High-level resection of the infundibulopelvic ligament during surgery of epithelial ovarian cancer is necessary: a retrospective comparative study.

Ovarian cancer is a malignant gynecological disease with a high mortality rate, surpassing that of cervical and endometrial cancers ( 1 , 2 ). The main type of ovarian cancer is epithelial ovarian cancer (EOC). Surgery followed by chemotherapy is the most common treatment for EOC ( 3 ). The thoroughness of surgery is one of the most crucial factors affecting patient prognosis and survival rate ( 4 ). Complete cytoreduction to eliminate residual tumors is one of the most important factors influencing survival in patients with EOC ( 3 , 5 , 6 ). The removal of all tumors is the goal of surgical treatment; furthermore, it is not advisable to depend on visual exam and palpation to evaluate the degree of metastasis. A combination of microscopic cytoreductive surgery and conventional surgery may improve survival rates. The risk of microscopic peritoneal metastases in patients with EOC after complete macroscopic cytoreductive surgery was 98.14% ( 7 ). Lymphatic, hematogenous, and transcoelomic routes are some of the potential pathways of EOC metastasis ( 8 ). Metastatic cells travel through the lymph vessels of the infundibulopelvic (IP) ligament, moving along with the ovarian artery and vein towards the para-aortic and pelvic lymph nodes ( 9 - 11 ). Direct extension of EOC into the IP ligament is another way of metastases. Hence, clinicians should consider the possibility of metastases in the IP ligament when treating patients with EOC. Resection of the IP ligament is a common component of salpingo-oophorectomy in both benign and malignant gynecological diseases. A recent study proposed the resection of the IP ligament at ≥2 cm away from the visual ovarian margins to ensure complete removal of the residual ovarian tissue ( 12 ). The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology suggest removing 2 cm of the proximal IP ligament during risk-reducing salpingo-oophorectomy ( 13 ). To the best of our knowledge, no previous study has identified the adequate length of IP ligament resection during cytoreductive surgery to reduce the metastasis risk in the IP ligament of patients with EOC. The decision to set the HLR of the IP ligament at ≥10 cm in this study was based on a combination of factors. From an anatomical perspective, this length extends beyond the typical area of potential tumor spread and reaches a region where the lymphatic and vascular connections to the primary tumor are more likely to be interrupted. In pilot analyses conducted at our institution, we observed that tumors often involved the IP ligament up to a certain distance from the ovarian margin, and a resection length of ≥10 cm appeared to effectively remove tissues with a higher probability of containing metastatic cells. Moreover, in terms of surgical feasibility, our experienced surgical team determined that a resection of this length could be performed safely with acceptable operative risks and without causing significant damage to adjacent structures such as the ureters and major blood vessels. In the context of EOC, which has a high mortality rate, understanding the role of the IP ligament in metastasis and the importance of its resection is crucial. The IP ligament serves as a potential pathway for cancer cell dissemination, with metastatic cells traveling through its lymph vessels to reach para-aortic and pelvic lymph nodes. Additionally, it may harbor residual ovarian tissue, which can cause various complications and even cancer recurrence. High-level resection (HLR) of the IP ligament could potentially improve patient prognosis by reducing the risk of lymph node metastasis, guiding surgical practice towards more effective treatment, and contributing to long-term disease control. This study aims to evaluate the necessity and clinical significance of HLR of the IP ligament during EOC surgery (≥10 cm), which is of great importance for enhancing our understanding of EOC treatment and improving patient outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://gpm.amegroups.com/article/view/10.21037/gpm-25-2/rc ).

