Abstract
Objective
The incidence of endometrial cancer (EC) has been increasing annually. Studies have reported that cesarean section (CS) is associated with a higher risk of developing EC than vaginal delivery (VD). However, few studies have examined the relationship between CS and EC development.
Methods
Data were extracted from the medical records of patients with EC and a history of childbirth who underwent EC treatment at 3 institutions. Factors contributing to EC development were analyzed between April 2010 and December 2024.
Results
Among patients EC and a history of childbirth, 8.7% (69/794) had undergone CS, and 50.7% (35/69) developed a CS scar. Compared with patients who had a VD or those without a CS scar, patients with a CS scar showed significantly shorter intervals from delivery to EC onset (VD: p=0.013; non-CS scar: p=0.031). A narrower residual myometrial thickness/adjacent myometrial thickness (RMT/AMT) ratio of the CS scar was significantly associated with a shorter interval from the last delivery to EC onset (p=0.034) and was independently associated with earlier EC onset after the last delivery in both univariate and multivariate analyses (p<0.001 and p=0.030, respectively).
Conclusion
A narrower RMT/AMT ratio in the CS scar was considerably associated with a shorter interval from the last delivery to EC onset.
Keywords: Endometrial Cancer, Cesarean Section, Cesarean Section Scar, Interval from Delivery to Endometrial Cancer Onset, Residual Myometrial Thicknes/Adjacent Myometrial Thickness Ratio
Synopsis
Cesarean section (CS) scar in endometrial cancer (EC) accounts for 50.7% of patients with CS. CS scar is associated with the short interval from last delivery to EC onset. A narrower residual myometrial thicknes/adjacent myometrial thickness ratio of the CS scar was considerably associated with a shorter interval from last delivery to EC onset.
INTRODUCTION
The prevalence of cesarean section (CS) has been steadily increasing worldwide [1], and Japan has not escaped this trend, with rates currently exceeding 20% [2]. Although CS has become a safe procedure, unexpected bleeding, infection, and damage to other organs can occur during surgery, and early and mid-term postoperative complications include pulmonary embolism and CS scar [3,4,5]. However, little research has been conducted on the long-term postoperative complications of CS.
CS scarring is currently one of the most popular topics in the field of obstetrics and gynecology. The incidence of CS scars in patients who have undergone CS ranges from 19% to 100% [6,7]. The presence of CS scars has been associated with various gynecological symptoms, such as postmenstrual spotting, dysmenorrhea, chronic pelvic pain, and dyspareunia [7,8,9,10,11,12]. Additionally, patient-related risk factors such as maternal body mass index (BMI) and gestational diabetes have been implicated [13,14].
Endometrial cancer (EC) is the only malignancy for which CS is associated with an increased risk [15,16]. Although EC development is associated with hypertensive disorders of pregnancy (HDP), diabetes mellitus (DM), obesity, and multiple births [16], the factors linking CS to EC development remain unclear. Therefore, in this study, we focused on and examined in detail the relationship between EC and CS, particularly CS scars, which represents one of the key topics in the field of obstetrics and gynecology.
MATERIALS AND METHODS
1. Patients and tissue specimens
This multicenter retrospective study was conducted at the Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; National Hospital Organization Iwakuni Clinical Center; and Kagawa Rosai Hospital and was approved by the Ethics Committee of Okayama University (approval No. 2505-023). In total, 794 patients with EC who had a history of childbirth between April 2010 and December 2024 were enrolled, examined, and analyzed in this study. The following data were extracted from the medical records of these patients: age at EC onset, premenopausal status, BMI, hypertension (HT), DM, hyperlipidemia (HL), HDP, number of pregnancies and deliveries, age at last delivery, interval from last delivery to EC onset, menopausal status, histopathological findings, disease stage, and the presence or absence of a CS scar. However, because this information was extracted from medical records, it was difficult to obtain detailed data regarding surgical indications, surgeon experience, suturing techniques, and suture materials.
