838
6 1990 The Japanese
Society of Pathology
Primary Adenocarcinoma of the Female Urethra with Three Histologic Patterns and Partial AFP Positivity
J u n Hanail and Meisui Lin2
A rare case of adenocarcinoma of the female urethra with alpha-fetoprotein (AFP) positivity in a 52-year-old woman is reported. The tumor was papillary polypoid, localized in the posterior wall of the mid-urethra and microscopically showed three histologic components. Upon immunostaining and histochemical staining, the tumor was characterized by intestinal-type cells positive for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), EMA-negative and AFP-positive columnar vacuolated cells and mainly EMA-positive clear cells. On the basis of these features together with the known embryogenesis of the urethra, an endodermal origin of the tumor is suggested, possibly arising from the reserve or stem cells in the urethral mucosa. This case and its immunohistochemical features are quite unique and the histologic combination is meaningful when considering the oncogenesis and histogenesis of urethral tumors. Acta Pathol Jpn 40: 838 844, 1990.
Key words : Urethral adenocarcinoma, Alpha-fetoprotein (AFP), EpitheliaI membrane antigen (EMA), Carcinoembryonic antigen (CEA)
INTRODUCTION Primary carcinomas of the female urethra are rather rare, accounting for less than 0.02% of all malignant diseases in women (1). Among them, adenocarcinoma is even more infrequent, constituting 10% of all primary carcinomas of the female urethra(2). Most of the others are squamous cell carcinoma and transitional cell carcinoma. There have been some single case reports
Received July 2, 1990. Accepted for publication August 30, 1990. 'Department of Pathology, Sakai Municipal Hospital, Sakai. 5econd Department o f Pathology, Medical School, Osaka University, Osaka. Department Mailing address: Jun Hanai, M.D. (E# of Pathology, Sakai Municipal Hospital, Nishi-2, Shukuincho, Sakai, Osaka 590, Japan.
'a),
of adenocarcinoma of the female urethra with reviews of the literature (2-6), as well as a review of cases studied clinicopathologically (7) but there have been few immunohistochemical studies. In this paper, we report a case of adenocarcinoma of the female urethra with a unique histologic appearance and showing immunohistochemical positivity for alpha-fetoprotein (AFP). On the basis of the morphology and immunohistochemical features of the tumor, its histogenesis is discussed.
CASEREPORT A 52-year-old woman presented with complaints of several episodes of gross painless hematuria and fatigue over a period of nearly two months. Clinical examina. tion showed nothing abnormal in the upper urogenital tract. Laboratory findings revealed normal renal function, but blood cells were found upon urinalysis and tumor cells were revealed by cytologic examination. From CT findings a tumor in the urinary bladder was suspected. Subsequent cystoscopic examination revealed a tumor in the urethra. The patient was soon admitted to hospital, and after a series of careful examinations to exclude the presence of metastasis, cystourethrectomy was done.
PATHOLOGIC FINDINGS
Gross appearance No abnormality could be seen in the urinary bladder, but there was a large papillary polypoid tumor measuring 4 ~ 3 . 5 c~m 3in the posterior wall of the mid-urethra (Figs. l a , b). A short, wide stalk 1.3 cm in diameterwas recognizable, attached to the wall by a fairly broad base. The tumor had a villous configuration with innumerable thin papillary projections from the mucosal surface into the lumen, and the tissue was friable. At the cut sur-
Acta Pathologica Japonica 40 (1 1): 1990
Figure 1. Gross appearance of the tumor (a) with a diagram of its outline (b). The upper part is the urinary bladder showing no abnormal features. The lower part shows a papillary polypoid tumor (arrow) in the urethra (formalin-fixed). (UB, urinary bladder; U, luminal side of the urethra ; V, luminal side of the vagina).
Figure 2. Microscopically, the tumor is composed of intestinal-type cells (a), columnar vacuolated cells (b) and clear cells (c) (HE).
839
840
AFP-positive Adenocarcinoma of Urethra (Hanai and Lin)
EMA( - AFP( i t )
Figure 3. Distribution of EMA (a), CEA (b) and AFP (c) in the tumor (peroxidase-antiperoxidase) with a diagram (d). (I, area of intestinal-type cells; 11, area of columnar vacuolated cells; Ill, area of clear cells) ( + means that more than 50% of carcinoma cells were positive; means that 5%50% of carcinoma cells were positive).