This retrospective comparative study involved 80 female patients with EOC of Federation International of Gynecology and Obstetrics (FIGO) stages I–IV who underwent HLR of the IP ligament (≥10 cm) (HLR) during cytoreductive surgery via laparotomy between October 2019 and June 2023 at West China Second University Hospital, Sichuan University, Chengdu, China ( 14 ). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the West China Second University Hospital [approval number: 2022(167)]. Informed consent was obtained from all individual participants. An experienced gynecological oncology team performed all surgeries. The patients whose IP ligaments could not be accurately measured without maintaining a long stripe shape and those with fertility-sparing requirements were excluded. A total of 93 patients with confirmed FIGO I–IV EOC who did not undergo HLR [i.e., without HLR (WHLR)] of the IP ligament during the same period but underwent non-fertility-sparing cytoreductive surgery were selected randomly as the WHLR group or control group. To achieve this, we first created a list of all eligible patients who met the criteria. Each patient on the list was assigned a unique identification number. Using a computer-generated random number table, we selected patients whose identification numbers corresponded to the generated random numbers until the sample size of 93 was reached. This random selection process was implemented to reduce selection bias and ensure the representativeness of the control group. The sample size for each group was not determined based on a formal power analysis. Instead, the sample size was based on the available patient population during the study period at the hospital. Given the retrospective nature of the study, all eligible patients who met the inclusion criteria were included. For the HLR group, 80 patients were identified who had undergone the specific surgery. In the control group, 93 patients were randomly selected from those who did not have HLR. While this approach may limit the statistical power to detect small differences between the groups, it provides valuable real-world data. Future studies could conduct a priori power analyses to determine an optimal sample size based on expected effect sizes and significance levels. The primary outcome of interest was the presence of metastatic cells in the IP ligament. After resection, the IP ligament specimens were carefully processed. They were fixed in 10% neutral buffered formalin, sectioned longitudinally at 10 mm intervals, embedded in paraffin, and further sectioned horizontally at a thickness of 4 µm for hematoxylin and eosin staining. Experienced pathologists examined the sections to identify any metastatic cells. The distance of metastatic cells from the visual ovarian margin was also measured. Another crucial set of outcomes focused on the relationship between IP ligament HLR and lymph node metastasis as well as recurrence. For lymph node metastasis, both preoperative and postoperative computed tomography (CT) scans were utilized. Preoperative CT results were examined to assess the initial status of lymph node involvement, while postoperative CT scans were obtained at various time points (2, 4–8, 12, 18, 24, and more than 36 months after surgery) to monitor the development of lymph node metastasis over time. Recurrence was also recorded based on clinical symptoms, imaging findings, and other relevant diagnostic methods during the follow-up period. Lymph node positivity on CT images was defined consistently for both preoperative and postoperative assessments. Specifically, a lymph node was considered positive if its short diameter was ≥10 mm on the CT scan. Secondary outcomes included other clinicopathological features such as the number of lymph nodes dissected (total, para-aortic, and pelvic), operative time, intraoperative bleeding volume, and the presence of intraoperative complications (ureteral or vascular injuries). The following baseline clinicopathological patient data were extracted from medical records: age (years), body mass index (BMI), menopausal status (pre- or postmenopausal), lymph-node metastasis, postoperative diagnosis, intraoperative conditions, and postoperative follow-up. Standard measurements included IP ligament length in vivo , fixed specimen length after resection, and dissemination distance of metastatic cells into IP ligament (cm). The in vivo IP ligament length was measured intraoperatively under the following standardized conditions. First, after the IP ligament was completely exposed at the level of the inferior mesenteric artery during the surgical procedure, it was carefully positioned in its natural anatomical state without applying any additional tension. This ensured that the measurement represented the true physiological length of the IP ligament in the patient’s body. To perform the measurement, a sterile, flexible measuring tape was used in the operating room. The measuring tape was placed along the entire length of the IP ligament, starting from the point of its origin near the pelvic sidewall (where it begins as a peritoneal fold containing the ovarian vessels, nerves, and lymphatics) and extending down to its insertion point at the ovarian end. Special care was taken to ensure that the measuring tape followed the natural curvature of the IP ligament without stretching or distorting it. Each measurement was made by an experienced surgical team member, and the value was recorded to the nearest 0.1 cm. This process was repeated at least twice for each IP