PRIMARY ADENOCARCINOMA O F THE FEMALE URETHRA A. J. TILTMAN Department of Pathology, University of Cape Town
PLATES L AND LI ITis generally accepted that primary adenocarcinomas of the female urethra are neoplasms of the paraurethral glands. However, two other possible derivations need to be considered. Adenocarcinomas may arise from previous glandular metaplasia of the urethral mucosa, urethritis glandularis, or they may arise from embryonic rests of either mesonephric or paramesonephric origin. It is the purpose of this study to present three cases of primary adenocarcinoma of the female urethra to demonstrate why these alternatives should be considered. CASEREPORTS Case I E. J., a 56-yr-old woman, 3 yr post-menopausal, who had never been pregnant, presented with post-menopausal bleeding. Examination revealed an endocervical polyp and a urethral caruncle. Histological examination of the endocervical lesion showed the features of a non-neoplastic endocervical polyp. Histological examination of the urethral caruncle showed a moderately differentiated adenocarcinoma (fig. 1). The tumour was entirely acinar and showed no papillary structures. Abundant mucicarminophylic material was present and alcian blue stains (PH 2) revealed the presence of acid mucopolysaccharides both within and without the cellular cytoplasm. Minimal amounts of glycogen were present. Subsequently sigmoidoscopy revealed no abnormality. Cystoscopy and retrograde pyelogram showed a normal urinary tract. A second biopsy of the urethra showed the features of urethritis glandularis (fig. 2) but no residual tumour. A laparotomy was performed 2 wk later and hysterectomy and bilateral oophorectomy completed. The uterus contained fibromyomata and one ovary contained a simple cyst but there was no evidence of a malignant neoplasm. No further treatment was given and the patient is well and free of tumour 1 yr after presentation. Comment. The carcinoma in this patient was associated with urethritis glandularis but this latter lesion was only discovered 2 wk after the initial biopsy and may have resulted from the inflammation following the minor surgery. It should be noted, however, that the initial biopsy was of the caruncle only and did not include the mucosa higher up the urethra. Therefore the carcinoma and the glandular metaplasia may have been co-existing. Moreover, it is unlikely that the degree of urethritis glandularis present could have been produced in just 2 wk. The carcinoma in this patient resembles, both morphologically and histochemically, many of the adenocarcinomas of the urinary bladder, some of which are thought to arise from previous glandular metaplasia. For these reasons, it is believed that the tumour in this patient arose from previous glandular metaplasia and not from the paraurethral glands. This is not the first occasion that such an association has been described. Engelking, de la Cruz and de Maldonado (1966) reported a urethral adenocarcinoma in a woman who ..
._
Received 1 Oct. 1974; accepted 4 Nov. 1974. J. PATH.-VOL.
117 (1975)
97
G
98
A . J. TILTMAN
had long suffered from chronic urethritis and who had urethritis glandularis co-existing with the adenocarcinoma. These authors concluded that the tumour arose on the basis of previous glandular metaplasia. Similarly, Posso et al. (1961) have described this association in a male patient. Case 2 M. S., a 57-yr-old woman, who had never been pregnant, presented with “ vaginal ” bleeding 6 yr after hysterectomy. Examination revealed that blood was coming from the external urethral meatus and that a tumour was present involving the entire urethra. A biopsy was performed and the histologicalexamination showed a clear cell papillary carcinoma (fig. 3). The papillary fronds were composed of a delicate fibrovascular core covered by columnar cells with basally situated nuclei and clear cytoplasm. Mucicarmine and alcian