+
Acta Pathologica Japonica 40 (11): 1990
Figure 4. Photomicrographs of immunostained sections. a. Clear cells of the tumor are positive for EMA b. Vacuolated cells with a perivascular structure show no reaction with antibody t o EMA. c. CEA is demonstrated in the intestinal-type cells d. Columnar vacuolated cells are positive for AFP (peroxidase antiperoxidase).
841
842
AFP-positive Adenocarcinoma of Urethra (Hanai and Lin)
face, the gray-white tumor tissue seemed to be limited mainly to the superficial area of the wall, i.e., the mucosa and submucosa. Histologic findings The tumor showed exophytic growth and minimal invasion into the submucosa. It was composed of three types of neoplastic cell and showed different architectural arrangements in discrete areas. These areas are described as follows: 1. A small part of the tumor was composed of columnar intestinal-type epithelial cells with eosinophilic cytoplasm and basal nuclei (Fig. 2a). The cells showed a degree of anaplasia and mitoses with foci of pseudostratification, but generally they were regular in shape and had brush borders in some areas. The structural pattern was papillary with connective tissue cores surmounted by the columnar intestinal-type epithelia and scattered goblet cells. These features resembled well differentiated adenocarcinoma of the intestine. 2. A large number of cells were arranged in a papillary or sheet-like pattern. These were low columnar or cuboidal, plump in shape, and had vacuolated or clear cytoplasm. Their nuclei were obviously atypical, with prominent nucleoli and the fairly rough chromatin. In some areas, the papillary formations exhibited special perivascular structures, somewhat similar to SchillerDuval bodies (Fig. 2b). Merging with these special structures, aggregates of poorly differentiated neoplastic cells were often present, associated with intracellular or extracellular hyaline droplets. These columnar vacuolated cells showed transition to the third type of cell described next. 3. Round, polygonal or cuboidal clear cells were also seen in the tumor. They were arranged in a sheet-like pattern with areas of gland or tubule formation, but no “hobnail cells” were present among them (Fig. 2 ~ ) . Throughout the whole tumor, no focus of transitional cell carcinoma or squamous cell carcinoma could be found. We tentatively termed the three cellular components described above intestinal-type cell, columnar vacuolated cell and clear cell. Histochemical staining done on the resected specimen included periodic acid-Schiff (PAS), diastase PAS, alcian blue, colloidal iron and mucicarmine. Goblet cells scattered among the intestinal-type cells were stained by all of these methods. The hyaline droplets which were found in some of the columnar vacuolated cells were PAS-positive and diastase-resistant, but showed no reaction by other staining methods. The clear cells showed fine granular staining by PAS with a certain
degree of diastase sensitivity.
I mmuno per0xida se st a inin g Peroxidase-a nti peroxidase immunosta ining was carried out on formalin-fixed, paraffin-embedded tissue. The primary antibodies used were commercially available ones, including epithelial membrane antigen (EMA) monoclonal antiserum ( x 2 0 DAKO), carcinoembryonic antigen (CEA) polyclonal antiserum ( x 5 0 0 Ortho), keratin polyclonal antiserum (x200 Ortho), S-100 protein polyclonal antiserum (x300 Ortho), neuron-specific enolase (NSE) polyclonal antiserum ( x 150 DAKO), alpha-fetoprotein (AFP) polyclonal antiserum ( x 300 Ortho) and human chorionic gonadotropin (HCG) polyclonal antiserum ( ~ 2 0 0DAKO). The results revealed clear differences of immunohistochemical expression among the tumor cell types, as illustrated in the low-power photomicrographs (Figs. 3ac) and the simulated diagram (Fig. 3d). EMA positivity was found in the intestinal-type cells and clear cells (Fig. 4a), but most of the columnar vacuolated cells had no reactivity with the antibody to EMA (Fig. 4b). CEA was present mainly in the intestinal-type cells (Fig. 4c), whereas the other cells were negative. On the other hand, the columnar vacuolated cells were exclusively positive for AFP (Fig. 4d), although some clear cells also showed a certain degree of AFP positivity. Positivity for S-100 protein and NSE was identified in some clear cells, but this was very weak. All tumor cells were negative for keratin and HCG.
