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Melanoma of the Female Urethra
0022-5347 /81/1264-0553$02.00/0 Vol. 126, October
THE JOURNAL OF UROLOGY
Copyright© 1981 by The Williams & Wilkins Co.
MELANOMA
Printed in U.S.A.
THE FEMALE URETHRA
C. J. GODEC, * A. S. CASS, C. R HITCHCOCK
AND
T. A. HILDRETH
From the Department of Surgery, Division of Urology, Hennepin County Medical Center, Minneapolis and Department of Urology, St. Paul-Ramsey Medical Center, St. Paul, Minnesota
ABSTRACT
Om patient had a highly malignant and poorly differentiated tumor in the distal urethra. A conservative operation was performed because the precise nature of the tumor was not dear with light microscopy. An ultrastructurnJ study established the final diagnosis of malignant urethral melanoma and anterior exenteration was performed. An aggressive operation should be considered as the primary approach once malignant melanoma is diagnosed. Ultrastructural studies should be introduced early in the diagnostic process when light microscopy is insufficient to provide a definitive diagnosi.s of urethral malignancy. Malignant urethral tumors are rare, occurring in approximately 1 per 1 million male and 1. 7 per 1 million female subjects. 1 In the majority of the cases the tumors are carcinomas and they occur far more often in female urethras. 2 ' 3 Although malignant melanoma arising from cutaneous tissue is a relatively common tumor, those originating from the urethra are exceedingly rare and constitute only a small percentage of primary urethral tumors. A literature search reveaied only 36 reported cases of primary urethral melanoma. 1' 3- 6 We report another case of urethral melanoma that was undifferentiated. The precise histogenesis was established by electron microscopy.
rated and she died 4 months later. Autopsy studies documented metastases to the small intestine, stomach, liver and Light microscopy and ultrastructural studies. The biopsy of the urethral tumor revealed a cellularly undifferentiated, diffusely infiltrating malignant tumor. The cells were fairly uniform in size and contained nuclei that varied from ovoid to spindled forms. The chromatin pattern was granular and dispersed. Mitoses were numerous and numbered up to 10 per high power field (X160). Cell membranes were indistinct and cytoplasm was scant, frequently having a clear or vacuolated appearance. Occasional cells contained scant eosinophilic cytoplasm (fig. 1). There was no evidence of an organoid pattern and stains for melanin pigment were narr,,·rrn·o Furthermore, there was no suggestion of a myogenic ·with either the trichrome or phosphotungstic acid-hematoxyhn staining techniques. Biopsies of the partial urethrectomy and vaginectomy revealed an undifferentiated malignant tumor with features similar to the initial biopsy. Histologic examination electron microscopy revealed the tumor to be composed undifferentiated cells with only occasional rudimentary tional complexes. There was no evidence of melanosomes these initial studies. Tissues were fixed in the normal manner and were exposed to 3:4-dihydroxyphenylalanine during fixation. Repeated histologic examination of the recurrent tumo:c continued to reveal an undifferentiated tumor of uncertain histogenesis. However, examination of the tumor that metastasized to the inguinal region before the anterior exenteration showed cuau;~"" suggestive of melanocytic differentiation. Light microscopy of the tumor cells displayed either an epithelioid or spindled appearance. Nuclei were moderately large and ovoid, and had peripherally dispersed chromatin and prominent nucleolt CelI membranes were distinct, cytoplasm was moderately abundant and rare cells contained fine granular, brown pigment suggestive of melanin (fig. 2). Melanoma was confirmed by ultrastructuraI studies, which revealed tumor cells containing fairly numerous melanosomes and premelanosomes. Since ultrastructural studies of the early biopsies were diagnostic additional multiple sections of the original were re-evaluated for the presence of melanosomes. studies did reveal an occasional tumor cell to contain rare, stage II melanosomes tha: were not present in the initial electron microscopic examination (fig. 3).
