Journal of Surgical Oncology 49:6&71 (1992)
Female Urethral Diverticula With Clear Cell Adenocarcinoma JOHN 5. WHEELER,
ROBERT C. FLANIGAN, MD, HI YOUNG HONG, MD, ANU JAM1L. WALLOCH, MD From the Departments of Urology ( I S . W., R.C.F.1 and Pathology (H.Y.H., j.L.W.I, Loyola University Medical Center, Maywood, and Hines Veterans Administration Hospital, Hines, lllinois JR., MD,
Clear cell adenocarcinoma in a urethral diverticulum in the female is a very rare and unusual tumor. We recently treated two patients with this tumor. Their presentation, histologic evaluation, and management are reviewed in light of the limited experience in the literature. KEYWORDS:urethral carcinoma. exenteration, histologic evaluation and management
INTRODUCTION The differential diagnosis of urethral and periurethral masses in females includes caruncles, diverticula, fibrous polyps, condylomas, abscesses, and rarely mesenchymal tumors and urethral carcinomas. Primary urethral carcinoma is prone to occur in females with a peak incidence in the sixth and seventh decades of life. Histologic types include squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, undifferentiated carcinoma, and melanoma. Squamous cell carcinoma comprises 53%, while adenocarcinoma constitutes 14% of the neoplasms [ I ] . Adenocarcinoma of the urethra is divided into two groups based on morphology: columnar/mucinous type and clear cell type [ 2 ] . Clear cell adenocarcinoma is a histologically distinct tumor, which has been also called “mesonephric carcinoma” because of its morphologic resemblance to clear cell carcinoma of the kidney. Since Konnack reported the first case in 1973 [3], 25 cases have been described to date [2-161. Two cases occurred in men 19,131. The age range was 27 to 73 years with the majority being in the sixth and seventh decades of life. Frequent clinical manifestations were hematuria, bloody discharge, recurrent urinary tract infection, pain or discomfort, and a vaginal mass or swelling. Associated diverticula were found in only 6 cases [2,6,10,11]. Nevertheless, these six tumors behaved clinically and pathologically in a manner similar to those from the urethra alone. Herein we describe two female patients who presented with periurethral masses initially suspected to be urethral diverticula. In each case cystoscopy revealed a mass in the diverticulum. The biopsy proved to be clear cell 0 1992 Wiley-Liss, Inc.
adenocarcinoma. The differential diagnosis, histogenesis, therapeutic management, and prognosis are reviewed.
CASE #1 A 56 year-old white female sought medical attention for intermittent gross hematuria and dyspareunia of 5 month duration. She also had decreased urinary flow, incomplete emptying, and straining to void for 20 years. She denied any urinary infections. Twenty years ago, she had a total abdominal hysterectomy and salpingooophorectomy for uterine leiomyomata. She was hypertensive and smoked one pack per day. General physical examination was unremarkable. Pelvic examination showed normal vaginal mucosa and an absent uterus. A cytologic cervico-vaginal smear was negative. A tender, firm, poorly mobile mass 3 cm in diameter was noted distal to the level of the bladder neck. Pressure upon the mass caused no drainage per urethra. No inguinal adenopathy was noted. Urinalysis revealed microhematuria. Urine culture was normal. An intravenous urogram showed normal upper tracts and a large filling defect at the base of the bladder with a thickened bladder wall (Fig. 1). A retrograde urethrogram showed a solid mass associated with a small cystic space, the diverticulum, communicating with the urethra at the bladder neck (Fig. 2). During cystoscopy, Accepted for publication March 12. 199I . Address reprint requests to John S. Wheeler, Jr., MD, Dept. of Urology, Loyola University Medical Center, 2160 S . First Ave., Maywood, IL 60153.
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Fig. 1. (Case 1 .) Cystogram showing a large filling defect at the base of the bladder.