ligament, and the average value was taken as the final in vivo IP ligament length. Postoperative follow-up data of all patients up to June 2023 were considered, excluding patients who did not follow-up. CT scans showed lymph node metastases that were defined by the short diameter of lymph nodes of ≥10 mm. Postoperatively, all patients were evaluated by gynecologic oncologists to receive adjuvant therapy regularly. Surgeries were performed according to the NCCN principles in both groups, with the only difference being the inclusion of HLR of the IP ligaments during salpingo-oophorectomy in the 80 EOC patients (HLR group). Before resection, the broad ligament of the uterus was incised, and the mesocolon surrounding the IP ligaments was separated carefully. The IP ligament was then exposed completely at the level of the inferior mesenteric artery and clamped using vascular forceps at least ≥10 cm away from the visible ovarian margin. The IP ligament was ligated with 0 Vicryl, and a stitch was placed to identify the distal edge of the uterus ( Figure 1 ). All the adipose tissues and other tissues surrounding the IP ligaments were removed to avoid contamination. Specimens that remained intact were measured and fixed in 10% neutral buffered formalin. The fixed specimens were sectioned longitudinally at 10-mm intervals, and each segment was labeled ( Figure 2 ). Each segment was then embedded in conventional paraffin and further sectioned horizontally. Each segment was sectioned serially at a thickness of 4 µm for hematoxylin and eosin staining. The 4-µm-thick sections were examined by experienced pathologists, and any segment of the IP ligament in which metastatic cells were microscopically identified was recorded. The distance at which the metastatic cells spread microscopically away from the visual margin of the ovary was determined to be the closest section of the IP ligament. The resected IP ligament was ligated with a stitch, placed to identify the distal edge from the uterus. IP, infundibulopelvic. The fixed IP ligament was sectioned longitudinally at 10-mm intervals, and label them sequentially from the proximal uterine end to the distal uterine end. The red arrow indicates from left to right. IP, infundibulopelvic. All analyses were performed using the SPSS Software Version 26.0 (IBM, Chicago, IL, USA). Quantitative data were tested for normality and conformed to a normal distribution. The data are presented as mean ± standard deviation (SD), and two independent samples t -tests were employed for the analysis and comparison of quantitative data. Qualitative data are expressed as rates and analyzed using the χ 2 test; for small sample sizes, Fisher’s exact test was utilized. A P value <0.05 indicated statistically significant differences. For the intraoperative bleeding volume data, we employed the Shapiro-Wilk test to assess its normality. The results of the test indicated that the data did not conform to a normal distribution. Consequently, we reported this variable using the median and interquartile range (IQR) rather than the mean and SD as a more appropriate measure of central tendency and dispersion.

The baseline and surgical characteristics of the 80 patients are provided in Table 1 . In all, 58 patients were diagnosed with FIGO stage III or IV EOC, and 22 patients were diagnosed with FIGO stage I or II EOC. Metastatic cells were found in the IP ligaments in 19 of the 80 patients (23.8%). The average length of resected IP ligaments in vivo was 11.6 cm (range, 10–15 cm); however, when measured on the fixed specimen, the length had reduced by 1–4 cm (7.48 cm, range, 6–10 cm) due to shrinkage. For all patients, an average of 36 lymph nodes (range, 10–74) were dissected. Of these, an average of 11 para-aortic lymph nodes (range, 3–41) and 24 pelvic lymph nodes (range, 6–48) were removed. The average operating time was 411.25±149.52 min, and the median intraoperative bleeding volume was 400 mL (IQR, 450 mL). Accidental intraoperative complications (ureteral or vascular injuries) did not occur in any of the patients. Data are presented as n (%), median [minimum–maximum], mean ± SD, or median [IQR]. FIGO, Federation International of Gynecology and Obstetrics; HLR, high-level resection; IP, infundibulopelvic; IQR, interquartile range; SD, standard deviation. The data of 19 patients whose IP ligaments showed metastatic cell involvement are shown in Table 2 . All patients with metastatic cells were diagnosed with FIGO stages II–IV EOC; no metastatic cells were found in the IP ligaments of patients diagnosed with stage I EOC. Metastatic cells in the IP ligaments of all patients except one were found on the same side of the EOC site. The distance at which metastatic cells were found in the IP ligament was 3–7 cm from the visual ovarian margin (3 cm in 11 patients, 4 cm in 5 patients, and 7 cm in 3 patients). The length of the IP ligaments in vivo was ≥10 cm; however, when measured on the fixed specimen, the length had reduced by 1–5 cm due to shrinkage. EOC, epithelial ovarian cancer; FIGO, Federation International of Gynecology and Obstetrics; IP, infundibulopelvic; L, left; R, right. The baseline and pathological characteristics of the patients stratified according to metastasis in the IP ligament are provided in Table 3 . There were 19 patients in the IP ligament-positive group [age, 32–73 years, average, 53.26±12.19 years; average BMI, 21.45±2.39 kg/m 2 ; 13 menopausal women (68.4%) and 6 non-menopausal women (31.6%)]; 10 patients (52.6%) had EOC complicated with internal