DISCUSSION Urethral carcinoma in females was first described by Boiven and Denges in 1837 (8),but the first case which was thought to be adenocarcinoma was reported by Battle in 1 9 0 1 (9). In 1960, Knoblich(2) reviewed 41 previously reported cases of primary adenocarcinoma of the female urethra and added three new ones. In 1973, Konnak (10) first named a clear cell variant of primary urethral adenocarcinoma, and thereafter 2 4 cases of clear cell variant were reported (11). In previous reports, two histologic types of urethral adenocarcinoma have been mentioned, the clear cell and columnar/mucinous variants (7). To our knowledge, this is the first time that a urethral adenocarcinoma with three components and AFP positivity has been reported. The tumor showed three morphologically distinct cell types in three areas of one growth, i.e., intestinal-type cells forming a well differentiated adenocarcinoma, columnar vacuolated cells forming a special papillary tumor, and clear cells forming clear cell carcinoma.
843
Acta Pathologica Japonica 40 (11) : 1990 These also differed from each other in immunohistoc hemica I staining. With respect t o AFP positivity, this has been found mainly in hepatoma and yolk sac tumor (12), but some papers have reported other AFP-producing tumors ; these have included germ cell t u m o r s ( l 3 ) , tumors of endodermal origin (14-17) and renal cell carcinomas
(18, 19). The immunostaining expression in this case was quite interesting. Before discussing it, the embryogenesis of the urethra should be reviewed. The female urethra as well as the urinary bladder is derived from the urogenital sinus, which was originally the anterior portion of the cloaca. The endodermal anlage gives rise t o the mucosal lining of the urethra and urinary bladder, and a downgrowth of the mesoderm invests them with musculature (20). Therefore, we think that the histologic findings and immunostaining results in this case are fairly consistent with the known development of the urethra. With regard to the fact that the urethra and colon are both derived from the cloaca, it is quite understandable that the tumor in this case had one part resembling intestinal adenocarcinoma, and like the latter, showed positivity for CEA. As an indicator of epithelial differentiation, EMA was reasonably well demonstrated in intestinal -type cells and clear cells, but it was not present in columnar vacuolated cells which, instead, were AFPpositive. This might imply that the cells were a t an early stage of development before epithelial differentiation, and that reflecting their endodermal origin, they might be closely related with the cloaca, which contains a certain amount of AFP (21). The reserve or stem cells in the urethral mucosa probably have the potential to revert to an embryonic state when undergoing of neoplastic transformation. The distinct difference observed among the three cell types in this one tumor yields an important clue t o the histogenesis of the tumor. Various origins have been proposed regarding the histogenesis of female urethral adenocarcinoma, e.g., the mesonephron ( l o ) , and paraurethral glands (2, 5 - 7 , 11, 22). According t o the findings in our present case and the embryogenesis of the urethra, we consider that the tumor originated directly from the urethral mucosa including the urethral glands, in which reserve cells, after malignant transformation, might have differentiated in different directions and give rise to a bizarre adenocarcinoma with three histologic components. Another possibility is that the tumor arose from three different clones of reserve cells in the mucosa. However, it seems difficult to conceive that a tumor might have arisen from diverse histologic foci of remnants or aberrant cells in the urethral wall which all turned malignant at the same time. In this tumor, there
was no element of transitional cell carcinoma or squamous cell carcinoma, and there was no other evidence t o suggest a n origin f r o m malignant proliferation of metaplastic cells o r transitional cells in the mucosa. This is probably the first time that the endodermal origin of urethra I adenoca rcinoma has been strongly suggested on the basis of morphologic and immunohistochemical evidence. Moreover, we postulate that in many respects adenocarcinoma of the urethra may be essentially the same as that of the urinary bladder, which has also been recognized t o have some similarities to colorectal adenocarcinoma (23) and t o have a clear cell variant (11). In conclusion, although this case is an unusual type of adenocarcinoma o f the urethra and its immunohistochemical expression is rather exceptional, it is of significance in helping t o clarify the histogenesis of urethral tumors. Acknowledgements : The authors thank Dr. Hiroshi Sakaguchi and Dr. Mitsumasa Kodama for clinical information, and Mr. Hitoshi Kawakami, Mr. Nobuhiko Uchino and Miss Minako Yonekawa for technical assistance.
