Abstract
To retrospectively analyze the preoperative and intraoperative influencing factors in predicting the escalation of surgical pathological staging in patients with clinical stage I endometrioid carcinoma. Patients with clinical stage I endometrioid carcinoma at Women’s Hospital, School of Medicine, Zhejiang University, between January 2002 and December 2015 were enrolled in this study. Due to preoperative or intraoperative surgical exploration, the patients with one or more preoperative or intraoperative high-risk factors underwent total hysterectomy, bilateral salpingo-oophorectomy and lymphadenectomy, totaling 535 cases. The preoperative and intraoperative influencing factors that could lead to the escalation of postoperative surgical pathological staging were further analyzed. 1. There were 535 patients diagnosed with clinical stage I endometrioid carcinoma before surgery, 125 patients were upgraded with postoperative pathological staging, for a rate of 23.36%. 2. Kaplan–Meier survival curve analysis showed that the prognosis in postoperative surgical pathological staging upgraded cases was worse than that in nonupgraded cases. The tumor-free survival and overall survival rates in the 2 groups were significantly different (P < .001). 3. Univariate analysis showed that preoperative degree of myometrial infiltration, intraoperative visual myometrial infiltration depth, massive size of tumor (diameter ≥ 4 cm) and preoperative abnormal serum cancer antigen 125 (CA125) level were associated with the escalation of surgical pathological staging (P < .05). Multivariate analysis indicated that massive size of tumor and preoperative serum abnormal CA125 level were independent predictors of whether postoperative pathological staging would be upgraded (P < .05). 4. The receiver operating characteristic curve drawn with the massive size of tumor and/or the preoperative serum CA125 level abnormality could be used to predict the probability of postoperative pathological upstaging. The results showed that the area from the combination of the 2 factors under the receiver operating characteristic curve was 0.723 (95% confidence interval, 0.672–0.773), suggesting that the combination of massive size of tumor and abnormal preoperative serum CA125 level may serve as an influencing factor for predicting the postoperative pathological staging upgrades. The clinical stage I endometrioid carcinoma patients with massive size of tumor and abnormal preoperative serum CA125 level need to be fully evaluated to ensure appropriate management as soon as possible, since they are more likely to experience postoperative pathological staging upgrades.
Keywords: CA125, clinical stage I endometrioid carcinoma, preoperative predictive factors, prognosis
1. Introduction
Endometrial cancer is the 4th most common gynecological malignancy in females in industrialized countries, especially for postmenopausal females in the sixth and seventh decades of life.[1,2] In the United States, the number of new cases and related deaths due to endometrial carcinoma were 61,880 and 12,160, respectively, in 2019.[2] Endometrioid carcinoma has a favorable prognosis, with 5-year disease-specific survival rates of approximately 80%, and the majority of endometrioid carcinomas appear in early stages at the time of diagnosis.[1,2] Presently, another noteworthy phenomenon is that the incidence of young premenopausal women with endometrial carcinoma is gradually increasing, with 5% to 30% represented by women aged ≤ 50 years at the time of diagnosis.[3] Approximately 20% of endometrial cancer patients die of disease due to aggressive tumors, advanced disease at diagnosis, or both. Hence, patients with a high risk of recurrence or insufficient surgical scope will be offered adjuvant radiotherapy and/or chemotherapy after surgical management for many decades.[4,5]
The standard surgical approach for endometrial carcinoma is based on total hysterectomy, bilateral salpingo-oophorectomy, and peritoneal cytology with or without pelvic and/or para-aortic lymph node dissection, according to the existence of preoperative high-risk factors.[6,7] As the most common endometrial carcinoma in young patients, endometrioid carcinoma is usually confined to clinical stage I, namely, located within the corpus uteri without malignant involvement extending beyond the uterus and metastasis to the pelvic and/or para-aortic lymph nodes.
According to the National Comprehensive Cancer Network and International Federation of Gynecology and Obstetrics (FIGO) guidelines,[8,9] total hysterectomy should be considered for stage I, radical hysterectomy for stage II, and tumor cell reduction for stage III or IV surgery. However, during the clinical work, we found that patients with the preoperative and intraoperative diagnosis of stage I endometrioid carcinoma complicated by high-risk factors still had a certain risk of postoperative pathological staging upgrades. Subsequently, this would increase the number of patients with postoperative adjuvant chemotherapy and/or radiotherapy, affecting the prognosis of patients due to insufficient surgical scope. Additionally, the complications of adjuvant radiotherapy and/or chemotherapy would increase, such as radiation dermatitis, radiation cystitis, proctitis, gastrointestinal reactions, myelosuppression, neurotoxicity, and nephrotoxicity. By the same token, excessive surgical scope seriously affects the quality of life of patients. Hence, if the postoperative pathological staging of patients with clinical stage I endometrioid carcinoma can be accurately predicted before surgery, combined with an appropriate surgical scope, an increase in postoperative adjuvant treatment and related complications due to insufficient preoperative estimation and unnecessary excessive increase in the scope of surgery can be avoided.