2. Assessment of the CS scar
The European Niche Task Force defines a CS scar as a depression of 2 mm or more in depth at the site of a CS scar on ultrasound examination [17,18]. In this study, we defined a CS scar as the presence of a depression having 2 mm or more in depth and height using excised tissue from patients with EC (fresh specimens immediately after surgery, not fixed in formalin), rather than the ultrasound examination used by the European Niche Task Force. We decided to use fresh specimens obtained immediately after surgery for morphological evaluation, as we believe that this would provide a more accurate evaluation than that based on diagnostic images. An internal scar is described as a defect at the CS with a depth of at least 2 mm on the internal border of the uterus. Conversely, an external scar is identified by a defect on the outer border at an acute angle that surpasses 2 mm in depth. Residual myometrial thickness (RMT) was determined by measuring the distance between the serous layer and the endometrium at the apex of the scar, where the myometrium is thinnest, while adjacent myometrial thickness (AMT) was defined as the distance between the 2 layers up to 1 cm above the base of the defect [19]. Using hysterectomy specimens, internal scar depth (ISD), external scar depth (ESD), internal scar height (ISH), external scar height (ESH), RMT, and AMT were measured. Measurements of the CS scar depth and height were performed in triplicate by 2 independent investigators using tissues excised from patients with EC. Fig. S1 demonstrates the measurements of each CS scar. Table S1 shows the characteristics of patients with CS scars in this study.
3. Statistical analysis
Our study employed rigorous statistical analyses, including the Mann–Whitney U test for comparisons with controls and one-way analysis of variance followed by Fisher’s protected least significant difference test for all pairwise comparisons. Differences between the delivery methods and scar status were evaluated using a log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model to identify the factors predicting the interval from the last delivery to the onset of EC. Statistical significance was defined as p<0.05. All analyses were conducted using the SPSS software (version 29.0; IBM Corp., Armonk, NY, USA) to ensure accuracy and reliability.
RESULTS
Table 1 summarizes the distribution of the clinical characteristics of the study population. Between the CS group—including those who subsequently had a vaginal delivery (VD)—and the VD group, significant differences were observed in age at EC onset (p<0.001), premenopausal status (p=0.024), BMI (p=0.021), DM (p=0.011), HL (p=0.013), HDP (p<0.001), number of pregnancies (p=0.001), number of deliveries (p=0.008), age at last delivery (p<0.001), and interval from last delivery to EC onset (p<0.001) (Table 2).
Table 1. Patient and tumor characteristics.
| Baseline characteristics | Numbers | % | |
|---|---|---|---|
| Age (yr) | |||
| <40 | 13 | 1.6 | |
| 40–49 | 56 | 7.1 | |
| 50–59 | 222 | 28 | |
| 60–69 | 265 | 33.4 | |
| 70–79 | 178 | 22.4 | |
| ≥80 | 60 | 7.6 | |
| BMI (kg/m2) | |||
| <18.5 | 61 | 7.7 | |
| 18.5–24.9 | 409 | 51.5 | |
| 25.0–29.9 | 209 | 26.3 | |
| 30.0–34.9 | 74 | 9.3 | |
| 35.0–39.9 | 33 | 4.2 | |
| ≥40.0 | 8 | 1 | |
| Stage | |||
| I | 591 | 74.4 | |
| II | 48 | 6 | |
| III | 101 | 12.7 | |
| IV | 54 | 6.8 | |
| Histology | |||
| Endometrioid adenocarcinoma G1 | 414 | 52.1 | |
| Endometrioid adenocarcinoma G2 | 126 | 15.9 | |
| Endometrioid adenocarcinoma G3 | 78 | 9.8 | |
| Serous adenocarcinoma | 64 | 8.1 | |
| Carcinosarcoma | 55 | 6.9 | |
| Mixed type | 27 | 3.4 | |
| CCC | 14 | 1.8 | |
| Other carcinoma | 16 | 2 | |
| Number of pregnancies | |||
| 1 | 102 | 12.8 | |
| 2 | 342 | 43.1 | |
| ≥3 | 450 | 44.1 | |
| Number of births | |||
| 1 | 137 | 17.3 | |
| 2 | 473 | 59.6 | |
| ≥3 | 184 | 23.1 | |
BMI, body mass index; CCC, clear cell carcinoma.
