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Primary Clear-Cell Adenocarcinoma of the Proximal Female Urethra: Case Report and Review of the Literature
Case Report
Primary Clear-Cell Adenocarcinoma of the Proximal Female Urethra: Case Report and Review of the Literature Joe Miller1 R. Jeffrey Karnes2 1Southern
Illinois University School of Medicine, Springfield, IL 2Department of Urology, Mayo Clinic, Rochester, MN
Abstract Primary carcinoma of the female urethra is a rare entity. Adenocarcinomas account for only 10% of cases. Clear cell adenocarcinoma (CCA) of the urethra is more common among women than men.1 We report a case of primary CCA of the urethra and review the literature concerning the histogenesis, management, and outcome of this uncommon tumor.
Case Report
Clinical Genitourinary Cancer, Vol. 6, No. 2, 131-133, 2008 Keywords: Anterior exenteration, Radical urethrectomy, Urethral carcinoma DOI: 10.3816/CGC.2008.n.022 Submitted: Oct 4, 2007; Revised: Dec 11, 2007; Accepted: Feb 25, 2008 Address for correspondence: Joe Miller, MD PO Box 19665 Springfield, IL 62794 Fax: 217-545-7305 E-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
A 48-year-old African American woman complained of a 2-month history of lower urinary tract symptoms and intermittent gross hematuria. Urine cultures had been negative. She denied incontinence, urethral discharge, fever, dyspareunia, or dysuria. She had a 30-pack-year smoking history and was treated for hypertension. The review of systems and physical examination including groins were normal except for a nonfixed urethral fullness to the bladder neck. Urinalysis revealed hematuria and small amount of leukocytes. Computed tomography showed uterine fibroids and a poorly characterized periurethral lesion. Office cystoscopy revealed an ulcerated lesion in the posterior aspect of the bladder neck with a bloody expression and areas of sloughing tissue. The distal urethra was normal. Cystoscopic biopsy of the bladder neck lesion was conducted under general anesthesia. Biopsies of the endocervix and uterus were also obtained and were negative. Urine cytology was positive for malignant cells consistent in appearance with an adenocarcinoma. Histologic examination of the bladder neck biopsies revealed tumor composed of papillary structures lined by cuboidal cells with irregular hyperchromic nuclei, prominent nucleoli, and prominent clear cytoplasm (Figure 1). Many of the atypical cells lining the papillary structure had a “hobnail” appearance, and there were frequent mitotic figures. Within the specimen, the tumor formed tubular structures and small nests. Magnetic resonance imaging of the pelvis showed a 2.5 cm × 2.2 cm peripheral enhancing lesion about the proximal urethral, without evidence of regional lymphadenopathy (Figure 2). A chest x-ray conducted for staging was normal. After a lengthy discussion, the patient elected to proceed with surgery. An anterior pelvic exenteration including radical urethrectomy with bilateral pelvic lymph node dissection, anterior vaginal wall resection, and vaginoplasty was conducted with an ileal conduit urinary diversion. The patient tolerated the procedure well, her postoperative course was uncomplicated, and she was without evidence of disease at 24 months. Adjuvant therapy was not provided. Pathologic examination of the surgical specimen revealed tumor invasion into the periurethral smooth muscle without infiltration through the full
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Primary CCA of the Proximal Female Urethra
Figure 2 Magnetic Resonance Imaging Demonstrating
Figure 1 Histology of Bladder Neck Biopsy
Intravesical Lesion
thickness of the muscular wall. There was no evidence of lymphovascular or perineural invasion. The resected portion of the anterior vaginal wall was negative for tumor, and pelvic lymph nodes were also negative. The right and left ureteral segments and the remainder of the bladder specimen were normal. The uterus, fallopian tubes, and ovaries were free of significant pathology. The TNM classification was stage II (pT2 pN0 pMX).