Here, we performed a retrospective study on patients with clinical stage I endometrioid carcinoma admitted to Women’s Hospital, School of Medicine, Zhejiang University, between 2002 and 2015, aiming to explore the possible preoperative or intraoperative predictive factors that may lead to the escalation of postoperative pathological staging, with a further view to optimizing therapeutic management.
2. Materials and methods
Patients with clinical stage I endometrioid carcinoma at Women’s Hospital, School of Medicine, Zhejiang University, between January 2002 and December 2015 were enrolled in the study. Due to preoperative or intraoperative surgical exploration, the patients with one or more preoperative or intraoperative high-risk factors, including preoperative high-grade tumor pathological classification (G3), preoperative imaging or an intraoperative depth of myometrial invasion >1/2, massive size of tumor (diameter of tumor larger than 4 cm), preoperative imaging or intraoperative special uterine lesion locations including the horns of the uterus or involving the internal cervix and positive intraoperative ascites cytology, accepted standard staging surgery, amounting to 535 cases in all. The median age of the patients was 56 years (31–78 years), 313 patients were postmenopausal, and 222 patients were premenopausal. Correspondingly, the clinicopathological data of patients were analyzed by interview at the clinic or by phone call. Standard staging operations for clinical stage I endometrial cancer include ascites cytology, total hysterectomy, bilateral adnexectomy and pelvic lymphadenectomy and/or para-aortic lymphadenectomy on account of National Comprehensive Cancer Network and FIGO guidelines. Basically, all enrolled patients did not receive chemotherapy or other antitumor treatments before surgery due to clinical stage I endometrioid carcinoma management options.
Clinicopathological factors including age, menopause, preoperative tumor pathological grade (G1–G2 or G3), preoperative imaging assessment or intraoperative gross examination of myometrial invasion depth (<1/2 or ≥1/2), or special uterine lesion locations including the horns of the uterus or involving the internal cervix, primary tumor diameter, peritoneal cytology, preoperative serum cancer antigen 125 (CA125) level (<35 U/mL or ≥35 U/mL) and postoperative surgical-pathological staging were recorded (Table 1). For surgical-pathological staging, we adopted the FIGO staging classification for cancer of the corpus uteri.[10] A retrospective study was performed to determine the associated with preoperative or intraoperative clinicopathological factors for predicting the upgrading of surgical-pathological staging in patients with clinical stage I endometrioid carcinoma. The patients were followed up postoperatively by interview at the clinic or by phone call. Regional tumor recurrence, distant metastasis, and patient survival were recorded. Disease-free survival (DFS) and overall survival (OS) were calculated from the day of the surgery until recurrence or death. The last day of follow-up was February 2019.
Table 1.
Preoperative and intraoperative influencing factors of 535 patients with preoperative clinical stage I endometrioid carcinoma.
| Influencing factors | N = 535 (%) | |
|---|---|---|
| Age | <60 | 381 (71.21%) |
| ≥60 | 154 (28.79%) | |
| Menopause | No | 222 (41.50%) |
| Yes | 313 (58.50%) | |
| Preoperative pathological grade | Low grade | 130 (24.30%) |
| Middle grade | 258 (48.22%) | |
| High grade | 147 (27.48%) | |
| Special uterine lesions locations | No | 459 (85.79%) |
| Yes | 76 (14.21%) | |
| Preoperative imaging assessment of myometrial invasion depth | <1/2 | 437 (81.68%) |
| ≥1/2 | 98 (18.32%) | |
| Intraoperative gross examination of myometrial invasion depth | <1/2 | 376 (70.28%) |
| ≥1/2 | 159 (29.72%) | |
| Primary tumor diameter (cm) | <4 | 411 (76.82%) |
| ≥4 | 124 (23.18%) | |
| Peritoneal cytology | Negative | 527 (98.50%) |
| Positive | 8 (1.50%) | |
| Preoperative serum CA125 (U/L) | <35 | 429 (80.19%) |
| ≥35 | 106 (19.81%) |
CA125 = cancer antigen 125.
