Female Urethra PDF

# CHAPTER 77 ## Female Urethra ### Tony Y. Eng ## INTRODUCTION Primary urethral carcinoma is a rare tumor accounting for <1% of all malignancies. Although previous data suggested that urethral cancer was more common in women than men, a recent Surveillance, Epidemiology, and End Results (SEER) stud...

# CHAPTER 77 ## Female Urethra ### Tony Y. Eng ## INTRODUCTION Primary urethral carcinoma is a rare tumor accounting for <1% of all malignancies. Although previous data suggested that urethral cancer was more common in women than men, a recent Surveillance, Epidemiology, and End Results (SEER) study reports that primary urethral cancer is more common in men. The ratio of female to male predominance is approximately 1:3. Because of its rarity and lack of prospective data, optimal management of female urethral cancer is based on retrospective data and depends on the clinical stage, tumor location, extent of nodal involvement, patient's health status, and treatment preference. ## ANATOMY The female urethra is approximately 3 to 4 cm long and 0.6 cm in resting diameter. It is embedded in the anterior vaginal wall behind the pubis symphysis, extending inferiorly and anteriorly from the urinary bladder through the urogenital diaphragm to the vestibule, where it forms the urethral meatus. Because of the proximity of the pubis symphysis, a small curve is formed with an anterior concavity. The lower distal half of the urethra is considered the anterior urethra, and the upper proximal half is considered the posterior urethra. The wall of the urethra consists of three layers. The muscular layer is continuous with that of the bladder. At the vesicular end of the urethra, this muscular wall forms the internal sphincter. The voluntary urethral sphincter is at the plane of the urogenital diaphragm. A thin layer of erectile tissue consisting of a plexus of veins and muscle fibers forms the middle layer of the wall. The inner layer is the mucous membrane, which is continuous with the bladder proximally and with the vulva distally. This membrane consists of transitional epithelium near the bladder but distally changes to nonkeratinizing stratified squamous epithelium and pseudostratified columnar epithelium. The distal urethra also contains small mucous recesses and periurethral or Skene glands, most of which are in the region of the meatus. The lymphatic drainage of the distal urethra and urethral meatus parallels that of the vulva to the superficial and deep inguinal and external iliac lymph nodes. The primary drainage of the posterior or entire urethra is mainly to the obturator and internal and external iliac nodes. ## EPIDEMIOLOGY AND ETIOLOGY The SEER database for 1973 to 2002 identified a total of 1,615 cases of primary urethral carcinoma, of which 540 were women. The overall annual incidence was 1.5 per million for women (4.3 per million for men). Although previous observation suggests that this cancer is more common in white women than in black women, the SEER data show the incidence to be higher for African Americans and increase steadily with age. As carcinoma of the urethra is rare in women, only a few cases are seen annually at major cancer centers. Carcinoma of the female urethra makes up 0.02% of all cancers in women and accounts for approximately 0.1% of all gynecologic cancers. The average patient age at the time of diagnosis is 60 years, with most patients between 50 and 80 years of age. Although chronic infection and local irritation have been proposed, the etiology of female urethral cancer remains obscure. Unlike other transitional cell carcinoma of the urinary tract, there is no reported correlation between cigarette smoking and urethral carcinoma. Wiener and Walther analyzed archival surgical specimens of women with urethral carcinoma. Human papillomavirus (HPV) was detected in 10 of 17 patients with invasive disease. HPV type 16 was found in eight patients. Eight women with squamous cell carcinoma and two with transitional cell carcinoma had HPV. Female urethral cancer may also be associated with urethral diverticula. Patients with transitional cell carcinoma of the bladder, especially the bladder neck, may have a higher risk of developing urethral cancer either synchronously or metachronously. ## NATURAL HISTORY Most urethral cancers