CASE REPORT
A 54-year-old white woman was hospitalized for a palpable tumor in the distal urethra that was visible at the external meatus. The remainder of the vagina, the uterus and the adnexa were normal. A biopsy was taken, and light microscopy revealed the tumor to be poorly differentiated and diffusely infiltrating. The patient subsequently underwent complete evaluation, including excretory urography, voiding cystourethrngraphy, chest tomography, liver and bone scans, upper gastrointestinal series, barium enema and routine urine and blood analysis. All parameters were normal. Cystoscopy revealed a normal bladder and proximal urethra. However, a soft, friable tumor was found in the distal urethra, and was excised partial urethrectomy and partial vaginectomy. Subsequent histologic examination revealed an undifferentiated tumor similar to the initial biopsy. Two months after local excision of the tumor a suspicious node was palpated in the right inguinal region. A right radical inguinal node dissection was performed and 1 of 12 nodes removed was found to be an undifferentiated tumor. A cuff of urethral tissue also was excised from the new urinary meatus and this was negative for malignancy. A recurrent tumor was found in the urethra 3 months later and an anterior exenteration, including bilateral pelvic lymphadenectomy, was performed. On frozen section at the time of the operation all lymph nodes were read as negative. A single lymph node in the vicinity of the right obturator nerve contained a metastatic tumor on permanent sections. The patient remained well for 8 months after the exenteration operation but then noticed small masses in the groin and sup:rapubically. These masses were biopsied and revealed metastatic tumors. The patient's condition progressively deterio-
DISCUSSION
Accepted for publication November 26, 1980. * Requests for reprints: Department of Surgery, Division of Urology, Hennepin County Medical Cente:r, 701 Park Ave. South, Minneapolis, Minnesota 55-415.
A high curability of primary malignant urethral tumors be anticipated because their location allows easy c.11o,au.«u,acivu, and ready access to biopsy and exfoliative 553
554
GODEC AND ASSOCIATES
Fm. 1. Initial biopsy consisted of undifferentiated tumor comprised of cells with fusiform pleomorphic nuclei, indistinct cell membranes and numerous mitoses (center). H & E, reduced from X160.
Fm. 2. Tumor morphology in biopsy obtained 15 months after biopsy in figure 1 is more suggestive of melanocytic differentiation. Cells contain ovoid nuclei, prominent nucleoli and fairly distinct cell membranes. H & E, reduced from X160.
more, the clinical symptoms frequently appear early and may stimulate either urethrovesical conditions, such as urinary frequency, dysuria and incontinence, or gynecologic symptoms of vaginal bleeding and discharge, pruritis and dyspareunia. In a study of primary urethral carcinoma in women, for example, urologic or gynecologic symptoms occurring early in the course of the disease were present in 83.5 per cent of the patients. 7 These observations underscore the feasibility and the importance of early diagnosis. From a clinical perspective early diagnosis of melanoma is quite relevant, since this might require more aggressive therapy in the early disease stage. Tissue biopsies of the urethral tumor in the early stages of the illness were interpreted as an undifferentiated malignant tumor of indeterminant histogenesis. Subsequent biopsies of recurrent tumors were similar in appearance until approxi-
mately 8 months after the exenteration operation, when the tumor differentiated sufficiently to diagnose melanoma based on the observation of numerous melanosomes and premelanosomes ultrastructurally. A review of the initial electron microscopic studies disclosed no evidence of melanosomes until later sectioning of the initial biopsy material. The rarity of urethral melanoma precludes the formulation of standardized, definitive treatment. It has been suggested that local excision and irradiation therapy should be attempted initially. 8 In instances of recurrent tumors subsequent to local excision and/ or irradiation an aggressive exenterative operation is recommended. Others advocate anterior exenteration with pelvic lymphadenectomy as the primary treatment for urethral melanoma because of the generally poor prognosis. 9 The rates of cases without lymph node metastases have been reported as
MELANOMA OF FEMALE URETHRA
555
reported by Das Gupta and Grabstald of 4 urethral melanomas in female patients, none of whom survived 5 years. 14 An early diagnosis of urethral melanoma is of foremost importance if an aggressive therapeutic approach is to be successful. In addition, diagnostic electron microscopy is essential for undifferentiated tumors and may require examination of multiple biopsies to establish the precise histogenesis. Dr. W. R. Anderson reviewed the slides and tomicrographs for this report.
Fm. 3. Electron microgiraphs of portions of several tumor cells show no hint as to origin. Note moderate ru--nount of cytoplasrnic glycogen. Lead citrate and uranyl acetate, reduced from X6,050. Inset, high power examination reveals ciga~-shaped stage H melanosomes. Reduced from X80,500.
