Sparing urethra in women at the time of cystectomy: retrospective comparison of cystectomies with and without urethrectomy

Introduction

Radical cystectomy is the standard of care for patients with muscle-invasive or treatment-resistant non-muscle-invasive bladder cancer. Due to anatomical differences between males and females, surgical techniques vary depending on whether the patient is a man or woman. In men, radical cystectomy involves removal of the bladder, prostate, and pelvic lymph nodes. In women, this surgery, known as anterior pelvic exenteration, involves removal of the bladder, anterior vaginal wall, ovaries, uterus, fallopian tubes, pelvic lymph nodes, and the entire urethra (1,2). Studies show that women experience more postoperative complications than men, even after adjusting for sex, race, smoking, and comorbidities, with some studies reporting worse cancer-specific outcomes (3-5). Pelvic-organ-sparing radical cystectomy is a modified surgical technique that preserves all or some of the reproductive organs and pelvic nerve. This approach has been shown to improve surgical outcomes in women by reducing complications and preserving quality of life (6,7). Although there is no standard of care for patient selection for this approach, it can be tailored to appropriate patients after an informed discussion, especially when preserving sexual function is a consideration. Although preserving nerves and reproductive organs are important considerations during cystectomy, often inadequate attention is paid to the function and role of the urethra, despite evidence showing the urethra plays a critical role in female sexual function (8). The external glans of the clitoris is situated just above the urethral opening, and its body extends internally beneath the pubic bone. The crura and bulbs, internal parts of the clitoral complex, are embedded within the pelvic anatomy, close to the urethra. The main nerve supply to the clitoris includes the dorsal nerve of the clitoris, arising from the pudendal nerve and the perineal nerve, both of which contribute to its high sensitivity. Autonomic nerves from the pelvic plexus are also involved in its erectile and vascular functions. Stimulation of the clitoris triggers a complex neural response, leading to arousal, increased blood flow, and lubrication, involving both the somatic and autonomic nervous systems. Given that the clitoris is key to achieving orgasm in many women, any surgical procedure near this area, such as a urethrectomy, poses a risk of damaging these nerves and disrupting sexual function (9). There is a paucity of data on outcomes after urethra-sparing radical cystectomies, especially in women undergoing non-neobladder urinary diversions. Since an intact urethra is an anatomical requirement for patients who are candidates for neobladders, we can study these patients to gain insights on safety after urethral preservation, particularly around cancer recurrence. Our retrospective study examined women with neobladders who underwent cystectomy as a surrogate for urethra-sparing cystectomy. We aimed to compare oncologic outcomes of women undergoing radical cystectomy with and without urethrectomy to better understand whether sparing the urethra confers additional oncologic risk to women with bladder cancer. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-24-601/rc).

Methods

This study was approved by the Institutional Review Board (IRB) of Johns Hopkins School of Medicine (No. NA_00081185), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was waived by the IRB on the basis that it is a retrospective study with many of the patients have either died of disease or are not available to consent. Sample inclusion/exclusion criteria: we retrospectively reviewed samples from a prospectively maintained database of urothelial cancer patients at Johns Hopkins Medicine and included women who received a radical cystectomy for primary bladder malignancy from June 2000 to December 2023. Cystectomies were performed by multiple experienced surgeons at a single institution using a standard open or laparoscopic robot-assisted radical cystectomy technique. Patients undergoing radical cystectomy for gynecological or colorectal malignancies were excluded. Urethra-sparing orthotopic neobladder creation was performed in 49 patients, and non-urethra-sparing ileal conduit or continent cutaneous diversion was performed in 298 patients. As a standard procedure, at the time of cystectomy on orthotopic neobladder, a sample of the urethral margin was obtained and frozen for intraoperative margin assessment. Hematoxylin and eosin (H&E) stained slides were re-examined by two board-certified genitourinary-trained pathologists (A.M. and S.K.) to confirm presence or absence of urethra in the surgical specimen and urethra involvement of urothelial carcinoma in situ (CIS), non-invasive papillary urothelial carcinoma, or invasive carcinoma. All clinical stages were included. Local recurrence was defined as recurrence within the soft tissue of the pelvis, including urethra, or any intrapelvic organs. Any recurrence outside the pelvis was categorized as extra pelvic, including lymph node recurrence. The patients had standard follow-up including scans and bloodwork every 3 months for the first 2 years, every 6 months until year 5, and annually after 5 years. Annual cytology was part of standard surveillance, and cystoscopy was performed as clinically indicated.

