Significance of Pelvic Fluid Observed during Ovarian Cancer Screening with Transvaginal Sonogram

1. Introduction

Ovarian cancer continues to be the most lethal gynecological cancer with most patients facing a diagnosis of late stage metastatic disease that is associated with a five-year survival of only 30%. While the lifetime risk of ovarian cancer is less than breast cancer, it has a death-to-incidence ratio that is three to four times more than breast cancer [1,2,3]. Ovarian cancer can arise from the ovary as well as the fallopian tube [4,5,6,7,8,9,10,11] and occur as five major histological subtypes (high-grade serous, low-grade serous, endometrioid, clear cell, and mucinous) that have been explored by immunochemical, genetic, and homologous recombination approaches [12]. Deleterious mutations in DNA repair genes can drive defective homologous recombination and are emerging biomarkers of sensitivity/insensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors which interfere with the ability of PARP to repair treatment-mediated DNA damage in cancer cells [13]. Despite technically advanced treatment strategies in precision medicine and immunotherapy, long-term durable treatment responses have not yet been achievable [14,15]. However, long-term survival rates that are greater than 90% in women with stage I ovarian cancer have focused on an advocacy for screening efforts to detect early-stage disease [16].

Transvaginal ultrasonography (TVS) is a safe, minimally invasive [17] and cost-effective [18,19] modality that allows the visualization of echogenic structures and non-echogenic fluid. TVS has been used as a major modality in four major screening trials for ovarian cancer including the Kentucky Ovarian Screening (KYOVS) trial [18,20], the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial [21], the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) [22,23], and the Shizuoka Cohort Study of Ovarian Cancer Screening (SCSOCS) trial [24]. The reported findings from these studies are summarized in Table 1. Routine TVS can identify free fluid in the abdomen or pelvis. Of the four major ovarian cancer screening trials that utilized TVS, none examined the degree to which free fluid is associated with malignancy. Consequently, there are no clear guidelines on the recommended management of free fluid incidentally identified during a gynecologic ultrasound. Historically, physicians performed culdocentesis to sample fluid in the pouch of Douglas [25], but this has been replaced by ultrasound-guided paracentesis. Clinical guidelines are even less clear on how to manage small-volume pelvic fluid collections.

In this report, we examined the frequency and duration of free fluid during TVS exams in a large screening population and correlated the findings with the patient diagnosis. Our primary objective was to determine if free fluid provides additional information in predicting ovarian malignancy compared to ultrasound alone.

2. Materials and Methods

3. Results

Since 1987, the University of Kentucky Ovarian Screening Program has performed 326,998 TVS screens on 48,925 women. We observed free fluid in 2001 (4.1%) of those encounters. TP screens included 78 ovarian malignancies (13 fluid-positive, 16.7%), 20 tumors of a low malignant potential (two fluid-positive, 10%), and 23 malignancies of a non-ovarian origin (three fluid-positive, 13%). Only one of the TP cases was observed to have fluid present in a prior normal TVS exam. There were 614 FP screens classified as high risk for ovarian cancer but found to have benign pathology (31 fluid-positive, 5%). Nine of these cases occurred in a prior normal TVS examination. The TN screens included 41,996 cases that screened negative for malignancy and did not develop ovarian carcinoma (1948 fluid-positive (4.6%): 1071 fluid-positive cases were associated with a normal TVS examination, while 877 were associated with an abnormal TVS examination). There were 21 cases of ovarian cancer diagnosed within 12 months of an FN TVS scan (four fluid-positive, 19%). All of these cases occurred in the absence of an abnormal TVS exam.

4. Discussion

Abdominopelvic ascites is a well-known sign of advanced ovarian, fallopian tube, or peritoneal malignancy, but the importance of free fluid during screening or diagnostic ovarian TVS is less evident. The findings of our investigation confirmed an association between free fluid identified on ovarian TVS and ovarian malignancy. To predict ovarian malignancy, the ADNEX model (Assessment of Different NEoplasias in the adneXa) created by the European International Ovarian Tumour Analysis study group considers nine variables in a polytomous prediction to categorize malignant risk [27,28]. The ADNEX model does not include pelvic fluid as a variable, nor does the Risk of Malignancy Index, or the Risk of Ovarian Malignancy Algorithm [29,30,31,32,33,34]. The University of Kentucky Morphology Index acknowledges fluid as a risk factor, particularly when associated with complex tumors [35]. Our study results support this conviction, as the presence of free fluid was highly associated with the diagnosis of ovarian malignancy (PR_TP = 36.14; OR_FN = 40.48). This is in keeping with the evidence that potentially malignant ovarian tumors become morphologically more complex as they progress toward malignancy over time [36]. Rarely, pelvic fluid may be the only early sonographic feature of gynecologic malignancy. Including free fluid as a risk variable for ovarian malignancy has the potential to improve detection sensitivity by reducing FN results.

