ORIGINAL RESEARCH

Growth Rate of Ovarian SerousCystadenomas andCystadenofibromasRoss P. Frederick, MD, Anika G. Patel , Scott W. Young, MD , Nirvikar Dahiya, MD,Maitray D. Patel, MD

Objectives—We analyzed growth rates of benign ovarian serous cystadenomasand cystadenofibromas to understand what percentage would show a volumedoubling time (DT) of less than 3 years, between 3 and 5 years, or greater than5 years.

Methods—We retrospectively reviewed pathology records (January 1, 2014, toJune 30, 2019) to find all surgically excised ovarian serous cystadenomas andcystadenofibromas. Imaging records were then reviewed to identify those that hadbeen confidently identified with ultrasound imaging, magnetic resonance imaging,or computed tomography at least twice before surgical removal, with at least a60-day interval between studies. Three orthogonal measurements were recordedon the first and last imaging studies on which the mass was detected, with volumecalculations by the prolate formula (product of 3 measurements multiplied by0.52). The volume DT was calculated and grouped into 1 of 5 categories: (1) DTof less than 1 year; (2) DT of 1 to 3 years; (3) DT of 3 to 5 years; (4) DT of 5 to10 years; and (5) no growth (any mass with a DT >10 years or showing adecrease in volume).

Results—A total of 102 of 536 cystadenomas and 44 of 227 cystadenofibromasmet inclusion criteria. Of the 146 tumors, 40 (27.4%) had a DT of less than1 year; 38 (26.0%) had a DT of 1 to 3 years; 22 (15.1%) had a DT of 3 to 5 years;10 (6.8%) had a DT of 5 to 10 years; and 36 (24.7%) showed no growth.

Conclusions—A total of 53.4% of ovarian serous cystadenomas/cystadenofibromas have a DT of less than 3 years; 15.1% have a DT between3 and 5 years; and 31.5% have a DT of greater than 5 years or show no growth.

Key Words—cystadenofibroma; cystadenoma; doubling time; growth rate;ovary

T he prevailing opinion regarding the management ofbenign-appearing ovarian cysts has moved to favor a moreconservative approach with periodic observation rather

than earlier surgical intervention.1–5 This conservative approach ispredicated on the recognition that non-neoplastic cysts arecommon in both premenopausal and postmenopausalpatients,6–10 and that ovarian cystadenocarcinoma does not arisefrom benign cystadenomas or cystadenofibromas.11–13 Withsurveillance, the concept is that benign ovarian neoplasms willenlarge, distinguishing them from non-neoplastic cysts, which aremore likely to be stable or resolve.6,7 This forms the basis for using2 years of ultrasound (US) follow-up as a threshold for

Received November 30, 2020, from theDepartment of Radiology, Mayo Clinic Ari-zona, Phoenix, Arizona, USA (R.P.F., A.G.P.,S.W.Y., N.D., M.D.P.). Manuscript acceptedfor publication December 2, 2020.

Supplemental material online atjultrasoundmed.org

We thank Nan Zhang, MS, for assistancewith the statistical analysis. All of the authors ofthis article have reported no disclosures.

Address correspondence to Maitray D. Patel, MD,Department of Radiology, Mayo Clinic Arizona,5777 E Mayo Blvd, Phoenix, AZ 85054, USA.E-mail: patel.maitray@mayo.edu

AbbreviationsCT, computed tomography; DT, doublingtime; MR, magnetic resonance; SRU, Soci-ety of Radiologists in Ultrasound; US,ultrasound

doi:10.1002/jum.15597

© 2020 American Institute of Ultrasound in Medicine | J Ultrasound Med 2020; 9999:1–8 | 0278-4297 | www.aium.org

distinguishing ovarian cysts that are more likely to bebenign neoplasms from ovarian cysts that are morelikely to be non-neoplastic, as articulated by the recentupdate to the Society of Radiologists in Ultrasound(SRU) consensus statement on follow-up of simpleadnexal cysts.2

It is known from longitudinal studies of otherUS-measured masses that measurement variabilitycan account for a spurious increase or decrease in themass volume in the absence of a true change.14 It hasbeen estimated that measurement variability foradnexal cysts could be as high as 10% to 15% on a

Figure 1. Flowchart of masses meeting both pathologic and imaging inclusion criteria in this study.