are clinically aggressive and historically carry a poor prognosis. During the later stages, cancers of the middle or posterior urethra tend to extend upward into the urinary bladder, downward to invade the remainder of the urethra, and posteriorly into the vaginal mucosa. Lesions involving the anterior urethra account for approximately 30% of all cases. Regional lymph node involvement is uncommon in early tumors (stage 0) of the urethral meatus. Advanced tumors (stages II and III) of the urethra have been associated with a 35% to 50% incidence of inguinal or pelvic lymph node involvement. Bilateral nodal involvement occurs in approximately one-third of patients with positive nodes. Grabstald confirmed nodal involvement in 24 of 25 patients with clinically palpable nodes. In his series of patients with advanced disease, 26 underwent pelvic lymph node sampling and 13 (50%) had nodal involvement. Distant metastases are found in approximately 10% of patients at presentation, and approximately 30% to 50% ultimately die of distant disease. The most common sites of metastasis are lung, liver, bone, and brain. ## CLINICAL PRESENTATION A majority of patients with urethral cancer present with some degree of irritative or obstructive urethral symptoms. Bleeding (hematuria) or spotting is the prevailing presenting sign in 50% to 60% of patients. Approximately 30% to 50% of patients experience pain or irritative symptoms, difficulty urinating, and frequent micturition. Urinary retention and overflow incontinence may occur in advanced cases. Less frequently cited signs and symptoms are a mass in the introitus (10% to 20% of patients), dyspareunia, perineal pain, and inguinal lymphadenopathy. Urethrovaginal and vesicovaginal fistulas may develop in advanced, neglected cases. Small tumors involving the urethral meatus are often mistakenly diagnosed as urethral caruncle; a benign, inflammatory lesion; or a prolapse of the mucosa through the urethral orifice. As the lesion progresses, it enlarges and eventually ulcerates. Tumors may arise in a urethral diverticulum. Larger lesions of the distal urethra are readily identified on inspection. Tumors occupying the proximal urethra may produce a fusiform enlargement that can be palpated during pelvic examination. ## DIAGNOSTIC WORKUP | | | :--- | | General | | | History | | | Physical examination, including detailed pelvic examination under anesthesia | | | Special procedures | | | Punch biopsy | | | Urethroscopy | | | Cystoscopy | | | Rectosigmoidoscopy (advanced stages or if symptomatic) | | | Radiographic evaluation | | | Standard | | | Chest radiographs | | | CT scan (abdomen and pelvis) | | | Intravenous urography | | | Magnetic resonance imaging | | | Complementary | | | Bone scan (if symptomatic or elevated alkaline phosphatase) | | | Barium enema (if symptomatic or advanced stages) | | | Ultrasound | | | Urethrography | | | Laboratory evaluation | | | Complete blood count | | | Chemistry profile | | | Urinalysis ## STAGING SYSTEMS Clinical staging is based on findings on physical examination, chest x-ray, and CT scan of the abdomen and pelvis. Many attempts have been made to formulate a staging system for carcinoma of the urethra. Urethral tumors can be classified in two groups: those involving the distal half of the urethra and those located in the proximal or entire urethra. Most authors have found that this classification correctly depicts the feasibility of treatment and the prognosis. A staging system based on location has been proposed by Prempree et al. (Table 77.2). The current TNM staging system of the American Joint Committee on Cancer is shown in Table 77.3. ## PATHOLOGIC CLASSIFICATION As the urethra is lined by transitional cells proximally and stratified squamous cells distally, transitional cell carcinoma occurs typically in the proximal urethra, whereas squamous cell carcinoma occurs frequently in the distal urethra. The SEER data report the most common histologic type is transitional cell carcinoma followed by squamous cell and adenocarcinoma. However, most published series suggest that squamous cell carcinoma is the most common histologic type in cancer of the female urethra, representing more than 50% of all cases whereas transitional cell carcinoma and adenocarcinoma represent approximately 15% to 