Discussion The proximal one third of the female urethra is lined by transitional epithelium, the distal two thirds by stratified squamous epithelium. Accordingly, the histology of urethral tumors is generally consistent with the location. Tumors located distally or those involving the urethral meatus are typically squamous cell carcinoma. Tumors of the proximal urethra are most commonly transitional cell carcinoma or adenocarcinoma. Adenocarcinomas occurring in the proximal female urethra can be of 2 broad classifications, clear cell adenocarcinoma (CCA) or non–clear-cell adenocarcinoma. Clear cell adenocarcinoma occurs less frequently and might display tubulocystic, tubular, papillary, or diffuse tissue architecture. A combination of patterns is common.1 Reports regarding the relation of primary CCA of the urethra to urethral diverticula and paraurethral glands, and the resemblance of CCA of the urethra to tumors of mesonephric origin have varied in their findings and conclusions; thus, the histogenesis of these tumors has been widely debated. Historically adenocarcinomas of the urethra were considered mesonephric in origin. Additionally, the histologic resemblance of portions of these tumors to nephrogenic adenomas supported the assertion that CCA of the urethra arose from their malignant degeneration. Contemporary authors such as Oliva and Young have highlighted the differences in morphology and concluded that, in the majority of patients, CCA of the urethra does not represent malignant transformation of nephrogenic adenomas or tumors of true mesonephric derivation.2 Findings of positive immunohistochemical staining for prostate specific antigen (PSA) and prostatic acid phosphatase (PAS) have suggested that CCA of the female urethra might derive from the
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paraurethral Skene’s glands, the female homologue of the prostate.3,4 Conflicting data from Oliva and Young, as well as more recent data from Murphy and colleagues and a case series and literature review by Drew et al, reported negative immunohistochemical staining for PSA and PAS in all cases of CCA.2,5,6 In the data published by Drew et al, 6 of 6 clear cell adenocarcinomas stained positive for cancer antigen (CA)-125 which, combined with the histologic similarities, led the authors to suggest the tumors were of a mullerian differentiation. They also concluded CCA of the urethra might be the result of heterogenous differentiation and a distinctive neoplasm, which was also suggested by Oliva and Young.2,6 Because of the rarity of urethral tumors in women, consensus on management and predictors of outcome have been slow to emerge. In Grigsby’s review of 44 women with urethral carcinoma, the reported 5-year overall survival and cause-specific survival was 42% and 40%, respectively. Tumor size and histology were found to be independent prognostic factors. At 5 years, none of the 13 women with adenocarcinoma, and only 10% of the women with a tumor > 4 cm, were alive, irrespective of treatment modality.7 DiMarco et al reported on 53 women, including 14 with adenocarcinoma, who underwent surgical treatment for urethral carcinoma at the Mayo Clinic from 1948 to 1999. Pathologic stage was found to be predictive of local recurrence. Pathologic T3-4 was associated with a 36% recurrence-free survival at 5 years. Those women who recurred had a cancer mortality rate of 71% at 5 years after recurrence. Treatment options of primary urethral carcinoma, regardless of histologic type, include local excision, radical urethrectomy, and anterior exenteration, with or without adjuvant radiation or chemotherapy. DiMarco’s review also concluded that treatment with local excision versus radical urethrectomy or anterior exenteration resulted in higher rates of local recurrence. Neither adjuvant radiation nor chemotherapy
September 2008
Joe Miller, R. Jeffrey Karnes was shown to improve rates of systemic recurrence or survival, but adjuvant radiation might decrease local recurrence.8 When compared with squamous cell carcinoma and transitional cell carcinoma, adenocarcinoma of the female urethra, including CCA, has a statistically significant lower cause-specific survival and recurrence-free survival. Grigsby’s review reported a 5-year cause-specific survival of 62% for women with squamous cell carcinoma compared with 30% in women with transitional cell carcinoma and 0 for those with adenocarcinoma.7 Similarly, in the series of 53 women presented by DiMarco, the 5-year recurrence-free survival among women with CCA was 46%, compared with 49% and 67% for transitional cell carcinoma and squamous cell carcinoma, respectively.8
Conclusion Primary clear cell adenocarcinoma of the female urethra is uncommon and its origin has been the subject of much debate. Carcinomas of the female urethra are aggressive, with tumor size and histology predictive of outcome. Pathologic stage is predictive of recurrence, and recurrence results in a high rate of
mortality. Radical urethrectomy and anterior exenteration result in lower rates of local recurrence compared to local excision while adjuvant radiation or chemotherapy have not been proven to improve survival.
