Abstract

Background: Isolated tumor cells (ITCs) are deposits measuring ≤0.2 mm, whereas micro metastasis (MM) measures >0.2 to ≤2 mm. The significance of these findings in endometrial cancer remains controversial. We sought to determine whether patient and disease characteristics correlate with ITCs/MM on sentinel lymph node (SLN) biopsy for endometrial cancer staging. Methods: We carried out an IRB-approved retrospective chart review of all women with endometrial cancer who underwent SLN biopsy during staging at two medical centers between 2013 and 2018. Results: A total of 472 patient charts met inclusion criteria. Among women included, 5.7% (n = 27) had ITCs/MM. The median age of women with ITCs/MM was 64 years and median BMI was 33.8. Neither was found to be related to ITCs/M. Lymphovascular space invasion (LVSI) was present in 73% (n = 19). Compared to patients without LVSI, those with LVSI were more likely to have ITCs/MM (OR = 7.61, 95% CI 3.00–19.32). Compared to patients with superficial invasion of the myometrium, those with a greater myometrial invasion were more likely to have ITCs/MM (OR = 6.37, 95% CI 1.90–21.37). Conclusion: ITCs/MM are relatively rare in women undergoing SLN biopsy for endometrial cancer. Additional data are needed to clarify risk factors and associated patient outcomes.

Introduction

Endometrial cancer is the most common gynecologic malignancy in the developed world, with over 60,000 new cases diagnosed annually in the United States alone. [1] Sentinel lymph node (SLN) biopsy has revolutionized the surgical staging of this prevalent disease. Prior to the development of this technique, patients with endometrial cancer routinely underwent comprehensive pelvic lymphadenectomy, potentially with removal of additional nodes in the paraaortic region, to detect nodal metastasis. [2] While lymphadenectomy is known to increase the detection of metastatic disease in patients with endometrial cancer, multiple studies have found increased morbidity associated with the procedure and no improvement in overall or disease-free survival.[3, 4] Recognizing an area for improvement, the first SLN biopsy for the surgical staging of endometrial cancer was reported by Burke et al. in 1996 [5]. Since then, studies comparing SLN biopsy with comprehensive lymphadenectomy have demonstrated not only a decrease in complications, but also similar or superior detection of nodal metastasis and similar survival outcomes associated with SLN biopsy [6-10]. As such, SLN biopsy has replaced routine lymphadenectomy in many institutions.

The superior detection of nodal metastasis is largely attributable to a pathology technique used to evaluate SLNs called ultrastaging. Traditional pathologic review of nodes obtained from lymphadenectomy involves examination of a bivalved specimen. Ultrastaging involves gross sectioning of a SLN, following by serial sectioning to obtain micron level segments throughout the node. Ultrastaging not only aids in superior detection of nodal gross metastasis; it also has led to an increase in the identification of isolated tumor cells (ITCs) and micrometastases (MM). ITCs are defined as tumor deposits measuring £ 0.2 mm, whereas MM are defined as metastatic deposits measuring > 0.2 mm to ≤ 2 mm. The prevalence of these low-volume nodal disease findings is estimated to range from 3-10% based upon studies of women with endometrial cancer undergoing SLN biopsy.[6-11]In breast cancer literature, for which SLN biopsy has been longer utilized and better studied, MM have been correlated with worse 5-year survival rates compared to node negative disease, while no difference in outcome has been associated with ITCs compared to node negative disease. [12] In endometrial cancer, the significance of low-volume disease as it relates to patient outcomes and therapy remains unclear.[613] One study by Plante et al. revealed no statistically significant difference in 3-year disease-free survival between patients with node negative, ITC positive, and MM positive disease, concluding that adjuvant therapy should not be offered solely on the basis of node positivity.[14] The largest investigation of ITCs by Backes et al. found that of 175 patients with endometrial carcinoma and ITCs, recurrence rates were low (5.1%) and adjuvant therapy was not statistically associated with an improvement in recurrence free survival.[11] Conversely, a study by Todo et al. suggested worse survival and recurrence rates associated with both ITCs and MM, though this study was limited by small sample sizes.[15]

While research regarding the prognostic value of low volume nodal disease and need for adjuvant therapy is ongoing, there is also more to be discovered regarding patient characteristics and predictors for the presence of ITCs and MM on SLN biopsy. A recent study found ITCs to be associated with larger tumor size and increasing depth of myometrial invasion compared to node negative disease. [16] We sought to add to the available knowledge by determining whether certain patient and disease characteristics correlate with the finding of ITCs or MM on SLN biopsy performed for endometrial cancer staging.