20% and 10% to 15%, respectively. The remainder of the histologic types include adenoid cystic carcinoma, melanoma, clear cell adenocarcinoma, anaplastic tumors, Kaposi sarcoma, lymphomas, and metastatic lesions. ## PROGNOSTIC FACTORS Conventional prognostic factors such as grade and histology have not been consistently predictive for recurrence or survival for female urethral cancer. In the literature, some of the most important factors in determining prognosis and survival are stage, depth of invasion, tumor size, and anatomic location. The 1983 to 2008 SEER database shows that advance age, T stage, node positivity, nonsquamous histology, and black race were associated with reduced cause-specific survival. Dasbagni, et al. showed that primary stage was one of the major independent predictors of survival in 72 female patients with a 5-year survival of 83% for low-stage tumors and 33% for high-stage tumors. Lesions located in the meatus or distal urethra tend to be superficial, with a better prognosis; lesions in the posterior urethra are often deeply invasive and tend to have a worse prognosis. Most investigators found that patients with advanced-stage disease do poorly, often irrespective of their treatment. Grigsby and associates demonstrated a worsening prognosis with increased tumor size. The 5-year progression-free survival was 81% for patients with lesions <2 cm, compared with 37% for those with lesions 2 to 4 cm and 7% for patients with lesions >4 cm (P = .0001). For lesions confined to the proximal urethra, local control was observed in all four patients. However, patients with tumors involving the distal urethra had a 5-year progression-survival rate of 69%, and there was a 12% survival rate for those with involvement of the entire free urethra (P = .0001). Patients with meatal tumors, if diagnosed early and treated appropriately, can achieve an 80% to 90% survival rate. Several investigators found that the use of brachytherapy improves local control. Milosevic et al. reported that patients who were treated with external beam therapy only were 4.2 times more likely to recur locally independent of other prognostic factors, compared with those who received brachytherapy as a component of management. Similarly, in a study of six patients with locally advanced urethral carcinoma, Dalbagni et al. noted that high-dose intraoperative brachytherapy followed by external beam radiation appeared to improve local control. The histology of the primary lesion appears to be less important as a prognostic factor in determining response to therapy and survival. Patients with adenocarcinoma have been reported to have a good prognosis, but most studies have shown no difference in survival among patients with adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma. Grigsby found a worse prognosis in patients with adenocarcinoma. Primary melanoma of the urethra, although rare, has a very poor prognosis. ## GENERAL MANAGEMENT Although various therapeutic approaches have been advocated for the management of carcinoma of the female urethra, there are no established therapeutic guidelines. The variety of treatments reflects the dimensions and locations of disease and the approaches of the treating physicians. In general, surgical resection is a primary mode of treatment. Radical urethral resection with urinary diversion and pelvic lymphadenectomy is commonly performed for lesions not involving the bladder neck. However, early-stage lesions of limited extent may be amenable to organ-sparing radiation therapy or conservative surgical management with or without adjuvant radiation therapy to minimize the morbidity associated with surgical intervention. Surgical approaches include neodymium:yttrium-aluminum-garnet (Nd:YAG) laser coagulation, Mohs micrographic surgery, and partial or total urethrectomy. Radiation therapy may include external-beam radiation, interstitial brachytherapy, or a combination of these treatments. For patients who are medically nonsurgical candidates because of potential risks of anesthesia, outpatient high-dose rate (HDR) intracavitary and intraluminal brachytherapy may be an option. ## Multimodality Therapy For patients with locally invasive urethral carcinoma, anterior exenteration may be required. Although most available data are insufficient, in