively indeterminate in nature (16).

Previous studies have demonstrated that serum tumor markers such as carbohydrate antigen 125 (CA 125) or CA 19-9 can be elevated in borderline ovarian tumors, and thus be useful for screening; about 30–70% of patients with borderline tumors show increased levels of tumor markers (17 –19). Based on this background, we assumed that the additional utilization of CA 125 or CA 19-9 in MRI evaluation for ovarian cystic masses might contribute to accurate identification of borderline ovarian tumors without remarkable septal thickening or solid nodules.

Thus, the purpose of our study was to retrospectively analyze the diagnostic performance of MRI combined with tumor markers for differentiating borderline tumors from benign ovarian tumors.

Material and Methods

Study subjects

The institutional review board approved this retrospective study and the requirement of informed consent was waived. Based on a search of electronic medical records from January 2005 to December 2013 at our institution, we found 133 consecutive patients who had undergone preoperative pelvic MRI and had surgically confirmed borderline or benign ovarian tumors (Fig. 1). Of the patients, 24 were excluded for the following reasons: (i) absence of available serum tumor markers such as CA 125 or CA 19-9 (n = 15); (ii) tumor size less than 5 cm (n = 9); (iii) co-morbid endometriosis (n = 9); and (iv) co-morbid endometrial cancer (n = 1). Ovarian cystic masses less than 5 cm were excluded because of the low risk of malignancy; consequently, they usually undergo active surveillance without surgical intervention unless morphologic changes or elevated tumor markers are detected (20,21). Patients with co-morbid endometriosis or endometrial cancer were also excluded because they may cause elevated serum tumor markers, regardless of ovarian pathology (22 –24). In addition, the presence of endometriosis could be correctly diagnosed by imaging because they showed typical manifestation of MRI in our patients, which was a cystic tubo-ovarian lesion of high signal intensity on T1-weighted (T1W) imaging with T2 shading (25).

Fig 1.

Flowchart of study group.

Thus, a total of 99 patients who had borderline ovarian (n = 62) or benign ovarian (n = 37) tumors were finally included in our study. None of the included subjects had evidence of diffuse uterine adenomyosis, mature cystic teratoma, or pelvic inflammatory disease clinically and radiologically. Of the 99 patients, four had bilateral ovarian lesions with the same pathologic results (borderline, n = 2; benign, n = 2). In patients with surgically confirmed bilateral lesions, a lesion with the solid portion or greater septal number was only included in analysis because these radiologic features suggested more aggressive histology (13,14). All of the lesions were mainly cystic masses radiologically and pathologically.

MRI protocols

The pelvic MRI was performed on one of three 3T scanners (Intera Archieva, Philips Medical System, Best, The Netherlands; Discovery MR750, GE Healthcare, Milwaukee, WI, USA; TrioTim, Siemens, Erlangen, Germany) with a phased-array body coil. T1W imaging, T2-weighted (T2W) imaging, and dynamic contrast-enhanced imaging (DCEI) were included on MRI. MRI protocols are summarized in Table 1. Before MRI, 20 mg of butyl scopolamine (Buscopan, Boehringer Ingelheim, Ingelheim am Rhein, Germany) was intramuscularly injected to suppress bowel peristalsis. For DCEI, the gadolinium-based contrast agent (Dotarem; Guerbet, Villepinte, France) was infused intravenously.

Table 1.

MRI protocols.

Parameter	T1W imaging	T2W imaging	DCEI
Orientation	Axial	Three planes*	Sagittal
TR (ms)	470–590	3500–4500	6.3
TE (ms)	10	80–120	1.7
Flip angle (°)	90	90	90
Matrix	256 × 256	(416–512) × (256–419)	320 × 180
NEX	2	1–3	1
FOV (mm)	240–300	240–300	240–300
Slice thickness (mm)	4–5	4–5	4–5

Three planes consisted of axial, sagittal, and coronal images.

NEX, number of excitations; TE, echo time; TR, repetition time.

Analysis of MRI and tumor markers

Two radiologists (with 15 and 3 years of pelvic MRI experience, respectively), who were blinded to clinical and pathological data, analyzed the MRI examinations in consensus. Mass size, septal number, and the presence of a solid portion were investigated with T1W imaging, T2W imaging, and DCEI. Mass size was defined as the longest diameter of a lesion to be measured on T2W imaging. Using T2W imaging, the septal number of a lesion was classified into one of three groups (0; 1–4; 5 or more) according to a previous classification method (26). The presence of a solid portion was defined as when an enhancing nodular portion or thickened septum or wall 5 mm or greater with iso or low signal intensity on T2W imaging was seen within the lesion (13). In all patients, preoperative serum CA 125 and CA 19-9 levels were recorded.