R EFER ENCES 1. Bracken RB, Johnson DE, Miller LS, et a/. Primary carcinoma of the female urethra. J Urol 116: 188192, 1976. 2. Knoblich R. Primary adenocarcinoma of the female urethra. A review and report of 3 cases. Am J Obstet Gynecol 80 : 353-364, 1960. 3. McCrea LE. Malignancy of the female urethra. Urol SUW 2 : 85-149, 1952. 4. De Haan QC. Paraurethral gland adenocarcinoma. Am J Obstet Gynecol 93: 903-904, 1965. 5. Styn J, Hall M, and Logie NJ. Adenocarcinoma of the female urethra. Br J Urol 3 9 : 504-505, 1967. 6. Schnitzer B. Primary adenocarcinoma of the female urethra. A review and report of two cases. J Urol 92 : 135-139, 1964. 7. Meis JM, Ayala AG, and Johnson DE. Adenocarcinoma of the urethra in women. A clinicopathologic study. Cancer 60: 1038-1052, 1987. 8. Levine RL. Urethral cancer. Cancer 4 5 : 19651972, 1980. 9. Battle WH. A case of carcinoma of the urethra and bladder. Removal of the growth with closure of the resulting pubic wound and establishment of permanent suprapubic drainage. Lancet 2 : 79-80, 1901. 10. Konnak JW. Mesonephric carcinoma involving the urethra. J Urol 110: 76-78, 1973. 11. Young RH and Scully RE. Clear cell adenocarcinoma of the bladder and urethra. A report of three cases and review of the literature. Am J Surg Pathol 9 : 816-826, 1985. 12. Rosai J. Ackerman’s surgical pathology, 7th ed. CV Mosby, St. Louis, Toronto, Washington D.C., 1989: 37.
844
AFP-positive Adenocarcinorna of Urethra (Hanai and Lin)
13. Kurman RJ, Ganjei P, and Nadji M. Contribution of immunocytochemistry to the diagnosis and study of ovarian neoplasm. Int J Gynecol Pathol 3 : 3-26, 1984. 14. Spragins J, Hall WH, and White HJ. Fetoprotein from esophageal squamous cell carcinoma. Ann Intern Med 77: 322-323, 1972. 15. Noda H, Maetani S, Tobe T, and Nohara T. A case of a-fetoprotein producing rectal cancer. Nippon Geka Gakkai Zasshi 8 5 : 616-620, 1984 (in Japanese). 16. Yasunami R, Hashimoto Z, Ozura T, Hirao F, and Yamamura Y. Primary lung cancer producing a-fetoprotein : A case report. Cancer 47 : 926-929, 1981. 17. Akai S and Kato K. Serum a-fetoprotein-positive stomach cancer. Gann Monogr Cancer Res 1 4 : 149154, 1973. 18. Morimoto H, Tanigawa N, lnoue H, et a/. Alpha-fetoprotein producing renal cell carcinoma. Cancer 61 :
84-88, 1988. 19. Okada H, Kawabata G, Kamidono S, lshigami J, and Nakatsuka E. A case of renal cell carcinoma of horse shoe kidney that produced AFP and caused hypercal. cemia. Acta Urol Jpn 3 0 : 1453-1458, 1984. 20. Robbins SL. Pathology, 3rd ed. WB Saunders, Philadelphia, London, 1968: 1053. 21. Gitlin D, Dericell A, and Gitlin GM. Synthesis of (Yfetoprotein by liver, yolk sac and gastrointestinal tract of the human conceptus. Cancer Res 3 2 : 617-620, 1972. 22. Gillenwater JY and Burros HM. Unusual tumors of the female urethra. Obstet Gynecol 31 : 617-620, 1968. 23. Wells M and Anderson K. Mucin histochemistry of cystitis glandularis and primary adenocarcinoma of the urinary bladder. Arch Pathol Lab Med 1 0 9 : 59-61, 1985.