patients with more advanced disease, some authors have advocated adjuvant radiation therapy and/or combined irradiation and chemotherapy including 5-fluorouracil, cisplatin, vinblastine, epirubicin, carboplatin, bleomycin, methotrexate, or mitomycin C after surgical extirpation. A subgroup of patients with positive nodes may also benefit from preoperative cisplatin-based chemotherapy. Multimodality therapy appears to achieve similar or better overall results, even though those patients who receive combined modality tend to have more advanced disease. Although most studies included a small number of patients, those patients who received combined therapy seem to have better disease-free survival. Combination therapy often consists of either chemotherapy with radiotherapy or radiotherapy with surgery. Combined chemotherapy and radiation therapy for locally advanced urethral cancer has shown a reasonable response in several reports. ## Anterior (Distal) Urethral Cancer For stage 0 and I (Ta, Tis, or small T1) lesions, open excision, electroexcision, fulguration, and laser (Nd:YAG or CO2) coagulation are possible for tumors at the meatus or with in situ involvement of the distal urethra (stage 0). For larger and more invasive lesions (stage T1 and T2), surgical resection of the distal third of the urethra is often adequate. Alternately, interstitial irradiation or a combination of interstitial and external-beam irradiation can be considered. For T3 to T4 or recurrent anterior urethral lesions previously treated by local excision or radiation therapy, anterior exenteration and urinary diversion may be curative. Adjuvant radiation therapy may be required, depending on surgical findings. If a limited number of inguinal nodes are involved, ipsilateral node dissection or irradiation is indicated because cure is still achievable. If no inguinal adenopathy exists, node dissection is not recommended, but prophylactic groin irradiation is recommended for patients with invasive lesions. ## Posterior (Proximal) Urethral Cancer Cancers of the posterior or entire urethra are usually associated with invasion of the bladder, a high incidence of inguinal and pelvic lymph node metastases, and a worse prognosis. For lesions <2 cm, radical resection, definitive radiation therapy, or combined treatment may provide adequate control. However, for larger lesions or locally advanced disease, the best results have been achieved with preoperative irradiation, exenterative surgery, and urinary diversion. Pelvic lymphadenectomy is performed and inguinal node dissection may be indicated if the inguinal nodes are involved. In selected patients, it is possible to remove part of the pubis symphysis and the inferior pubic rami to maximize the surgical margin. A transpubic approach has been advocated by Golimbu et al. Perineal closure and vaginal reconstruction can be accomplished with the use of myocutaneous flaps. Hedden et al. have advocated the use of bladder-sparing surgery with or without irradiation. ## Recurrent Urethral Cancer In most cases, locally recurrent urethral cancer after surgery alone should be considered for combination radiation therapy and wider surgical resection. Locally recurrent urethral cancer after radiation therapy should be treated by surgical excision. For those who are not surgical candidates, local reirradiation (i.e., hyperfractionated intensity-modulated radiation therapy or brachytherapy) may be considered if radiation tolerance has not been exceeded. Patients with metastatic urethral cancer should be considered for investigational chemotherapy protocols. Palliative radiation therapy may provide good symptomatic relief. ## RADIATION THERAPY TECHNIQUES Small meatal and distal urethral lesions are curable with limited therapy. Interstitial implants have been the usual method for treating meatal carcinomas. Radioactive needles, forming a double-plane or a volume implant, have been used. Both low-dose rate (LDR) and HDR afterloading implants using 192Ir have replaced radium. For early localized disease without involvement of adjacent organs, a volume implant composed of 8 to 12 needles arranged in an arc around the urethral orifice is used. Radiographs may be used to verify needle placement. Computer planning with CT-based simulation and 3-D treatment planning