Material and Methods

A retrospective chart review was performed of all women over the age of 18 who underwent SLN mapping and biopsy during surgical staging for endometrial cancer at the University of Rochester Medical Center and Women & Infants Hospital of Brown University between 2013 and 2018. IRB approval was obtained at each institution. Further study criteria necessary for inclusion were endometrioid histology, successful SLN biopsy without full lymphadenectomy in which pathology confirmed presence of nodal tissue, and availability of access to records.

All cases were identified by the Departments of Pathology and Divisions of Gynecologic Oncology. Medical record numbers provided by the departments were used to access only pertinent data from patients’ electronic medical records. Information of interest included demographic variables (age, race, ethnicity, menopausal status, body mass index (BMI), major medical problems, known genetic mutations), pathologic variables (histology, grade, presence or absence of lymphovascular space invasion (LVSI), depth of invasion, tumor size, tumor location, positivity of SLN, number and location of SLN, SLN MM vs metastasis, SLN ITCs, MSI tumor status) and outcome variables (surgical complications, disease recurrence, vital status), when available. Data extracted from chart review were managed using the HIPAA-compliant REDCap system hosted by the University of Rochester Wilmot Cancer Institute.

 The primary patient characteristics of interest for this study included age and BMI. The primary disease characteristics of interest included disease grade, LVSI, and depth of myometrial invasion. Secondary variables of interest for this study were outcome-related and included disease recurrence and mortality.

Descriptive characteristics of the sample were displayed as medians with ranges for continuous variables or frequencies with proportions for categorical variables. The independent, or adjusted, association of baseline characteristics with either or both ITCs and

MM relative to negative SLNs were estimated using a logistic regression model with a Firth correction for sparse data. [17] Odds ratios (OR) are presented with 95% confidence intervals (CI). Analyses were conducted using SAS software (v 9.4, SAS Institute, Cary NC).

Results

In total, 576 patient charts were reviewed. Of these, 64 were excluded due to non-endometrioid histology, 38 were excluded for SLN biopsy failure, and 2 were excluded for incomplete records, leaving a total of 472 cases eligible for inclusion in the study. Within the study population, 27 patients (5.7%) were identified to have either ITCs or MM without macrometastasis upon pathologic evaluation of identified SLNs, including 10 with ITCs and 17 with MM. Macrometastasis (tumor deposits >2 mm) was identified in 15 patients (3.2%). Characteristics of these patients are found in Table 1.

Table 1: Characteristics of Patients with Negative SLNs vs Macro Metastasis vs ITCs or MM only on SLN Biopsy. Percentages that do not add up to 100 are a Result of Rounding.

The primary patient characteristics of interest were age and BMI. Race was also of interest, though the vast majority of patients (95%) were white, therefore limiting analysis. Patient age among women with ITCs or MM ranged from 54 to 92 years, with a median age of 64. By comparison, the median age of women with negative SLNs was 62. BMI ranged from 21 to 53 among women with ITCs or MM, with a median of 33.8. The median BMI for women with negative SLNs was 35.4. There was no statistical association identified between the presence of ITCs or MM and either age (OR 1.02, 95% CI 0.97-1.07) or BMI (1.02, 95% CI 0.96-1.08). This was true for ITCs alone, MM alone, or ITCs or MM combined, as shown in Table 2.

Table 2: Adjusted patient and disease associations with ITC, MM, or either. After adjusting for age, BMI, grade, and myometrial invasion, LVSI is significantly associated with ITCs. After adjusting for age, BMI and grade, LVSI and myometrial invasion are independently associated with MM.