blue stains were negative. Best’s carmine stain for glycogen was positive and became negative after diastase digestion. Review of the hysterectomy specimen showed the presence of fibromyomata but no evidence of malignancy. Local resection of the tumour was attempted but 6 mth later a total cystectomy was required. The tumour in both these specimens was morphologically and histochemically identical to the biopsy. The patient returned 3 yr later with tumour extending through the anterior vaginal wall. The histological examination of this recurrence showed essentially the same features as before except for some cytological atypism which was absent from the first biopsy. The patient then received radiotherapy. She was last seen 5 yr after initial presentation, still with tumour in the pelvis. She was then lost to follow up and is presumed dead. Comment. The tumour in this patient bears a close morphological and histochemical resemblance to the so-called clear-cell carcinomas of the lower female genital tract and is histochemically dissimilar, as will be described below, from the paraurethral glands. For these reasons the tumour in this patient is regarded as an example of these clear-cell carcinomas. The clear-cell tumours of the lower female genital tract were long thought to be of mesonephric (Gartner’s) duct origin but recent evidence has shown that some may be of Miillerian duct origin (Silverberg and De Giorgi, 1972). There is no evidence in this case to support either contention but Gertner’s duct may run antero-lateral to the vagina in close proximity to the urethra whereas the Miillerian duct forms the uterine cervix and the upper vagina. In either event a tumour, arising from these structures in the urethra would presumably be from an embryonic rest. Case 3 E. A., a 62-yr-old, post-menopausal woman, who had had one pregnancy, presented with haematuria and dysuria. Examination revealed the presence of a tumour involving the entire urethra, apparently &xed to the symphysis pubis. Cystoscopy showed a normal urinary bladder. Rectal examination and sigmoidoscopy revealed no abnormalities and a full gynaecological examination showed a normal genital tract. A biopsy of the urethral tumour showed a moderately differentiated, papillary adenocarcinoma (fig. 4). The papillary fronds were wider than those in Case 2 and the covering epithelium was pseudostratified and composed of cells roughly columnar in shape with centrally placed nuclei. In some areas, cells with clear cytoplasm could be found and in others the papillary pattern was not obvious. Mucicarmine stains showed that some cells contained neutral mucopolysaccharides and this substance was also found on cell surfaces. Alcian blue stains were negative. Minimal amounts of glycogen could be demonstrated by Best’s carmine stain prior to digestion. The patient received local radiotherapy as the tumour was regarded as irresectable but she died 6 mth after presentation. No autopsy was performed but clinically no tumour was detectable outside the anterior pelvis. Comment. Morphologically this tumour conforms to some of the previous descriptions of urethral adenocarcinomas (de Haan and Johnson, 1960; Knoblich, 1960; Teoh, 1966) and histochemically is similar to the paraurethral glands. Huffman (1948) has described these glands in some detail. He has shown that they are of the branching tubular type lined by
URETHRAL ADENOCARCINOMA
99
columnar epithelium. Some of the cells within the acini and ducts contain mucinocarminophilic material. Examination of autopsy material by the present author has confirmed these findings and in addition has shown that acid mucopolysaccharides are not present within the glands but are found on the surface of the urethral mucosa. Therefore, on the basis of probability and histochemical compatibility, the tumour in this patient is regarded as being of paraurethral gland origin.