medicine diseases: seven patients had hypertension, one had hyperthyroidism, one had arrhythmia, and one had asthma. Patients with para-aortic lymph node metastasis were more likely than those with no metastasis to have metastatic involvement in the IP ligament (12 of 19, 63.2%, P=0.005), while patients with no para-aortic lymph node metastasis had a lower risk of IP ligament involvement. There were 61 patients in the IP ligament negative group [age, 27–83 years, average of 53.81±10.62 years; average BMI, 22.65±2.58 kg/m 2 ; 41 menopausal women (67.2%) and 20 non-menopausal women (32.8%)]; in all, 18 patients (29.5%) had medical diseases: nine had hypertension, three had diabetes, three had arrhythmia, one had hyperthyroidism, one had hypothyroidism, and one had chronic renal failure. There was no statistically significant difference in the baseline characteristics between the two groups of patients (P>0.05). Furthermore, there was no statistically significant difference in terms of clinical pathological characteristics [FIGO stage, histology, degree of cancer cell differentiation, preoperative carbohydrate antigen 125 (CA125), and preoperative neoadjuvant chemotherapy] between the two subgroups (P>0.05). Results are presented as mean ± SD or n (%). BMI, body mass index; CA125, carbohydrate antigen 125; FIGO, Federation International of Gynecology and Obstetrics; IP, infundibulopelvic; SD, standard deviation. In the IP ligament positive group, 12 patients (63.2%) had metastasis to the para-aortic lymph nodes with or without pelvic lymph node metastasis, 1 (5.3%) had no para-aortic lymph node metastasis but pelvic lymph node metastasis, and 6 (31.6%) had no lymph node metastasis; in the IP ligament negative group, 37 (60.6%) had no lymph node metastasis, 17 (27.9%) had para-aortic lymph node metastasis with or without pelvic lymph node metastasis, and 7 (11.5%) had no para-aortic lymph node metastasis but pelvic lymph node metastasis. There was a statistically significant difference in the incidence of lymph node metastasis between the two subgroups (P=0.005). However, there was no significant statistical difference in the incidence of pelvic lymph node metastasis between them (P=0.25). The average follow-up period was 10.8±7.8 months. The HLR group had 56 and 24 patients who did and did not complete follow-up, respectively. Meanwhile, the corresponding values for the WHLR group were 69 and 24, respectively. Baseline and pathological follow-up characteristics of the HLR and WHLR groups are provided in Table 4 . There were no significant differences (P>0.05) in the baseline and pathological characteristics (age, BMI, menstrual status, comorbidity, preoperative neoadjuvant chemotherapy, FIGO stage, histological type, differentiation grade) between the two groups of patients, indicating statistical comparability. Results are presented as mean ± SD or n (%). BMI, body mass index; FIGO, Federation International of Gynecology and Obstetrics; HLR, high-level resection; IP, infundibulopelvic; SD, standard deviation; WHLR, without high-level resection. The postoperative follow-up CT scanning results are summarized in Table 5 . The incidence of postoperative para-aortic lymph node metastasis in the WHLR group was higher than that in the HLR group. With the extension of follow-up time, postoperative para-aortic lymph node metastasis was more like to occur in the WHLR group. Results are presented as n (%). CT, computed tomography; HLR, high-level resection; IP, infundibulopelvic; WHLR, without high-level resection.

In a previous study, the incidence of lymph node metastasis among patients with early EOC was 14.2%, with para-aortic lymph node metastasis and both para-aortic and pelvic lymph node accounting for 50% and 30% of the cases, respectively ( 9 ). The IP ligament is considered one of the potential pathways of para-aortic lymph node metastasis in patients with EOC ( 9 - 11 ). Owing to the high risk of para-aortic lymph node metastasis in EOC patients, HLR of the IP ligament during surgery for EOC may cut off the potential lymph node metastasis pathways and reduce the risk of cancer cell metastasis to para-aortic lymph nodes. Adnexectomy is a common surgical intervention for gynecological benign and malignant diseases that can be performed through laparotomy, laparoscopy, transvaginal approach, etc. The basic surgical principle is to completely remove the ovaries and residual ovarian tissue. The residual ovarian tissue after surgery may give rise to pelvic mass, chronic pelvic pain, persistent endometriosis, and even ovarian cancer ( 15 ). The incidence of ovarian cancer was reduced by 69–100% after salpingo-oophorectomy in women with the BRCA1 and BRCA2 genes ( 16 ). Considering the need for “complete removal of residual ovarian tissue after adnexectomy” and the “position of residual ovarian tissue in the pelvic funnel ligament after adnexectomy”, many guidelines have suggested that the IP ligament should be removed during adnexectomy. A few studies have defined the favorable resection length of the IP ligament during surgery. Depending on the position of residual ovarian tissue in the IP ligament after salpingo-oophorectomy, it is suggested that at least 2 cm of the IP ligament should be resected during adnexectomy ( 12 ). The NCCN Clinical Practice Guidelines in Oncology recommend removing 2 cm of the proximal IP ligament to perform total risk-reducing salpingo-oophorectomy for patients with hereditary breast and ovarian cancer syndrome (HBOC) ( 13 ). To our knowledge, no