Uterine fibroids reduce the sensitivity of ultrasound to detect endometrioid and serous endometrial cancer: a retrospective cohort study

Introduction

Endometrial cancer (EC) is the most common gynecologic cancer in the United States, and annual incidence is increasing with 69,120 new diagnoses in the year 2025 (1-3). Five-year survival of EC shows one of the most striking cancer survival disparities by race, with 64% non-Hispanic Black individuals surviving compared to 86% non-Hispanic White individuals (3). Aggressive histologic subtypes that spread more rapidly are more commonly diagnosed in Black people. Stage at diagnosis (the strongest possibly modifiable prognostic factor) is estimated to account for 33% of the 5-year survival disparity by race controlling for histology (4). Besides Medicaid expansion, little progress has been made in reducing EC stage at diagnosis (5,6). Given the increasing attention on the potential impact of diagnostic timeliness in EC stage (7), a simulated cohort of Black women, accounting for fibroid prevalence, reported that the negative predictive value of thin (4 mm) endometrium (EM) on transvaginal ultrasound (TVUS) with EC was only 91.7% (vs. >99% as previously believed) (8,9). A diagnostic challenge associated with fibroids may be particularly relevant for diagnosing non-endometrioid EC subtypes (serous being the most common of these), as these subtypes do not typically arise from a background of hyperplasia like endometrioid EC potentially increasing the likelihood of being obscured by fibroids (1,10).

The gold standard for assessing the EM is tissue sampling (11) which is sensitive across EC subtypes (12). TVUS is a guideline-concordant alternative for evaluation of an initial episode of postmenopausal bleeding (PMB) with a negative predictive value of >99% when the EM is ≤4 mm and can be completely evaluated (9). Of note, the studies that informed this guideline included predominantly White populations and either excluded or did not quantify incidence of non-endometrioid histologies in their study populations (13-16). Nondiagnostic TVUS should not cause significant diagnostic delay in a guideline-concordant practice, but guideline-concordant diagnostic practices are less commonly employed for Black than White people (70% vs. 79%, respectively) (17). Thus, fibroids, which also disproportionately impact Black people (18), may contribute to disparate diagnostic delays, though this has not been demonstrated in a non-simulated population. Given our diverse population with high rates of non-endometrioid EC, we sought to determine if fibroids impacted the timeliness of diagnosis of serous compared to endometrioid EC. We present this article in accordance with the STROBE reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-34/rc).

Methods

A retrospective cohort was created with the Montefiore Einstein Cancer Center Tumor Registry which identified medical record numbers for electronic chart review. Serous and endometrioid histologies alone were included because of the relative paucity of literature comparing ultrasound features between non-endometrioid histologies, and therein the value of making a focused and specific comparison of TVUS features.

All cases of serous EC diagnosed between January 2012 and October 2022 were included for review with an equally sized comparator group of endometrioid EC that was created by random selection of cases in the same calendar years. Exclusion criteria included missing information on the date or location of presentation, missing information on the date of diagnosis, absence of TVUS as part of evaluation, or unavailability of the TVUS report for review by study personnel. Sociodemographic data were collected for those excluded to assess for inclusion bias. Data were obtained through duplicate chart review by two different authors to ensure accuracy. Radiographic data were obtained through review of the study reports.

Since serous EC may not arise from a background of hyperplasia, TVUS reports were assessed for endometrial thickening as well as other suspicious features. Suspicious features included (19,20): abnormal endometrial vascularity, myometrial mass (not specifically described as a uterine fibroid), adnexal mass with malignant features, free fluid more than minimal/mild. For postmenopausal people, additional suspicious features included endometrial echo complex (EEC) >4 mm in thickness, intracavitary fluid, or focal endometrial or intracavitary lesion. Focal suspicious features were defined as the above except for the diffuse findings of thickened EM or abnormal free fluid. In the absence of a validated method of defining fibroid burden as it relates to EM visibility on TVUS, to define larger fibroid burden, the greatest diameter of each fibroid was summated, and those with total fibroid diameter >5 cm were estimated to have fibroid burden that could plausibly impede TVUS measurement of the EEC or success of EMB. Those with no fibroids were included in the category with low fibroid burden. This definition of larger fibroid burden was tested with area under the curve (AUC) comparisons of prediction for visualized EM and was considered clinically appropriate per discussion with an expert in gynecologic sonography (author O.D.R.).