28, 8 35, 3 47 10 and 50 per cent 11 in various studies. Metastases to lymph nodes in these patients were considered. U!JlHACVCm findings. Although successful application of irradiation has been rein some properly selected cases, urethral melanoma is radioresistant. 12 Herbut documented that unlike other tumors of epithelial origin melanoma of mucous membrane has a poor prognosis because of delay in treatment, ulceration or a location that may compromise successful cal removal. 13 The poor prognosis is exemplified in the
REFERENCES 1. Payne, P.: Malignant tumors of the female urethra 1961-1971. Cited by Skeet, R. G.: Epidemiology of urogenital tumors. In: Scientific Foundations of Urology. Edited by D. I. Williams and G. D. Chisholm. London: William Heinemann Medical Books Ltd., 2, chapt. 24,p. 206, 1976. 2. Thompson, I. M. and Bivings, F. G.: Aspects of urethral carcinoma. J. Urol., 87: 891, 1962. 3. Pointon, R. C. and Poole-Wilson, D. S.: Primary carcinoma of the urethra. Brit. J. Urol., 40: 682, 1968. 4. Abeshouse, B. S.: Primary and secondary melanoma of genitourinary tract. South. Med. J., 51: 994, 1958. 5. Grabstald, H.: Proceedings: tumors of the urethra in men and women. Cancer, 32: 1236, 1973. 6. Peterson, D. T., Dockerty, M. B., Utz, D. C. and Symmonds, R. E.: The peril of primary carcinoma of the urethra in woman. J. U ro;., 110: 72, 1973. 7. Zeigerman, J. H. and Gordon, S. F.: Cancer of the female urethra. A curable disease. Obst. Gynec., 36: 785, 1970. 8. Ray, B. and Guinan, P. D.: Primary carcinoma of the urethra. In: Principles and Management of Urologic Cancer. Edited by N. Javadpour. Baltimore: The Williams & Wilkins Co., chapt. 16, p. 467, 1979. 9. Geelhoed, G. W. and Myers, G. H., Jr.: Primary melanoma of the male urethra. J. Urol., Hl9: 634, 1973. 10. Staubitz, W. J., Carden, L. M., Oberkircher, 0. J., Lent, M. H. and Murphy, W. T.: Management of urethral carcinoma in the female. J. U:rol., 73: 1045, 1955. 11. Riches, E.W. and Cullen, T. H.: Carcinoma of the urethra. Bnt. J. Urol., 23: 209, 1951. 12. Seng, M. and Siminovich, M.: Carcinoma of the urethra in the female. Canad. Med. Ass. J., 58: 29, 1948. 13. Herbut, P. A.: Urological Pathology. Philadelphia: Lea & Febiger, vols. 1 and 2, pp. 121, 309, 744, 686, 1217, 1952. 14. Das Gupta, T. and G.rabstald, H.: Melanoma of the genitourinary tract. J. UroL, 93: 607, 1965.
THE JOURNAL OF UROLOGY
Copyright© 1981 by The Williams & Wilkins Co.
MELANOMA
Printed in U.S.A.
THE FEMALE URETHRA
C. J. GODEC, * A. S. CASS, C. R HITCHCOCK
AND
T. A. HILDRETH
From the Department of Surgery, Division of Urology, Hennepin County Medical Center, Minneapolis and Department of Urology, St. Paul-Ramsey Medical Center, St. Paul, Minnesota
ABSTRACT
Om patient had a highly malignant and poorly differentiated tumor in the distal urethra. A conservative operation was performed because the precise nature of the tumor was not dear with light microscopy. An ultrastructurnJ study established the final diagnosis of malignant urethral melanoma and anterior exenteration was performed. An aggressive operation should be considered as the primary approach once malignant melanoma is diagnosed. Ultrastructural studies should be introduced early in the diagnostic process when light microscopy is insufficient to provide a definitive diagnosi.s of urethral malignancy. Malignant urethral tumors are rare, occurring in approximately 1 per 1 million male and 1. 7 per 1 million female subjects. 1 In the majority of the cases the tumors are carcinomas and they occur far more often in female urethras. 2 ' 3 Although malignant melanoma arising from cutaneous tissue is a relatively common tumor, those originating from the urethra are exceedingly rare and constitute only a small percentage of primary urethral tumors. A literature search reveaied only 36 reported cases of primary urethral melanoma. 1' 3- 6 We report another case of urethral melanoma that was undifferentiated. The precise histogenesis was established by electron microscopy.