should be the standard of care to spare the adjacent normal organs. A dose of 60 to 70 Gy (LDR) should be given in 6 to 7 days (0.4 to 0.5 Gy/h to the target volume) when an implant alone is used. Alternatively, in patients with small localized disease receiving radiation therapy alone, noninvasive intracavitary or intraluminal HDR brachytherapy without sedation or anesthesia after pelvic external beam radiation has been used. Figure 77.10 illustrates an intraluminal HDR brachytherapy using a Foley catheter. The resultant conformal radiation dose covers the periurethral tissue well while sparing the surrounding normal structures. At the University of Texas Health Science Center in San Antonio, we deliver 500 to 600 cGy at twice a week, 3 days apart, to a total dose of 2,400 to 2,500 cGy with good response. Large tumors or advanced disease extending into the labia, vagina, entire urethra, or base of the bladder should not be treated with an implant alone. For these patients, a combination of external-beam irradiation and implant is recommended. The external-beam portal should flash the perineum to cover the entire urethra. The conventional portal should be wide enough to cover the inguinal nodes and should extend cephalad to the L5-S1 interspace to include the pelvic nodes. A bolus, appropriate for the photon energy used, should be added to the groin when inguinal nodes are positive. This technique minimizes the hazard of groin failure due to underdosing of gross tumor. Hahn et al. have demonstrated the importance of treating the inguinal lymph nodes in all patients. The whole pelvis is treated to a dose of 45 to 50 Gy. A boost of 10 to 15 Gy is delivered to positive groin nodes through reduced anteroposterior fields. After pelvic radiation therapy, the primary tumor can be treated with a vaginal cylinder to bring the dose to the entire urethra to approximately 60 Gy. An interstitial implant is administered to raise the total tumor dose to 70 to 80 Gy. For patients undergoing postoperative therapy, the tumor bed is treated after pelvic radiation therapy with an additional 10 to 15 Gy using interstitial brachytherapy. Intracavitary irradiation with the vaginal cylinder and an interstitial implant are almost never used simultaneously because of the resultant high dose rate at the vaginal mucosa interface of the intracavitary and interstitial implant fields. A vaginal cylinder with partial shielding posteriorly can be used in select patients. Gerbaulet et al. have demonstrated the use of a catheter or a vaginal mold applicator for intraluminal/intracavitary brachytherapy and needles or guide gutters for interstitial brachytherapy. At the University of Texas Health Science Center in San Antonio, we commonly deliver external beam therapy, 4,500 to 5,040 cGv, to the primary tumor and pelvic lymphatics using intensity-modulated radiation therapy technique (IMRT) with CT image guidance. This is followed by interstitial HDR brachytherapy, 500 to 600 cGy twice a day, 6 hours apart. A vaginal cylinder is always employed to provide spatial protection of the posterior vagina and rectum. The HDR brachytherapy is repeated in one week to achieve a total dose of 2,000 to 2,400 cGy. The major advantage of interstitial HDR brachytherapy is geometric or volume optimization by changing the dwell time and dwell position of the radioactive source along the afterloading catheter so that the target volume is well covered with good conformity while the doses to the vaginal mucosa and surround structures are kept below their tolerances. Modification of dose and fractionation may be made depending on the tumor size and response to external beam therapy. The HDR brachytherapy is performed as an outpatient treatment. One of the limiting factors in the use of external-beam irradiation is the tolerance of the perineal and vulva skin (i.e., confluent moist desquamation). Extensive disease combined with advanced age can be a formidable obstacle to completing the irradiation course. Proper radiation therapy techniques and diligent personal hygiene and individualized skin care during and after treatment are necessary if patients are to complete the course of treatment. ## RESULTS OF THERAPY The SEER 1983 to 2008 database identified 722 women with urethral cancer. The median overall survival