The secondary outcome was diagnostic timeliness. The start of the diagnostic interval was defined as the date that the patient presented for EC symptoms, presented for care of another complaint or for primary care without complaint at which point findings concerning for EC were identified. The diagnostic interval ends when the biopsy that first diagnoses of cancer is obtained, or when imaging is obtained that is suspicious enough to proceed with treatment. A diagnostic interval greater than 4 weeks was considered delayed, as 4 weeks is generally sufficient to receive an outpatient TVUS appointment and return for biopsy in this hospital system. For those with imaging before biopsy, time from imaging until first biopsy attempt was considered delayed if greater than 2 weeks.

Area deprivation index was used to estimate socioeconomic status from zip codes (21).

Statistical analysis

The minimum sample to assess sensitivity of TVUS to detect EC was calculated to be 20 observations for each of the two categories of fibroid burden for a two-tailed hypothesis with significance level of 0.05 and power of 0.80, with estimated standard deviation and delta based on prior literature (8). The study was not powered for secondary outcome analysis. Univariate analysis was completed with Fisher’s exact tests for categorical data and Student’s t-test for continuous variables. The P value cutoff was 0.05. Multivariate logistic regression was used to model dichotomous outcomes. Stata/IC 16.1 (StataCorp, College Station, TX) was used for data analysis.

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Montefiore Medical Center and the Albert Einstein College of Medicine (#11-10-352E). Individual consent for this retrospective analysis was waived.

Results

Of the 620 charts reviewed, 330 met eligibility criteria. Approximately 61% had a fibroid burden ≤5 cm (n=201), while 39% had a fibroid burden >5 cm (n=129) (Figure 1). Thirty individuals had no fibroids noted on TVUS. There were no statistically significant differences in sociodemographics between those who met eligibility criteria and those who did not (P>0.05). Serous EC was diagnosed in 31.8% of those with fibroids ≤5 cm and 55.0% of those with fibroids >5 cm [95% confidence interval (CI): 2.0–4.1, P<0.001]. There were no statistically significant differences between fibroid burden and age or body mass index (BMI) (Table 1).

Figure 1 Cohort selection. Serous EC with randomized selection of endometrioid EC diagnosed in the study timeframe totaled 620. Applying exclusion criteria eliminated 290 records. There were a total of 330 records meeting eligibility criteria. EC, endometrial cancer; TVUS, transvaginal ultrasound; US, ultrasound.

As anticipated, those with higher fibroid burden had a statistically significantly higher burden of social barriers to health, with higher prevalence of Black race as proxy for exposure to racism (58.9% vs. 30.4%), and higher area deprivation index (62.0% vs. 48.8%). Differences in insurance status or prior contact with a primary care provider in the year before diagnosis were not statistically significant. Factors anticipated to impact evaluation timeliness were not significantly different (P>0.05) between fibroid burden groups, including stage of disease at presentation, presence of PMB at presentation, and whether initial presentation was to the emergency department or clinic (Table 1).

When comparing TVUS features between histologies, a higher percentage of serous than endometrioid EC had any suspicious feature (97.0% vs. 86.1%, P<0.001) and abnormal free fluid specifically (11.1% vs. 3.1%, 95% CI: 1.4–12.5, P=0.005). There was no statistically significant difference between serous and endometrioid EC in other individual suspicious features including EM >4 mm (86.1% vs. 92.0%, P=0.14), focal EM lesion (45.9% vs. 41.5%, P=0.43), intracavitary fluid (31.1% vs. 25.6%, P=0.31), non-fibroid myometrial mass/irregularity (10.4% vs. 16.4%, P=0.14), adnexal mass with malignant features (7.9% vs. 4.5%, P=0.29) (Table 2). Notably, among those diagnosed with EC despite TVUS without suspicious features (serous n=13, endometrioid n=11), all reported PMB.

Individuals with a larger fibroid burden had EM visualized in 15.9% fewer cases (73.8% vs. 89.7%, P<0.001), identification of thickened EM in 3.6% fewer cases (87.5% vs. 91.1%, P=0.40), identification of any TVUS feature suspicious for malignancy in 10.9% fewer cases (86.1% vs. 97.0%, P<0.001), and identification of focal TVUS features suspicious for malignancy in 14.6% fewer cases (48.1% vs. 62.7%, P=0.01). Among the 30 individuals with no fibroids, the sensitivity to detect any TVUS suspicious for malignancy was 100%.