Table 2. Comparison of clinical characteristics of EC by mode of delivery.
| Variable | VD (n=725) | CS (n=69) | p-value |
|---|---|---|---|
| Age at EC onset | 63.93±11.14 | 59.48±9.80 | <0.001*** |
| Pre-menopause status | 113 (15.6%) | 18 (26.1%) | 0.024* |
| Stage (≥III) | 143 (19.7%) | 13 (18.8%) | 0.881 |
| Histology (aggressive type) | 233 (32.1%) | 22 (31.9%) | 0.965 |
| BMI (≥30.0 kg/m2) | 24.51±5.37 | 26.30±6.13 | 0.021* |
| HT (present) | 204 (28.1%) | 19 (27.5%) | 0.915 |
| DM (present) | 82 (11.3%) | 15 (21.7%) | 0.011* |
| HL (present) | 110 (15.2%) | 3 (4.3%) | 0.013* |
| HDP (present) | 5 (0.7%) | 5 (7.2%) | <0.001*** |
| Number of pregnancies | 2.53±1.01 | 2.19±0.81 | 0.001** |
| Number of deliveries | 2.11±0.70 | 1.87±0.71 | 0.008** |
| Age at last delivery | 29.26±4.02 | 31.12±4.37 | <0.001*** |
| Interval from last delivery to EC onset | 34.57±12.86 | 28.36±10.81 | <0.001*** |
Values are presented as mean ± standard deviation or number (%).
BMI, body mass index; CS, caesarean section; DM, diabetes mellitus; EC, endometrial cancer; HDP, hypertensive disorders of pregnancy; HL, hyperlipidemia; HT, hypertension; VD, vaginal delivery.
*p<0.05, **p<0.01, ***p<0.001.
Upon comparing the presence or absence of CS scars, significant differences were found in age at EC onset (p=0.009), premenopausal status (p=0.033), histology (p=0.031), and interval from last delivery to EC onset (p=0.011) (Table 3). Furthermore, in this study, patients with EC were divided into three groups: those with CS scars, those without (non-CS scars), and those with a history of VD. Significant differences were identified in the age at onset, premenopausal status, and interval from last delivery to onset of EC (VD: p<0.001, p<0.001, and p=0.013; non-CS scars: p=0.009, p=0.011, and p=0.031, respectively) (Fig. S2). Interestingly, the interval from the last delivery to EC onset in patients with a CS scar was markedly shorter than that in patients with a VD or a non-CS scar.
Table 3. Comparison of CS with or without scar in EC.
| Variable | CS scar(−) (n=34) | CS scar(+) (n=35) | p-value |
|---|---|---|---|
| Age at EC onset | 62.53±9.64 | 56.51±9.14 | 0.009** |
| Pre-menopause status | 5 (14.7%) | 13 (37.1%) | 0.033* |
| Stage (≥III) | 8 (23.5%) | 5 (14.3%) | 0.326 |
| Histology (aggressive type) | 15 (44.1%) | 7 (20.0%) | 0.031* |
| BMI (≥30.0 kg/m2) | 25.56±5.71 | 27.02±6.50 | 0.326 |
| HT (present) | 10 (29.4%) | 9 (25.7%) | 0.731 |
| DM (present) | 9 (26.5%) | 6 (17.1%) | 0.348 |
| HL (present) | 1 (2.9%) | 2 (5.7%) | 0.572 |
| HDP (present) | 2 (5.9%) | 3 (8.6%) | 0.666 |
| Number of pregnancies | 2.12±0.69 | 2.26±0.92 | 0.476 |
| Number of deliveries | 1.88±0.64 | 1.86±0.77 | 0.882 |
| Age at last delivery | 30.88±4.45 | 31.30±4.35 | 0.665 |
| Interval from last delivery to EC onset | 31.64±10.56 | 25.17±10.19 | 0.011* |
Values are presented as mean ± standard deviation or number (%).