Statistical analysis

For comparison of mass size, CA 125, and CA 19-9 between borderline and benign ovarian tumors, the Mann–Whitney test was used because the data did not have a normal distribution. For comparison of the number of septa and the ratio of subjects with a solid portion, the Fisher’s exact test was used.

Multivariate analysis via logistic regression was applied to determine which MRI parameters or tumor markers were predictive factors for discriminating borderline tumors from benign ones. Receiver operating characteristic (ROC) curve analysis was performed to analyze the areas under the curve (AUCs) or optimal cutoff values of MRI parameters and tumor markers for predicting borderline tumors. Finally, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the combined MRI/CA 125 analysis for predicting borderline tumors were calculated.

Statistical analyses were performed using SPSS (version 20.0; SPSS, Inc., Chicago, IL, USA) and MedCalc (version 13.0, MedCalc Software, Mariakierke, Belgium). A P value <0.05 was considered statistically significant.

Results

Table 2 summarizes the MRI parameters and tumor markers between borderline and benign ovarian tumors. In univariate analysis, the ratio of tumors with solid portions was higher in borderline tumors than in benign tumors (67.6% versus 3.2%, respectively, P < 0.001). Both CA 125 and CA 19-9 were significantly higher in borderline tumors than benign tumors (P < 0.05). However, tumor size and septal number were not significantly different between the two groups (P > 0.05).

Table 2.

Univariate analysis of MRI parameters and tumor markers between benign and borderline ovarian tumors.

Parameter	All subjects (n = 99)			Subjects without a solid portion (n = 72)
Parameter	Benign (n = 62)	Borderline (n = 37)	P value	Benign (n = 60)	Borderline (n = 12) 12) 12)	P value
Size (cm)	14.4 (5.1–37.7)*	12.5 (5.6–36.2)	0.607	14.2 (5.1–37.7)	21.3 (8.9–36.2)	0.083
Septal number			0.267			0.047
0	16.1% (10/62)	8.1% (3/37)		16.7% (10/60)	0% (0/12)
1–4	19.4% (12/62)	10.8% (4/37)		20.0% (12/60)	0% (0/12)
≥5	64.5% (40/62)	81.1% (30/37)		63.3% (38/60)	100% (12/12)
Solid portion	3.2% (2/62)	67.6% (25/37)	<0.001	N.A.	N.A.	N.A.
CA125 (U/mL)	19.4 (4.4–232.0)	38.8 (5.1–1009.6)	0.001	19.0 (4.4–232.0)	59.7 (11.4–537.8)	0.004
CA19-9 (U/mL)	10.4 (0.1–320.0)	40.4 (0.0–1580.0)	0.021	10.4 (0.1–320.0)	31.1 (0.0–1580.0)	0.380

Data are presented as the median (range).

CA 125, carbohydrate antigen 125; CA19-9, carbohydrate antigen 19-9.

In subjects without a solid portion, the septal number and CA 125 were only significantly different between two groups (P < 0.05), while tumor size and CA 19-9 were similar (P > 0.05). The ROC curve analysis revealed the optimal cutoff values of the two significant parameters, number of septa, and CA 125, for predicting borderline tumor in subjects without a solid portion as follows: (i) septal number ≥5 (P < 0.001); and (ii) CA 125 > 44.1 U/mL (P = 0.003). With a septal number cutoff of ≥5 and of CA 125 > 44.1 U/mL, eight of 12 borderline tumors without a solid portion (66.7%) were additionally diagnosed, while there were only four false-positive cases from among 38 benign tumors without a solid portion (10.5%) (Fig. 2).

Fig 2.

MRI of two patients with an ovarian cystic mass. (a) A 35-year-old woman with a surgically confirmed borderline tumor of the right ovary. T2W axial image shows a cystic mass measuring 15.0 cm with multiseptation (more than five) in the pelvic cavity. No solid portion 0.5 cm or larger was found. The serum CA 125 and CA 19-9 levels were 72.0 U/mL and 9.6 U/mL, respectively. Combined analysis of MRI and CA 125 correctly predicted borderline tumor. (b) A 40-year-old woman with a surgically confirmed benign tumor of the left ovary. T2W axial image shows a cystic mass measuring 14.6 cm with multiseptation (more than five) in the pelvic cavity. No solid portion 0.5 cm or larger was found. Serum CA 125 and CA 19-9 were 19.1 U/mL and 10.5 U/mL, respectively. Combined analysis of MRI and CA 125 correctly predicted benign tumor.