CONCLUSION Primary adenocarcinomas of the female urethra have been described as glandular, columnar cell, papillary or colloid carcinomas. Thus there is a wide morphological range of tumour types found in this region. This range, which is demonstrated by the three cases in this report, may represent no more than a variation within a single tumour type. Very few reports of these neoplasms discuss the histochemical properties. Some have been described as containing mucicarminophilic material but nowhere is there a report on the presence or absence of acid mucopolysaccharides or glycogen. The features of cell morphology and function serve to categorise certain neoplasms. Whereas it is not possible to predict with certainty what characteristics a neoplasm from a specific source will show, one cannot assume that all tumours in a given region of the body have the same cell origin. The three tumours reported in this communication are not presented as indisputable examples of neoplasms arising from three different sources but are presented to indicate that adenocarcinomas of the female urethra need not necessarily be of paraurethral gland origin. SUMMARY
Three cases of primary adenocarcinoma of the female urethra are presented. The tumour in the first case was associated with urethritis glandularis and is thought to arise from previous glandular metaplasia of the urethral mucosa. The tumour in the second case resembled the clear-cell carcinomas of the lower female genital tract and is thought to be of embryonic rest origin. The tumour in the third case is thought to arise from the paraurethral glands. REFERENCES HAAN,Q. C., AND JOHNSON, C. G. 1960. Adenocarcinoma of the paraurethral glands. Am. J. Obstets. Gynec., 80, 1108. ENGELKING, R. L., DE LA CRUZ,J. V., AND DE MALDONADO, M. E. F. 1966. Mucinous adenocarcinoma of the urinary tract. Trans. Am. Assoc. Genito-urinary Surg., 58, 144. HUFFMAN, J. W. 1948. The detailed anatomy of the paraurethral ducts in the adult human female. Am. J . Obstcts. Gynec., 55, 86. KNOBLICH,R. 1960. Primary adenocarcinoma of the female urethra. Am. J. Obstets. Gynec., 80, 353. Posso, M. A., BFRG,G . A., MURPHY,A. I., AND TO'ITEN, R. S. 1961. Mucinous adenocarcinoma of the urethra: Report of a case associated with urethritis glandularis. J. Urol., 85, 944. SILVERBERG, S. G., AND DE GIORGI,L. S. 1972. Clear cell carcinoma of the vagina. Cancer, 29, 1680. TEoH, T. B. 1966. Papillary adenocarcinoma of the female urethra: A case report. Brit. J. Surg., 48. 151. DE
PLATEL
TILTMAN URETHRAL ADENOCARCINOMA
FIG.1.-Case
I . Adenocarcinoma showing acinar pattern. Haematoxylin and eosin (HE). x 250.
FIG.2.-Case
I. Urethral mucosa showing urethritis glandularis. The superficial mucosa has been denuded. Periodic acid-Schiff. x 64.
PLATELI
TILTMAN
URETHRAL ADENOCARCINOMA
FIG.3.-Case
FIG.4.-Case
2. Clear-cell papillary carcinoma. HE. x 250.
3. Papillary carcinoma. Some clear cells can be seen in the lower left. HE. x 250.
PLATES L AND LI ITis generally accepted that primary adenocarcinomas of the female urethra are neoplasms of the paraurethral glands. However, two other possible derivations need to be considered. Adenocarcinomas may arise from previous glandular metaplasia of the urethral mucosa, urethritis glandularis, or they may arise from embryonic rests of either mesonephric or paramesonephric origin. It is the purpose of this study to present three cases of primary adenocarcinoma of the female urethra to demonstrate why these alternatives should be considered. CASEREPORTS Case I E. J., a 56-yr-old woman, 3 yr post-menopausal, who had never been pregnant, presented with post-menopausal bleeding. Examination revealed an endocervical polyp and a urethral caruncle. Histological examination of the endocervical lesion showed the features of a non-neoplastic endocervical polyp. Histological examination of the urethral caruncle showed a moderately differentiated adenocarcinoma (fig. 1). The tumour was entirely acinar and showed no papillary structures. Abundant mucicarminophylic material was present and alcian blue stains (PH 2) revealed the presence of acid mucopolysaccharides both within and without the cellular cytoplasm. Minimal amounts of glycogen were present. Subsequently sigmoidoscopy revealed no abnormality. Cystoscopy and retrograde pyelogram showed a normal urinary tract. A second biopsy of the urethra showed the features of urethritis glandularis (fig. 2) but no residual tumour. A laparotomy was performed 2 wk later and hysterectomy and bilateral oophorectomy completed. The uterus contained fibromyomata and one ovary contained a simple cyst but there was no evidence of a malignant neoplasm. No further treatment was given and the patient is well and free of tumour 1 yr after presentation. Comment. The carcinoma in this patient was associated with urethritis glandularis but this latter lesion was only discovered 2 wk after the initial biopsy and may have resulted from the inflammation following the minor surgery. It should be noted, however, that the initial biopsy was of the caruncle only and did not include the mucosa higher up the urethra. Therefore the carcinoma and the glandular metaplasia may have been co-existing. Moreover, it is unlikely that the degree of urethritis glandularis present could have been produced in just 2 wk. The carcinoma in this patient resembles, both morphologically and histochemically, many of the adenocarcinomas of the urinary bladder, some of which are thought to arise from previous glandular metaplasia. For these reasons, it is believed that the tumour in this patient arose from previous glandular metaplasia and not from the paraurethral glands. This is not the first occasion that such an association has been described. Engelking, de la Cruz and de Maldonado (1966) reported a urethral adenocarcinoma in a woman who ..