Statistical analysis

Frequencies of demographic, pathologic, and treatment-related variables were obtained for the full cohort. Propensity matching analysis was utilized to compare the urethrectomy group vs. the non-urethrectomy group. Patients were matched in a 2:1 fashion according to age at the time of cystectomy, tumor stage, lymph-node stage, and variant histology. Tumor stage was further grouped to include T3 and T4 as advanced stage and T0, Ta, Tis, T1, and T2 as early stage. Lymph node staging was grouped as follows: node positive and N0. Variant histology was defined as any histology that was not urothelial carcinoma. Kaplan-Meier analysis for overall survival was utilized for the matched cohort. Cox regression model was also utilized for analysis of survival with matched cohort while adjusting for variant histology, tumor stage, lymph-node stage, and age at time of cystectomy. Statistical analyses were performed using SPSS Statistics (IBM, NY, USA, version 25), with P≤0.05 considered statistically significant and P values >0.05 reported as not significant (NS).

Results

We evaluated a total of 347 radical cystectomy specimens. Mean age at cystectomy was 65.4 (range, 60–73) years. Table 1 shows the clinicopathological variables between the two groups. Perivesical soft tissue margins were positive in 22 (7%) patients, including 5 patients with vaginal involvement. The urethral margin/urethra was positive in 15 (5%) patients, including 14 of 276 (5%) of urethrectomy patients, and the bladder neck/urethra margin was positive in 1 of 41 (2%; P=0.70) of patients who received a neobladder. The neobladder patient with positive urethral margin had CIS at the bladder neck margin. The average follow-up was 44.5 months (range, 14.5–60 months) and at most recent follow-up 188 (54.2%) of patients show no evidence of disease. Within the urethrectomy cohort, 157 (52.7%) patients had no evidence of disease and 30 (61.2%) patients in the non-urethrectomy cohort showed no evidence of disease. A total of 76 (21.9%) patients were alive with disease. Specifically, 62 patients were alive with disease in the urethrectomy group and 14 patients in the non-urethrectomy group. Utilizing Kaplan-Meier analysis, the median overall survival for the urethrectomy cohort was 159 months [95% confidence interval (CI): 159, not available] and the mean overall survival was 246.9 months. The mean overall survival for the non-urethrectomy group was 173.9 months. Matched propensity scoring was performed for further analysis of overall survival (Table 2). Patients were matched in a 2:1 fashion with the following covariates: age at time of cystectomy, tumor staging, lymph node staging, and variant histology. Tumor staging was further grouped for comparison as follows: T3 and T4 as advanced tumor stage and T0, Ta, Tis, T1, and T2 as earlier tumor stage. Lymph node staging was grouped as follows: node positive and node negative. Variant histology was defined as any histology that was not urothelial carcinoma. Taking these definitions into account: the urethrectomy group consisted of 70 patients and the non-urethrectomy group consisted of 35 patients. Table 2 highlights the specific stages, follow-up data, mean age at cystectomy, variant histology, and other clinical characteristics. The status of last follow-up for the propensity scored group consisted of 19 (54.3%) patients in the non-urethrectomy group and 13 (37.1%) patients in the urethrectomy group with no evidence of disease. The status of last follow-up for patients that were alive with disease was 13 (37.1%) patients without a urethrectomy and 15 (21.4%) patients with a urethrectomy. A Kaplan-Meier analysis was used to compare the overall survival of the urethrectomy versus non-urethrectomy groups in the matched propensity scored cohorts (Figure 1). The overall survival was deemed not significant between the two groups (P=0.07). A cox regression model for overall survival comparison with the matched propensity urethrectomy vs. non urethrectomy patients was adjusted for the age of cystectomy, variant histology, tumor stage, lymph node stage as detailed above. The results of the cox regression model were not significant. Within the neobladder group, no subsequent urethrectomies were performed for cancer recurrence in all cases. However, there was one patient who had a recurrence in the urethra after a negative urethral margin on the initial specimen. This patient had urothelial carcinoma with squamous differentiation on the biopsy specimen of the recurrence. Re-review of the original cystectomy specimen revealed soft tissue tumor involvement of the area around the bladder neck, but the urethra stump/bladder neck was negative for in situ or invasive carcinoma. This recurrence was treated with local radiotherapy. The patient with neobladder and a positive urethral margin, in whom CIS at the bladder neck margin was discovered on final pathology, was free of disease at 5 years of follow-up.