Frederick et al—Growth Rate of Ovarian Serous Cystic Benign Neoplasms

2 J Ultrasound Med 2020; 9999:1–8

linear basis.2 Doubling time (DT) calculation is aconventional measure of the growth rate of a massbased on size measurements at 2 points in time; itrefers to the calculated amount of time it would takefor a mass to double in volume.15–17 Based on vol-ume, an ovarian cyst that doubles in size at a rate ofevery 3 years would show a 16.7% increase in themean diameter with 2 years of surveillance, and anovarian cyst that doubles in size at a rate of every5 years would show a 9.7% increase in the meandiameter at 2 years of surveillance (assuming uniformexponential growth).15 Therefore, an ovarian cystenlarging with a DT of less than 3 years should bereadily recognized as growing with 2 years of

surveillance, since the greater than 16.7% increase indiameter should be distinguishable from technical var-iation in the measurement; on the other hand, anovarian cyst enlarging with a DT of greater than5 years would almost certainly not be recognized asgrowing with 2 years of surveillance, since the meanlinear diameter would have increased less than 9.7%over 2 years, a change that may not be distinguishablefrom technical variation in the measurement.

There are very little if any published data lookingat the growth rate of benign cystadenomas andcystadenofibromas; this paucity of data has beenhighlighted as a knowledge gap in the recent SRUconsensus statement.2 We pursued this investigation

Table 1. Doubling Times of Ovarian Serous Cystadenomas and Cystadenofibromas

PathologicDT <1 y DT 1–3 y DT 3–5 y DT 5–10 y No Growth

TotalType n % n % n % n % n % n

Cystadenoma 29 28.4 26 25.5 14 13.7 8 7.8 25 24.5 102≤50 y old 12 40.0 8 26.7 2 6.7 2 6.7 6 20.0 30>50 y old 17 23.6 18 25.0 12 16.7 6 8.3 19 26.4 72

Cystadenofibroma 11 25.0 12 27.3 8 18.2 2 4.5 11 25.0 44≤50 y old 5 33.3 2 13.3 2 13.3 1 6.7 5 33.3 15>50 y old 6 20.7 10 34.5 6 20.7 1 3.4 6 20.7 29

Combined 40 27.4 38 26.0 22 15.1 10 6.8 36 24.7 146≤50 y old 17 37.8 10 22.2 4 8.9 3 6.7 11 24.4 45>50 y old 23 22.8 28 27.7 18 17.8 7 6.9 25 24.8 101

Figure 2. Bar graph showing percentages of ovarian serous cystadenomas and cystadenofibromas in different growth rate categories.

Frederick et al—Growth Rate of Ovarian Serous Cystic Benign Neoplasms

J Ultrasound Med 2020; 9999:1–8 3

to understand the variability of the growth rate ofpathologically proven ovarian cystadenomas andcystadenofibromas. In particular, we aimed to betterunderstand how often one can expect these neo-plasms to have a DT of less than 3 years, whichshould be recognized as enlarging on a 2-year follow-up; how often these neoplasms have a DT of greaterthan 5 years, which should not be readily recognizedas enlarging on a 2-year follow-up; and how oftenthese benign neoplasms have a DT between 3 to5 years, which may be difficult to recognize as enlarg-ing on a 2-year follow-up because of potential techni-cal variability.

