Background
Endometrial intraepithelial neoplasia, also known as complex atypical hyperplasia, is a precancerous lesion of the endometrium associated with a 40% risk of concurrent endometrial cancer at the time of hysterectomy. Although a majority of endometrial cancers diagnosed at the time of hysterectomy for endometrial intraepithelial neoplasia are low risk and low stage, approximately 10% of patients ultimately diagnosed with endometrial cancers will have high-risk disease that would warrant lymph node assessment to guide adjuvant therapy decisions. Given these risks, some physicians choose to refer patients to a gynecologic oncologist for definitive management. Currently, few data exist regarding preoperative factors that can predict the presence of concurrent endometrial cancer in patients with endometrial intraepithelial neoplasia. Identification of these factors may assist in the preoperative triaging of patients to general gynecology or gynecologic oncology.
Objective
To determine whether preoperative factors can predict the presence of concurrent endometrial cancer at the time of hysterectomy in patients with endometrial intraepithelial neoplasia; and to describe the ability of preoperative characteristics to predict which patients may be at a higher risk for lymph node involvement requiring lymph node assessment at the time of hysterectomy.
Materials and Methods
We conducted a retrospective cohort study of women undergoing hysterectomy for pathologically confirmed endometrial intraepithelial neoplasia from January 2004 to December 2015. Patient demographics, imaging, pathology, and outcomes were recorded. The “Mayo criteria” were used to determine patients requiring lymphadenectomy. Unadjusted associations between covariates and progression to endometrial cancer were estimated by 2-sample t- tests for continuous covariates and by logistic regression for categorical covariates. A multivariable model for endometrial cancer at the time of hysterectomy was developed using logistic regression with 5-fold cross-validation.
Results
Of the 1055 charts reviewed, 169 patients were eligible and included. Of these patients, 87 (51.5%) had a final diagnosis of endometrial intraepithelial neoplasia/other benign disease, whereas 82 (48.5%) were ultimately diagnosed with endometrial cancer. No medical comorbidities were found to be strongly associated with concurrent endometrial cancer. Patients with endometrial cancer had a thicker average endometrial stripe compared to the patients with no endometrial cancer at the time of hysterectomy (15.7 mm; standard deviation, 9.5) versus 12.5 mm; standard deviation, 6.4; P = .01). An endometrial stripe of ≥2 cm was associated with 4.0 times the odds of concurrent endometrial cancer (95% confidence interval, 1.5–10.0), controlling for age. In all, 87% of endometrial cancer cases were stage T1a (Nx or N0). Approximately 44% of patients diagnosed with endometrial cancer and an endometrial stripe of ≥2 cm met the “Mayo criteria” for indicated lymphadenectomy compared to 22% of endometrial cancer patients with an endometrial stripe of <2 cm.
Conclusion
Endometrial stripe thickness and age were the strongest predictors of concurrent endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia. Referral to a gynecologic oncologist may be especially warranted in endometrial intraepithelial neoplasia patients with an endometrial stripe of ≥2 cm given the increased rate of concurrent cancer and potential need for lymph node assessment.
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Endometrial intraepithelial neoplasia (EIN), formally known as complex atypical hyperplasia (CAH), is a premalignant lesion of the endometrium that is of clinical significance because of an approximately 40% risk of progression to endometrial cancer (EC). Furthermore, the prevalence of concurrent EC in patients diagnosed with EIN undergoing hysterectomy approaches 43%. Risk factors for the development of EIN include obesity, anovulation, nulliparity, and diabetes. A diagnosis of EIN can be made by outpatient endometrial biopsy or by dilation and curettage, with or without hysteroscopy. Given the high risk of concurrent cancer and the risk of progression, the standard treatment of EIN is surgical management with hysterectomy, with or without bilateral salpingo-oophorectomy. This treatment protocol allows for full pathologic evaluation and assessment of concurrent cancer, and provides definitive therapy. Nonsurgical management may be appropriate for patients desiring future fertility or for those patients with comorbidities precluding surgical management.