rated and she died 4 months later. Autopsy studies documented metastases to the small intestine, stomach, liver and Light microscopy and ultrastructural studies. The biopsy of the urethral tumor revealed a cellularly undifferentiated, diffusely infiltrating malignant tumor. The cells were fairly uniform in size and contained nuclei that varied from ovoid to spindled forms. The chromatin pattern was granular and dispersed. Mitoses were numerous and numbered up to 10 per high power field (X160). Cell membranes were indistinct and cytoplasm was scant, frequently having a clear or vacuolated appearance. Occasional cells contained scant eosinophilic cytoplasm (fig. 1). There was no evidence of an organoid pattern and stains for melanin pigment were narr,,·rrn·o Furthermore, there was no suggestion of a myogenic ·with either the trichrome or phosphotungstic acid-hematoxyhn staining techniques. Biopsies of the partial urethrectomy and vaginectomy revealed an undifferentiated malignant tumor with features similar to the initial biopsy. Histologic examination electron microscopy revealed the tumor to be composed undifferentiated cells with only occasional rudimentary tional complexes. There was no evidence of melanosomes these initial studies. Tissues were fixed in the normal manner and were exposed to 3:4-dihydroxyphenylalanine during fixation. Repeated histologic examination of the recurrent tumo:c continued to reveal an undifferentiated tumor of uncertain histogenesis. However, examination of the tumor that metastasized to the inguinal region before the anterior exenteration showed cuau;~"" suggestive of melanocytic differentiation. Light microscopy of the tumor cells displayed either an epithelioid or spindled appearance. Nuclei were moderately large and ovoid, and had peripherally dispersed chromatin and prominent nucleolt CelI membranes were distinct, cytoplasm was moderately abundant and rare cells contained fine granular, brown pigment suggestive of melanin (fig. 2). Melanoma was confirmed by ultrastructuraI studies, which revealed tumor cells containing fairly numerous melanosomes and premelanosomes. Since ultrastructural studies of the early biopsies were diagnostic additional multiple sections of the original were re-evaluated for the presence of melanosomes. studies did reveal an occasional tumor cell to contain rare, stage II melanosomes tha: were not present in the initial electron microscopic examination (fig. 3).
CASE REPORT
A 54-year-old white woman was hospitalized for a palpable tumor in the distal urethra that was visible at the external meatus. The remainder of the vagina, the uterus and the adnexa were normal. A biopsy was taken, and light microscopy revealed the tumor to be poorly differentiated and diffusely infiltrating. The patient subsequently underwent complete evaluation, including excretory urography, voiding cystourethrngraphy, chest tomography, liver and bone scans, upper gastrointestinal series, barium enema and routine urine and blood analysis. All parameters were normal. Cystoscopy revealed a normal bladder and proximal urethra. However, a soft, friable tumor was found in the distal urethra, and was excised partial urethrectomy and partial vaginectomy. Subsequent histologic examination revealed an undifferentiated tumor similar to the initial biopsy. Two months after local excision of the tumor a suspicious node was palpated in the right inguinal region. A right radical inguinal node dissection was performed and 1 of 12 nodes removed was found to be an undifferentiated tumor. A cuff of urethral tissue also was excised from the new urinary meatus and this was negative for malignancy. A recurrent tumor was found in the urethra 3 months later and an anterior exenteration, including bilateral pelvic lymphadenectomy, was performed. On frozen section at the time of the operation all lymph nodes were read as negative. A single lymph node in the vicinity of the right obturator nerve contained a metastatic tumor on permanent sections. The patient remained well for 8 months after the exenteration operation but then noticed small masses in the groin and sup:rapubically. These masses were biopsied and revealed metastatic tumors. The patient's condition progressively deterio-
DISCUSSION
Accepted for publication November 26, 1980. * Requests for reprints: Department of Surgery, Division of Urology, Hennepin County Medical Cente:r, 701 Park Ave. South, Minneapolis, Minnesota 55-415.
A high curability of primary malignant urethral tumors be anticipated because their location allows easy c.11o,au.«u,acivu, and ready access to biopsy and exfoliative 553
554
GODEC AND ASSOCIATES
Fm. 1. Initial biopsy consisted of undifferentiated tumor comprised of cells with fusiform pleomorphic nuclei, indistinct cell membranes and numerous mitoses (center). H & E, reduced from X160.
Fm. 2. Tumor morphology in biopsy obtained 15 months after biopsy in figure 1 is more suggestive of melanocytic differentiation. Cells contain ovoid nuclei, prominent nucleoli and fairly distinct cell membranes. H & E, reduced from X160.
