Cervical cancer is the most common gynecologic tumor type and has one of the highest morbidity and mortality rates among female malignancies worldwide [1]. The World Health Organization (WHO) officially released “The Global Strategy to Accelerate the Elimination of Cervical Cancer” in November 2020 [2]. Surgery is one of the main modes of treatment for early-stage cervical cancer and National Comprehensive Cancer Network (NCCN) guidelines recommend radical open hysterectomy with bilateral pelvic lymphadenectomy [3]. Laparoscopy, which enables a precise operation as well as identification and selective sparing of pelvic and abdominal nerves, resulting in an improved postoperative quality of life. By 2018, owing to the advantages of less trauma and faster recovery of patients, the procedure was widely adopted on a global scale. In 2018, the New England Journal of Medicine published a randomized controlled trial of the Laparoscopic Approach to Cervical Cancer (LACC) conducted at M.D. Anderson Cancer Center in the United States [4] as well as the results of a real-world study (RWS) conducted at the Harvard Medical School [5]. These articles highlighted higher mortality and recurrence rates of cervical cancer patients undergoing minimally invasive surgery. Disease-free survival (DFS) and overall survival (OS) rates were poorer in these patients relative to those subjected to open surgery. However, the LACC study indicated that the results were not applicable to low-risk cervical cancer patients with tumor diameters 2 cm. The findings of these two studies led to changes in the in the clinical guidelines as related to the recommended procedure for early-stage cervical cancer. Several controversial reports have been published regarding the utility of open and laparoscopic surgery procedures for cervical cancer following the LACC trial. In 2020, the Chinese Expert Consensus on Laparoscopic Surgery for Cervical cancer published by Chinese gynecologic oncologists [6] proposed that laparoscopic surgery may be suitable for low-risk patients with stage IB1 cervical cancer and tumor diameters 2 cm. Chunlin and co-workers from Southern Medical University published a comparison of the 5-year OS and DFS rates following laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) for stage IIA1 cervical squamous cell carcinoma which demonstrated no significant differences between the two groups [7]. Early-stage cases with small lesions and common pathologic types were selected for this study. The clinical data of patients subjected to laparoscopic nerve-sparing radical hysterectomy and transabdominal radical hysterectomy were compared, with the aim of evaluating the safety of the laparoscopic nerve-sparing procedure.

This study was approved by the ethics committee of the Second People’s Hospital of Wuhu (the Second People’s Hospital of Wuhu was renamed Wuhu Hospital affiliated to East China Normal University in 2020) (approval number: MER-2019-07-15). All subjects provided informed consent prior to participation. Procedures were conducted in accordance with the Declaration of Helsinki.

Ninety patients with cervical cancer admitted to the Department of Gynecology of Wuhu Hospital (affiliated with East China Normal University and the First Affiliated Hospital of Wannan Medical University) from January 2015 to January 2021 were selected for the study, including 45 who underwent laparoscopic nerve-sparing radical hysterectomy (LNSRH) as the study group and 45 who underwent traditional ARH as the control group. This study was a retrospective non-randomized design. The patients underwent the surgery they preferred after being informed of the risks and benefits of each procedure. Participants were enrolled according to the mode of operation.

Inclusion criteria were as follows: ① age 75 years; ② pathologic diagnosis of cervical squamous cell carcinoma, cervical adenocarcinoma or cervical adenosquamous carcinoma, and classification as stage IB1 and stage IIA1 with tumor diameters 2 cm according to the 2018 International Federation of Obstetrics and Gynecology (FIGO) system; ③ no serious complications during and after surgery, such as bladder, ureter or rectum injury; ④ patients with complete clinical data and timely follow-up after surgery. Exclusion criteria were as follows: ① patients who did not meet surgical indications or had contraindications; ② evidence of bladder and rectal dysfunction before surgery; ③ exposure to radiotherapy and chemotherapy before surgery; ④ patients diagnosed with other malignant tumors, mental or cognitive disorders; ⑤ cases where clinical data were incomplete and lost; ⑥ serious chronic diseases of the heart, kidney, liver, and other organs; ⑦ patients who did not implement chemoradiotherapy according to the protocol. Prior to surgery, all patients were required to undergo routine blood and urine tests, biochemical tests, electrocardiogram analysis, and pelvic magnetic resonance imaging or computed tomography (CT) scan. The medical condition, surgical method and potential risks were explained in detail to patients and consent was obtained prior to surgery.