Based on the cutoff values for septal number and CA 125 derived from ROC curve analysis, the diagnostic criteria of MRI combined with tumor markers (i.e. CA 125) for predicting borderline tumor were defined as follows: (i) the presence of solid portion; or (ii) CA 125 > 44.1 U/mL and septal number ≥5. In all patients, without combined MRI/tumor marker prediction, multivariate analysis revealed that the presence of a solid portion (odds ratio = 104.574, P < 0.001) and CA 125 (odds ratio = 1.015; P = 0.039) were significant predictors of borderline tumors (Table 3). When combined analysis of MRI with CA 125 was added to the multivariate analysis, it was only significant factor (odds ratio = 77.449, P = 0.001).

Table 3.

Multivariate analysis of MRI parameters, tumor markers, and combined MRI with CA 125 for predicting borderline ovarian tumor.

Parameter	Before combined MRI/CA 125 analysis		After combined MRI/CA 125 analysis
Parameter	Odds ratio	P value	Odds ratio	P value
Size	0.991 (0.912–1.077)	0.844	0.972 (0.855–1.104)	0.663
Septal number	2.284 (0.714–7.298)	0.163	2.120 (0.362–12.406)	0.404
Solid portion	104.574 (15.643–699.061)	<0.001	2.364 (0.095–58.495)	0.599
CA 125	1.015 (1.001–1.030)	0.039	0.988 (0.969–1.007)	0.238
CA 19-9	1.003 (0.999–1.007)	0.097	1.006 (0.998–1.013)	0.120
MRI combined with CA 125	N.A.	N.A.	77.449 (5.693–1053.490)	0.001

CA 125, carbohydrate antigen 125; CA19-9, carbohydrate antigen 19-9.

The AUC of MRI combined with CA 125 was 0.906, followed by the presence of the solid portion (AUC = 0.822), for predicting borderline ovarian tumors in all subjects (Table 4 and Fig. 3). In addition, the sensitivity, specificity, PPV, NPV, and accuracy of the combined MRI/CA 125 analysis for predicting borderline tumors were 89.1%, 91.9%, 86.8%, 93.4%, and 90.9%, respectively.

Fig 3.

ROC curves of MRI parameters and tumor markers for differentiating borderline ovarian tumors from benign tumors. Combined analysis of MRI and CA 125 had the best diagnostic performance (AUC = 0.906), followed by the presence of an enhancing solid portion (AUC = 0.822).

Table 4.

ROC curve analysis of MRI parameters and tumor markers for predicting borderline ovarian tumor in all subjects.

Parameter	Diagnostic performance
Parameter	Cutoff	AUC	Sensitivity	Specificity	P value
Size (cm)	≤26.0	0.531	94.6%	19.4%	0.599
Septum (n)	≥5	0.584	81.1%	35.5%	0.064
Solid portion	Positive	0.822	67.6%	96.8%	<0.001
CA 125 (U/mL)	>36.2	0.689	54.1%	80.6%	0.001
CA 19-9 (U/mL)	>17.8	0.639	64.9%	69.4%	0.025
MRI combined with CA 125	Positive	0.906	89.2%	91.9%	<0.001

AUC, area under the curve; CA 125, carbohydrate antigen 125; CA19-9, carbohydrate antigen 19-9.

Discussion

In our study, the presence of a solid portion (an enhancing nodular portion, or thickened septum or wall 5 mm or greater) within the mass was a powerful radiologic predictor for differentiating borderline tumors from benign tumors (AUC = 0.822). A solid portion was found in more than half of the patients with borderline ovarian tumors (67.6%) on MRI, while it was seen in only 3.2% of patients with benign tumors (P < 0.001). Thus, we can confidently suggest the possibility of borderline or more aggressive types of ovarian tumors when MRI demonstrates a solid portion within a cystic mass. However, the usefulness of this characteristic may still be limited in characterizing large ovarian cystic masses because 10–40% of borderline tumors may not exhibit a definite solid portion (11,13,14). Concordantly, for 32.4% of patients with borderline tumors in our study, a solid portion was not seen on MRI.