Non-visualized EM (n=53, 16.2%) was associated with total fibroid diameter >5 cm [adjusted odds ratio (aOR) 0.99, 95% CI: 0.36–1.61, P=0.002] though not reaching statistical significance, and inversely associated with BMI ≥35 kg/m² (aOR −1.15, 95% CI: −2.06 to −0.25, P=0.01), adjusting for fibroids, EC stage, and BMI (Table 3). Variables with significant univariate association with non-visualized EM and those with a presumed association based on prior literature were considered for the multivariate model. Uterine size was not included given close co-variance with fibroid burden. Disease stage was included instead of histology under the theory that stage would mediate the impact of histology on EM visualization. Too few have axial EM to include this variable in the model for visualized EM. TVUS reports did not routinely document whether the EM was isoechoic with the myometrium and thus was not included in the model.

If total fibroid diameter ≤5 cm, sensitivity was 96.9% for serous EC and 97.1% for endometrioid EC, reduced to 84.5% for serous EC and 87.9% for endometrioid EC if total fibroid diameter >5 cm, 12.4% and 9.2% lower for serous and endometrioid EC, respectively (P=0.02).

Regarding the secondary objective of assessing care delays, those with larger fibroid burden had no statistically significant difference in having >2 weeks from TVUS until first biopsy attempt or >4 weeks from presentation until diagnosis (Table 1). Neither measure of care delay was significantly associated with fibroid burden, visualization of the EM on TVUS, any suspicious TVUS features identified, or with race, ethnicity, preferred language, or BMI.

Endometrial polyps were the only ultrasound feature significantly associated with time >2 weeks from TVUS to first biopsy attempt. Those with polyps noted on TVUS reports were more likely to receive hysteroscopy rather than pipelle EM biopsy (29.0% vs. 8.8%, P=0.002) which was associated with waiting an average of 4 weeks longer for biopsy (4.4 vs. 8.4 weeks, P=0.003). There were too few TVUS without any suspicious features to compare diagnostic time with vs. without suspicious features.

Discussion

Principal findings

In this retrospective cohort study of serous and endometrioid EC cases, individuals with a larger fibroid burden had a 15.9% fewer cases with visualized EM (P<0.001). Larger fibroid burden was also associated with 10.9% fewer cases with identification of any TVUS feature suspicious for malignancy (P<0.001). Non-visualized EM (16.2% of TVUS) was inversely associated with BMI ≥35 kg/m² (aOR −1.15, 95% CI: −2.06 to −0.25, P=0.01) and non-statistically significantly associated with total fibroid diameter >5 cm (aOR 0.99, 95% CI: 0.36–1.61, P=0.002) adjusting for fibroids, EC stage, and BMI. Larger fibroid burden reduced the sensitivity of TVUS to detect any feature suspicious for malignancy 3.2% more for serous than endometrioid histology (P=0.02). No statistically significant associations were observed between diagnostic delays and fibroid burden or sociodemographic characteristics.

Results in the context of what is known

To our knowledge, this is the first study to assess the impact of fibroid burden on sensitivity of TVUS to detect features of EC in a real-world patient population. Consistent with prior literature, we found that our Black patients were more likely to have aggressive non-endometrioid and advanced stage EC, and more likely to have larger fibroid burden (1,22). This study also demonstrated the predicted association between fibroids and non-visualized EM on TVUS by using a novel and easily ascertained estimation of fibroid burden.

Given the paucity of literature on TVUS characteristics of serous EC, it was beneficial to describe TVUS findings of serous EC in this cohort. Population differences between this and prior studies preclude direct comparison of results but allow this study to add important diversification of knowledge on TVUS in serous EC. Compared to prior literature, our cohort is larger (with the largest prior study n=58 vs. n=135 in our cohort), with more specific pathology (prior studies included all non-endometrioid EC without histologic subdivision), with more advanced stage disease (33–39.7% vs. 50.8%), and more diverse patient population (Black race 3.5% in the study that reported race vs. 62.2% in our cohort) (19,20). These studies reported comparatively lower prevalence of thickened EM (in these studies defined as >5 mm, 65.4–75.0% vs. 80.2% EM >5 mm for serous EC in this cohort), focal EM lesions (11.5–31.0% vs. 45.9%), intracavitary fluid (7.7–12.1% vs. 31.1%), enlarged uteri (defined as >8 cm, 25.0–53.5% vs. 77.5%) (19,20). The percentage with indistinct EEC was similar (17.3–27.6% vs. 25.2%), and percentage with myometrial masses was lower (31–44.2% vs. 82.2%).