References
1. Amin MB, Young, RH. Primary carcinomas of the urethra. Semin Diagn Pathol 1997; 14:147-60. 2. Oliva E, Young RH. Clear cell adenocarcinoma of the urethra: a clinicopathologic analysis of 19 cases. Mod Pathol 1996; 9:513-20. 3. Spencer JR, Brodin AG, Ignatoff JM. Clear cell adenocarcinoma of the urethra: evidence for origin within paraurethral ducts. J Urol 1990; 143:122-5. 4. Ebisumno S, Miyai M, Nagareda T. Clear cell adenocarcinoma of the female urethra showing positive staining with antibodies to prostate-specific antigen and prostatic acid phosphatase. Urology 1995; 45:682-5. 5. Murphy DP, Pantuck AJ, Amenta PS, et al. Female urethral adenocarcinoma: immunohistochemical evidence of more than 1 tissue of origin. J Urol 1999; 161:1881-4. 6. Drew PA, Murphy WM, Civantos F, et al. The histogenesis of clear cell adenocarcinoma of the lower urinary tract: case series and review of the literature. Hum Pathol 1996; 27:248-52. 7. Grigsby PW. Carcinoma of the urethra in women. Int J Radiat Oncol Biol Phys 1998; 41:535-41. 8. DiMarco DS, DiMarco CS, Zincke H, et al. Surgical treatment for local control of female urethral carcinoma. Urol Oncol 2004; 22; 404-9.
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Primary Clear-Cell Adenocarcinoma of the Proximal Female Urethra: Case Report and Review of the Literature Joe Miller1 R. Jeffrey Karnes2 1Southern
Illinois University School of Medicine, Springfield, IL 2Department of Urology, Mayo Clinic, Rochester, MN
Abstract Primary carcinoma of the female urethra is a rare entity. Adenocarcinomas account for only 10% of cases. Clear cell adenocarcinoma (CCA) of the urethra is more common among women than men.1 We report a case of primary CCA of the urethra and review the literature concerning the histogenesis, management, and outcome of this uncommon tumor.
Case Report
Clinical Genitourinary Cancer, Vol. 6, No. 2, 131-133, 2008 Keywords: Anterior exenteration, Radical urethrectomy, Urethral carcinoma DOI: 10.3816/CGC.2008.n.022 Submitted: Oct 4, 2007; Revised: Dec 11, 2007; Accepted: Feb 25, 2008 Address for correspondence: Joe Miller, MD PO Box 19665 Springfield, IL 62794 Fax: 217-545-7305 E-mail: [email protected] Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1558-7673, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
A 48-year-old African American woman complained of a 2-month history of lower urinary tract symptoms and intermittent gross hematuria. Urine cultures had been negative. She denied incontinence, urethral discharge, fever, dyspareunia, or dysuria. She had a 30-pack-year smoking history and was treated for hypertension. The review of systems and physical examination including groins were normal except for a nonfixed urethral fullness to the bladder neck. Urinalysis revealed hematuria and small amount of leukocytes. Computed tomography showed uterine fibroids and a poorly characterized periurethral lesion. Office cystoscopy revealed an ulcerated lesion in the posterior aspect of the bladder neck with a bloody expression and areas of sloughing tissue. The distal urethra was normal. Cystoscopic biopsy of the bladder neck lesion was conducted under general anesthesia. Biopsies of the endocervix and uterus were also obtained and were negative. Urine cytology was positive for malignant cells consistent in appearance with an adenocarcinoma. Histologic examination of the bladder neck biopsies revealed tumor composed of papillary structures lined by cuboidal cells with irregular hyperchromic nuclei, prominent nucleoli, and prominent clear cytoplasm (Figure 1). Many of the atypical cells lining the papillary structure had a “hobnail” appearance, and there were frequent mitotic figures. Within the specimen, the tumor formed tubular structures and small nests. Magnetic resonance imaging of the pelvis showed a 2.5 cm × 2.2 cm peripheral enhancing lesion about the proximal