Materials and Methods

This retrospective study was compliant with theHealth Insurance Portability and Accountability Act,deemed to be of minimal risk without needinginformed consent, and approved by the InstitutionalReview Board. A data-mining program (Softek Illumi-nate, Overland Park, KS) was used to query all surgi-cal pathology reports in our multisite institutionaldatabase between January 1, 2014, and June 30, 2019,to identify patients with a diagnosis of ovarian serouscystadenoma or serous cystadenofibroma. Any massin which the pathologic examination showed

Figure 3. Images from a 45-year-old woman with serous cystadenoma of the left ovary with a DT of less than 1 year. Longitudinal (A) andtransverse (B) sonograms of the left ovary show a simple cyst with a thin peripheral septation measuring 7.4 cm in average diameter, with acalculated volume 185.3 cm3. Follow-up longitudinal (C) and transverse (D) sonograms obtained 127 days after the initial study show thesame cyst, now 8.5 cm in average diameter, with a calculated volume of 301.2 cm3. This represented a 62.5% increase in volume, with a cal-culated DT of 0.5 years; the mass was classified as having a DT of less than 1 year. Benign serous cystadenoma was confirmed pathologi-cally at surgical removal 46 days after the second study.

Frederick et al—Growth Rate of Ovarian Serous Cystic Benign Neoplasms

4 J Ultrasound Med 2020; 9999:1–8

coexisting ovarian invasive carcinoma, a borderlinetumor, a tumor with low malignant potential, ormucinous components was excluded. Imaging recordson patients with pathologically proven cystadenomasor cystadenofibromas were then reviewed to identifythose who had at least 2 imaging studies (pelvic USimaging with both transabdominal and transvaginalimaging, pelvic magnetic resonance [MR] imagingwith 2 planes of imaging of the pelvis with theT2-weighted technique, or pelvic contrast-enhancedcomputed tomography [CT]) greater than 60 daysapart showing the surgically removed mass. Whenmore than 2 studies showed the mass, the 2 studies

separated by the longest interval were selected for themass measurement comparison. Ultrasound examina-tions were performed with endocavitary transducersup to 9 MHz (S2000 and S3000; Siemens MedicalSolutions, Issaquah, WA; and LOGIQ 9 and LOGIQ10; GE Healthcare, Chicago, IL). Computed tomo-graphic examinations required intravenous contrastand were performed on 64-slice helical scanners withsource images at a 0.625-mm slice thickness,reconstructed in axial, sagittal, and coronal planes at3.75 mm (GE Healthcare). Magnetic resonanceexaminations were performed on 1.5-T scanners andrequired T2-weighted images of the pelvis at a 3-mm

Figure 4. Images from a 53-year-old woman with serous cystadenoma of the right ovary showing no growth. Longitudinal (A) and trans-verse (B) sonograms of the right ovary show a simple cyst measuring 3.4 cm in average diameter, with a calculated volume of 20.1 cm3.Follow-up longitudinal (C) and transverse (D) sonograms obtained 746 days after the initial study show the cyst measuring 3.2 cm in aver-age diameter, with a calculated volume of 16.2 cm3. This represented a 19.1% decrease in volume, with a calculated DT of −6.7 years; themass was classified as having no growth. Benign serous cystadenoma was confirmed pathologically at surgical removal 45 days after thesecond study.

Frederick et al—Growth Rate of Ovarian Serous Cystic Benign Neoplasms

J Ultrasound Med 2020; 9999:1–8 5

thickness in 2 orthogonal planes but did not requireintravenous contrast (GE Healthcare; Siemens Medi-cal Solutions, Malvern, PA; Phillips, Latham, NY).

After determining which 2 studies to compare, allimages from each study pair were reviewed to identify3 comparable orthogonal imaging planes on the firstand last imaging studies on which the mass wasdetected. Orthogonal measurements were obtainedby either using measurements obtained during USstudies when electronic calipers had been determinedto have been placed accurately or using measurementsperformed on the picture archiving and communicationsystem workstation using the most representativeimages (when electronic calipers had not been placed,had not been placed accurately, or when using CT orMR images), ensuring a similar measuring techniqueon both studies with respect to anatomic landmarksand sonographer labeling. To ensure consistency, a sin-gle observer (R.P.F.) made each measurement for eachpaired set of studies. Volume calculations were madeby the prolate formula (product of 3 measurementsmultiplied by 0.52). Volume DTs were calculated by anequation based on a modified Schwartz formula of anexponential growth model, which has been used in pre-vious published imaging studies15–17: DT(days) = [ln2 × ΔT]/[ln(V2/V1)], where V2 and V1are the final and initial volumes, respectively, and ΔT(days) is the interval between the 2 imaging studies.The volume DT was expressed in years and groupedinto 1 of 5 categories: (1) DT of less than 1 year;(2) DT of 1 to 3 years; (3) DT of 3 to 5 years; (4) DTof 5 to 10 years; and (5) no growth (any mass with aDT >10 years or showing a decrease in volume). TheFisher exact test was used to statistically evaluatewhether the DT categories differed betweencystadenomas and cystadenofibromas, with statisticalsignificance set at P = .05.