Figure 1 Kaplan-Meier curves for patients with urethra-spared during surgery vs. urethrectomy (urethra not spared). Median OS for urethra spared: not reached. 95% CI: NA, NA. Mean OS for urethra spared: 173.9 months. Median OS for urethrectomy: 159 months. 95% CI: 159, NA. Mean OS for urethrectomy: 246.9 months. CI, confidence interval; NA, not available; OS, overall survival.

Discussion

Women with bladder cancer who are candidates for radical cystectomy traditionally undergo anterior pelvic exenteration. This procedure in women can produce several negative consequences, including alteration of the pelvic floor anatomy and damage to the pelvic nerve plexus. Despite the high prevalence of pelvic floor disorders and sexual dysfunction in women after cystectomy, studies have shown that some women are not aware of all the changes associated with this procedure and are not offered reproductive organ- and nerve-sparing cystectomy (10,11). Even with increased awareness, there is a paucity of studies on this topic. Modifications to the female radical cystectomy technique include preservation of some or all reproductive organs, such as the ovaries, uterus, and anterior vaginal wall (12). Over the past few years, data have accumulated showing that recurrences in female reproductive organs after cystectomies are rare (2–16%), and patients at risk for adjacent organ involvement can be screened out (13). The risk of primary gynecologic malignancy is very low in the absence of increased risk factors, and at-risk patients can also be screened (14,15). On the other hand, benefits of preserving reproductive organs for women are significant, including avoidance of pelvic organ prolapse and preservation of functional vaginal length for sexually active women. Also, by decreasing disturbance to the pelvic plexus, which is posterior to the uterus and lateral to the vagina, the risk of sexual dysfunction can be minimized. In women with orthotopic urinary diversion, sparing the pelvic organs and neurovascular plexus can also help reduce the rates of invasive bladder cancer incorporates guidelines to preserve female reproductive organs and sexual function, urinary incontinence, urinary retention, and vesicovaginal fistula (16-18). Hence, the 2024 updates to American Urologic Association (AUA) guidelines for treating non-metastatic MIBC where possible based on the disease characteristics (19). Despite updates to the 2024 AUA guidelines, current evidence points to room for improvement in how cystectomies in women are being carried out, and the negative effects of urethrectomy are frequently overlooked. While these guidelines emphasize preservation of reproductive organs and pelvic nerves, they do not explicitly address the importance of avoiding urethrectomy when feasible. Therefore, even with these updated guidelines, there remains a need for further emphasis on urethra-sparing approaches to improve outcomes for women.