6 1990 The Japanese
Society of Pathology
Primary Adenocarcinoma of the Female Urethra with Three Histologic Patterns and Partial AFP Positivity
J u n Hanail and Meisui Lin2
A rare case of adenocarcinoma of the female urethra with alpha-fetoprotein (AFP) positivity in a 52-year-old woman is reported. The tumor was papillary polypoid, localized in the posterior wall of the mid-urethra and microscopically showed three histologic components. Upon immunostaining and histochemical staining, the tumor was characterized by intestinal-type cells positive for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA), EMA-negative and AFP-positive columnar vacuolated cells and mainly EMA-positive clear cells. On the basis of these features together with the known embryogenesis of the urethra, an endodermal origin of the tumor is suggested, possibly arising from the reserve or stem cells in the urethral mucosa. This case and its immunohistochemical features are quite unique and the histologic combination is meaningful when considering the oncogenesis and histogenesis of urethral tumors. Acta Pathol Jpn 40: 838 844, 1990.
Key words : Urethral adenocarcinoma, Alpha-fetoprotein (AFP), EpitheliaI membrane antigen (EMA), Carcinoembryonic antigen (CEA)
INTRODUCTION Primary carcinomas of the female urethra are rather rare, accounting for less than 0.02% of all malignant diseases in women (1). Among them, adenocarcinoma is even more infrequent, constituting 10% of all primary carcinomas of the female urethra(2). Most of the others are squamous cell carcinoma and transitional cell carcinoma. There have been some single case reports
Received July 2, 1990. Accepted for publication August 30, 1990. 'Department of Pathology, Sakai Municipal Hospital, Sakai. 5econd Department o f Pathology, Medical School, Osaka University, Osaka. Department Mailing address: Jun Hanai, M.D. (E# of Pathology, Sakai Municipal Hospital, Nishi-2, Shukuincho, Sakai, Osaka 590, Japan.
'a),
of adenocarcinoma of the female urethra with reviews of the literature (2-6), as well as a review of cases studied clinicopathologically (7) but there have been few immunohistochemical studies. In this paper, we report a case of adenocarcinoma of the female urethra with a unique histologic appearance and showing immunohistochemical positivity for alpha-fetoprotein (AFP). On the basis of the morphology and immunohistochemical features of the tumor, its histogenesis is discussed.
CASEREPORT A 52-year-old woman presented with complaints of several episodes of gross painless hematuria and fatigue over a period of nearly two months. Clinical examina. tion showed nothing abnormal in the upper urogenital tract. Laboratory findings revealed normal renal function, but blood cells were found upon urinalysis and tumor cells were revealed by cytologic examination. From CT findings a tumor in the urinary bladder was suspected. Subsequent cystoscopic examination revealed a tumor in the urethra. The patient was soon admitted to hospital, and after a series of careful examinations to exclude the presence of metastasis, cystourethrectomy was done.
PATHOLOGIC FINDINGS
Gross appearance No abnormality could be seen in the urinary bladder, but there was a large papillary polypoid tumor measuring 4 ~ 3 . 5 c~m 3in the posterior wall of the mid-urethra (Figs. l a , b). A short, wide stalk 1.3 cm in diameterwas recognizable, attached to the wall by a fairly broad base. The tumor had a villous configuration with innumerable thin papillary projections from the mucosal surface into the lumen, and the tissue was friable. At the cut sur-
Acta Pathologica Japonica 40 (1 1): 1990
Figure 1. Gross appearance of the tumor (a) with a diagram of its outline (b). The upper part is the urinary bladder showing no abnormal features. The lower part shows a papillary polypoid tumor (arrow) in the urethra (formalin-fixed). (UB, urinary bladder; U, luminal side of the urethra ; V, luminal side of the vagina).
Figure 2. Microscopically, the tumor is composed of intestinal-type cells (a), columnar vacuolated cells (b) and clear cells (c) (HE).
839
840
AFP-positive Adenocarcinoma of Urethra (Hanai and Lin)
EMA( - AFP( i t )
Figure 3. Distribution of EMA (a), CEA (b) and AFP (c) in the tumor (peroxidase-antiperoxidase) with a diagram (d). (I, area of intestinal-type cells; 11, area of columnar vacuolated cells; Ill, area of clear cells) ( + means that more than 50% of carcinoma cells were positive; means that 5%50% of carcinoma cells were positive).