urethral, without evidence of regional lymphadenopathy (Figure 2). A chest x-ray conducted for staging was normal. After a lengthy discussion, the patient elected to proceed with surgery. An anterior pelvic exenteration including radical urethrectomy with bilateral pelvic lymph node dissection, anterior vaginal wall resection, and vaginoplasty was conducted with an ileal conduit urinary diversion. The patient tolerated the procedure well, her postoperative course was uncomplicated, and she was without evidence of disease at 24 months. Adjuvant therapy was not provided. Pathologic examination of the surgical specimen revealed tumor invasion into the periurethral smooth muscle without infiltration through the full
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Primary CCA of the Proximal Female Urethra
Figure 2 Magnetic Resonance Imaging Demonstrating
Figure 1 Histology of Bladder Neck Biopsy
Intravesical Lesion
thickness of the muscular wall. There was no evidence of lymphovascular or perineural invasion. The resected portion of the anterior vaginal wall was negative for tumor, and pelvic lymph nodes were also negative. The right and left ureteral segments and the remainder of the bladder specimen were normal. The uterus, fallopian tubes, and ovaries were free of significant pathology. The TNM classification was stage II (pT2 pN0 pMX).
Discussion The proximal one third of the female urethra is lined by transitional epithelium, the distal two thirds by stratified squamous epithelium. Accordingly, the histology of urethral tumors is generally consistent with the location. Tumors located distally or those involving the urethral meatus are typically squamous cell carcinoma. Tumors of the proximal urethra are most commonly transitional cell carcinoma or adenocarcinoma. Adenocarcinomas occurring in the proximal female urethra can be of 2 broad classifications, clear cell adenocarcinoma (CCA) or non–clear-cell adenocarcinoma. Clear cell adenocarcinoma occurs less frequently and might display tubulocystic, tubular, papillary, or diffuse tissue architecture. A combination of patterns is common.1 Reports regarding the relation of primary CCA of the urethra to urethral diverticula and paraurethral glands, and the resemblance of CCA of the urethra to tumors of mesonephric origin have varied in their findings and conclusions; thus, the histogenesis of these tumors has been widely debated. Historically adenocarcinomas of the urethra were considered mesonephric in origin. Additionally, the histologic resemblance of portions of these tumors to nephrogenic adenomas supported the assertion that CCA of the urethra arose from their malignant degeneration. Contemporary authors such as Oliva and Young have highlighted the differences in morphology and concluded that, in the majority of patients, CCA of the urethra does not represent malignant transformation of nephrogenic adenomas or tumors of true mesonephric derivation.2 Findings of positive immunohistochemical staining for prostate specific antigen (PSA) and prostatic acid phosphatase (PAS) have suggested that CCA of the female urethra might derive from the
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paraurethral Skene’s glands, the female homologue of the prostate.3,4 Conflicting data from Oliva and Young, as well as more recent data from Murphy and colleagues and a case series and literature review by Drew et al, reported negative immunohistochemical staining for PSA and PAS in all cases of CCA.2,5,6 In the data published by Drew et al, 6 of 6 clear cell adenocarcinomas stained positive for cancer antigen (CA)-125 which, combined with the histologic similarities, led the authors to suggest the tumors were of a mullerian differentiation. They also concluded CCA of the urethra might be the result of heterogenous differentiation and a distinctive neoplasm, which was also suggested by Oliva and