was 42 months, and the 5- and 10- year overall survival was 43% and 32% respectively. The median cause-specific survival was 78 months, and the 5- and 10-year cause-specific survival was 53% and 46%, respectively. Table 77.4 summarizes the recent treatment results from various institutions. Depending on the various prognostic and treatment factors, the 5-year overall survival and cause-specific survival rates range from 32% to 59% and 40% to 61%, respectively. The recurrence rates range from 58% to 64%. ## Surgery There is a paucity of long-term outcome data. In general, female urethral cancers are clinically aggressive with high recurrence and poor survival rates. DiMarco et al. reviewed 53 female patients with primary urethral carcinoma undergoing partial urethrectomy or radical extirpation. The estimated 10-year cancer-specific survival was 60%. In a study of 72 patients treated at Memorial Sloan Kettering Cancer Center between 1925 and 1994, the 5-year disease-specific survival was 89% for low-stage tumors and 33% for high-stage tumors. The overall survival was 78% and 22%, respectively, as shown in Table 77.4. ## Radiation Therapy Although DiMarco et al. found that adjuvant radiation did not improve local control or survival in the study of 53 female patients with urethral carcinoma, treatment selection bias may have played a role as the higher-stage tumors tended to receive adjuvant radiation therapy. Eng et al. reported only one of six patients with low-stage disease was referred for adjuvant radiation therapy, whereas four of five patients with advanced disease received radiation therapy. The one who did not receive radiation died 10 months after surgery. Case review of early-stage urethral cancer treated with external beam radiotherapy, brachytherapy, or a combination of both seems to have equivalent results as surgery alone. Control of tumors of the urethral meatus or the distal urethra with irradiation alone is often satisfactory. Early meatal tumors have cure rates of 70% to 90%. Chu reported a 5-year progression-free survival rate of 64% for 11 patients with tumor involvement of the anterior urethra treated with irradiation alone. Prempree et al. treated three patients with stage I disease with interstitial irradiation alone (50 to 65 Gy) and achieved local control in all three. In the same series, two of four patients with stage II disease achieved local control and were alive 5 years after treatment. Weghaupt et al. reported a 5-year survival rate of 71% for 42 patients with cancer of the anterior urethra. Their doses ranged from 55 to 70 Gy from intracavitary and external irradiation. Princess Margaret Hospital reported an 87% relapse-free survival rate in patients with stage I or II disease. The majority of patients with small primary tumors received brachytherapy as a component of their treatment. Patients receiving brachytherapy and external-beam radiation therapy had a median total dose of 65 Gy. Tumors of the proximal urethra or the entire urethra are more difficult to treat. The overall local control rate is 20% to 30%. Bracken et al. treated 81 patients, and the 5-year survival rate was approximately 25% for patients with stage III and 20% for those with stage IV disease. Princess Margaret Hospital reported stage III and IV tumors to have cause-specific survival rates of 26% and 16%, respectively. Weghaupt et al. reported a 5-year survival rate of 50% among 20 patients with tumor involvement of the posterior urethra who received irradiation alone or preoperative irradiation and surgery. Garden et al. treated 86 patients with irradiation only after excision or biopsy of the primary lesion. Radiation doses ranged from 40 to 106 Gy (median, 65 Gy). The 5-year disease-specific survival rate was 49%, and the 5-year local control rate was 64%. Preoperative irradiation combined with radical surgery is an approach used by Klein et al. They treated five women in this manner and achieved a 5-year survival rate of 40%. Dalbagni et al. used anterior pelvic exenteration with intraoperative tumor bed interstitial brachytherapy using 192Ir, followed several weeks later by pelvic external beam radiation therapy. A variety of chemosensitizing agents were used. The median brachytherapy dose was 15 Gy, and pelvic radiation therapy given was 45 Gy. Local