BMI, body mass index; CS, caesarean section; DM, diabetes mellitus; EC, endometrial cancer; HDP, hypertensive disorders of pregnancy; HL, hyperlipidemia; HT, hypertension.
*p<0.05, **p<0.01.
The study population was divided into two groups: those with a time interval between last birth and EC onset of 25 years or more, and those with a time interval between last birth and EC onset of less than 25 years, with 25 years as the cutoff value. The results showed that ISD, ESH, and the RMT/AMT ratio significantly contributed to the onset of early EC (p=0.045, p=0.042, and p=0.034, respectively) (Table 4), with the RMT/AMT ratio being more closely associated with a shorter time interval between the last birth and EC onset than the other CS scar parameters.
Table 4. Relationship between patient interval from last delivery to endometrial cancer onset (<25 years) and caesarean section.
| Variable | <25 yr (n=24) | ≥25 yr (n=45) | p-value |
|---|---|---|---|
| ISD (mm) | 4.24±4.23 | 2.22±3.21 | 0.045* |
| ISH (mm) | 4.04±4.44 | 2.70±4.66 | 0.244 |
| ESD (mm) | 1.92±2.58 | 0.75±1.78 | 0.051 |
| ESH (mm) | 1.60±2.44 | 0.50±1.13 | 0.042* |
| RMT/AMT (%) | 63.10±28.31 | 78.40±27.73 | 0.034* |
Values are presented as mean ± standard deviation.
AMT, adjacent myometrial thickness; ESD, external scar depth; ESH, external scar height; ISD, internal scar depth; ISH, internal scar height; RMT, residual myometrial thickness.
*p<0.05.
Correlations between clinical factors and a short interval from the last delivery to EC onset (<25 years) were assessed using univariate and multivariate analyses. In the univariate analysis, histology (p<0.001), HT (p=0.001), HL (p<0.001), and the RMT/AMT ratio (p<0.001) were significantly associated with a short interval from the last delivery to EC onset. In the multivariate analysis, histology (p<0.001), HT (p<0.001), HL (p=0.012), and the RMT/AMT ratio (p=0.003) remained independent predictors of a short interval from the last delivery to EC onset (Table 5).
Table 5. Factors for interval from last delivery to EC onset (<25 years) selected by Cox’s univariate and multivariate analysis.
| Variable | Exp(B) | Univariate analysis | Exp(B) | Multivariate analysis | ||
|---|---|---|---|---|---|---|
| 95% CI | Cox’s test p-value | 95% CI | Cox’s test p-value | |||
| BMI (≥30.0 kg/m2) | 1.193 | 0.806–1.766 | 0.378 | 1.261 | 0.842–1.888 | 0.260 |
| Stage (≥III) | 1.446 | 0.960–2.177 | 0.078 | 1.019 | 0.665–1.561 | 0.933 |
| Histology (aggressive type) | 0.342 | 0.227–0.515 | <0.001*** | 0.354 | 0.231–0.544 | <0.001*** |
| HT (present) | 0.324 | 0.207–0.506 | <0.001*** | 0.373 | 0.235–0.591 | <0.001*** |
| DM (present) | 0.618 | 0.365–1.049 | 0.075 | 0.884 | 0.513–1.523 | 0.656 |
| HL (present) | 0.356 | 0.194–0.656 | 0.001*** | 0.451 | 0.242–0.840 | 0.012* |
| HDP (present) | 0.907 | 0.225–3.656 | 0.891 | 0.849 | 0.207–3.481 | 0.820 |
| RMT/AMT (%) | 2.870 | 1.717–4.798 | <0.001*** | 2.251 | 1.330–3.809 | 0.003** |
AMT, adjacent myometrial thickness; BMI, body mass index; CI, confidence interval; DM, diabetes mellitus; EC, endometrial cancer; HDP, hypertensive disorders of pregnancy; HL, hyperlipidemia; HT, hypertension; RMT, residual myometrial thickness.
*p<0.05, **p<0.01, ***p<0.001.
