Pathologic Guidelines for Orthotopic Urinary Diversion in Women With Bladder Cancer: A Review of the Literature

Therapeutic Challenges

RIU0260_04-20.qxd 26/4/06 4:00 Page 54 THERAPEUTIC CHALLENGES Pathologic Guidelines for Orthotopic Urinary Diversion in Women With Bladder Cancer: A Review of the Literature Simon D. Wu, MD, Vannita Simma-Chang, MD, John P. Stein, MD, FACS University of Southern California, Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, CA Orthotopic lower urinary tract reconstruction to the native intact urethra following radical cystectomy for bladder cancer was slower to gain clinical acceptance for women than for men. Until the 1990s, little was known about the natural history of urethral involvement by urothelial carcinoma in women with primary bladder cancer. The increasing availability of pathologic data to define the incidence of and risks for urethral involvement in women sparked an increasing interest in orthotopic diversion in female patients. Pathologic guidelines have been suggested to identify women suitable for orthotopic diversion. Preoperative involvement of the bladder neck is a significant risk factor for secondary tumor of the urethra, but is not an absolute contraindication, as long as full-thickness, intraoperative frozen-section analysis demonstrates no tumor involvement of the proximal urethra. Although less common, anterior vaginal wall tumor involvement may be a significant risk factor for urethral tumor involvement. Other pathologic parameters, including tumor multifocality, carcinoma in situ of the bladder, and tumor grade and stage, do not seem to be absolute contraindications. Long-term follow-up is critical for all patients. Women undergoing orthotopic reconstruction, if appropriately selected, should be assured of an oncologically sound operation and good function with their neobladder. [Rev Urol. 2006;8(2):54-60] © 2006 MedReviews, LLC Key words: Orthotopic urinary diversion • Orthotopic neobladder • Female bladder cancer • Cystectomy • Urethrectomy • Urethral recurrence uring the mid-1990s, orthotopic lower urinary tract reconstruction to the native intact urethra became an oncologically acceptable and clinically appropriate option of urinary diversion for women undergoing radical cystectomy for bladder cancer. However, because little was known about the natural history of urethral involvement by urothelial carcinoma in women with D 54 VOL. 8 NO. 2 2006 REVIEWS IN UROLOGY RIU0260_04-20.qxd 26/4/06 4:00 Page 55 Orthotopic Urinary Diversion in Women With Bladder Cancer primary bladder cancer, orthotopic diversion for women did not gain the rapid clinical acceptance that was seen for men with this disease.1 The relative paucity of information on urethral tumor involvement in women before 1990 reflects the lower incidence of transitional cell carci- with TCC of the bladder. Ashworth3 reported in 1956 a lower incidence of urethral tumor involvement in women (1.4%) with bladder cancer than in men (4.1%). This finding was based on a cystoscopic study of 293 patients. Other studies, in the 1970s and 1980s, dealt with urethral in- The relative paucity of information on urethral tumor involvement in women before 1990 reflects the lower incidence of transitional cell carcinoma in women than in men. noma (TCC) in women than in men. It is estimated that in 2005, 47,010 new cases of bladder cancer will have been diagnosed in men, compared with just 16,200 in women.2 This gender imbalance, coupled with the notion that the shorter female urethra is closer to the bladder neck and thus potentially closer to tumor, made total urethrectomy during radical cystectomy the standard of care from an oncologic perspective. However, the increasing availability of pathologic data to define the incidence of and risks for urethral involvement in women sparked an increasing interest in, and subsequent clinical application of and experience with, orthotopic diversion in female patients. As a result, pathologic guidelines have been suggested to identify women suitable for orthotopic diversion following cystectomy for bladder cancer. We review the current literature on the pathologic guidelines for orthotopic diversion in women and the outcomes of the retained urethra following this form of urinary diversion. Developing Guidelines: Preserving the Urethra in Women Before 1990, minimal pathologic information was available on urethral involvement by cancer in women volvement with little or no attention to women.4-6 In 1990, De Paepe and colleagues7 reported urethral tumor involvement in 8 of 22 (36%) female cystectomy specimens involved by TCC. This retrospective study suggested a frequent concurrence of carcinoma in situ (cis) of the bladder with involvement of the urethra in female