control was achieved in four of six women with T2 and T4 disease. ## Chemotherapy and Multimodality Dayyani et al. reported the response rate of 72% in 36 patients with locally advanced urethral cancer who had received definitive or preoperative platinum-based chemotherapy. The median overall survival was 25.6 months. Gheiler et al. reported a disease-free survival rate of 60% in selected patients with advanced T3 or higher disease treated with a multimodality regimen consisting of neoadjuvant chemotherapy and radiation therapy. A phase 2 study has shown the combination of ifosfamide, paclitaxel, and cisplatin used in 45 patients with advanced transitional carcinoma of the urothelial tract is well tolerated and results in a median survival of 20 months. Similar encouraging results have been reported in patients with advanced urethral cancer receiving concomitant fluorouracil, mitomycin C, and radiation therapy. ## SEQUELAE OF THERAPY Complications as a result of surgery, irradiation, or combined-modality therapy vary greatly, from 0% to 42%, because of different tumor stages, the extent of surgery, and various irradiation doses. In general, more aggressive treatment is expected to result in a higher complication rate. Garden et al. reported that 27 of 55 patients (49%) achieving local control had complications, including urethral stenosis, fistula, necrosis, cystitis, and hemorrhage. Urethral strictures develop in some patients, necessitating dilation or urinary diversion. Others may experience incontinence, cystitis, and vaginal stenosis. Severe complications include fistula formation, bowel obstruction, and, occasionally, operative death. In the case of advanced neoplasms, fistula formation may be unavoidable because of tumor erosion of adjacent organs and subsequent tumor necrosis. Unlike the male counterpart, the physical loss of the female urethra is not uniformly associated with sexual impotence; nevertheless, the associated treatment side effects and negative self-image may affect sexual function and quality of life. ## FUTURE DIRECTION Early detection and intervention provide the best chance of organ preservation and cure. Although most clinical information comes from retrospective case series accumulated over a long span of time using various treatment modalities, multimodality shows encouraging results and should always be considered, especially in patients with locally advanced or metastatic disease. Clinical trials are clearly needed to obtain prospective data. Improved knowledge of tumor and normal tissue radiobiology along with continued technologic advances in external-beam radiation therapy and brachytherapy delivery will maximize organ preservation and minimize some of the treatment-related complications. ## REFERENCES 1. Swartz MA, Porter MP, Lin DW, et al. Incidence of primary urethral carcinoma in the United States. Urology 2006;68(6):1164-1168. 2. Dalbagni G, Zhang ZF, Lacombe L, et al. Female urethral carcinoma: an analysis of treatment outcome and a plea for a standardized management strategy. Br J Urol 1998;82(6):835-841. 3. Garden AS, Zagars GK, Delclos L. Primary carcinoma of the female urethra. Results of radiation therapy. Cancer 1993;71(10):3102-3108. 4. Levine RL. Urethral cancer. Cancer 1980;45(7 Suppl):1965-1972. 5. Sailer SL, Shipley WU, Wang CC. Carcinoma of the female urethra: a review of results with radiation therapy. J Urol 1988;140(1):1-5. 6. Srinivas V, Khan SA. Female urethral cancer-an overview. Int Urol Nephrol 1987;19(4):423-427. 7. Johnson DE, O'Connell JR. Primary carcinoma of female urethra. Urology 1983;21(1):42-45. 8. Weghaupt K, Gerstner GJ, Kucera H. Radiation therapy for primary carcinoma of the female urethra: a survey over 25 years. Gynecol Oncol 1984;17(1):58-63. 9. Grabstald H. Proceedings: tumors of the urethra in men and women. Cancer 1973;32(5):1236-1255. 10. Pointon RC, Poole-Wilson DS. Primary carcinoma of the urethra. Br J Urol 1968;40(6):682-693. 11. Turner AG, Hendry WF. Primary carcinoma of the female urethra. Br J Urol 1980;52(6):549-554. 12. Wiener JS, Walther PJ. A high association of oncogenic human papillomaviruses with carcinomas of the female urethra: polymerase chain reaction-based analysis of multiple histological types. J Urol 1994;151(1):49-53. 