+
Acta Pathologica Japonica 40 (11): 1990
Figure 4. Photomicrographs of immunostained sections. a. Clear cells of the tumor are positive for EMA b. Vacuolated cells with a perivascular structure show no reaction with antibody t o EMA. c. CEA is demonstrated in the intestinal-type cells d. Columnar vacuolated cells are positive for AFP (peroxidase antiperoxidase).
841
842
AFP-positive Adenocarcinoma of Urethra (Hanai and Lin)
face, the gray-white tumor tissue seemed to be limited mainly to the superficial area of the wall, i.e., the mucosa and submucosa. Histologic findings The tumor showed exophytic growth and minimal invasion into the submucosa. It was composed of three types of neoplastic cell and showed different architectural arrangements in discrete areas. These areas are described as follows: 1. A small part of the tumor was composed of columnar intestinal-type epithelial cells with eosinophilic cytoplasm and basal nuclei (Fig. 2a). The cells showed a degree of anaplasia and mitoses with foci of pseudostratification, but generally they were regular in shape and had brush borders in some areas. The structural pattern was papillary with connective tissue cores surmounted by the columnar intestinal-type epithelia and scattered goblet cells. These features resembled well differentiated adenocarcinoma of the intestine. 2. A large number of cells were arranged in a papillary or sheet-like pattern. These were low columnar or cuboidal, plump in shape, and had vacuolated or clear cytoplasm. Their nuclei were obviously atypical, with prominent nucleoli and the fairly rough chromatin. In some areas, the papillary formations exhibited special perivascular structures, somewhat similar to SchillerDuval bodies (Fig. 2b). Merging with these special structures, aggregates of poorly differentiated neoplastic cells were often present, associated with intracellular or extracellular hyaline droplets. These columnar vacuolated cells showed transition to the third type of cell described next. 3. Round, polygonal or cuboidal clear cells were also seen in the tumor. They were arranged in a sheet-like pattern with areas of gland or tubule formation, but no “hobnail cells” were present among them (Fig. 2 ~ ) . Throughout the whole tumor, no focus of transitional cell carcinoma or squamous cell carcinoma could be found. We tentatively termed the three cellular components described above intestinal-type cell, columnar vacuolated cell and clear cell. Histochemical staining done on the resected specimen included periodic acid-Schiff (PAS), diastase PAS, alcian blue, colloidal iron and mucicarmine. Goblet cells scattered among the intestinal-type cells were stained by all of these methods. The hyaline droplets which were found in some of the columnar vacuolated cells were PAS-positive and diastase-resistant, but showed no reaction by other staining methods. The clear cells showed fine granular staining by PAS with a certain
degree of diastase sensitivity.
I mmuno per0xida se st a inin g Peroxidase-a nti peroxidase immunosta ining was carried out on formalin-fixed, paraffin-embedded tissue. The primary antibodies used were commercially available ones, including epithelial membrane antigen (EMA) monoclonal antiserum ( x 2 0 DAKO), carcinoembryonic antigen (CEA) polyclonal antiserum ( x 5 0 0 Ortho), keratin polyclonal antiserum (x200 Ortho), S-100 protein polyclonal antiserum (x300 Ortho), neuron-specific enolase (NSE) polyclonal antiserum ( x 150 DAKO), alpha-fetoprotein (AFP) polyclonal antiserum ( x 300 Ortho) and human chorionic gonadotropin (HCG) polyclonal antiserum ( ~ 2 0 0DAKO). The results revealed clear differences of immunohistochemical expression among the tumor cell types, as illustrated in the low-power photomicrographs (Figs. 3ac) and the simulated diagram (Fig. 3d). EMA positivity was found in the intestinal-type cells and clear cells (Fig. 4a), but most of the columnar vacuolated cells had no reactivity with the antibody to EMA (Fig. 4b). CEA was present mainly in the intestinal-type cells (Fig. 4c), whereas the other cells were negative. On the other hand, the columnar vacuolated cells were exclusively positive for AFP (Fig. 4d), although some clear cells also showed a certain degree of AFP positivity. Positivity for S-100 protein and NSE was identified in some clear cells, but this was very weak. All tumor cells were negative for keratin and HCG.