patients, and advocated routine urethrectomy with cystectomy in women, specifically for those having invasive bladder cancer with associated cis of the bladder. However, the authors emphasized that 64% of these patients had no urethral involvement, struction), Coloby and colleagues8 retrospectively reviewed and mapped 47 female cysto-urethrectomy specimens. Three women (6%) had carcinomatous involvement of the urethra. All 3 cases of primary bladder tumor demonstrated bladder-neck involvement and were high stage (pT3 or greater) and high grade. Six of 9 patients (67%) with bladder-neck involvement in this study, however, did not have secondary urethral involvement. These findings suggested that urethral tumor involvement in women undergoing cystectomy for TCC of the bladder was rare and that certain pathologic characteristics (eg, bladder-neck involvement) could possibly be used to select appropriate female candidates for orthotopic diversion. Stenzl and associates9 studied the long-term risk of secondary urethral tumors in 356 women with bladder cancer, to further define these pathologic risk factors. Overall, 7 of the 356 (2%) had urethral tumor at presentation, similar to the rate reported by Ashworth.3 Localization studies revealed a statistically significant correlation between bladder-neck involvement by the primary bladder tumor The findings suggested that urethral tumor involvement in women undergoing cystectomy for transitional cell carcinoma of the bladder was rare and that certain pathologic characteristics (eg, bladder-neck involvement) could possibly be used to select appropriate female candidates for orthotopic diversion. and information on previous treatments (before cystectomy) and the location of the primary bladder tumor was not provided or evaluated for these women. To determine criteria for the preservation of the urethra in women (specifically for the application of orthotopic lower urinary tract recon- and the presence of secondary urethral tumor in 19% of patients with bladder-neck tumor. Importantly, urethral involvement did not occur without simultaneous bladder-neck involvement in these women. Tumors located at the trigone showed a weak correlation with urethral tumor involvement. Furthermore, pathologic VOL. 8 NO. 2 2006 REVIEWS IN UROLOGY 55 RIU0260_04-20.qxd 26/4/06 4:00 Page 56 Orthotopic Urinary Diversion in Women With Bladder Cancer continued stage, tumor multifocality, number of tumors, presence of cis, or duration of disease did not seem to predict urethral tumor involvement. Interestingly, when considering only patients who were candidates for radical cystectomy (those with invasive localized disease; ie, T2-3b, N0, M0), only 1% with tumor extending into the vaginal wall (P4) had tumor at the bladder neck; 50% of these women had urethral involvement. The association between multifocal cis and bladder and/or urethral involvement, however, was not significant. All patients with urethral involvement had blad- The female urethra is pathologically suitable for orthotopic lower urinary tract reconstruction in the vast majority of women with invasive bladder cancer. (1/104) had secondary urethral tumor. The authors appropriately concluded that the female urethra is pathologically suitable for orthotopic lower urinary tract reconstruction in the vast majority of women with invasive bladder cancer, provided that neither preoperative bladder-neck biopsies nor intraoperative frozen section of the bladder-neck margin shows any tumor or significant atypia. Stein and associates10 sought to define the incidence of urethral involvement in women following cystectomy for primary bladder cancer, in order to better clarify which women are appropriate candidates for orthotopic diversion. Sixty-seven women who underwent radical cystectomy for TCC were pathologically evaluated. In this retrospective series, 9 patients demonstrated urethral tumor involvement (13%). Of the patients with bladder-neck involvement, 53% (9/17) had urethral involvement. However, no patient with an unaffected bladder neck had urethral tumor involvement. The association between bladder-neck and urethral involvement was statistically significant (P