._
Received 1 Oct. 1974; accepted 4 Nov. 1974. J. PATH.-VOL.
117 (1975)
97
G
98
A . J. TILTMAN
had long suffered from chronic urethritis and who had urethritis glandularis co-existing with the adenocarcinoma. These authors concluded that the tumour arose on the basis of previous glandular metaplasia. Similarly, Posso et al. (1961) have described this association in a male patient. Case 2 M. S., a 57-yr-old woman, who had never been pregnant, presented with “ vaginal ” bleeding 6 yr after hysterectomy. Examination revealed that blood was coming from the external urethral meatus and that a tumour was present involving the entire urethra. A biopsy was performed and the histologicalexamination showed a clear cell papillary carcinoma (fig. 3). The papillary fronds were composed of a delicate fibrovascular core covered by columnar cells with basally situated nuclei and clear cytoplasm. Mucicarmine and alcian blue stains were negative. Best’s carmine stain for glycogen was positive and became negative after diastase digestion. Review of the hysterectomy specimen showed the presence of fibromyomata but no evidence of malignancy. Local resection of the tumour was attempted but 6 mth later a total cystectomy was required. The tumour in both these specimens was morphologically and histochemically identical to the biopsy. The patient returned 3 yr later with tumour extending through the anterior vaginal wall. The histological examination of this recurrence showed essentially the same features as before except for some cytological atypism which was absent from the first biopsy. The patient then received radiotherapy. She was last seen 5 yr after initial presentation, still with tumour in the pelvis. She was then lost to follow up and is presumed dead. Comment. The tumour in this patient bears a close morphological and histochemical resemblance to the so-called clear-cell carcinomas of the lower female genital tract and is histochemically dissimilar, as will be described below, from the paraurethral glands. For these reasons the tumour in this patient is regarded as an example of these clear-cell carcinomas. The clear-cell tumours of the lower female genital tract were long thought to be of mesonephric (Gartner’s) duct origin but recent evidence has shown that some may be of Miillerian duct origin (Silverberg and De Giorgi, 1972). There is no evidence in this case to support either contention but Gertner’s duct may run antero-lateral to the vagina in close proximity to the urethra whereas the Miillerian duct forms the uterine cervix and the upper vagina. In either event a tumour, arising from these structures in the urethra would presumably be from an embryonic rest. Case 3 E. A., a 62-yr-old, post-menopausal woman, who had had one pregnancy, presented with haematuria and dysuria. Examination revealed the presence of a tumour involving the entire urethra, apparently &xed to the symphysis pubis. Cystoscopy showed a normal urinary bladder. Rectal examination and sigmoidoscopy revealed no abnormalities and a full gynaecological examination showed a normal genital tract. A biopsy of the urethral tumour showed a moderately differentiated, papillary adenocarcinoma (fig. 4). The papillary fronds were wider than those in Case 2 and the covering epithelium was pseudostratified and composed of cells roughly columnar in shape with centrally placed nuclei. In some areas, cells with clear cytoplasm could be found and in others the papillary pattern was not obvious. Mucicarmine stains showed that some cells contained neutral mucopolysaccharides and this substance was also found on cell surfaces. Alcian blue stains were negative. Minimal amounts of glycogen could be demonstrated by Best’s carmine stain prior to digestion. The patient received local radiotherapy as the tumour was regarded as irresectable but she died 6 mth after presentation. No autopsy was performed but clinically no tumour was detectable outside the anterior pelvis. Comment. Morphologically this tumour conforms to some of the previous descriptions of urethral adenocarcinomas (de Haan and Johnson, 1960; Knoblich, 1960; Teoh, 1966) and histochemically is similar to the paraurethral glands. Huffman (1948) has described these glands in some detail. He has shown that they are of the branching tubular type lined by
URETHRAL ADENOCARCINOMA
99
columnar epithelium. Some of the cells within the acini and ducts contain mucinocarminophilic material. Examination of autopsy material by the present author has confirmed these findings and in addition has shown that acid mucopolysaccharides are not present within the glands but are found on the surface of the urethral mucosa. Therefore, on the basis of probability and histochemical compatibility, the tumour in this patient is regarded as being of paraurethral gland origin.