Statistical analyses were performed using SPSS 16.0 for Windows (SPSS Inc., Chicago, IL). The χ2 test was used to detect the relationship between the upgrading of surgical-pathological staging and associated clinicopathological factors. Multivariate analysis was conducted using a logistic regression model. Survival curves were generated by the Kaplan–Meier method, and survival rates were compared using the log-rank test. The receiver operating characteristic curve was plotted, and the area under the curve (AUC) was calculated to evaluate the predictive value of clinicopathological factors. All statistical tests were two-sided, and P values of .05 were considered statistically significant.
The present study was approved by the Institutional Review Board, Women’s Hospital, School of Medicine, Zhejiang University (Approval number: 20170197). Informed consent was given and obtained from all individual participants included in the study.
3. Results
Of 535 patients diagnosed with clinical stage I endometrioid carcinoma, 125 (23.36%) were upgraded to higher surgical-pathological staging, including 61 (11.40%) upgraded to stage II, 62 (11.59%) upgraded to stage III and 2 (0.37%) upgraded to stage IV. Among the 62 patients upgraded to stage III, 28 (45.16%) were stage IIIA, 2 (3.23%) were stage IIIB, and 32 (51.61%) were stage IIIC. The rate of lymph node metastasis was 6.36%. Those with insufficient scope of surgery received supplemental radiotherapy and chemotherapy according to the guidelines after operation. The median follow-up was 79 months (range 14–182). During follow-up, 45 patients (8.4%, 45/535) were lost to follow-up, 47 patients experienced recurrence (9.59%, 47/490), and 41 patients died (8.37%, 41/490).
Among the 490 cases in the follow-up, 106 patients were upgraded to higher surgical-pathological staging, with 30 patients (28.30%, 30/106) experiencing recurrence and 29 patients (27.36%, 29/106) dying. The original staging was maintained in a total of 384 patients, of which 17 patients (4.43%) relapsed and 12 patients (3.13%) died. Kaplan–Meier survival curve analysis showed that the prognosis of postoperative surgical pathological staging-upgraded patients was worse than that of nonupgraded patients, and the tumor-free survival and overall survival rates of the 2 were significantly different (P < .001). The tumor-free survival time and the average overall survival time of patients with an upgraded stage were 118.2 ± 6.1 and 120.0 ± 5.9 months, respectively, which were significantly lower than those without an increase in the stage (174.2 ± 1.9 and 176.5 ± 1.6 months, respectively) (P < .01). The survival curves in Figure 1 show the association of surgical-pathological staging upgrading with DFS and OS in 490 patients with clinical stage I endometrioid carcinoma. The Kaplan–Meier analysis showed that patients with surgical-pathological staging upgrading had significantly shorter DFS (P = 3.90E−14, Fig. 1A) and OS (P = 6.42E−16, Fig. 1B). The 5-year DFS and OS were 70.4% and 72.9% for the upgraded staging group and 95.2% and 98.1% for the former staging group (P < .01).
Figure 1.
Kaplan–Meier curves showing the relationship between surgical-pathological staging upgrading and disease-free survival (DFS) and overall survival (OS) in 490 patients with clinical stage I endometrioid carcinoma. The patients with surgical-pathological staging upgrading were significantly associated with shorter DFS (A) and OS (B).
Univariate and multivariate regression models were applied to determine the preoperative or intraoperative factors in predicting the escalation of surgical pathological staging in 535 patients with clinical stage I endometrioid carcinoma. Univariate analysis showed that preoperative imaging examination and intraoperative visual inspection of the depth of myometrial invasion, massive size of tumor (≥4 cm), and preoperative serum CA125 level were significantly correlated with postoperative surgical pathological staging (P < .05) (Table 2). Next, multivariate analysis showed that the size of the tumor and preoperative serum CA125 level were independent risk factors that affected the escalation of postoperative surgical pathological staging (P < .05) (Table 3). Finally, receiver operating characteristic curves were generated with the factors of massive size of tumor and preoperative serum CA 125 level and a combination of the 2 factors. The AUC was 0.718 (95% confidence interval [CI], 0.667–0.770) for the preoperative serum CA125 level alone group, 0.675 (95% CI, 0.622–0.729) for the massive tumor-alone group and 0.723 (95% CI, 0.672–0.773) for the combination group. The combination of the preoperative serum CA125 level and massive-tumor factors displayed a medium-intensity predictive value for the postoperative escalation of surgical pathological staging in 535 patients with clinical stage I endometrioid carcinoma (Fig. 2).
Table 2.