DISCUSSION
EC is the most common gynecologic malignancy and the fourth most common cancer in women in the United States, following breast, lung, and colorectal cancers [20]. The established risk factors for EC include early menarche, late menopause, nulliparity, infertility or ovulation disorders, and polycystic ovarian syndrome, primarily due to prolonged estrogen exposure in the endometrium [21]. Additional risk factors include obesity, HT, DM, and HDP [16,22]. A large-scale data synthesis study including Asian populations reported that late menarche, early menopause, and increased parity were strongly associated with a reduced risk of EC [16]. Although increased parity lowers the risk of EC, several studies have suggested that CS might be a risk factor for EC compared with VD [15,16]. Given these findings, we investigated the type of delivery, particularly the presence of CS scars, in patients with EC who had a history of childbirth.
Our results demonstrated that, compared with the VD group, the CS group exhibited an earlier age at onset, a higher proportion of premenopausal patients, higher BMI, higher prevalence of DM and HDP, lower prevalence of HL, fewer pregnancies and deliveries, higher age at last delivery, and a shorter interval from last delivery to EC onset. Furthermore, compared with the non-CS scar group, the CS scar group had an earlier age at onset, a higher proportion of premenopausal patients, and a shorter interval from the last delivery to onset. Notably, a narrower RMT/AMT ratio of the CS scar was strongly associated with a shorter interval from the last delivery to EC onset in univariate and multivariate analyses. Interestingly, we report for the first time that a narrower RMT/AMT ratio in CS scars was significantly associated with a shorter interval between the last birth and onset of EC.
To date, HDP, DM, obesity, and multiple births have been recognized as risk factors for the development of EC following CS [16]; however, the underlying mechanisms remain unknown. In this study, we found that CS, HDP, DM, and obesity were associated with the development of EC, consistent with previous reports. Additionally, we observed differences in the number of deliveries and identified a role of CS scars in EC development. The only evidence for EC development in CS is suggested to be the malignant transformation of endometriotic lesions within the CS scar [23,24,25,26]; however, no other reports have been published to date. Further investigations, including those on the underlying mechanism, are warranted.
However, this study had some limitations. The sample size was relatively small, and the study design was retrospective. Further prospective studies involving more patients and facilities should provide definitive data to confirm the significance of our findings.
In conclusion, this study found that CS scars were present in 4.4% of patients with EC. Compared with patients who had VD or no CS scars, those with CS scars developed EC after a shorter interval from the last delivery to disease onset. In particular, a narrower RMT/AMT ratio in the CS scar was strongly associated with a shorter interval from the last delivery to EC onset. To our knowledge, this is the first study to explore the relationship between CS scars and EC.
Footnotes
Conflict of Interest: No potential conflict of interest relevant to this article was reported.
Data Availability: Data available on request from the corresponding author.
- Conceptualization: N.K.
- Formal analysis: N.K., T.Y., I.H., S.M., D.L.H.T., N.H., O.K., O.C.
- Funding acquisition: N.K.
- Methodology: N.K., O.K.
- Supervision: N.K., M.H.
- Validation: D.L.H.T., N.K.
- Visualization: N.K.
- Writing - original draft: N.K., D.L.H.T., N.K. O.K., O.C.
- Writing - review & editing: O.K., E.E., M.H.
SUPPLEMENTARY MATERIALS
CS scar characteristics in patients with endometrial cancer
The images depict both internal and external niches at the cesarean scar site. ①: ISD, ② ISH, ③ ESD, ④ ESH, ⑤ AMT, and ⑥ RMT.
Comparison of the 3 groups of patients with EC—VD, no CS scar (−), and CS scar (+)—with respect to age at onset, premenopausal status, and the interval from the last delivery to EC onset.
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Associated Data
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Supplementary Materials
CS scar characteristics in patients with endometrial cancer
The images depict both internal and external niches at the cesarean scar site. ①: ISD, ② ISH, ③ ESD, ④ ESH, ⑤ AMT, and ⑥ RMT.
Comparison of the 3 groups of patients with EC—VD, no CS scar (−), and CS scar (+)—with respect to age at onset, premenopausal status, and the interval from the last delivery to EC onset.