Why was this study conducted?
To determine whether there are preoperative predictors of concurrent uterine adenocarcinoma at time of hysterectomy for endometrial intraepithelial neoplasia, and need for lymph node assessment at time of surgical management.
Key findings
Both preoperative endometrial stripe thickness and smoking status predicted the presence of concurrent cancer at time of hysterectomy for endometrial intraepithelial neoplasia. Endometrial stripe thickness of ≥2 cm was associated with a 4-fold increase in odds of concurrent cancer compared to endometrial stripe thickness of <2 cm. In all, 44% of patients with an endometrial stripe of ≥2 cm met clinical criteria for lymph node assessment.
What does this add to what is known?
This study suggests that referral to gynecologic oncology may be warranted for patients with endometrial intraepithelial neoplasia, especially if endometrial stripe thickness is ≥2 cm, given the increased rate of concurrent cancer and the potential need for lymph node assessment.
The majority of EIN patients ultimately diagnosed with EC will have early stage, low-risk disease. However, approximately 12% will have high-grade tumors with deep myometrial invasion and a 3–7% risk of lymph node involvement. Although the comprehensive surgical staging with lymph node assessment via full lymphadenectomy or sentinel lymph node approach for all patients with EIN would result in overtreatment in a large proportion of patients, there remains a subset of patients for whom lymph node assessment as a guide to adjuvant therapy is beneficial in reducing the risk of over- or undertreatment. In addition, hysterectomy results in disruption of the lymphatic channels, making sentinel lymph node assessment impossible to perform after hysterectomy, in the event of an EC diagnosis on intraoperative or final pathology. This fact has resulted in ongoing discussions about whether or not a referral to a gynecologic oncologist is warranted in all cases of EIN.
Given the challenging management decisions associated with EIN, interest exists in identifying factors that may improve preoperative risk prediction of EC. Previous studies have identified sampling method as being associated with EC risk, with EIN diagnosed on office biopsy alone being more strongly associated with EC on follow-up. A retrospective study identified pathologic characteristics such as extent of EIN or involvement of a polyp or other suspicious feature as important in the prediction of underlying cancer risk, with the highest risk in patients assigned the designation of EIN suspicious. However, few data exist on the impact of objective preoperative factors that may be used to predict the risk of underlying EC.
The primary purpose of this study was to determine whether preoperative factors, including imaging and patient characteristics, can predict the presence of concurrent EC at the time of hysterectomy in patients diagnosed with EIN. A secondary outcome was to describe the ability of preoperative characteristics to predict which patients may require a lymph node dissection.
Materials and Methods
After obtaining institutional review board approval, a retrospective chart review was performed, encompassing all patients undergoing hysterectomy and bilateral salpingo-oophorectomy for confirmed EIN at The Ohio State University from January 2004 to December 2015. Confirmation of an EIN diagnosis by an Ohio State University pathologist was required for inclusion. Lymph node assessment was performed either at the time of primary surgery or, in rare cases, in a second surgery based on intraoperative frozen section, final pathology diagnosis, and/or provider choice. Patients with no preoperative imaging or those who had undergone prehysterectomy endometrial ablation were excluded. Patient demographics, imaging results, pathologic data, and outcomes were recorded from the medical record.
We used the widely accepted “Mayo criteria” to calculate for whom a lymph node dissection would be recommended. The Mayo criteria recommend a lymph node dissection for patients with the following: grade 1 or grade 2 endometrioid adenocarcinoma ≥2 cm and >50% myometrial invasion, any grade 3 endometrioid adenocarcinomas, and all non-endometrioid adenocarcinomas (serous, clear cell, mixed, carcinosarcoma). Descriptive statistics (counts, frequency, mean, and standard deviation) were reported. Initial associations with progression to EC were made by 2-sample t tests for continuous covariates and by the estimation of odds ratios (OR), and 95% confidence intervals (CI), for categorical covariates. A predictive multivariable logistic model for progression to EC was developed by forward selection of covariates with crude association at the 10% level and 5-fold cross-validation. Model discrimination was assessed by the area under the receiver operating characteristic curve (AUC), and model calibration was assessed using the Hosmer−Lemeshow goodness-of-fit test. The associations between the Mayo criteria and either LND, lymphadenectomy, or EMS thickness were assessed using the Fisher exact test. All reported P values are 2 sided. Data were analyzed in Stata version 15.1 (StataCorp, College Station, TX).