13. Nakamura Y, Takahashi M, Suga A, et al. A case of adenocarcinoma arising within a urethral diverticulum diagnosed only by the surgical specimen. Gynecol Obstet Invest 1995;40(1):69-70. 14. Narayan P, Konety B. Surgical treatment of female urethral carcinoma. Urol Clin North Am 1992;19(2):373-382. 15. Rajan N, Tucci P, Mallouh C, et al. Carcinoma in female urethral diverticulum: case reports and review of management. J Urol 1993;150(6):1911-1914. 16. Chen ME, Pisters LL, Malpica A, et al. Risk of 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(6):2120-2123. 17. De Paepe ME, Andre R, Mahadevia P. Urethral involvement in female patients with bladder cancer. A study of 22 cystectomy specimens. Cancer 1990;65(5):1237-1241. 18. Taggart CG, Castro JR, Rutledge FN. Carcinoma of the female urethra. Am J Roentgenol Radium Ther Nucl Med 1972;114(1):145-151. 19. Chu AM. Female urethral carcinoma. Radiology 1973;107(3):627-630. 20. Grabstald H, Hilaris B, Henschke U, et al. Cancer of the female urethra. JAMA 1966;197(11):835-842. 21. Klein FA, Whitmore WF, Herr HW, et al. Inferior pubic rami resection with en bloc radical excision for invasive proximal urethral carcinoma. Cancer 1983;51(7):1238-1242. 22. Peterson DT, Dockerty MB, Utz DC, et al. The peril of primary carcinoma of the urethra in women. J Urol 1973;110(1):72-75. 23. Dimarco DS, DiMarco CS, Zincke H, et al. Surgical treatment for local control of female urethral carcinoma. Urol Oncol 2004;22(5):404-409. 24. Grigsby PW. Carcinoma of the urethra in women. Int J Radiat Oncol Biol Phys 1998;41(3):535-541. 25. Moinuddin Ali M, Klein FA, Hazra TA. Primary female urethral carcinoma. A retrospective comparison of different treatment techniques. Cancer 1988;62(1):54-57. 26. Nakatsuka S, Taguchi I, Nagatomo T, et al. A case of clear cell adenocarcinoma arising from the urethral diverticulum: utility of urinary cytology and immunohistochemistry. Cytojournal 2012;9:11. 27. Hruby G, Choo R, Lehman M, et al. Female clear cell adenocarcinoma arising within a urethral diverticulum. Can J Urol 2000;7(6):1160-1163. 28. Thyavihally YB, Wuntkal R, Bakshi G, et al. Primary carcinoma of the female urethra: single center experience of 18 cases. Jpn J Clin Oncol 2005;35(2):84-87. 29. Hricak H, Secaf E, Buckley DW, et al. Female urethra: MR imaging. Radiology 1991;178(2):527-535. 30. Morikawa K, Togashi K, Minami S, et al. MR and CT appearance of urethral clear cell adenocarcinoma in a woman. J Comput Assist Tomogr 1995;19(6):1001-1003. 31. Fisher M, Hricak H, Reinhold C, et al. Female urethral carcinoma: MRI staging. AJR Am J Roentgenol 1985;144(3):603-604. 32. Quick HH, Serfaty JM, Pannu HK, et al. Endourethral MRI. Magn Reson Med 2001;45(1):138-146. 33. Chou CP, Levenson RB, Elsayes KM, et al. Imaging of female urethral diverticulum: an update. Radiographics 2008;28(7):1917-1930. 34. Fanti S, Nanni C, Ambrosini V, et al. PET in genitourinary tract cancers. Q J Nucl Med Mol Imaging 2007;51(3):260-271. 35. Nguyen BD. Clear cell adenocarcinoma of the urethra: 18 F-FDG PET/CT imaging. Clin Nucl Med 2015;40(3):241-243. 36. Larson SM, Schoder H. Advances in positron emission tomography applications for urologic cancers. Curr Opin Urol 2008;18(1):65-70. 37. Shvarts O, Han KR, Seltzer M, et al. Positron emission tomography in urologic oncology. Cancer Control 2002;9(4):335-342. 38. Prempree T, Amornmarn R, Patanaphan V. Radiation therapy in primary carcinoma of the female urethra. II. An update on results. Cancer 1984;54(4):729-733. 39. Amin MB, Edge SB, Greene FL, et al. AJCC cancer staging manual. 8th ed. Switzerland: Springer Nature, 2017. 40. Meis JM, Ayala AG, Johnson DE. Adenocarcinoma of the urethra in women. A clinicopathologic study. Cancer 1987;60(5):1038-1052. 41. Nash PA, Bihrle R, Gleason PE, et al. Mohs' micrographic surgery and distal urethrectomy with immediate urethral reconstruction for glanular carcinoma in situ with significant urethral extension. Urology 1996;47(1):108-110. 42. Ali SZ, Smilari TF, Gal D, et al. Primary adenoid cystic carcinoma of Skene's glands. Gynecol Oncol 1995;57(2):257-261. 43. Pandey PK, Vijay MK, Goel H, et al. Primary malignant melanoma of female urethra: a rare neoplasm. J Cancer Res Ther 2014;10(3):758-760. 44. Inuzuka S, Koga S, Imanishi D, et al. Primary malignant lymphoma of the female urethra. Anticancer Res