study has defined the adequate resection length of the IP ligament when metastasis is observed in the IP ligament during surgery for EOC. In this study, the resection length of the IP ligament was fixed at ≥10 cm. Although certain explorations on the effects of HLR have been carried out, the impact of different resection lengths on patient prognosis has not been compared. Therefore, the resection length associated with the optimal outcome remains undetermined. Future research needs to set up comparison groups with different resection lengths to further clarify this key issue. Our study is an observational study, suggesting the necessity and feasibility of HLR of the IP ligament (at least 10 cm from the ligature point to the ovarian margin) during staging surgery or cytoreductive surgery in patients with EOC. Our preliminary evidence showed that metastasis may be present in the IP ligament of EOC and the probability of its occurrence is not related to FIGO staging. Therefore, we believe that it is necessary to perform HLR of the IP ligament in patients with both early and late-stage EOC surgery to eliminate the potential involvement of cancer lesions. Metastatic cells were 3–7 cm away from the visual ovarian margin in 19 samples in our study, raising concerns about the risk of residual tumors in the IP ligament in the absence of HLR. In addition, we found that the involvement of metastatic cells in the IP ligament had no correlation with tissue type, differentiation degree, and other factors but only with the occurrence of lymph node metastases; patients with para-aortic lymph node metastasis were more likely to have metastatic cells in the IP ligament. In addition, based on Table 5 , the incidence of postoperative para-aortic lymph node metastasis may increase with extended follow-up in patients who did not undergo HLR of the IP ligament (≥10 cm) during surgery. To the best of our knowledge, this study is the first to define an adequate length of the resected IP ligament during cytoreductive surgery based on the potential risk of metastasis in the IP ligament of patients diagnosed with EOC. Referring to Table 1 , the fact that we did not observe any common complications like urinary tract injury and vascular injury suggests that this procedure may be safe and feasible. Given our experience, the average operative time, and the bleeding volume of the surgeries performed in this study, we propose that HLR of the IP ligament as part of cytoreductive surgery does not increase the burden on surgeons or patients. Surgeons with experience could perform this operation ( 17 - 19 ). Owing to the dense distribution of blood vessels and nerves around the pelvic infundibular ligament, these structures may be injured during the surgical procedure, resulting in issues such as bleeding, hematoma formation, nerve injury, and postoperative pain. Furthermore, the HLR of the IP ligament may also impact the blood supply to the ovary and thereby affect its function. Simultaneously, the surgery itself has the risk of infection. If postoperative care is improperly handled, complications such as pelvic infection may be triggered. Hence, when conducting HLR of the IP ligament, physicians need to meticulously assess the specific circumstances of the patient to ensure the necessity of the surgery. After the operation, the recovery of the patient needs to be closely monitored, and any potential complications should be dealt with in a timely manner. The length of IP ligaments may be different in people of different heights, and we found that the left side of the IP ligament was difficult to resect because of anatomical differences between bilateral IP ligaments. However, IP ligaments are elastic and can be stretched in vivo . The length of resected IP ligaments in vivo could be more than 10 cm during surgery. The possible limitations of this study are the relatively small number of patients and the short follow-up duration. A large prospective study is required to evaluate the necessity of HLR of the IP ligament during surgical treatment for EOC. Longitudinal studies are required to evaluate the long-term effects of this procedure. Our preliminary findings indicate the need for multicenter, prospective randomized controlled studies aimed at comparing progression-free and overall survival rates between patients with and WHLR of IP ligaments. Furthermore, metastases may be present in the IP ligament of patients with cervical cancer and endometrial cancer. Further research is needed to evaluate the incidence of metastases in the IP ligament of patients with gynecological malignant diseases and to determine the optimal length of the resected IP ligaments.

Involvement of IP ligaments is a common phenomenon in patients with EOC that is correlated with para-aortic lymph node metastasis, and the IP ligament may be one of the main pathways of lymph-node metastasis. In addition, intraoperative HLR of the IP ligament may reduce the risk of postoperative para-aortic lymph node metastasis. Therefore, HLR of the IP ligament (≥10 cm) may be necessary and feasible as part of cytoreductive surgery to further reduce the risk of residual tumors and postoperative lymph node metastasis in patients with EOC. When this surgical procedure was carried out by an experienced surgical team, we did not observe common intraoperative complications, such as urinary tract injury or vascular injury. Therefore, HLR of the IP ligament is a safe and feasible surgical procedure with clinical value.

The article’s supplementary files as