DISCUSSION Urethral carcinoma in females was first described by Boiven and Denges in 1837 (8),but the first case which was thought to be adenocarcinoma was reported by Battle in 1 9 0 1 (9). In 1960, Knoblich(2) reviewed 41 previously reported cases of primary adenocarcinoma of the female urethra and added three new ones. In 1973, Konnak (10) first named a clear cell variant of primary urethral adenocarcinoma, and thereafter 2 4 cases of clear cell variant were reported (11). In previous reports, two histologic types of urethral adenocarcinoma have been mentioned, the clear cell and columnar/mucinous variants (7). To our knowledge, this is the first time that a urethral adenocarcinoma with three components and AFP positivity has been reported. The tumor showed three morphologically distinct cell types in three areas of one growth, i.e., intestinal-type cells forming a well differentiated adenocarcinoma, columnar vacuolated cells forming a special papillary tumor, and clear cells forming clear cell carcinoma.
843
Acta Pathologica Japonica 40 (11) : 1990 These also differed from each other in immunohistoc hemica I staining. With respect t o AFP positivity, this has been found mainly in hepatoma and yolk sac tumor (12), but some papers have reported other AFP-producing tumors ; these have included germ cell t u m o r s ( l 3 ) , tumors of endodermal origin (14-17) and renal cell carcinomas
(18, 19). The immunostaining expression in this case was quite interesting. Before discussing it, the embryogenesis of the urethra should be reviewed. The female urethra as well as the urinary bladder is derived from the urogenital sinus, which was originally the anterior portion of the cloaca. The endodermal anlage gives rise t o the mucosal lining of the urethra and urinary bladder, and a downgrowth of the mesoderm invests them with musculature (20). Therefore, we think that the histologic findings and immunostaining results in this case are fairly consistent with the known development of the urethra. With regard to the fact that the urethra and colon are both derived from the cloaca, it is quite understandable that the tumor in this case had one part resembling intestinal adenocarcinoma, and like the latter, showed positivity for CEA. As an indicator of epithelial differentiation, EMA was reasonably well demonstrated in intestinal -type cells and clear cells, but it was not present in columnar vacuolated cells which, instead, were AFPpositive. This might imply that the cells were a t an early stage of development before epithelial differentiation, and that reflecting their endodermal origin, they might be closely related with the cloaca, which contains a certain amount of AFP (21). The reserve or stem cells in the urethral mucosa probably have the potential to revert to an embryonic state when undergoing of neoplastic transformation. The distinct difference observed among the three cell types in this one tumor yields an important clue t o the histogenesis of the tumor. Various origins have been proposed regarding the histogenesis of female urethral adenocarcinoma, e.g., the mesonephron ( l o ) , and paraurethral glands (2, 5 - 7 , 11, 22). According t o the findings in our present case and the embryogenesis of the urethra, we consider that the tumor originated directly from the urethral mucosa including the urethral glands, in which reserve cells, after malignant transformation, might have differentiated in different directions and give rise to a bizarre adenocarcinoma with three histologic components. Another possibility is that the tumor arose from three different clones of reserve cells in the mucosa. However, it seems difficult to conceive that a tumor might have arisen from diverse histologic foci of remnants or aberrant cells in the urethral wall which all turned malignant at the same time. In this tumor, there
was no element of transitional cell carcinoma or squamous cell carcinoma, and there was no other evidence t o suggest a n origin f r o m malignant proliferation of metaplastic cells o r transitional cells in the mucosa. This is probably the first time that the endodermal origin of urethra I adenoca rcinoma has been strongly suggested on the basis of morphologic and immunohistochemical evidence. Moreover, we postulate that in many respects adenocarcinoma of the urethra may be essentially the same as that of the urinary bladder, which has also been recognized t o have some similarities to colorectal adenocarcinoma (23) and t o have a clear cell variant (11). In conclusion, although this case is an unusual type of adenocarcinoma o f the urethra and its immunohistochemical expression is rather exceptional, it is of significance in helping t o clarify the histogenesis of urethral tumors. Acknowledgements : The authors thank Dr. Hiroshi Sakaguchi and Dr. Mitsumasa Kodama for clinical information, and Mr. Hitoshi Kawakami, Mr. Nobuhiko Uchino and Miss Minako Yonekawa for technical assistance.