Young.2,6 Because of the rarity of urethral tumors in women, consensus on management and predictors of outcome have been slow to emerge. In Grigsby’s review of 44 women with urethral carcinoma, the reported 5-year overall survival and cause-specific survival was 42% and 40%, respectively. Tumor size and histology were found to be independent prognostic factors. At 5 years, none of the 13 women with adenocarcinoma, and only 10% of the women with a tumor > 4 cm, were alive, irrespective of treatment modality.7 DiMarco et al reported on 53 women, including 14 with adenocarcinoma, who underwent surgical treatment for urethral carcinoma at the Mayo Clinic from 1948 to 1999. Pathologic stage was found to be predictive of local recurrence. Pathologic T3-4 was associated with a 36% recurrence-free survival at 5 years. Those women who recurred had a cancer mortality rate of 71% at 5 years after recurrence. Treatment options of primary urethral carcinoma, regardless of histologic type, include local excision, radical urethrectomy, and anterior exenteration, with or without adjuvant radiation or chemotherapy. DiMarco’s review also concluded that treatment with local excision versus radical urethrectomy or anterior exenteration resulted in higher rates of local recurrence. Neither adjuvant radiation nor chemotherapy
September 2008
Joe Miller, R. Jeffrey Karnes was shown to improve rates of systemic recurrence or survival, but adjuvant radiation might decrease local recurrence.8 When compared with squamous cell carcinoma and transitional cell carcinoma, adenocarcinoma of the female urethra, including CCA, has a statistically significant lower cause-specific survival and recurrence-free survival. Grigsby’s review reported a 5-year cause-specific survival of 62% for women with squamous cell carcinoma compared with 30% in women with transitional cell carcinoma and 0 for those with adenocarcinoma.7 Similarly, in the series of 53 women presented by DiMarco, the 5-year recurrence-free survival among women with CCA was 46%, compared with 49% and 67% for transitional cell carcinoma and squamous cell carcinoma, respectively.8
Conclusion Primary clear cell adenocarcinoma of the female urethra is uncommon and its origin has been the subject of much debate. Carcinomas of the female urethra are aggressive, with tumor size and histology predictive of outcome. Pathologic stage is predictive of recurrence, and recurrence results in a high rate of
mortality. Radical urethrectomy and anterior exenteration result in lower rates of local recurrence compared to local excision while adjuvant radiation or chemotherapy have not been proven to improve survival.
References
1. Amin MB, Young, RH. Primary carcinomas of the urethra. Semin Diagn Pathol 1997; 14:147-60. 2. Oliva E, Young RH. Clear cell adenocarcinoma of the urethra: a clinicopathologic analysis of 19 cases. Mod Pathol 1996; 9:513-20. 3. Spencer JR, Brodin AG, Ignatoff JM. Clear cell adenocarcinoma of the urethra: evidence for origin within paraurethral ducts. J Urol 1990; 143:122-5. 4. Ebisumno S, Miyai M, Nagareda T. Clear cell adenocarcinoma of the female urethra showing positive staining with antibodies to prostate-specific antigen and prostatic acid phosphatase. Urology 1995; 45:682-5. 5. Murphy DP, Pantuck AJ, Amenta PS, et al. Female urethral adenocarcinoma: immunohistochemical evidence of more than 1 tissue of origin. J Urol 1999; 161:1881-4. 6. Drew PA, Murphy WM, Civantos F, et al. The histogenesis of clear cell adenocarcinoma of the lower urinary tract: case series and review of the literature. Hum Pathol 1996; 27:248-52. 7. Grigsby PW. Carcinoma of the urethra in women. Int J Radiat Oncol Biol Phys 1998; 41:535-41. 8. DiMarco DS, DiMarco CS, Zincke H, et al. Surgical treatment for local control of female urethral carcinoma. Urol Oncol 2004; 22; 404-9.
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