CONCLUSION Primary adenocarcinomas of the female urethra have been described as glandular, columnar cell, papillary or colloid carcinomas. Thus there is a wide morphological range of tumour types found in this region. This range, which is demonstrated by the three cases in this report, may represent no more than a variation within a single tumour type. Very few reports of these neoplasms discuss the histochemical properties. Some have been described as containing mucicarminophilic material but nowhere is there a report on the presence or absence of acid mucopolysaccharides or glycogen. The features of cell morphology and function serve to categorise certain neoplasms. Whereas it is not possible to predict with certainty what characteristics a neoplasm from a specific source will show, one cannot assume that all tumours in a given region of the body have the same cell origin. The three tumours reported in this communication are not presented as indisputable examples of neoplasms arising from three different sources but are presented to indicate that adenocarcinomas of the female urethra need not necessarily be of paraurethral gland origin. SUMMARY
Three cases of primary adenocarcinoma of the female urethra are presented. The tumour in the first case was associated with urethritis glandularis and is thought to arise from previous glandular metaplasia of the urethral mucosa. The tumour in the second case resembled the clear-cell carcinomas of the lower female genital tract and is thought to be of embryonic rest origin. The tumour in the third case is thought to arise from the paraurethral glands. REFERENCES HAAN,Q. C., AND JOHNSON, C. G. 1960. Adenocarcinoma of the paraurethral glands. Am. J. Obstets. Gynec., 80, 1108. ENGELKING, R. L., DE LA CRUZ,J. V., AND DE MALDONADO, M. E. F. 1966. Mucinous adenocarcinoma of the urinary tract. Trans. Am. Assoc. Genito-urinary Surg., 58, 144. HUFFMAN, J. W. 1948. The detailed anatomy of the paraurethral ducts in the adult human female. Am. J . Obstcts. Gynec., 55, 86. KNOBLICH,R. 1960. Primary adenocarcinoma of the female urethra. Am. J. Obstets. Gynec., 80, 353. Posso, M. A., BFRG,G . A., MURPHY,A. I., AND TO'ITEN, R. S. 1961. Mucinous adenocarcinoma of the urethra: Report of a case associated with urethritis glandularis. J. Urol., 85, 944. SILVERBERG, S. G., AND DE GIORGI,L. S. 1972. Clear cell carcinoma of the vagina. Cancer, 29, 1680. TEoH, T. B. 1966. Papillary adenocarcinoma of the female urethra: A case report. Brit. J. Surg., 48. 151. DE
PLATEL
TILTMAN URETHRAL ADENOCARCINOMA
FIG.1.-Case
I . Adenocarcinoma showing acinar pattern. Haematoxylin and eosin (HE). x 250.
FIG.2.-Case
I. Urethral mucosa showing urethritis glandularis. The superficial mucosa has been denuded. Periodic acid-Schiff. x 64.
PLATELI
TILTMAN
URETHRAL ADENOCARCINOMA
FIG.3.-Case
FIG.4.-Case
2. Clear-cell papillary carcinoma. HE. x 250.
3. Papillary carcinoma. Some clear cells can be seen in the lower left. HE. x 250.