Univariate logistic analysis showed the preoperative and intraoperative predictive factors in predicting the escalation of surgical pathological staging in 535 patients with clinical stage I endometrioid carcinoma.
| Factors | Escalation of surgical pathological staging (%) | χ2 | P-value | |
|---|---|---|---|---|
| No | Yes | |||
| Age (year) | 1.264 | .261 | ||
| <60 | 287 (53.6) | 94 (17.6) | ||
| ≥60 | 123 (23.0) | 31 (5.8) | ||
| Menopause | 1.616 | .204 | ||
| No | 164 (30.7) | 58 (10.8) | ||
| Yes | 246 (46.0) | 67 (12.5) | ||
| Preoperative pathological grade | 1.135 | .287 | ||
| Low and middle grade | 302 (56.4) | 86 (16.1) | ||
| High grade | 108 (20.2) | 39 (7.3) | ||
| Special uterine lesions locations | 1.938 | .164 | ||
| No | 347 (64.9) | 112 (20.9) | ||
| Yes | 63 (11.8) | 13 (2.4) | ||
| Preoperative imaging assessment of myometrial invasion depth | 18.091 | 2.1E−5 | ||
| <1/2 | 351 (65.6) | 86 (16.1) | ||
| ≥1/2 | 59 (11.0) | 39 (7.3) | ||
| Intraoperative gross examination of myometrial invasion depth | 11.022 | .001 | ||
| <1/2 | 303 (56.6) | 73 (13.6) | ||
| ≥1/2 | 107 (20.0) | 52 (9.7) | ||
| Primary tumor diameter (cm) | 28.448 | 9.62E−8 | ||
| <4 | 337 (63.0) | 74 (13.8) | ||
| ≥4 | 73 (13.6) | 51 (9.5) | ||
| Peritoneal cytology | 0.282 | .595 | ||
| Negative | 405 (75.7) | 122 (22.8) | ||
| Positive | 5 (0.9) | 3 (0.6) | ||
| Preoperative serum CA125 (U/L) | 56.153 | 6.71E−14 | ||
| <35 | 358 (66.9) | 71 (13.3) | ||
| ≥35 | 52 (9.7) | 54 (10.1) | ||
CA125 = cancer antigen 125.
Table 3.
Multivariate logistic analysis display the preoperative and intraoperative predictive factors in predicting the escalation of surgical pathological staging in 535 patients with clinical stage I endometrioid carcinoma.
| Characteristics | Regression coefficient (B) | Standard error (SE) |
χ 2 (Wald) |
P-value |
|---|---|---|---|---|
| Preoperative imaging assessment of myometrial invasion depth | 0.543 | 0.299 | 3.292 | .070 |
| Intraoperative gross examination of myometrial invasion depth | 0.136 | 0.270 | 0.254 | .614 |
| The massive tumor | 0.740 | 0.246 | 9.031 | .003 |
| Preoperative serum CA125 | 1.403 | 0.244 | 33.000 | 9.22E−9 |
CA125 = cancer antigen 125.
Figure 2.
The AUC of the multivariate base model (the combination of preoperative serum CA125 level and massive size of tumor) could have a medium-intensity predictive value for postoperative escalation of surgical pathological staging in 535 patients with clinical stage I endometrioid carcinoma.
4. Discussion
Worldwide, endometrioid cancer is one of the most common gynecologic malignancies, and its incidence is increasing. Although endometrioid carcinoma has a quite favorable prognosis, exhibiting 5-year disease-specific survival rates of approximately 80% in total and 93% in women younger than 40 years, the mortality from this cancer has not apparently declined, primarily driven by insufficient surgical scope and/or postoperative pathological staging upgrades, which ultimately led to relapse in recent decades.[11] Patients with the preoperative and intraoperative diagnosis of clinical stage I endometrioid carcinoma complicated by certain high-risk factors still display risk of postoperative pathological staging upgrades. Overall, tumor stage upgrading was found in 23.36% of our patients, and our findings were similar to those reported in other studies. Cowles et al 1985 reported 21.7%, and Suwannee et al 2009 reported 25.5%.[12,13] Ultimately, such upgrading will prompt patients to receive postoperative auxiliary chemotherapy and/or radiotherapy, which will affect the prognosis of patients and increase adjuvant therapy complications due to the insufficient estimation of surgical scope. By the same token, excessive surgical scope (such as lymphadenectomy and/or omentectomy) affects the quality of patient life. Therefore, accurate preoperative pathological staging and awareness of the possible preoperative or intraoperative predictive factors that may lead to the escalation of postoperative pathological staging seem be particularly important for the aim of further optimizing therapeutic management.
