Authored by Devon Smith*
Abstract
Objectives: The purpose of this study was to determine predictive factors of para-aortic lymph node (PALN) involvement in low-grade endometrial cancer of endometrioid type. These factors may influence treatment algorithms and determine the extent of lymph node dissection in patients with low grade endometrial cancer. Our hypothesis was that tumor size, location, and depth of myometrium invasion may be independent predictors of PALN involvement in low grade endometrial cancer.
Methods: A retrospective chart review was performed on patients with grades 1 or 2 endometrial cancer of endometroid type who underwent hysterectomy with lymph node removal from January 1, 2004 to August 1, 2014. Data was evaluated using independent t-tests, Mann Whitney U test, and chi square tests. Sensitivity, specificity, positive and negative predictive values were calculated for tumor size, location, and myometrium invasion in association with PALN and pelvic lymph node (PLN) involvement.
Results: A total of 259 patients met the inclusion criteria. Tumor size was not significantly different between positive and negative PALN samples (4.5cm vs 3.5cm, respectively; p=0.29). Location was not significantly different among positive and negative PALN groups, as the majority of patients in both groups had tumors in the fundal region (75% vs 70.5%, respectively; p=1.00). Myometrial invasion was not significantly different between positive and negative PALN groups (48% vs 28%, respectively; p=0.14). Myometrial invasion was significantly different among positive and negative PLN groups (71% vs 26%, respectively. p<0.001). Lymphovascular space invasion (LVSI) demonstrated a significant association with both positive PALN and PLN groups (100% vs 22.31%, and 81.25% vs 19.67%, respectively; p=0.003, <0.001).
Conclusions: LVSI may be an independent predictor of both PALN and PLN involvement in low grade endometrial tumors. It remains unclear whether tumor size, location, and myometrial invasion can be used to predict para-aortic nodal involvement in these cases.
Keywords: Low grade endometrial cancer; Endometrioid adenocarcinoma; Para-aortic lymph nodes; Nodal metastasis; Tumor size; Tumor location; Myometrial invasion; Lymphovascular space invasion
Introduction
Endometrial cancer is the 4th leading cause of cancer among women and the most common malignancy among the female reproductive organs in the United States [1,2]. It is essential to determine the most effective way to both correctly diagnose and subsequently treat affected patients. Treatment is founded on proper staging, and the extent of lymph node involvement is a critical determinant of tumor stage. Prior authors have attempted to identify predictive factors of pelvic lymph node (PLN) involvement in low grade endometrial cancer [3-7]. However, there is a paucity of research regarding factors such as tumor location, associated specifically with para-aortic lymph node (PALN) involvement in low grade tumors. This is likely due to variations in incidence rates. The overall frequency of PALN dissemination within endometrial adenocarcinoma has been reported as low and also as high as 17%, depending on the tumor stage [4,7-10]. Further delineation of these factors may potentially help guide surgeons in the extent of required surgical dissection. The primary purpose of this study is to evaluate the following factors and their correlation to PALN involvement in low grade endometrial adenocarcinoma of endometrioid type: myometrial invasion, tumor size, tumor location, and lymphovascular space invasion (LVSI). By characterizing these variables, we can further risk stratify patients who may require additional surgical dissection and extensive nodal biopsy.
Materials and Methods
This study was a retrospective chart review designed to assess the best predictive factors of PALN involvement in low grade endometrial cancer. The protocol and all study materials were submitted and approved by the university’s Institutional Review Board. Approval was obtained before any subjects were enrolled. The study was conducted in accordance with the protocol, applicable regulations, and guidelines governing clinical study conduct. To protect subjects’ confidentiality, all subjects were assigned a numerical study identifier.
A chart review was performed for all women admitted to Cooper University Hospital with endometrial cancer and subsequent hysterectomy in the identified time frame. Included patients demonstrated grades 1 or 2 endometrial adenocarcinoma with primary histology of endometroid type with surgical lymph node removal during hysterectomy, nonspecific to operative approach, from January 1, 2004 to August 1, 2014. Operative approaches included open total abdominal hysterectomy, robotic hysterectomy, and laparoscopic assisted vaginal hysterectomy. Patients with primary histology of endometrioid cancer and secondary histology of alternative endometrial pathology were still included. Charts were abstracted for demographics such as age, which helped to define the patient population. Exclusion criteria included patients with concurrent gynecologic malignancies such as cervical or ovarian, any non-endometrioid primary histology, and any extensively incomplete pathology or operative reports. No criteria for patient follow up was included as this was strictly a retrospective chart review.
Demographic data and presurgical tumor grade were extracted from individual charts. Size of the tumor, location of the tumor, histology, PALN involvement, PLN involvement, the number of nodes removed, lymphovascular space involvement (LVSI), tumor stage, and the depth of myometrial invasion were all collected directly from pathology reports.