LNSRH was performed in the study group as follows: after successful anesthesia, a puncture was induced with the laparoscopic trocar to form an artificial pneumoperitoneum. The puncture was made 2 cm above the pubic symphysis in the midline of the abdomen using 0.5 cm trocar. A needle holder was inserted to suture the bottom of the uterus in a figure of eight loop. The needle holder clamp coil was used to adjust the position of the uterus for performance of the LNSRH. Four key steps were followed for nerve preservation. (A) The inferior hypogastric nerve is situated below the ureteral mesangium on the lateral side of the sacrospinous ligament. During surgery, Ganglin’s gap was initially separated, following which the sacrospinous ligament was cut after pushing the inferior hypogastric nerve outward. (B) The bladder and rectal side gaps were separated, the cardinal ligament exposed, and uterine artery and the deep uterine vein identified. Next, the uterine artery was ligated at the root, the deep uterine vein ligated 1 cm away from the internal iliac vein, the bladder branch ligated, the deep uterine vein and uterine artery turned laterally toward the body of the uterus, and the pelvic visceral nerve below the deep uterine vein preserved. (C) The anterior lobe of the vesico-cervical ligament was cut, the posterior lobe of the vesico-cervical ligament separated, the superior and middle vesical veins exposed, the blood vessel ligated, and nerve tissue below the blood vessel preserved. (D) Next to the cervix and below the deep uterine vein, the hypogastric nerve (HN) within the lateral rectal ligament intersects with the pelvic splanchnic nerve (PSN) within the cardinal ligament to form the inferior hypogastric plexus (IHP). The uterine and bladder branches innervated by the inferior hypogastric plexus were carefully identified. The uterine branch was cut and bladder branch retained. Nerve fibers of the bladder branch were pushed outward. The tissue around the vagina was excised. The vagina was ringed with a lasso 3 cm below the cervical or vaginal tumor to isolate neoplastic foci, followed by incision of the vagina and suture below the lasso. The remaining surgical steps were the same as those used in a traditional abdominal radical hysterectomy.

ARH was performed in the control group as follows: pelvic lymph node dissection was initially conducted according to the standard procedure, followed by radical hysterectomy through the abdomen [8].

Comparison of age, FIGO clinical stage, pathologic type and body mass index (BMI) of the two groups revealed no significant differences (p $>$ 0.05) (Table 1).

The Visual Analogue Scale (VAS) [9] was used to assess the degree of pain in patients at 8, 24 and 48 hours after surgery, with scores ranging from 1 to 10. Higher scores were indicative of a more severe degree of pain.

Attempts were made to remove the urinary catheter 1 week after surgery in the two groups of patients. In cases where the patient was unable to urinate or the residual urine volume in the bladder detected with ultrasound was greater than 100 mL, the catheter was retained and removed every three days until the residual urine volume was less than 100 mL. Catheter retention time and postoperative urinary symptoms, such as frequent and urgent urination, incontinence, dysuria and abdominal pressure urination, were recorded for both groups.

The time to first postoperative flatus and defecation and postoperative digestive symptoms, such as constipation and diarrhea, were recorded to evaluate the recovery of rectal function.

Urodynamic parameters of the two groups before and 12 months after surgery, including maximum flow rate (MFR), average flow rate (AFR), initial urinary bladder volume, maximum urinary bladder volume and maximum detrusor pressure (MDP), were compared.

Patients were followed up by telephone, Wechat and return visits over a period of 27–80 months. The surgeons maintained contact with patients after surgery and provided guidance regarding lifestyle and medical treatments.

We observed no significant differences in the amount of blood loss, number of dissected lymph nodes, length of vaginal resection and length of parametrial resection between the two groups. However, the operation time for LNSRH was significantly longer than that for ARH (p 0.0001). Surgery was successfully completed in both groups without abdominal or pelvic organ injury (Table 2).

VAS scores were significantly different at 8, 24 and 48 hours between the two groups, with lower scores obtained for the study group relative to the control group (p 0.0001) (Table 3).

Postoperative indwelling catheter retention time, first time of flatus and spontaneous defecation time of the two groups were significantly different (p 0.0001). The proportion of patients with dysuria, abdominal pressure urination, incomplete urination, constipation, and prolonged urination time at 6 months after surgery in the LNSRH group was significantly lower than those in the ARH group (p 0.05) (Table 2).

Urodynamic parameters of the two groups were comparable before surgery (p $>$ 0.05) but significantly different at 12 months after surgery (p 0.05). All indices in the LNSRH group at 12 months post-surgery returned to preoperative levels. In contrast, urodynamic parameters in the ARH group at 12 months postoperative remained markedly different from the corresponding pre-surgery values (p 0.05; Table 4).