Historically, one of the reasons women have had urethrectomies at the time of cystectomy is that removing the urethra is perceived to be easier in women compared to men, due to anatomical differences. There is also a perceived belief that eliminating the urothelium may reduce the chances of cancer recurrence. Urethrectomy is not routinely performed in men at the time of radical cystectomy for bladder cancer, and studies have shown that this does not translate into inferior oncologic outcomes (20-22). Since urethral involvement with urothelial cancer is very uncommon, at-risk patients can be screened out, and frozen section analysis at the time of the cystectomy is reliable (23,24) we may be unnecessarily causing harm to female patients by routinely performing urethrectomies in these cases. Even when female reproductive organs and pelvic plexus are preserved, urethrectomy can disturb peri-urethral glandular tissue and the adjacent clitoris, potentially leading to sexual dysfunction. The nerves of the clitoris, a highly innervated organ critical to female sexual function, are intricately woven into the pelvic region. The benefits of sparing the urethra include minimization of disturbance to the branches of the clitoral nerves, which arise from the pelvic nerve plexus, and preservation of hemodynamic integrity of the ilio-hypogastric-pudendal arterial bed to the vagina and clitoris, resulting in improved overall sexual function through the preservation of sensation and vaginal lubrication (25,26).

In this study, we retrospectively reviewed radical cystectomies in women over the past 25 years and compared patients with urethra-sparing cystectomy who had orthotopic neobladder urinary diversion to patients who underwent cystectomies and urethrectomies. Given the results of overall survival calculated for the total cohort using Kaplan-Meier analysis and the results for the Kaplan-Meier match propensity scored cohort and cox regression score, there is no significantly detectable difference in survival between urethrectomy and non-urethrectomy in cystectomy for women with bladder cancer. Therefore, preservation of the urethra during cystectomy for patients with no contraindications may be beneficial and not lead to a compromise in overall survival. Factors that have been studied and found to be associated with urethral recurrence in both sexes include multifocal disease, CIS, and involvement of the bladder neck, or prostatic urethra in males. In women, the only reported risk factors for urethral involvement are presence of advanced disease as indicated by hydronephrosis, vaginal wall involvement, or cancer in the bladder neck (22). In our study, patients with urethral involvement had a higher risk of pelvic recurrence, which aligns with previous findings in males with prostatic urethral involvement. Other than positive margins in the urethra, perivesical area, and vagina, this higher risk likely reflects underlying biology of the disease.

Our study had several limitations, primarily the small size of the cohort. However, despite small numbers, clinicopathologic features were evenly distributed between the two groups, making the comparison suitable for interpretation. The retrospective nature of the study could introduce selection bias inherent to any retrospective review, particularly if patients chosen for neobladders had more favorable features. There are limitations associated with propensity score analysis given the post-selection bias. We would like to reiterate that the surgical approach was uniform for all patients following standard radical cystectomy techniques. Additionally, the single institution setting of the study may affect generalizability of the findings to other institutions or clinical settings with different surgical experiences. Expanding this research effort in a prospective, multi-center approach, may decrease the bias associated with retrospective review and increase the cohort sizes. Multi-center participation may also increase patient demographics. These studies could help to further refine patient selection criteria and optimize surgical techniques for women undergoing radical cystectomy. Future qualitative studies seeking to understand how urethra-sparing surgeries in women affect future sexual function and quality of life are also key to assessing importance of urethral preservation in female bladder cancer patients. For qualitative studies, measurable patient reported outcomes may include quality of life surveys and/or the Female Sexual Function Index (FSFI) to better understand how urethrectomy in radical cystectomy affects sexual function in women.

Conclusions

Reproductive organ-sparing cystectomy is increasingly recognized as a safe and functionally superior alternative to traditional anterior exenteration in women with bladder cancer. Our retrospective review suggests that urethra-sparing procedures are not associated with a compromise in overall survival. Large multi-center randomized prospective studies of women treated with standard radical cystectomy versus organ- and urethra-sparing cystectomy, regardless of the type of urinary diversion, are needed to further optimize patient selection so we can better understand the effects of surgical modifications on overall survival, recurrence, and quality of life for women with bladder cancer.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-24-601/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-601/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-24-601/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-24-601/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Institutional Review Board (IRB) of Johns Hopkins School of Medicine (No. NA_00081185), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was waived by the IRB on the basis that it is a retrospective study with many of the patients have either died of disease or are not available to consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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