Results

There were 536 ovarian serous cystadenomas and227 ovarian serous cystadenofibromas surgically excisedin 5.5 years. Of these excised masses, 102 cystadenomasand 44 cystadenofibromas in 134 women (mean,57 years; median, 59 years; range, 18–87 years) metthe imaging inclusion criteria (Figure 1). Imaging stud-ies used to evaluate growth consisted of paired US

examinations for 116 masses, US and CT for19 masses, US and MR imaging for 6 masses, CT andMR imaging for 2 masses, paired MR imaging for2 masses, and paired CT for 1 mass. The mean andmedian intervals between the first and last studiesshowing the mass were 727 and 456 days, respectively(range, 66–5196 days). The largest mean mass diame-ter was 4.8 cm on the first study (median, 4.2 cm;range, 1.0–12.6 cm); the largest mean diameter was6.2 cm on the last study (median, 5.4 cm; range,1.6–18.7 cm). The mean mass volume was 77 cm3 onthe first study (median, 24 cm3; range, 1–1035 cm3);the mean volume was 158 cm3 on the last study(median, 46 cm3; range, 2–3245 cm3).

Table 1 and Figure 2 show the distribution ofgrowth rates for the 102 cystadenomas and44 cystadenofibromas for the entire cohort and sub-divided by 50 years of age as a proxy for menopause;there was no significant difference in the distributionof growth rates between the pathologic types(P = .938). Online supplemental Appendix 1 showsthe mathematical relationship between the percentchange in the mean diameter and the observationinterval on the calculated DT based on the modifiedSchwartz formula, to put the DT in a more practicalcontext. A total of 27.4% of all tumors (40 of 146)had a DT of less than 1 year (Figure 3); 24.7% of alltumors (36 of 144) were classified as having nogrowth (Figure 4), with 20.1% (29 of 144) of allserous tumors showing a decrease in size on the laststudy compared to the first (mean, 8% decrease inaverage diameter; range, 1%–23% decrease).

Discussion

The premise of periodic follow-up of benign-appearingovarian cysts is rooted in the notion that a neoplasmwould have a propensity to enlarge over time, whereasa non-neoplastic cyst would be more likely to be sta-ble, get smaller, or resolve over time.6 If a benign-appearing ovarian cyst was enlarging over periodicfollow-up, one might reasonably conclude that the cystis more likely to be a benign neoplasm (cystadenomaor cystadenofibroma) rather than a non-neoplastic cystand manage the mass accordingly. To this end, theSRU updated the 2019 consensus conference recom-mendations, articulating an approach in which simple

Frederick et al—Growth Rate of Ovarian Serous Cystic Benign Neoplasms

6 J Ultrasound Med 2020; 9999:1–8

adnexal cysts over specified size thresholds are man-aged conservatively, aiming for 2 or possibly 3 follow-up studies over the 2 years after initial characterization,to make a conclusion as to whether the cyst is enlarg-ing.2 Although the SRU recommendations were gearedtoward simple ovarian cysts, the rationale and algo-rithm for conservative observation and periodic follow-up could arguably apply equally well to possible benignovarian serous cystadenomas and cystadenofibromas,which are not simple cysts.