After surgery, a number of patients from both groups received additional chemotherapy and radiation therapy. Sedlis criteria were used to determine whether adjuvant therapy was required [3]. Postoperative treatment of patients with cervical adenocarcinoma or adenosquamous carcinoma was additionally based on the “four-factor model” [10]. Tumor tissue samples were obtained from the cervix and parametrial areas of invasion. Samples were fixed and stained with hematoxylin-eosin (H&E) to investigate the presence of perineural invasion (PNI). This represents a condition whereby tumor cells gather and wrap around $\ge$1/3 of the nerve circumference or the phenomenon of local infiltration and metastasis of any of the three layers of the nerve sheath with tumor invasion and expansion along the nerve [11]. In the LNSRH group, 16 patients (35.6%) were administered radiation therapy, 10 of whom received concurrent chemoradiotherapy. In the ARH group, 15 patients (33.3%) were administered radiation therapy, 9 of whom received concurrent chemoradiotherapy. The rates of postoperative chemoradiotherapy and radiation therapy were not significantly different between the two groups (p $>$ 0.05). A total of 11 patients (12.2%) had PNI, including 6 and 5 patients in the LNSRH and ARH groups, respectively, with no significant difference between the groups. The follow-up time was 27–80 months with a follow-up rate being 100%. Nine patients experienced recurrence during the follow-up period, with four deaths due to recurrence and metastasis. Specifically, in the LNSRH group, 4 relapse cases were reported, including 2 deaths, while in the ARH group, 5 patients relapsed, leading to 2 deaths. The 5-year OS rate was comparable between the two groups (94.25% in the LNSRH group and 95.94% in the ARH group, p = 0.986). The 5-year DFS rate was 94.81% in the LNSRH group and 95.61% in the ARH group. Again, the difference between the 2 groups was not significant (p = 0.977). The survival curves of both treatment groups are depicted in Fig. 1.

The present study evaluated the utility of laparoscopic nerve-sparing radical hysterectomy as a minimally invasive procedure associated with less trauma, reduced pain, and a lower impact on vesical and intestinal function that could promote more rapid postoperative recovery. Stringent surgical criteria must be met for LNSRH, requiring surgeons with extensive experience in laparoscopic surgery to identify the nerves in the pelvic cavity. Ye et al. [12] considered the application of deep uterine and bladder veins as potential markers of nerve-sparing surgery. The Li et al. [13] demonstrated that water-jet dissection of the IHP during LNSRH could restore normal urodynamics more rapidly without affecting survival outcomes. Previous studies recommended the optimal use of non-energy or low-energy surgical instruments and an ultrasonic scalpel in combination with a vascular clip to avoid electrothermal injury in surgery for cervical cancer with pelvic autonomic nerve preservation [14]. In the LNSRH group, a self-made intraperitoneal irrigation device with moderate pressure was used to repeatedly wash and separate connective tissue surrounding the nerves to facilitate exposure. Endoscopic vascular clips, such as Hemolok or titanium clips, were used to ligate blood vessels around the nerve to ensure preservation, following which the blood vessels were cut. This not only avoided thermal damage to pelvic nerves, but also reduced intraoperative bleeding and favored postoperative recovery of bladder and rectum function. The operative time for LNSRH was significantly longer than that for ARH due to the need for delicate surgical identification of the protective nerves.

The sympathetic nerve fibers of the IHP innervate the bladder to store urine while the parasympathetic nerve fibers innervate the bladder for release of urine. Parasympathetic nerve injury leads to voiding dysfunction, representing the main cause of long-term bladder dysfunction [15]. Damage to the rectal branches from IHP can cause delayed defecation and passage of flatus. Urodynamic examination provides objective measurements of bladder dysfunction [16]. Initial and maximum bladder capacity of urinary urgency reflect sympathetic nerve damage, while MFR, MDP and abdominal pressure during urination reflect parasympathetic nerve damage. Notably, the reported post-surgical incidence of urinary system dysfunction is 25–47%. Therefore, surgery with pelvic autonomic nerve preservation is highly beneficial for patients with cervical cancer [17]. Our study demonstrated that urodynamic parameters in the LNSRH group recovered to preoperative levels at 12 months after surgery, but not in the ARH group. A potential explanation for this finding is that sympathetic and parasympathetic nerve injuries occurred during the operation, resulting in abdominal pressure urination, difficulty in defecation and other symptoms in the ARH group. The results support the conclusion that LNSRH is more beneficial for the recovery of bladder and rectal function in patients with early cervical cancer.