Clinical implications

We have identified a potential care quality gap for those with larger fibroid burden and populations with higher prevalence of non-endometrioid EC. Caution and a lower threshold for endometrial sampling may be necessary when evaluating whether TVUS adequately visualizes EM to reassure individuals with PMB and fibroids.

Despite the limitations of TVUS to detect serous EC with a comorbid larger fibroid burden, we found that TVUS was especially important in identifying serous EC in cases where patients presented without PMB (18.7% vs. 7.6% endometrioid EC) but with pain (38.7% vs. 27.7% endometrioid EC) or ascites-related symptoms (14.2% vs. 3.6% endometrioid EC) and received a TVUS as part of a general initial evaluation that identified a suspicious feature that prompted endometrial sampling. We also found that the percentage with thickened EM vs. any suspicious feature was 4.3% lower for serous and 2.4% lower for endometrioid EC, which supports a thorough assessment of TVUS in the setting of PMB, although this study was not designed to assess the positive predictive value of alternate TVUS findings.

Research implications

This study has described the sensitivity of TVUS to detect features of EC in the setting of larger fibroid burden for serous and endometrioid EC. Before translation to practice, this analysis of TVUS features and sensitivity should be applied to a cohort that includes all EC histologies. Furthermore, to reassess the appropriateness of current guidelines for evaluating PMB in settings with higher fibroid burden and non-endometrioid EC, a large sample size (or pool) is necessary to determine the negative predictive value of a reassuring TVUS with robust representation of non-endometrioid histologies.

The use of total fibroid diameter >5 cm to define larger fibroid burden performed well in this study. Future studies are needed to validate the performance of this variable across various practice settings and in relation to factors that account for International Federation of Gynecology and Obstetrics (FIGO) stage and uterine location.

Black people have higher rates of late stage at diagnosis of EC in adjusted analyses of national databases, suggesting presence of significant delays in accessing care and/or in diagnostic timeliness (17). This study demonstrated the plausibility that lower TVUS sensitivity in the setting of larger fibroid burden and serous EC could lead to diagnostic delays, especially for Black people, but was not powered to (and did not identify) a significant association with delay. Future studies aiming to identify delays in diagnostic timeliness are crucial and should seek to include or pool a broad sample of institution types and social contexts, as many significant health disparities in the United States are only evident when assessing trends across larger regions of the country or nationally (23).

Strengths and limitations

This is the largest review of serous EC evaluated by TVUS that we are aware of. The institution serves a diverse patient population, providing important representation in the literature on this topic. Our chart review allowed us to generate more comprehensive and nuanced data than would have been possible with a multi-center database, enabling us to examine patient symptoms that may not have received a diagnostic code to follow the diagnostic pathway of each individual. However, the retrospective nature of this study limits our ability to draw causal inferences.

The diversity of our patient population adds important representation to the literature and is necessary to answer the clinical question posed by this study, but also may limit generalizability of our findings. Our patients have a high burden of social barriers to health, present late and acutely, are at risk of loss to follow-up and have a high prevalence of fibroids—which has created a low threshold for endometrial biopsy. Thus, only a small subset of our cohort experienced the diagnostic pathway when TVUS could be used as an initial stand-alone assessment of PMB and future studies in less acute patient populations may be useful.

There are no established superior means of assessing overall fibroid burden in the context of endometrial visualization. While a total fibroid diameter >5 cm was significantly associated with ability to visualize the EM, predictive power was poor with an AUC of 0.64. This AUC was superior to that of a 4 cm cutoff and equivalent to cutoffs greater than 5 cm. For methodological practicality, fibroid location, FIGO classification, and size of single largest fibroid were not incorporated. These factors in addition to expert consensus rationalized its selection. Future studies in other patient populations are required to validate this measure.

Additional limitations are that the study was not powered for secondary outcome analysis and that fibroid location was not included in this study.

Conclusions

Uterine fibroid burden is associated with lower sensitivity of TVUS to detect features of serous and endometrioid EC. Serous EC and fibroids disproportionately impact Black individuals, thus TVUS sensitivity limitations may contribute to the known care gap in EC diagnosis.