The results reported here indicated that the presence of fluid is highly probable in cases of frank ovarian malignancy and less so in cases of benign findings and LMP tumors. The authors appreciate that free fluid is present in many benign conditions, including hemorrhagic cysts, fibromas, endometriomas, and ruptured serous or mucinous cystadenomas. However, our results showed a statistically less frequent association of free fluid in benign tumors versus ovarian malignancy (PR = 12.16 vs. PR = 36.14; p < 0.05). For non-malignant cases, more than half (56.7%) of the TN screens had fluid present for one encounter, 9% for more than three, and 1.4% for more than 10 encounters. Thus, our data indicates that free fluid mostly disappears in non-malignant scenarios if serially monitored. Because of this observation, it can be asked if fluid might be due to follicular fluid entering the peritoneal cavity during ovulation. This possibility is unlikely, because premenopausal TN screens were similarly low in the observation of fluid as postmenopausal cases (Figure 1 A–L). In addition, the six TP cases that were premenopausal at diagnosis were negative for fluid. We recommend serial surveillance with TVS, until a malignant morphology is suspected or the fluid resolves. Speculation on the source of fluid associated with malignant cases could include the leakage of cyst fluid from ovarian cysts containing malignancy as an explanation for fluid observed in the adnexa.

Only a few studies have reported the presence of pelvic fluid in investigations of ovarian cancer. An underpowered study of 17 women evaluated an intra-ovarian blood flow with 3-dimensional power Doppler ultrasound before surgical intervention in women suspected of having ovarian carcinoma [37] and found no difference in pelvic fluid for women with (16.7%) or without ovarian malignancy (18.2%; p = 0.938). Another study of 60 women with histologically confirmed primary peritoneal cancer investigated disseminated peritoneal carcinomatosis using TVS and documented the presence of free pelvic fluid [38]. Given the advanced stage of disease at inclusion, it is not unexpected that the study found 83% of women had free fluid present in the pelvic cul-de-sac. Lastly, investigators studied free pelvic fluid with magnetic resonance imaging (MRI) in women with ovarian tumors. Eighty-seven women underwent surgery for pelvic tumors of unknown malignant potential. Preoperative MRI indicated that the presence of large peritoneal fluid pockets is moderately predictive of malignancy or peritoneal spread of the tumor [39]. Despite this, the recent American College of Radiology Ovarian-Adnexal Reporting and Data System did not include fluid as a variable in the scoring algorithm for sonographically indeterminate adnexal masses [40,41].

This study has several strengths. These data resulted from a substantial cohort of patients all screened in one program where operations and techniques were well standardized. Throughout this study, the same Director of Research, Edward J. Pavlik (PhD) provided consistent oversight and the same clinician, John R. VanNagell Jr., (MD) reviewed all TVS scans. Lastly, it is relatively easy to identify free fluid on pelvic ultrasound because of the inherent contrast between water-dense fluid and pelvic soft tissue.

There are also some study limitations. First, sonographers did not quantify the volume of the pelvic free fluid on all studies. As a result, we included those with recorded fluid volumes and test entries indicating fluid, possible fluid, ascites, and possible ascites. This approach may have underestimated the number of subjects who had pelvic fluid present, because it was not a required outcome measure. Since the peritoneal cavity contains typically 50–75 mL of physiologic fluid that serves to lubricate the abdominal wall and viscera [42,43,44], some fluid-positive cases may be a result of the pooling of this physiologic fluid. In addition, because the views obtained in this screening study were limited to the ovaries, it is possible that abdominal fluid above the pelvic brim or less likely fluid in the pouch of Douglas may not have been observed, especially since the size of the uterus varied in each individual [45]. Lastly, some demographic variables showed small statistical differences between TN fluid-positive and -negative subgroups contributing to potential bias.

5. Conclusions

Pelvic fluid identified during TVS screening is associated with ovarian malignancy and should not be disregarded. The presence of free fluid during TVS should heighten awareness for malignancy, particularly for an ovarian tumor with a high-risk morphology. When free fluid associated with benign ovarian tumors is present for more than one encounter, half of the cases resolve within 24 months. Since free fluid is associated with ovarian malignancy, we recommend serial ultrasound surveillance, until a malignant morphology is suspected or the fluid resolves.

Author Contributions

Conceptualization, E.J.P., J.R.v.N.J. and C.S.D.III; methodology, E.J.P. and J.W.G.; software, E.J.P. and J.W.G.; validation, E.J.P. and C.S.D.III; formal analysis, E.J.P. and J.W.G.; investigation, C.D., L.E., H.D. and N.J.P.; resources, E.J.P. and J.R.v.N.J.; data curation, E.J.P.; writing—original draft preparation, J.W.G. and E.L.F.; writing—review and editing, E.J.P., F.R.U., C.S.D.III, A.B.M., M.J.R., M.L.H., L.A.B.-B., R.W.M., C.P.D., H.H.G. and J.R.v.N.J.; visualization, J.W.G.; supervision, E.J.P., J.R.v.N.J., F.R.U. and C.S.D.III; project administration, E.J.P.; funding acquisition, J.W.G., E.J.P. and J.R.v.N.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partially funded by the National Cancer Institute (grant number: T32 CA160003).

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the University of Kentucky (88-GYN-I3 Transvaginal Ultrasonography As a Screening Method for Ovarian Cancer, IRB #45030, renewed on 3 December 2021).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

The data presented in this study are available on request from the corresponding author. The data are not publicly available due to the concern for infringement on research subjects’ privacy.

Acknowledgments

The authors would like to acknowledge the principal investigator B. Mark Evers, who is responsible for the acquisition of National Cancer Institute T32 funding which helped partially support this project.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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