.0001), consistent with Stenzl and colleagues’ findings.9 In the same study,10 anterior vaginal wall tumor involvement was also identified as a major risk factor for urethral involvement. All women 56 VOL. 8 NO. 2 2006 der-neck involvement, regardless of the presence or absence of cis. The finding of vaginal wall involvement as a significant risk factor for urethral involvement was further substantiated by Maralani and associates.11 In their study, 43 women with primary bladder cancer underwent radical cystectomy, and the specimens were then retrospectively reviewed. Seven patients (16%) were found to have urethral tumor. Of the potential risk factors for urethral involvement operatively. This finding underscores the importance of obtaining an intraoperative full-thickness frozen section of the proximal urethra at the distal margin of the cystectomy specimen to exclude any urethral tumor involvement. In another important female cystectomy series, contrary to the previous studies,8-10 Chen and associates12 reported “skip lesions” of tumor involving the urethra in the absence of bladder-neck involvement. Overall, 9 of 115 (8%) female cystectomy specimens demonstrated urethral tumor. Again, bladder-neck involvement was significantly associated with the presence of urethral tumor. Two patients, however, had pathologic apparent skip lesions, with a negative bladderneck section from the cystectomy specimen. This again underscores the importance of an intraoperative fullthickness frozen section of the proximal urethra to rule out urethral involvement. Furthermore, preoperative biopsies of the bladder neck may be insufficient to rule out submucosal extension of tumor into the urethra or Of the potential risk factors for urethral involvement that were analyzed (presence or absence of cis, multifocality, location of tumor, stage, grade, vaginal involvement), only vaginal involvement was significantly associated. that were analyzed (presence or absence of cis, multifocality, location of tumor, stage, grade, vaginal involvement), only vaginal involvement was significantly associated. Contrary to the previous series demonstrating strong associations between bladderneck and urethral tumor involvement,8-10 there was no significant association of this type in this series. Interestingly, 5 of the 7 patients with urethral involvement demonstrated only submucosal involvement of the urethra by tumor, and none of these were found to have gross disease pre- REVIEWS IN UROLOGY even skip lesions of the urethra in women with bladder cancer. Table 1 shows the percentage of women with primary bladder cancer found also to have urethral involvement by tumor. These data are only from those women who were selected and underwent cystectomy. Evaluating Outcomes of Orthotopic Diversion in Women Stein and associates13 prospectively evaluated the pathologic risk factors in women described earlier,10 to determine whether the proposed risk factors RIU0260_04-20.qxd 26/4/06 4:00 Page 57 Orthotopic Urinary Diversion in Women With Bladder Cancer Table 1 Secondary Urethral Tumor Involvement in Women With Bladder Cancer Treated With Radical Cystectomy Study* Number of patients Number (percent) with urethral involvement Coutts et al. (1985)5 13† 6 (46%) De Paepe et al. (1990)7 22 8 (36%) 8 Coloby et al. (1994) 47 3 (6%) Stein et al. (1995)10 67 9 (13%) 43 7 (16%) 115 9 (8%) Maralani et al. (1997)11 Chen et al. (1997)12 13 Stein et al. (1998) Total 71 5 (7%) 378 47 (12.4%) *All studies are retrospective except Stein et al. 1998,13 which is a prospective study. † Although 18 women underwent cystectomy, only 13 urethras were available for study, due to faulty fixation or loss of tissue. would in fact select for appropriate candidates for orthotopic diversion. From January 1992 through June 1997, 71 consecutive cystectomy specimens from women who had undergone anterior pelvic exenteration for primary bladder TCC were pathologically evaluated. Specimens were evaluated for cell of origin, number and location of tumor (focal and multifocal), grade, stage, and presence of cis. In addition, the women undergoing orthotopic diversion had intraoperative frozen-section analysis of the distal surgical margin (proximal urethra), which was compared with the permanent or final histologic diagnosis of the proximal urethra. Tumor involving the urethra was found in 5 of the 71 patients (7%), all of whom had bladder-neck tumor. No specimen with an uninvolved bladder neck had tumor involvement of the urethra. Bladder-neck involvement occurred in 14 patients (20%). Concurrent urethra and bladder-neck involvement by tumor showed a statistically significant association. This again confirmed previous retrospective studies8-10,12 and the observation that bladder-neck involvement is a significant risk factor for secondary tumor of the urethra. No other pathologic parameters showed statistically significant associations with urethral involvement by tumor. Even though bladder-neck involvement was shown to be the strongest pathologic risk factor for urethral involvement, the majority of women with bladder-neck involvement have diversion in women undergoing radical cystectomy. Stein and associates13 also reported 100% correlation between intraoperative sections and the final histologic diagnosis of the proximal urethra. When the data from this (prospective) series