Tumor size was defined as the largest dimension of the tumor listed in the pathology report, in centimeters (cm). If the tumor was listed as “unmeasurable” due to small size, it was reported as 0.1cm for statistical purposes. Final statistics categorized tumor size as greater or less than 5cm. Tumor location was categorized as “fundus” or “lower uterine segment”. By standards directly defined by the university board-certified pathologist involved in the study, if the pathology report did not clearly define either location, the measurement of < 3.5cm from ectocervix was used as a cutoff for lower uterine segment location. If no exact measurement was listed but was reported as “close to endocervical junction” or “involved in the lower uterine segment,” the specimen was categorized as lower uterine segment. Depth of myometrial invasion was reported as a percentage, either directly stated in the pathology report or calculated from the total myometrial depth.
Data was then evaluated using independent t-tests to compare continuous variables with normal distribution, Mann Whitney U to compare non-parametric continuous variables, and chi square tests to compare proportions. We also evaluated positive and negative predictive values, sensitivity and specificity to examine the predictive values of tumor size, tumor location and myometrium invasion in para-aortic lymph node and pelvic node involvement in the selected cases.
Results
In total, 498 patient charts were reviewed over the given time period. Of these charts, primary histology was reviewed providing the following findings; 418 endometrioid adenocarcinoma, 63 papillary serous carcinoma, 13 malignant mullerian mixed tumor, 2 clear cell carcinomas, and 2 specimens classified as mixed primary histology (papillary serous with clear cell and mixed papillary serous with endometrioid). Of the patients with primary histology of endometrioid adenocarcinoma, 367 were listed as grade 1 or 2 tumors, and 51 were grade 3. Pelvic and/or para-aortic lymph node sampling was performed on 269 specimens of the grade 1 and 2 tumors. Ten charts were then excluded due to concurrent ovarian or cervical cancer or an extensive amount of missing data from the chart or pathology report. These patients then met inclusion criteria and were included in this retrospective chart review. There were 162 Grade 1 tumors and 97 Grade 2 tumors. Four patients were identified with positive PALN involvement, 16 patients were identified with positive PLN involvement, and 1 patient had both positive PALN and PLN identified. All positive samples were reported by Cooper University Hospital’s Department of Pathology (Figure 1).
Tumor size
Primary outcome compared tumor size with PALN involvement, with additional findings comparing tumor size and PLN involvement. Tumor size was not found to be statistically significantly between positive and negative PALN samples. Mean tumor size for paraaortic positive tumors was 4.12cm (+/-2.0) and the median was 4.5 cm. The mean tumor size for para-aortic negative tumors was 3.9 cm (+/-3.7) with a median of 3.5 cm (p=0.29, Figure 2). Tumors measuring 5cm or more were found to have the following associations with positive PALN involvement: a positive predictive value (PPV) of 2.94%, a negative predictive value (NPV) of 98.92%, sensitivity of 50.00% and specificity of 73.60% (Figure 3). Tumors of 5cm or more were found to have the following associations with positive PLN involvement: PPV of 14.71%, NPV of 96.77%, sensitivity of 62.50% and specificity of 75.63% (Figure 4).
Tumor location
Tumor location, which was defined as “lower uterine segment” or “fundus”, was compared to pelvic and para-aortic lymph node involvement. Three of the four patients (75%) who had positive PALN identified, had a tumor located in the fundal region. Of the 254 patients without PALN involvement, 179 (70.50%) also had tumors located in the fundal region (p=1.00, Figure 5). Fundal tumors had a PPV of 1.66%, NPV of 98.70%, SN of 75.00% and SP of 29.92% for PALN involvement. When comparing PLN metastasis and tumor location; 7 out of the total 16 positive pelvic node samples had a tumor located in the uterine fundus (43.75%). Out of the 242 negative pelvic node specimens, 174 samples (71.90%) were also fundal tumors (p=0.02). Fundal tumors had a PPV of 3.87%, NPV of 88.31%, sensitivity of 43.75% and specificity of 28.10% for PLN involvement.
Myometrial Invasion
Myometrial invasion was not statistically significant between positive and negative PALN samples. Mean percentage of myometrial invasion for tumors with positive para-aortic lymph nodes (N=4) versus tumors with negative para-aortic lymph nodes (N=255) was compared. Mean myometrial invasion for para-aortic positive tumors was 50.25% (+/-18.8). The mean myometrial invasion for para-aortic negative tumors was 31.3% (+/29.59) (p=0.14, Figure 6). Results comparing pelvic and para-aortic lymph node involvement were also dichotomized by the median of myometrial invasion percentage of 28%. All four patients identified with positive PALN involvement had greater than 28% myometrial invasion. Of the remaining 255 patients, 125 samples also had >28% myometrial invasion, producing a PPV of 3.10%, NPV of 100.0%, sensitivity of 100.0% and specificity of 50.98% (Figure 7). In the positive PLN samples (N=16), myometrial invasion had a reported median of 71% compared to a median of 26% invasion in the negative group (N=243) (p<0.001). Patients identified with PLN metastasis and >28% myometrial invasion were calculated to have a PPV of 10.85%, NPV of 98.46%, sensitivity of 87.50%, and specificity of 52.67% (Figure 8).
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