R EFER ENCES 1. Bracken RB, Johnson DE, Miller LS, et a/. Primary carcinoma of the female urethra. J Urol 116: 188192, 1976. 2. Knoblich R. Primary adenocarcinoma of the female urethra. A review and report of 3 cases. Am J Obstet Gynecol 80 : 353-364, 1960. 3. McCrea LE. Malignancy of the female urethra. Urol SUW 2 : 85-149, 1952. 4. De Haan QC. Paraurethral gland adenocarcinoma. Am J Obstet Gynecol 93: 903-904, 1965. 5. Styn J, Hall M, and Logie NJ. Adenocarcinoma of the female urethra. Br J Urol 3 9 : 504-505, 1967. 6. Schnitzer B. Primary adenocarcinoma of the female urethra. A review and report of two cases. J Urol 92 : 135-139, 1964. 7. Meis JM, Ayala AG, and Johnson DE. Adenocarcinoma of the urethra in women. A clinicopathologic study. Cancer 60: 1038-1052, 1987. 8. Levine RL. Urethral cancer. Cancer 4 5 : 19651972, 1980. 9. Battle WH. A case of carcinoma of the urethra and bladder. Removal of the growth with closure of the resulting pubic wound and establishment of permanent suprapubic drainage. Lancet 2 : 79-80, 1901. 10. Konnak JW. Mesonephric carcinoma involving the urethra. J Urol 110: 76-78, 1973. 11. Young RH and Scully RE. Clear cell adenocarcinoma of the bladder and urethra. A report of three cases and review of the literature. Am J Surg Pathol 9 : 816-826, 1985. 12. Rosai J. Ackerman’s surgical pathology, 7th ed. CV Mosby, St. Louis, Toronto, Washington D.C., 1989: 37.
844
AFP-positive Adenocarcinorna of Urethra (Hanai and Lin)
13. Kurman RJ, Ganjei P, and Nadji M. Contribution of immunocytochemistry to the diagnosis and study of ovarian neoplasm. Int J Gynecol Pathol 3 : 3-26, 1984. 14. Spragins J, Hall WH, and White HJ. Fetoprotein from esophageal squamous cell carcinoma. Ann Intern Med 77: 322-323, 1972. 15. Noda H, Maetani S, Tobe T, and Nohara T. A case of a-fetoprotein producing rectal cancer. Nippon Geka Gakkai Zasshi 8 5 : 616-620, 1984 (in Japanese). 16. Yasunami R, Hashimoto Z, Ozura T, Hirao F, and Yamamura Y. Primary lung cancer producing a-fetoprotein : A case report. Cancer 47 : 926-929, 1981. 17. Akai S and Kato K. Serum a-fetoprotein-positive stomach cancer. Gann Monogr Cancer Res 1 4 : 149154, 1973. 18. Morimoto H, Tanigawa N, lnoue H, et a/. Alpha-fetoprotein producing renal cell carcinoma. Cancer 61 :
84-88, 1988. 19. Okada H, Kawabata G, Kamidono S, lshigami J, and Nakatsuka E. A case of renal cell carcinoma of horse shoe kidney that produced AFP and caused hypercal. cemia. Acta Urol Jpn 3 0 : 1453-1458, 1984. 20. Robbins SL. Pathology, 3rd ed. WB Saunders, Philadelphia, London, 1968: 1053. 21. Gitlin D, Dericell A, and Gitlin GM. Synthesis of (Yfetoprotein by liver, yolk sac and gastrointestinal tract of the human conceptus. Cancer Res 3 2 : 617-620, 1972. 22. Gillenwater JY and Burros HM. Unusual tumors of the female urethra. Obstet Gynecol 31 : 617-620, 1968. 23. Wells M and Anderson K. Mucin histochemistry of cystitis glandularis and primary adenocarcinoma of the urinary bladder. Arch Pathol Lab Med 1 0 9 : 59-61, 1985.