are combined with those from Stein and colleagues’ previous retrospective study,10 31 of 138 patients (22%) had bladder-neck tumors, but only 14 (10%) demonstrated urethral involvement. Of the women with bladder-neck involvement, approximately 50% had a normal urethra. Thus, bladder-neck involvement is not necessarily an absolute contraindication to orthotopic lower urinary tract reconstruction in women, but rather is an important risk factor. Follow-up of women who have undergone radical cystectomy is paramount in validating the aforementioned pathologic risk factors and criteria for construction of an orthotopic neobladder (Table 2). Stein and associates14 provided their clinical follow-up data on the first 88 women to receive orthotopic diversion at the University of Southern California (study period of June 1990 through August 1999). Median follow-up was 30 months. Eighty-one patients (92%) had surgery for pelvic malignancy, including 71 (80%) with TCC. Seven Bladder-neck involvement is not necessarily an absolute contraindication to orthotopic lower urinary tract reconstruction in women, but rather is an important risk factor. a normal (tumor-free) urethra. In the same study by Stein and colleagues,13 9 of 14 patients (64%) with bladderneck tumor had a normal urethra, confirming the earlier pathologic finding.10 These authors therefore advocate intraoperative frozen-section analysis of the proximal urethra (distal surgical margin) to determine the appropriateness for orthotopic patients (8%) underwent an orthotopic diversion for benign conditions. No urethral recurrences of malignancy were reported during this follow-up period. Ali-El-Dein and associates15 similarly reported their clinical experience with orthotopic bladder substitution in women after radical cystectomy. A total of 145 women underwent VOL. 8 NO. 2 2006 REVIEWS IN UROLOGY 57 RIU0260_04-20.qxd 26/4/06 4:00 Page 58 Orthotopic Urinary Diversion in Women With Bladder Cancer continued Table 2 Tumor Recurrence in Retained Urethra of Women Undergoing Radical Cystectomy and Orthotopic Urinary Diversion Median follow-up (months) Number of patients Study Number (percent) of urethral recurrences Stenzl et al. (2001)18 102 26 0 (0%) Stein et al. (2002)14 88 30 0 (0%) 145 17 2 (1.4%) 53 24 0 (0%) 43 0 (0%) 15 Ali-El-Dein et al. (2004) Lee et al. (2004)16 17 Hassan et al. (2004) 29 20 Table does not include the case report by Jones et al. of urethral recurrence in a female patient. A series by Studer and Zingg22 evaluated 200 patients (including 8 women) who underwent radical cystectomy and orthotopic bladder substitution; overall urethral recurrence rate was 3.5% (7/200). Because no distinction was made between male and female recurrence, these results are not included in the table. orthotopic diversion between January 1995 and December 2001, with mean follow-up of 17 months. Histologic subtypes of bladder cancer consisted of squamous cell carcinoma in 88 (60.7%), TCC in 31 (21.4%), and adenocarcinoma in 17 (11.7%). Isolated urethral recurrence developed in 2 patients (1.4%). One of the 2 patients had cis that involved the trigone in the cystectomy specimen. The second patient with a urethral recurrence had lymph node–positive disease at the time of cystectomy. The authors speculate that urethral involvement may have been from caudal (retrograde) spread of tumor to involve the urethra. It is hypothesized that bladder cancer adjacent to the bladder neck with grossly enlarged lymph nodes can cause reverse lymphatic flow and subsequent tumor cell drainage to the external inguinal nodes. This could potentially lead to periurethral involvement by tumor cells in the remnant urethra. Other reports analyzing urethral recurrence rates in women undergoing cystectomy and orthotopic diversion have also been published. Lee 58 VOL. 8 NO. 2 2006 and associates16 prospectively evaluated 53 women who underwent radical cystectomy and orthotopic diversion (from September 1995 to February 2003), with mean follow-up of 24 months. Fifty-two patients (98%) were treated for bladder carcinoma. The authors found 42 patients (80%) alive and disease-free at followup and 2 patients alive and with disease (3.8%); 6 patients (11.5%) had died of the disease; 2 (3.8%) had died of other or unknown causes. All cancer deaths resulted from metastatic disease, and no urethral or local recurrences were reported. Hassan and colleagues17 retrospectively reviewed their experience with orthotopic diversions following radical cystectomy in both male and female patients. Of the 196 patients who underwent radical cystectomy and orthotopic diversion, only 29 (14.8%) were female. Overall, 1 urethral recurrence was identified in a male patient and none in the female group. None of the women had