Results
In total, 169 individuals were eligible to be included in the study. EIN was diagnosed by endometrial biopsy in 44% of the patients, whereas EIN was initially diagnosed by dilation and curettage in 56% of the patients. In all, 73 patients (43%) had a final diagnosis of EIN; 82 (48%) were diagnosed with endometrial cancer at the time of hysterectomy, whereas 14 (8%) had other benign disease.
Demographics for the study population are reported in Table 1 according to final pathologic diagnosis. The average age of patients diagnosed with EC at the time of hysterectomy was 56 years (standard deviation [SD], 10.0), compared to 54 years (SD, 10.0) for those with EIN/other benign disease. As women aged, they were more often diagnosed with EC (≥65 years vs ≤50 years: OR, 2.7; 95% CI, 1.1–6.8), P = .08). In both groups, most patients were of white race/ethnicity, were postmenopausal, and had never used hormone replacement therapy. The most commonly noted medical comorbidity in both groups was obesity (83% in both groups). Median body mass index was 39.5 (minimum, maximum: 21.0, 64.3) for those progressing to EC and 41.5 (minimum, maximum: 19.9, 69.2) for those who did not. The rate of hypertension, diabetes, and breast cancer were similar between the 2 groups.
| Characteristic | Endometrial cancer (n = 82), n (%) | Benign Pathology (n = 87), n (%) | Unadjusted OR (95% CI) | Adjusted OR a (95% CI) |
|---|---|---|---|---|
| EMS thickness | ||||
| <2 cm | 59 (42.4) | 80 (57.6) | Reference | Reference |
| ≥2 cm | 23 (76.7) | 7 (23.3) | 4.5 (1.8–11.1) | 4.0 (1.6–10.1) |
| Smoking status b | ||||
| Never smoker | 55 (52.9) | 49 (47.1) | Reference | |
| Ever smoker | 25 (41.7) | 35 (58.3) | 0.6 (0.3–1.2) | |
| Age, y | ||||
| ≤50 | 23 (42.6) | 31 (57.4) | Reference | Reference |
| 51–64 | 39 (45.9) | 46 (54.1) | 1.1 (0.6–2.3) | 1.2 (0.6–2.4) |
| ≥65 | 20 (66.7) | 10 (33.3) | 2.7 (1.1–6.8) | 2.3 (0.9–5.9) |
| Race/ethnicity | ||||
| Nonwhite | 7 (53.8) | 6 (46.2) | Reference | |
| White | 75 (48.1) | 81 (51.9) | 0.8 (0.3–2.5) | |
| Menopausal status c | ||||
| Premenopausal | 25 (41.0) | 36 (59.0) | Reference | |
| Postmenopausal | 56 (52.8) | 50 (47.2) | 1.6 (0.9–3.0) | |
| Comorbidities | ||||
| BMI | ||||
| Not obese (<30) | 14 (48.3) | 15 (51.7) | Reference | |
| Obese d (≥30) | 68 (48.6) | 72 (51.4) | 1.0 (0.5–2.3) | |
| Hypertension | ||||
| No | 25 (44.6) | 31 (55.4) | Reference | |
| Yes | 57 (50.4) | 56 (49.6) | 1.3 (0.7–2.4) | |
| Diabetes | ||||
| No | 58 (47.5) | 64 (52.5) | Reference | |
| Yes | 24 (51.1) | 23 (48.9) | 1.2 (0.6–2.3) |
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