Acknowledgments

None

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-34/rc

Data Sharing Statement: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-34/dss

Peer Review File: Available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-34/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-34/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of Montefiore Medical Center and the Albert Einstein College of Medicine (#11-10-352E). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Cote ML, Ruterbusch JJ, Olson SH, et al. The Growing Burden of Endometrial Cancer: A Major Racial Disparity Affecting Black Women. Cancer Epidemiol Biomarkers Prev 2015;24:1407-15. [Crossref] [PubMed]
2. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
3. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9-29. [Crossref] [PubMed]
4. Doll KM, Winn AN, Goff BA. Untangling the Black-White mortality gap in endometrial cancer: a cohort simulation. Am J Obstet Gynecol 2017;216:324-5. [Crossref] [PubMed]
5. Albright BB, Nasioudis D, Craig S, et al. Impact of Medicaid expansion on women with gynecologic cancer: a difference-in-difference analysis. Am J Obstet Gynecol 2021;224:195.e1-195.e17. [Crossref] [PubMed]
6. Barrington DA, Sinnott JA, Calo C, et al. Where you live matters: A National Cancer Database study of Medicaid expansion and endometrial cancer outcomes. Gynecol Oncol 2020;158:407-14. [Crossref] [PubMed]
7. Najor A, Melson V, Lyu J, et al. Disparities in Timeliness of Endometrial Cancer Care: A Scoping Review. Obstet Gynecol 2023;142:967-77. [Crossref] [PubMed]
8. Doll KM, Romano SS, Marsh EE, et al. Estimated Performance of Transvaginal Ultrasonography for Evaluation of Postmenopausal Bleeding in a Simulated Cohort of Black and White Women in the US. JAMA Oncol 2021;7:1158-65. [Crossref] [PubMed]
9. ACOG Committee Opinion No. 734: The Role of Transvaginal Ultrasonography in Evaluating the Endometrium of Women With Postmenopausal Bleeding. Obstet Gynecol 2018;131:e124-9. [Crossref] [PubMed]
10. Hendrickson M, Ross J, Eifel P, et al. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 1982;6:93-108. [Crossref] [PubMed]
11. American College of Obstetricians and Gynecologists. ACOG practice bulletin, clinical management guidelines for obstetrician-gynecologists, number 65, August 2005: management of endometrial cancer. Obstet Gynecol 2005;106:413-25. [Crossref] [PubMed]
12. Huang GS, Gebb JS, Einstein MH, et al. Accuracy of preoperative endometrial sampling for the detection of high-grade endometrial tumors. Am J Obstet Gynecol 2007;196:243.e1-5. [Crossref] [PubMed]
13. Karlsson B, Granberg S, Wikland M, et al. Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding--a Nordic multicenter study. Am J Obstet Gynecol 1995;172:1488-94. [Crossref] [PubMed]
14. Ferrazzi E, Torri V, Trio D, et al. Sonographic endometrial thickness: a useful test to predict atrophy in patients with postmenopausal bleeding. An Italian multicenter study. Ultrasound Obstet Gynecol 1996;7:315-21. [Crossref] [PubMed]
15. Gull B, Karlsson B, Milsom I, et al. Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic measurement of the endometrium as predictors of endometrial cancer. Am J Obstet Gynecol 2003;188:401-8. [Crossref] [PubMed]
16. Wong AS, Cheung CW, Fung LW, et al. Development and validation of prediction models for endometrial cancer in postmenopausal bleeding. Eur J Obstet Gynecol Reprod Biol 2016;203:220-4. [Crossref] [PubMed]
17. Doll KM, Khor S, Odem-Davis K, et al. Role of bleeding recognition and evaluation in Black-White disparities in endometrial cancer. Am J Obstet Gynecol 2018;219:593.e1-593.e14. [Crossref] [PubMed]
18. Laughlin-Tommaso SK, Jacoby VL, Myers ER. Disparities in Fibroid Incidence, Prognosis, and Management. Obstet Gynecol Clin North Am 2017;44:81-94. [Crossref] [PubMed]
19. Wang J, Wieslander C, Hansen G, et al. Thin endometrial echo complex on ultrasound does not reliably exclude type 2 endometrial cancers. Gynecol Oncol 2006;101:120-5. [Crossref] [PubMed]
20. Billingsley CC, Kenne KA, Cansino CD, et al. The Use of Transvaginal Ultrasound in Type II Endometrial Cancer. Int J Gynecol Cancer 2015;25:858-62. [Crossref] [PubMed]
21. Kind AJH, Buckingham WR. Making Neighborhood-Disadvantage Metrics Accessible - The Neighborhood Atlas. N Engl J Med 2018;378:2456-8. [Crossref] [PubMed]
22. Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol 2003;188:100-7. [Crossref] [PubMed]
23. Anderson NB, Bulatao RA, Cohen B, et al. Critical Perspectives on Racial and Ethnic Differences in Health in Late Life. Washington (DC): National Academies Press (US); 2004.