bladderneck involvement documented preoperatively or on final pathologic evaluation. REVIEWS IN UROLOGY Stenzl and associates18,19 evaluated results from a multicenter study of 102 women who underwent radical cystectomy and orthotopic urinary diversion for pelvic malignancies. Ninety-six patients (94.1%) had primary bladder cancer (TCC in 81 patients, adenocarcinoma in 8, squamous cell carcinoma in 5, small cell carcinoma in 1, and 1 unclassified). The remainder included cervical cancer (2 patients), vaginal carcinoma (1), fallopian tube carcinoma (1), uterine sarcoma (1), and rectal carcinoma (1). Mean follow-up was 26 months. All patients receiving orthotopic bladders had negative results on preoperative staging bladder-neck biopsies and intraoperative frozen section of the distal margin (proximal urethra). No urethral recurrences were reported in the 88 patients (86.3%) alive at the completion of the study. Jones and associates20 reported the case of a 63-year-old woman who underwent a radical cystectomy and orthotopic ileal neobladder for pT1, N2, grade 3 TCC of the bladder. The patient presented 3 years later with obstructive voiding symptoms and was found to have a recurrence at the neobladder-urethra anastomosis. The tumor was found to be infiltrating the anterior vaginal wall. Although the tumor was resected, the patient died 3 months later from metastatic disease. The authors speculate on the potential of metastatic lymphadenopathy as a contraindication to orthotopic diversion. This idea, although controversial, has been discussed in previous reports.15,19 The available literature suggests that women may have a smaller risk of urethral recurrence after orthotopic diversion than men.21,22 Again, it has been noted that women with primary bladder cancer seem to have a lower incidence of secondary urethral tumor involvement than men.3,9 It must be kept in mind that the number of RIU0260_04-20.qxd 26/4/06 4:00 Page 59 Orthotopic Urinary Diversion in Women With Bladder Cancer women undergoing orthotopic diversion is significantly smaller than the number of men, and the follow-up is shorter in women. Stenzl and associates9 suggest that this gender difference might also be the result of a smaller area of urethral transitional cell mucosa at risk (in women) for developing TCC. Furthermore, the area diminishes even more with advancing age as the demarcation line between squamous and transitional cell mucosa migrates cranially, leaving more of the urethra to be covered by metaplastic squamous cell mucosa.23 Summary The pathologic findings reported here strongly support the performance of orthotopic lower urinary tract diversion in appropriately selected women following radical cystectomy for pri- mary bladder malignancy. Preoperative involvement of the bladder neck, although a significant risk factor, does not seem to be an absolute contraindication, as long as full-thickness, intraoperative frozen-section analysis demonstrates no tumor involvement of proximal urethra (distal surgical margin on cystectomy specimen). Furthermore, although rare, anterior vaginal wall tumor involvement may also be a significant risk factor for urethral tumor involvement in women. Other pathologic parameters, including tumor multifocality, cis of the bladder, tumor grade, and pathologic stage, do not seem to be absolute contraindications (in the face of normal findings on intraoperative frozen section of the proximal urethra) for orthotopic diversion in women. Although long-term follow- up is critical in all patients, women undergoing orthotopic reconstruction, if appropriately selected, can be assured of receiving an oncologically sound operation and good function with their neobladder.14,19,22 References 1. 2. 3. 4. 5. 6. Stein JP, Skinner DG. Orthotopic urinary diversion. In: Campbell’s Urology, 8th ed. Philadelphia: Saunders; 2002:3835-3867. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA: Cancer J Clin. 2005;55:10-30. Ashworth A. Papillomatosis of the urethra. Br J Urol. 1956;28:3. Richie JP, Skinner DG. Carcinoma in situ of the urethra associated with bladder carcinoma: the role of urethrectomy. J Urol. 1978;119:80-81. Coutts AG, Grigor KM, Fowler JW. Urethral dysplasia and bladder cancer in cystectomy specimens. Br J Urol. 1985;57:535-541. Schellhammer PF, Whitmore WF Jr. Transitional cell carcinoma of the urethra in men having cystectomy for bladder cancer. J Urol. 1976; 115:56. Main Points • With the increasing availability of pathologic data on urethral involvement in women with primary bladder cancer, the use of orthotopic lower urinary tract reconstruction has become an increasingly acceptable option for women undergoing radical cystectomy. • A retrospective study of cysto-urethrectomy specimens from women with