The Association Between BMI and Diagnosis of Endometrial Intraepithelial Neoplasia at an Early Age
December 1, 2023
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By Alexandra Samborski, MD
Adjunct Instructor, Department of Obstetrics & Gynecology, University of Rochester Medical Center, NY
SYNOPSIS: In premenopausal patients, there was a linear association between increasing body mass index and decreased age at the time of endometrial intraepithelial neoplasia diagnosis.
SOURCE: Nicholson K, Macharia A, Furuya R, et al. Association of body mass index with early age at diagnosis of endometrial intraepithelial neoplasia. Gynecol Oncol 2023;175:15-19.
Endometrial intraepithelial neoplasia (EIN) is recognized as a precursor lesion to endometrial endometrioid adenocarcinoma. Approximately 40% of patients who undergo hysterectomy for EIN ultimately will be diagnosed with an invasive cancer.1 Risk factors for development of EIN and endometrial cancer include exposure to unopposed estrogen, nulliparity, polycystic ovary syndrome (PCOS), and late onset of menopause.
Obesity is one of the strongest risk factors, with higher body mass index (BMI) being associated with increased risk.2,3 One study showed that as BMI increased, the age at diagnosis of endometrial cancer decreased. This study aimed to assess the association between age at the time of diagnosis of EIN and BMI.
This was an Institutional Review Boards (IRB)-approved retrospective cohort study including all patients diagnosed with EIN at a single academic center over a 10-year period (2010 to 2020). Pathology reporting EIN or complex hyperplasia with atypia from either an endometrial biopsy or dilation and curettage were included. International Classification of Diseases 10th Revision (ICD-10) codes were used to identify patients, and the pathology report was reviewed to confirm diagnosis. The pathology then was confirmed by an institutional pathologist. Patients with endometrial cancer on their initial specimen were excluded. Data on demographics, self-reported race, comorbidities, and medical history were extracted from the medical records. The initial treatment modality for EIN and final pathology for patients undergoing hysterectomy also were recorded.
For statistical analysis, patients were categorized by BMI < 30 kg/m2, 30 kg/m2 to 40 kg/m2, 40 kg/m2 to 50 kg/m2, and > 50 kg/m2. A Shapiro-Wilk test was used to confirm normal distribution of continuous variables and a linear regression was used to calculate the parameter estimate (β) and 95% confidence interval for the association of BMI and age at diagnosis. Patients also were compared based on menopausal status. PCOS and parity were assessed as potential confounders. Chi-square and t-tests were used, with P < 0.05 considered statistically significant.
Throughout the study period, 588 patients with EIN were identified by ICD codes, and this was confirmed on a pathology report for 513 of them. Medical records were unable to be accessed for 10 patients, so the final number included in the study was 503 patients. Seventy percent of patients identified as white, 12% as Black, 10% as Asian, and 8% did not report their race. In terms of BMI, 29% of patients had a BMI < 30 kg/m2, 36% had a BMI 30 kg/m2 to 40 kg/m2, and 35% had a BMI > 40 kg/m2.
A total of 361 patients (72%) had at least one medical comorbidity, of which 53% had hypertension, 33% had hyperlipidemia, 22% had type 2 diabetes, 8% had PCOS, and 20% had a history of tobacco use. Thirty-eight percent of patients were premenopausal and 62% were perimenopausal or postmenopausal. Premenopausal patients were more likely to be nulliparous and have PCOS (both P < 0.001). Postmenopausal patients were more likely to have hypertension, diabetes, and hyperlipidemia (all P < 0.02). Additionally, premenopausal patients primarily were white and Asian, whereas postmenopausal patients mostly were white and Black (P < 0.001).
The mean BMI and age at diagnosis were 37 kg/m2 (± 11) and 54 years (± 7). For premenopausal patients, the means were 35 kg/m2 (± 11) and 42 years (± 7), and for postmenopausal patients the means were 38 kg/m2 (± 10) and 61 years (± 8). In the premenopausal patients, there was a significant linear association between increasing BMI and decreasing age at the time of diagnosis (β = -19; 95% confidence interval, -0.27 to -0.10). This means that, in these patients, for every one unit increase in BMI, the age at diagnosis decreased by 0.19 years. After adjusting for nulliparity or PCOS, this still was statistically significant, although with slightly less magnitude (β = -0.14 for nulliparity and β = -0.11 for PCOS). There was no association of BMI and age at diagnosis for postmenopausal patients.
In terms of treatment, 72% of patients underwent major surgery (hysterectomy with or without lymph node assessment), 22% of patients received hormonal therapy with or without minor surgery (dilation and curettage, hysteroscopy), 2% of patients proceeded with observation, and 4% were lost to follow-up. Premenopausal patients were more likely to have hormonal management, and postmenopausal patients were more likely to undergo surgical management (all P < 0.001). Of the patients who underwent hysterectomy, 28% were diagnosed with endometrial cancer on final pathology. Most patients diagnosed with cancer on final pathology were postmenopausal (78%).
