A Commentary Addressing the Surgical Management of Endometrial Intraepithelial Neoplasia

Endometrial Intraepithelial Neoplasia (EIN) is a precancerous lesion of the endometrium associated with a significant risk of progression to Endometrial Carcinoma (EC). Among patients with a preoperative diagnosis of EIN, more than 40% are found to have occult carcinoma at the time of hysterectomy [1]. In the United States, the incidence of EC continues to rise, with the American Cancer Society estimating approximately 70,000 new cases in 2025 [2]. Hysteroscopic-guided sampling is recommended by national guideline for patients with EIN, as it enhances diagnostic accuracy compared to blind biopsy, though a residual risk of undetected carcinoma remains [3]. Despite improved sampling techniques, up to 24% of patients are ultimately diagnosed with cancer on final surgical pathology [3]. Preoperative imaging findings, such as a markedly thickened endometrial stripe (>20 mm), can help identify patients at highest risk for concurrent carcinoma [4]. 

In patients who have completed childbearing, hysterectomy is the definitive treatment for EIN. Lymph node assessment during hysterectomy is a routine part of surgical staging for EC; however, its utility in EIN is less clear. Most EC diagnoses found on final pathology have low-grade uterine-confined disease with an overall low risk of lymph node involvement, approximately 3% or less, depending on preoperative risk factors [1,5]. In well-resourced healthcare settings, EIN is often managed by a Gynecologic Oncologist (GO). However, in many cases, a GO may not be accessible, especially in rural areas. As Obstetrician/Gynecologists (OB/GYN) can perform a simple hysterectomy, it may be appropriate in certain circumstances for patients with EIN to be surgically managed by an OB/GYN in their local area rather than referral to a GO. Our work joins other recent publications that seek to identify risk factors that increase the risk of detecting cancer on final pathology to aid in selection of patients for care by OB/GYN vs. GO.

We recently published a retrospective observational cohort study conducted at two military treatment facilities over a 10-year period which aimed to investigate the surgical management of EIN in the military [6]. The study included 95 patients with a preoperative diagnosis of EIN or complex atypical hyperplasia (the historical name for EIN). In our cohort, 45.3% of patients with EIN were diagnosed with EC on final pathology, which was concordant with other studies [1,4,5,7,8]. All EC cases were classified as low-grade endometrioid endometrial carcinoma, with the majority being FIGO Stage IA. Notably, among the 24 patients who underwent lymph node assessment and were ultimately diagnosed with EC, none had positive lymph nodes on final pathology. This finding aligns with other studies reporting low rates of lymph node involvement in patients with a preoperative diagnosis of EIN. 

Multivariate analysis revealed that older age and greater preoperative endometrial thickness were associated with a higher risk of upstaging to EC. Specifically, patients aged 65 years or older were over 13 times more likely to be diagnosed with cancer compared to those younger than 50 years. Preoperative ES thickness of ≥15 mm was also associated with a 4-fold increased risk. While we did not have enough patients with an ES ≥20 mm to report statistical significance, Vetter et al., showed that an ES ≥20 mm was associated with a 4-fold increases in the risk of endometrial cancer compared with ES < 20 mm, even when controlling for age [4]. Additionally, in our study, patients diagnosed with EIN via hysteroscopy were less likely to be diagnosed with EC on final pathology, compared to those diagnosed by endometrial biopsy.

Our study and others demonstrate a very low lymph node positivity rate in patients with a preoperative diagnosis of EIN [1,7,9-12]. This raises questions about the necessity of routine lymph node sampling during hysterectomy for EIN patients. The findings also highlight the importance of considering patient age and preoperative endometrial thickness in determining the risk of upstaging to EC. Given the low rates of lymph node involvement in EIN, a risk-factor-based approach could be employed to identify patients at greatest risk of lymph node involvement, potentially guiding referral to a GO. 

Our group has recently published best practice recommendations for the Military Health System to help select patients for management by OB/GYN vs GO in situations where GO may not be readily available [13]. Our decision tree incorporated patient distance to GO, risk factors for underlying carcinoma, expert pathology review, and virtual consultation with GO to determine eligibility for surgical management by OB/GYN. When we proposed this management algorithm to military OB/GYNs, over 80% indicated that they would be willing to manage these EIN patients [14]. We believe this tool could be applied in the civilian healthcare system, especially in rural areas or in situations where GO clinical load is saturated with invasive cancer.

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