Our results suggested that massive size of tumor and preoperative serum CA125 level were predictive risk factors for the escalation of postoperative surgical pathological staging in clinical stage I endometrial carcinoma patients, and their recognition could facilitate the preoperative counseling of patients and clinical decision-making for the first time. Univariate and multivariate logistic analyses further validated preoperative imaging of massive tumor and serum CA125 as independent risk predictors of escalation of postoperative surgical pathological staging. Consistently, AUC data showed that the combination of preoperative massive size of tumor and serum CA125 had a medium predictive value for the postoperative escalation of surgical pathological staging to a certain degree. These results suggest that the appropriate surgical scope, lymphadenectomy, and/or omentectomy during the surgery may be fully evaluated in the clinical stage I endometrioid carcinoma patients with massive size of tumor and abnormal preoperative serum CA125 level.
As a tumor marker of female genital tract epithelial tumor markers, CA125 has been widely used in the clinic since its discovery 30 years ago.[14] The preoperative serum CA125 level has been previously identified as a prognostic factor in ovarian metastasis.[15] A total of 80% of primary epithelial ovarian carcinomas and 70% of secondary ovarian tumors are diagnosed based on elevated CA125 levels.[16,17] Moreover, Reijnen et al found CA125 elevation in 26.2% of women with grade 1 or 2 endometrioid cancer. Elevated CA125 was significantly associated with advanced stage and deep myometrial invasion.[18] Jiang and colleagues reported that preoperative serum CA125 is an effective predictor of lymph node metastasis in patients with endometrial cancer, particularly clinical stage I.[19] CA125 was independently associated with the escalation of postoperative surgical pathological staging in our study.
There is mounting evidence that the estimation of tumor size may improve endometrial cancer treatment. According to the current approach, systematic lymph node dissection is recommended for a primary tumor diameter >2 cm.[20] When tumor size increased, both tumor stage and grading were significantly increased. Moreover, tumor size was correlated with CA125 serum values, node metastasis and peritoneal cytology status.[21] The combination of the factors of preoperative serum CA125 level and massive size of tumor may thus present an effective predictive risk factor for postoperative escalation of surgical pathological staging in patients with clinical stage I endometrioid carcinoma. Analysis of the combined factors also revealed utility as a predictive marker of postoperative escalation of surgical pathological staging to some extent. Other preoperative risk factors, including age at diagnosis, depth of muscular invasion, and peritoneal lavage cytology,[22] have not exhibited predictive value, similar to our research.
Our study was a single-center retrospective study and had some limitations that should be addressed. Large-scale prospective clinical studies are necessary to ascertain whether the combination of massive size of tumor and preoperative serum CA125 level can predict the escalation of postoperative pathological staging to reduce bias.
5. Conclusion
Our results showed that the incidence of upgrading to higher surgical-pathological staging was approximately 23.36% in patients with clinical stage I endometrioid carcinoma. These upgraded patients had a relatively poor prognosis. The clinical stage I endometrioid carcinoma patients with massive size of tumor and abnormal preoperative serum CA125 level need to be fully evaluated to ensure appropriate management as soon as possible, since they are more likely to experience postoperative pathological staging upgrades.
Author contributions
Conceptualization: Baohua Li.
Data curation: Na Li, Qin Chen.
Investigation: Na Li, Qin Chen.
Methodology: Na Li, Baohua Li.
Project administration: Baohua Li.
Software: Na Li, Baohua Li.
Writing – original draft: Na Li.
Writing – review & editing: Na Li, Qin Chen, Baohua Li.
Abbreviations:
- AUC
- area under the curve
- CA125
- cancer antigen 125
- DFS
- disease-free survival
- FIGO
- International Federation of Gynecology and Obstetrics
- OS
- overall survival
This work was supported by Zhejiang Provincial Natural Science Foundation of China (No. LY18H160004, https://zjnsf.kjt.zj.gov.cn), the Medical and Health Science and Technology Plan Project of Zhejiang Province (No. 2015KYA124, http://www.zjmed.org.cn), and the Clinical Research Foundation of Women’s Hospital, School of Medicine, Zhejiang University.
The authors have no conflicts of interest to disclose.
All data generated or analyzed during this study are included in this published article [and its supplementary information files].
How to cite this article: Li N, Chen Q, Li B. The analysis of preoperative or intraoperative factors in predicting the escalation of surgical pathological staging of patients with clinical stage I endometrioid carcinoma: A retrospective clinical study. Medicine 2024;103:11(e37465).
Contributor Information
Na Li, Email: lbh19787@zju.edu.cn.
Qin Chen, Email: daisychenqin@zju.edu.cn.
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