COMMENTARY
Endometrial cancer is the most common gynecologic malignancy in the United States, with women having a 1 in 32 lifetime chance of developing uterine cancer.4 Unfortunately, the rates of endometrial cancer are rising, with an estimated incidence of 66,200 cases and 13,030 deaths in 2023.5 Although multiple risk factors have been delineated, obesity continues to be a prominent and increasingly prevalent risk. From 2000 to 2020, the prevalence of obesity in the United States rose from 30.5% to 41.9%, and the rates of severe obesity increased from 4.7% to 9.2%.6 Currently, American College of Obstetricians and Gynecologists (ACOG) guidelines recommend endometrial sampling for patients older than 45 years with abnormal uterine bleeding or in patients younger than 45 years with a history of unopposed estrogen, such as obesity.7 The guidelines do not further specify thresholds for what BMI requires sampling, so this is left up to the judgment of the provider.
One retrospective study of more than 900 premenopausal patients demonstrated a four-times increased risk in developing complex endometrial hyperplasia/EIN or cancer in patients with a BMI ≥ 30 kg/m2.8 More than half of the patients included in this study were younger than 45 years of age, which adds to the evidence that younger patients with obesity need a low threshold for endometrial sampling. This study also expands on the data from the current study that patients with a BMI in the 30 kg/m2 to 40 kg/m2 range are at increased risk of developing these precancerous lesions. With the rising rates of obesity, and particularly morbid obesity, BMIs in the 30 kg/m2 to 40 kg/m2 range may seem commonplace, but it is important to remember that these patients also are at increased risk and need evaluation accordingly. Additionally, in this premenopausal population, ultrasonography is less helpful in triaging the need for endometrial sampling, which increases the importance of obtaining a tissue sample.
The clear association of obesity with EIN lends itself to the question of whether screening or risk-reducing measures should be offered to this population. Oral contraceptives are known to decrease the risk of endometrial cancer and are an option for chemoprevention in patients with Lynch syndrome, and screening with endometrial biopsies every one to three years is considered reasonable.9 More evidence is needed, but perhaps this would be a strategy for screening patients with high BMIs in the future as well. The PROTEC trial is a prospective clinical trial that evaluated the levonorgestrel intrauterine device (LNG-IUD) as endometrial cancer prevention in patients with a BMI > 40 kg/m2. Twenty-five patients were included, and use of the LNG-IUD for six months was associated with endometrial morphologic change but no change in circulating biomarkers.1 Larger-scale studies over a longer period of time would provide valuable information on whether this ultimately decreases the risk of EIN or endometrial cancer for these patients. Options for treating obesity, such as lifestyle changes, medications, or surgical options, also may be an effective means to prevent endometrial cancer, but data are needed to determine what methods are most effective at mitigating this risk.
Disparities in care and outcomes for patients with endometrial cancer are important to address as we move forward with how best to screen, diagnose, and treat these patients. Black patients with endometrial cancer have a 55% higher five-year mortality than white patients.5 Black adults also have the highest prevalence of obesity in the country at 49.9%.6 Thus, not only are these patients at higher risk for developing uterine cancer as a result of the high rates of obesity, but they have worse outcomes once diagnosed.
Given the increasing incidence of EIN/endometrial cancer and obesity, it will be important to develop more specific guidelines for endometrial sampling for premenopausal patients. Screening or risk-reducing measures for these patients would be beneficial as well. Being thoughtful of how any future changes address the current disparities is critical.
REFERENCES
- Derbyshire AE, Allen JL, Gittins M, et al. PROgesterone Therapy for Endometrial Cancer Prevention in Obese Women (PROTEC) trial: A feasibility study. Cancer Prev Res (Phila) 2021;14:263-274.
- Soliman PT, Oh JC, Schmeler KM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol 2005;105:575-580.
- Epplein M, Reed SD, Voigt LF, et al. Risk of complex and atypical endometrial hyperplasia in relation to anthropometric measures and reproductive history. Am J Epidemiol 2008;168:563-570; discussion 571-576.
- Ring KL, Mills AM, Modesitt SC. Endometrial hyperplasia. Obstet Gynecol 2022;140:1061-1075.
- [No authors listed]. Management of endometrial intraepithelial neoplasia or atypical endometrial hyperplasia: ACOG Clinical Consensus No. 5. Obstet Gynecol 2023;142:735-744.
- Centers for Disease Control and Prevention. Adult obesity facts. Last reviewed May 17, 2022. https://www.cdc.gov/obesity/data/adult.html
- Committee on Practice Bulletins – Gynecology. Practice bulletin no. 128: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol 2012;120:197-206.
- Wise MR, Gill P, Lensen S, et al. Body mass index trumps age in decision for endometrial biopsy: Cohort study of symptomatic premenopausal women. Am J Obstet Gynecol 2016;215:598.e1-598.e8.
- [No authors listed]. ACOG Practice Bulletin No. 147: Lynch syndrome. Obstet Gynecol 2014;124:1042-1054.
In premenopausal patients, there was a linear association between increasing body mass index and decreased age at the time of endometrial intraepithelial neoplasia diagnosis.
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