transitional cell carcinoma (TCC) of the bladder found that urethral tumor involvement and certain pathologic characteristics (eg, bladder-neck involvement) could be used as risk factors in selecting female candidates for orthotopic diversion. • Bladder-neck involvement is not necessarily an absolute contraindication to orthotopic urinary diversion in women, but is an important risk factor. Intraoperative frozen sections of the bladder-neck margin that show any tumor or significant atypia are contraindications. • Anterior vaginal wall tumor involvement is also a major risk factor for urethral involvement. • One female cystectomy series reported “skip lesions” of tumor involving the urethra in the absence of bladder-neck involvement. • A prospective study looking at whether the proposed risk factors select for appropriate candidates for orthotopic diversion confirmed that bladder-neck involvement is a significant risk factor. No other pathologic parameters showed statistically significant associations with urethral involvement. • In a clinical follow-up study of women undergoing orthotopic diversion, 80% of whom had surgery for TCC, no urethral recurrences were reported. In another clinical follow-up, isolated urethral recurrence developed in only 1.4%. • In a clinical follow-up study in which 98% of patients underwent orthotopic diversion for bladder carcinoma, 80% were alive and disease-free at follow-up. • In a multicenter study of women who underwent radical cystectomy and orthotopic urinary diversion for pelvic malignancies, 94.1% for primary bladder cancer and all with negative results on preoperative staging bladder-neck biopsies and intraoperative frozen section of the distal margin, no urethral recurrences were reported. • The pathologic findings reported in these studies strongly support the performance of orthotopic lower urinary tract diversion in appropriately selected women. VOL. 8 NO. 2 2006 REVIEWS IN UROLOGY 59 RIU0260_04-20.qxd 26/4/06 4:00 Page 60 Orthotopic Urinary Diversion in Women With Bladder Cancer continued 7. 8. 9. 10. 11. 12. 60 De Paepe ME, Andre R, Mahadevia P. Urethral involvement in female patients with bladder cancer. Cancer. 1990;65:1237-1241. Coloby PJ, Kakizoe T, Tobisu K, Sakamoto M. Urethral involvement in female bladder cancer patients: mapping of 47 consecutive cystourethrectomy specimens. J Urol. 1994;152: 1438-1442. Stenzl A, Draxl H, Posch B, et al. The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol. 1995;153:950-955. Stein JP, Cote RJ, Freeman JA, et al. Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens. J Urol. 1995;154:1329-1333. Maralani S, Wood DP Jr, Grignon D, et al. Incidence of urethral involvement in female bladder cancer: an anatomic pathologic study. Urology. 1997;50:537-541. Chen ME, Pisters LL, Malpica A, et al. Risk of VOL. 8 NO. 2 2006 13. 14. 15. 16. 17. REVIEWS IN UROLOGY urethral, vaginal and cervical involvement in patients undergoing radical cystectomy for bladder cancer: results of a contemporary cystectomy series from M.D. Anderson Cancer Center. J Urol. 1997;157:2120-2123. Stein JP, Esrig D, Freeman J, et al. Prospective pathologic analysis of female cystectomy specimens: risk factors for orthotopic diversion in women. Urology. 1998;51:951-955. Stein JP, Ginsberg DA, Skinner DG. Indications and technique of the orthotopic neobladder in women. Urol Clin N Am. 2002;29:725-734. Ali-El-Dein B, Abdel-Latif M, Ashamallah A, et al. Local urethral recurrence after radical cystectomy and orthotopic bladder substitution in women: a prospective study. J Urol. 2004;171: 275-278. Lee CT, Hafez KS, Sheffield JH, et al. Orthotopic bladder substitution in women: nontraditional applications. J Urol. 2004;171:1585-1588. Hassan JM, Cookson MS, Smith JA Jr, Chang SS. Urethral recurrence in patients following ortho- 18. 19. 20. 21. 22. 23. topic urinary diversion. J Urol. 2004;172:13381341. Stenzl A, Jarolim L, Coloby P, et al. Urethrasparing cystectomy and orthotopic urinary diversion in women with malignant pelvic tumours. Cancer. 2001;92:1864-1871. Stenzl A, Holtl L. Orthotopic bladder reconstruction in women—what we have learned over the last decade. Crit Rev Oncol Hematol. 2003;47:147-154. Jones J, Melchior SW, Gillitzer R, et al. Urethral recurrence of transitional cell carcinoma in a female patient after cystectomy and orthotopic ileal neobladder. J Urol. 2000;164:1646. Freeman JA, Tarter TA, Esrig D, et al. Urethral recurrence in patients with orthotopic ileal neobladders. J Urol. 1996;156:1615-1619. Studer UE, Zingg EJ. Ileal orthotopic bladder substitutes: what we have learned from 12 years’ experience with 200 patients. Urol Clin N Am. 1997;24:781-793. Packham DA. The epithelial lining of the female trigone and urethra. Br J Urol. 1971;43:201-205.