What has not been well studied previously,however, is what fraction of benign ovarian neoplasmscan be expected to show an increased size in a 2-yeartime frame. In the 2019 SRU update, the absence ofliterature on the growth rate of benign ovarian cysticneoplasms was identified as an important knowledgegap.2 Our study addresses this gap and shows that asubstantial proportion of ovarian masses that prove tobe pathologically classified as benign serous ovarianneoplasms grow very slowly, if at all. In this regard, theSRU algorithm regarding conclusions that can be madeafter 2 years of “stability” of an adnexal cyst is pre-scient in articulating that such a cyst without demon-strable enlargement over 2 years is “either a non-neoplastic cyst or an indolent benign neoplasm.”2

This begets an even more fundamental questionabout whether all masses that are pathologicallyshown to be ovarian serous cystadenomas orcystadenofibromas are even really neoplasms at all.There is increasing evidence that suggests that manyserous cystadenomas and cystadenofibromas are mis-classified as neoplastic, actually representing a type ofnon-neoplastic cyst.11 This is supported by theabsence of substantial epithelial proliferation beyondthat which can be considered reactive in most ofthese tumors, as well as evidence that most of thesetumors are polyclonal.18 Invasive ovarian serouscystadenocarcinoma is now well understood to beunrelated to so-called ovarian cystadenomas andcystadenofibromas, as the former arises from cellsoriginating in the fallopian tube.12 Our observationthat approximately 20% of masses with the pathologicdiagnosis of serous cystadenoma or cystadenofibromameasured smaller on extended follow-up (mean, 8%smaller in diameter) than when initially characterizedalso supports the idea that many of these tumors maynot be neoplastic, since size reduction without ther-apy is hardly typical for other neoplasms, allowing for

the limitation that a small apparent size reductioncould just reflect measurement variability.

Periodic surveillance of benign-appearing ovariancysts can serve 2 main purposes: (1) reduce the possi-bility that more sinister findings in the mass thatwould be suggestive of possible malignancy, such aswall nodules, were not overlooked or underestimatedon the initial evaluation; and (2) understand whetherthe mass is progressively enlarging such that it mayaccount for symptoms or be expected to lead tosymptoms over time.2 However, our study indicatesthat follow-up may not be able to distinguish betweena cyst that would be classified as a benign neoplasmunder the existing pathologic classification paradigmversus a cyst that is pathologically designated as non-neoplastic. Understanding that 31.5% of serouscystadenomas and cystadenofibromas either grow tooslowly to be recognized as enlarging with 2 years offollow-up or do not meaningfully grow at all helpsput the conclusions one can make after 2 years of sur-veillance in context, even if it does not affect patientoutcomes regardless of whether the mass that is notgrowing is neoplastic.

This study had a number of important limitations.We do not know whether ovarian cystadenomas andcystadenofibromas inherently show spurts of growth,as we used a method that assumes continuous constantexponential growth over time. Although discontinuousgrowth is not a phenomenon that has been shownto be common with other benign neoplasms, ifcystadenomas and cystadenofibromas have periods of agrowth spurt and other periods of quiescence, then wemay underestimate or overestimate the growth rate ifour period of observation for any given mass reflects agrowth spurt or quiescence. Even if not discontinuous,the growth rate of these tumors may decrease overtime as the mass enlarges and has less relative bloodflow to support growth. The true growth rate of eachmass in our study was subject to error based on inher-ent measurement variability. There was almost cer-tainly some degree of intraobserver variability thatcould have affected the accuracy of the calculatedgrowth rate for any ovarian mass in our study(in which a single observer assessed all measurements),and there is almost certainly interobserver variabilitythat would affect the determination of the growth ratefor any ovarian mass in clinical practice. Having saidthat, this reflects standard clinical practice and would

Frederick et al—Growth Rate of Ovarian Serous Cystic Benign Neoplasms

J Ultrasound Med 2020; 9999:1–8 7

likely not be unidirectional in terms of impact (meaningthis error should not cause all masses to appear to growfaster or slower and so is unlikely to substantially changethe distribution of masses in each of our broad catego-ries). Another limitation of our study was the use of CTor MR imaging to establish mass dimensions at 1 orboth time points for 30 of the 146 masses (20.5%),although the technical parameters we used for thesestudies should have limited inaccuracies due to theslice thickness and volume averaging. Finally, the numberof masses on which we made our observations wasmodest.