In the comparison between borderline and benign ovarian tumors without a solid portion, all of the patients with borderline tumors exhibited multiseptation (5 or more) (100%, 12/12; P = 0.047) and a higher serum level of CA 125 than those with benign tumors (median, 59.7 U/mL versus 19.0 U/mL; P = 0.004). Accordingly, with a septal number cutoff of ≥5 and CA 125 > 44.1 U/mL derived from ROC curve analysis, eight of 12 borderline tumors without a solid portion (66.7%) were additionally diagnosed, while there were only four false-positive cases in 38 benign tumors without a solid portion (10.5%). For this reason, two steps of analysis ((i) the presence of solid portion, or (ii) CA 125 > 44.1 U/mL and septal number ≥5) with combined MRI/CA 125 analysis showed the best diagnostic performance (AUC = 0.906) and was the only significant predictor in multivariate analysis (odds ratio = 77.449, P = 0.001). To the best of our knowledge, the current combined approach with MRI and tumor markers is the first attempt to differentiate borderline ovarian tumors from benign tumors and seems to provide good diagnostic performance (accuracy, 90.9%).

A previous study conducted by deSouza et al. reported that patients with borderline ovarian tumors had marginally elevated CA 125 (median, 45 U/mL) (11). Lenhard et al. also reported that patients with borderline ovarian tumors showed a higher CA 125 level (median, 34.7 U/mL) than healthy women (median, 13.5 U/mL) (27). Our data for 37 patients with borderline tumors were also in line with the results of deSouza et al. (median, 38.8 U/mL; range, 5.1–1009.6 U/mL). Generally, a serum level of 35 U/mL of CA 125 has been accepted as the normal upper limit (28). Thus, marginal elevation of CA 125 in patients with a multiseptated cystic mass of the ovary may be suggestive of borderline tumor.

Meanwhile, in our study, CA 19-9 was not a significant parameter in differentiating between borderline and benign tumors in cases without a solid portion (P > 0.05), although it was a significant predictor when all patients were included in analysis (borderline, 40.4 U/mL; benign, 10.4 U/mL; P = 0.021). Although CA 19-9 may be elevated in patients with mucinous types of ovarian epithelial tumors, there remains controversy regarding the utility of using CA 19-9 to characterize tumor histologic type (whether the mass is benign, borderline, or malignant) (29). Further studies with a larger population are needed.

In terms of the surgical approach for benign ovarian tumors, laparoscopic excision leads to a significant reduction in operative morbidity, hospital stay, and recovery period in comparison with laparotomy (30), thereby it is generally performed for benign tumors. Even for benign cystic masses larger than 10 cm, the use of laparoscopy allows safe excision after the aspiration of cystic content (31). However, methods such as laparoscopic cystectomy after cystic aspiration are not well established for the treatment of borderline tumors, because spilling needs to be avoided (3). From this point of view, our data may support the safety of laparoscopic cystectomy for cystic ovarian masses with few septa, but not those with a solid portion or elevated tumor markers, regardless of size. Conversely, when the combination of MRI with CA 125 suggests a high likelihood of borderline tumor, radiologists should recommend a more invasive surgical approach, such as laparotomy, to avoid understaging or tumor rupture.

Our study had several limitations. First, malignant ovarian tumors were not analyzed. Because there was clinical, radiological, and even pathological (i.e. frozen section analysis) overlap between borderline tumors and early-stage malignant tumors (11,19,32), our criteria derived from the combination of MRI with CA 125 may be limited in predicting borderline tumors. Nevertheless, the current study may be meaningful because preoperative underestimation and following insufficient surgery may be reduced with our combined analysis (4). When the lesion meets our criteria for borderline tumors, the interpretation should suggest at least borderline tumor, with the potential for malignancy. Second, tumor markers other than CA 125 or CA 19-9 were not analyzed. Researchers have reported that various markers (i.e. carcinoembryonic antigen, CA 72-4, or tissue polypeptide antigen) have shown promise as markers for borderline tumor or early-stage ovarian cancer (33 –36). The combined analysis of those laboratory markers with the current parameters may be useful for characterizing ovarian tumors. Third, the quantitative or semi-quantitative analysis with DCEI was not performed although literatures introduced its feasibility in assessing the tumor aggressiveness (37,38). However, in our study, the presence of a solid portion itself was a powerful predictor, and the quantitative or semi-quantitative analysis using a region of interest may cause the measurement error in cystic masses with only very thin septi. Finally, our study had a retrospective design. Hence, there might have been potential selection bias. However, we tried to include consecutive patients with data available on MRI, tumor markers, and surgical confirmation during the study period.

In conclusion, the combination of MRI with CA 125 may enable better differentiation between borderline and benign ovarian tumors compared with MRI or tumor markers alone by detecting borderline tumors with multiseptation and an elevated CA 125 level that do not exhibit a solid portion. Further prospective studies are required to validate our results.

Footnotes

Conflict of interest

None declared.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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