more, the clinical symptoms frequently appear early and may stimulate either urethrovesical conditions, such as urinary frequency, dysuria and incontinence, or gynecologic symptoms of vaginal bleeding and discharge, pruritis and dyspareunia. In a study of primary urethral carcinoma in women, for example, urologic or gynecologic symptoms occurring early in the course of the disease were present in 83.5 per cent of the patients. 7 These observations underscore the feasibility and the importance of early diagnosis. From a clinical perspective early diagnosis of melanoma is quite relevant, since this might require more aggressive therapy in the early disease stage. Tissue biopsies of the urethral tumor in the early stages of the illness were interpreted as an undifferentiated malignant tumor of indeterminant histogenesis. Subsequent biopsies of recurrent tumors were similar in appearance until approxi-
mately 8 months after the exenteration operation, when the tumor differentiated sufficiently to diagnose melanoma based on the observation of numerous melanosomes and premelanosomes ultrastructurally. A review of the initial electron microscopic studies disclosed no evidence of melanosomes until later sectioning of the initial biopsy material. The rarity of urethral melanoma precludes the formulation of standardized, definitive treatment. It has been suggested that local excision and irradiation therapy should be attempted initially. 8 In instances of recurrent tumors subsequent to local excision and/ or irradiation an aggressive exenterative operation is recommended. Others advocate anterior exenteration with pelvic lymphadenectomy as the primary treatment for urethral melanoma because of the generally poor prognosis. 9 The rates of cases without lymph node metastases have been reported as
MELANOMA OF FEMALE URETHRA
555
reported by Das Gupta and Grabstald of 4 urethral melanomas in female patients, none of whom survived 5 years. 14 An early diagnosis of urethral melanoma is of foremost importance if an aggressive therapeutic approach is to be successful. In addition, diagnostic electron microscopy is essential for undifferentiated tumors and may require examination of multiple biopsies to establish the precise histogenesis. Dr. W. R. Anderson reviewed the slides and tomicrographs for this report.
Fm. 3. Electron microgiraphs of portions of several tumor cells show no hint as to origin. Note moderate ru--nount of cytoplasrnic glycogen. Lead citrate and uranyl acetate, reduced from X6,050. Inset, high power examination reveals ciga~-shaped stage H melanosomes. Reduced from X80,500.
28, 8 35, 3 47 10 and 50 per cent 11 in various studies. Metastases to lymph nodes in these patients were considered. U!JlHACVCm findings. Although successful application of irradiation has been rein some properly selected cases, urethral melanoma is radioresistant. 12 Herbut documented that unlike other tumors of epithelial origin melanoma of mucous membrane has a poor prognosis because of delay in treatment, ulceration or a location that may compromise successful cal removal. 13 The poor prognosis is exemplified in the
REFERENCES 1. Payne, P.: Malignant tumors of the female urethra 1961-1971. Cited by Skeet, R. G.: Epidemiology of urogenital tumors. In: Scientific Foundations of Urology. Edited by D. I. Williams and G. D. Chisholm. London: William Heinemann Medical Books Ltd., 2, chapt. 24,p. 206, 1976. 2. Thompson, I. M. and Bivings, F. G.: Aspects of urethral carcinoma. J. Urol., 87: 891, 1962. 3. Pointon, R. C. and Poole-Wilson, D. S.: Primary carcinoma of the urethra. Brit. J. Urol., 40: 682, 1968. 4. Abeshouse, B. S.: Primary and secondary melanoma of genitourinary tract. South. Med. J., 51: 994, 1958. 5. Grabstald, H.: Proceedings: tumors of the urethra in men and women. Cancer, 32: 1236, 1973. 6. Peterson, D. T., Dockerty, M. B., Utz, D. C. and Symmonds, R. E.: The peril of primary carcinoma of the urethra in woman. J. U ro;., 110: 72, 1973. 7. Zeigerman, J. H. and Gordon, S. F.: Cancer of the female urethra. A curable disease. Obst. Gynec., 36: 785, 1970. 8. Ray, B. and Guinan, P. D.: Primary carcinoma of the urethra. In: Principles and Management of Urologic Cancer. Edited by N. Javadpour. Baltimore: The Williams & Wilkins Co., chapt. 16, p. 467, 1979. 9. Geelhoed, G. W. and Myers, G. H., Jr.: Primary melanoma of the male urethra. J. Urol., Hl9: 634, 1973. 10. Staubitz, W. J., Carden, L. M., Oberkircher, 0. J., Lent, M. H. and Murphy, W. T.: Management of urethral carcinoma in the female. J. U:rol., 73: 1045, 1955. 11. Riches, E.W. and Cullen, T. H.: Carcinoma of the urethra. Bnt. J. Urol., 23: 209, 1951. 12. Seng, M. and Siminovich, M.: Carcinoma of the urethra in the female. Canad. Med. Ass. J., 58: 29, 1948. 13. Herbut, P. A.: Urological Pathology. Philadelphia: Lea & Febiger, vols. 1 and 2, pp. 121, 309, 744, 686, 1217, 1952. 14. Das Gupta, T. and G.rabstald, H.: Melanoma of the genitourinary tract. J. UroL, 93: 607, 1965.