Previous studies suggest that preservation of nerve-connected parametrial tissue during cervical cancer surgery can lead to PNI and the possibility of tumor residual, which poses a high risk of recurrence. Therefore, nerve-sparing surgery should be cautiously performed on patients with smaller tumors. A study by Wei et al. [18] analyzed 174 patients with early-stage cervical cancer who underwent open radical hysterectomy (ORH), LRH and LNSRH. Overall, PNI-positive patients had lower DFS and OS than PNI-negative patients, which was not related to surgical type. In this study, several patients with PNI were included in both groups. However, survival outcomes were not significantly different between the groups. Previous research indicated that survival outcome of PNI is not independently associated with the type of surgery. Another report suggested that the poor oncological outcomes of minimally invasive surgery (MIS) could be attributable to the use of the uterine manipulator, CO${}_2$ pneumoperitoneum pressure, and spillage of tumor cells during the vagina opening procedure [19]. Fusegi et al. [20] demonstrated that application of the no-look no-touch technique during LNSRH could effectively avoid tumor contact with tissue of the abdominal cavity and vagina, thus helping to reduce the risk of recurrence. In this study, the research team took careful measures to avoid tumor spread during laparoscopic surgery. For example, the uterine manipulator was not used, with a view to preventing tumor spread caused by pressing of the cervical tumor during the operation. Resected lymph nodes were immediately placed into a specimen bag that was closed to avoid implantation and metastasis of cancer cells. The vagina was ringed with a lasso to isolate neoplastic foci before incision. At the end of the operation, the abdominal cavity was irrigated repeatedly to prevent retention of cancer cells. Survival time is the gold standard for evaluating the success of tumor surgery. Our results showed no significant differences in postoperative survival rates between the LNSRH and ARH groups, indicating comparable outcomes with both procedures under specific conditions.

Several limitations of our study should be taken into consideration that may affect data interpretation. First, we did not perform sub-analyses for histology and grading of cervical cancer. The effects of two types of radical hysterectomy on survival and quality of life in patients with early cervical cancer were compared. In the cervical cancer guidelines prior to 2023, radical hysterectomy is the standard procedure recommended for patients with stage IB1 and IIA1 disease [3]. The 2023 NCCN Guidelines recommend extrafascial hysterectomy plus pelvic lymphadenectomy (or sentinel lymph node (SLN) mapping) for stage IA2–IB1 cervical carcinoma (based on cone biopsy and meeting all the criteria for conservative surgery) [21]. The criteria for conservative surgery include no lymph-vascular space invasion (LVSI), negative cone margins, squamous cell (any grade) or usual type adenocarcinoma (grade 1 or 2 only), tumor size $\le$2 cm, depth of invasion $\le$10 mm, and negative imaging for metastatic disease. Only 2 stage IB1 patients in each group met all the criteria for conservative treatment, which was too small a proportion to affect the results of our study. Second, the follow-up time was relatively short. An earlier 10-year outcome study following surgery for cervical cancer showed that approximately 1 of 3 patients with recurrent disease developed recurrence at 5 years or later [22]. Third, the number of patients included for this study was relatively small due to the stringent enrollment criteria. A number of studies have reported similar therapeutic outcomes between ARH and LRH groups [23, 24, 25]. However, these earlier studies included patients with tumors $>$2 cm. Data from the current study provide further real-world evidence that may aid in decision-making on the choice of the surgical procedure for cervical cancer. Future research on minimally invasive surgical procedures for cervical cancer should additionally focus on robotic surgery, which has been shown to have oncologic outcomes comparable to open surgery [25].

Laparoscopic pelvic autonomic nerve-sparing radical hysterectomy has beneficial effects on patients with common pathologic types of early-stage cervical cancer and small tumors. The method can effectively improve the postoperative bladder and rectal function of patients and facilitate rapid recovery without exerting adverse effects on survival outcomes. However, the number of cases included in this current study is relatively small and further clinical trials on a larger scale are necessary to validate the efficacy and safety of LNSRH.

The data that support this study will be shared upon reasonable request to the corresponding author.

HX designed the research study. HX and SL performed the experimental procedures. HX participated in analyzing data, drafting the manuscript, and reviewing and proofreading papers. SL collected some of the patient data and completed follow-up of these patients. MC participated in performance of the operation, patient follow-up, and collection and analysis of data. YZ conducted analysis of data. All authors contributed to editorial changes, read and approved the final manuscript, participated sufficiently in the work and agreed to be accountable for all aspects of the content.

All subjects provided informed consent for inclusion in the study. This research was conducted in accordance with the Declaration of Helsinki and the protocol was approved by the ethics committee of the Second People’s Hospital of Wuhu (the Second People’s Hospital of Wuhu was renamed Wuhu Hospital affiliated to East China Normal University in 2020) (approval number: MER-2019-07-15).

We are grateful to the peer reviewers for their opinions and suggestions.

This study was supported by the Natural Science Foundation of Anhui Province (No: 2008085MH245) and the Scientific Research Project of the Second People’s Hospital of Wuhu City (No. 2019B10).

The authors declare no conflict of interest.