Despite these limitations, we conclude that thegrowth rate of ovarian serous cystadenomas andcystadenofibromas is variable, with slightly more thanhalf of masses (53.4%) showing enlargement thatshould be readily recognized with 2 years of follow-up (DT <3 years) and with nearly a third of masses(30.5%) showing minimal growth or even a decreasein size that would not be considered enlargementwith 2 years of surveillance (DT >5 years or nogrowth). This understanding helps begin to close theknowledge gap that exists regarding the growth rateof these so-called neoplasms.

References

1. Patel MD, Ascher SM, Horrow MM, et al. Management of inci-dental adnexal findings on CT and MRI: a white paper of theACR Incidental Findings Committee. J Am Coll Radiol 2020; 17:248–254.

2. Levine D, Patel MD, Suh-Burgmann EJ, et al. Simple adnexalcysts: SRU consensus conference update on follow-up andreporting. Radiology 2019; 293:359–371.

3. American College of Obstetricians and Gynecologists. PracticeBulletin No. 174: evaluation and management of adnexal masses.Obstet Gynecol 2016; 128:e210–e226.

4. Gonzalez DO, Minneci PC, Deans KJ. Management of benignovarian lesions in girls: a trend toward fewer oophorectomies. CurrOpin Obstet Gynecol 2017; 29:289–294.

5. Guraslan H, Dogan K. Management of unilocular or multilocularcysts more than 5 centimeters in postmenopausal women. Eur JObstet Gynecol Reprod Biol 2016; 203:40–43.

6. Patel MD. Practical approach to the adnexal mass. Radiol ClinNorth Am 2006; 44:879–899.

7. Sarkar M, Wolf MG. Simple ovarian cysts in postmenopausalwomen: scope of conservative management. Eur J Obstet GynecolReprod Biol 2012; 162:75–78.

8. Modesitt SC, Pavlik EJ, Ueland FR, DePriest PD, Kryscio RJ, vanAngell NJR. Risk of malignancy in unilocular ovarian cystic tumorsless than 10 centimeters in diameter. Obstet Gynecol 2003; 102:594–599.

9. Nardo LG, Kroon ND, Reginald PW. Persistent unilocular ovariancysts in a general population of postmenopausal women: is there aplace for expectant management? Obstet Gynecol 2003; 102:589–593.

10. Valentin L, Skoog L, Epstein E. Frequency and type of adnexallesions in autopsy material from postmenopausal women: ultra-sound study with histological correlation. Ultrasound Obstet Gynecol2003; 22:284–289.

11. Seidman JD, Mehrotra A. Benign ovarian serous tumors: a re-evaluation and proposed reclassification of serous “cystadenomas”and “cystadenofibromas.”. Gynecol Oncol 2005; 96:395–401.

12. Erickson BK, Conner MG, Landen CN Jr. The role of thefallopian tube in the origin of ovarian cancer. Am J Obstet Gynecol2013; 209:409–414.

13. Parazzini F, Frattaruolo MP, Chiaffarino F, Dridi D, Roncella E,Vercellini P. The limited oncogenic potential of unilocular adnexalcysts: a systematic review and meta-analysis. Eur J Obstet GynecolReprod Biol 2018; 225:101–109.

14. Brauer VF, Eder P, Miehle K, Wiesner TD, Hasenclever H,Paschke R. Interobserver variation for ultrasound determination ofthyroid nodule volumes. Thyroid 2005; 15:1169–1175.

15. Schwartz M. A biomathematical approach to clinical tumorgrowth. Cancer 1961; 14:1272–1294.

16. Song YS, Park CM, Park SJ, Lee SM, Jeon YK, Goo JM. Volumeand mass doubling times of persistent pulmonary subsolid nodulesdetected in patients without known malignancy. Radiology 2014;273:276–284.

17. Li J, Xia T, Yang X, et al. Malignant solitary pulmonary nodules:assessment of mass growth rate and doubling time at follow-upCT. J Thorac Dis 2018; 10:S797–S806.

18. Cheng EJ, Kurman RJ, Wang M, et al. Molecular genetic analysisof ovarian serous cystadenomas. Lab Invest 2004; 84:778–784.

Frederick et al—Growth Rate of Ovarian Serous Cystic Benign Neoplasms

8 J Ultrasound Med 2020; 9999:1–8