a small edematous bleb with friable urethral mucosa was noted at the proximal urethra and the diverticulum was not well appreciated. The bladder was trabeculated. Transvaginal excision revealed a firm, irregular mass associated with the diverticulum. Subsequent metastatic work-up was negative. The patient then received 15 Gy of radiation in five fractions to the lower pelvis followed by a radical cystourethrectomy , excising the entire urethra and anterior vagina, leaving the posterior vaginal wall for vaginal closure. The transvaginal biopsy consisted of a 1 X 0.5 X 0.1 cm elliptical portion of the urethral diverticulum wall and multiple firm tan-yellow polypoid fragments of tissue, 2.1 X 1 X 0.8 cm in toto. The radical cystourethrectomy specimen contained a 1.5 x 1.0 x 1.0 cm polypoid grey-white gritty mass in the septum between the proximal urethra and vagina. The vaginal and urethral mucosa and urinary bladder were unremarkable. Microscopic examination of the periurethral mass revealed a urothelial lined diverticulum and a polypoid mass composed of branched and closely packed glands with open lumina and rare papillary fronds lined by cuboidal and hobnailed cells with granular easinophilic cytoplasm (Fig. 3 ) . Solid areas of clear cells with well-demarcated cell borders were evident (Fig. 4). The nuclei had a vesicular chromatin pattern with nuclear membrane clumping and conspicuous nucleoli. The mucicarmine and diastase-resistant periodic acid-Schiff (D-PAS) stains were negative, while periodic acid-Schiff (PAS) was positive in the cytoplasm of occasional hobnail cells. The mitotic rate was one per ten highpower fields. The bladder showed chronic cystitis, while the urethral and vaginal mucosa were unremarkable. Two deep hypogastric lymph nodes embedded in the perivesicular fibroadipose tissue were positive for metastatic clear cell adenocarcinoma.
Fig. 2. (Case 1.) Urethrogram showing a small cystic connection to bladder neck, a diverticulum (see arrow).
The patient subsequently received post-operative radiation of 45 Gy in 27 fractions to the pelvis, beginning 6 weeks after surgery, without complication. The followup at 30 months revealed no residual disease.
CASE #2 A 75 year-old white female sought medical attention for vaginal spotting, urgency, incontinence, and dysuria of recent onset. She denied any previous urologic problems. She was an insulin-dependent diabetic. The general physical examination and pelvic examination were unremarkable. Urinalysis showed many white and red blood cells per high-powered field. The urine culture was negative. Intravenous urography revealed an elevated floor of the bladder and a urethral diverticulum. Cystoscopy showed edematous and erythematous mucosa of the trigone and bladder neck, with a 1.5 cm mobile polypoid mass within
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Fig. 3. (Case 1 . ) Closely packed glands lined by hobnailed cells.
Fig. 4. (Case 1.) Solid areas containing clear cells.
the urethra and associated with the diverticulum. A biopsy was taken. Metastatic work-up was unremarkable. The patient then underwent anterior exenteration and pelvic node dissection. The anterior exenteration included the urinary bladder, urethra, anterior portion of the vagina, cervix, uterus, and bilateral adnexal structures. A 2.5 X 1.5 X 1.O cm soft tan-yellow polypoid mass was present extending from the proximal urethral to the bladder neck. Longitudinal sections showed a 1.5 X 1.O cm posterior urethral diverticulum with the anterior and lateral wall involved with the tumor which was continuous with the polypoid mass (Fig. 5 ) . The tumor deeply invaded the urethrovaginal septum. There were several small satellite nodules in the bladder mucosa adjacent to the main mass. The vaginal mucosa, fallopian tubes, and ovaries were unremarkable. The uterus was not enlarged but the endometrium was lush, 0.3 cm thick.
Fig. 5. (Case 2 . ) Anterior exenteration specimen; anterior-posterior longitudinal section. A: 1.5 cm lobulated tumor within a urethral diverticulum. B: Posterior urethra. C: Anterior vagina. D: Uterine corpus. E: Posterior wall of bladder.
Microscopic examination of the periurethral mass and satellite nodules revealed papillary fronds and closely packed glands lined by cuboidal cells. Occasional glands and papillae showed hobnailed epithelium with eosinophilic cytoplasm. Solid areas of clear cells with welldemarcated cytoplasmic borders were also present. The nuclei were vesicular with a clumped chromatin pattern. Small nucleoli were seen in a few cells. The cytoplasm contained PAS-positive and diastase-sensitive material. Intraluminal mucin was demonstrated by mucicarmine stain. The intracytoplasmic mucin was, however, not identified. The mitotic rate was two per ten high-power fields. Abrupt transition from normal transitional epithe-
Urethral Diverticular Adenocarcinoma
hum to neoplastic cells was noted in the diverticulum. Psammoma bodies were occasionally seen (Fig. 6). There was focal necrosis. Electron microscopic examination disclosed polygonal cells encompassed by a well-formed basal lamina. Junctional complexes were present between the cells. The luminal surface showed abundant short microvilli without internal structures. The cytoplasm contained numerous mitochondria, polyribosomes, and stacks of granular endoplasmic reticulum (Fig. 7). Glycogen was not prominent, which might be due to prolonged fixation of the tissue. No lipid droplets were identified. The uninvolved bladder showed follicular cystitis. The uterine corpus contained an endometrial adenocarcinoma. It was composed of glands and papillary fronds lined by columnar cells with fusiform nuclei. There was squamous metaplasia. No hobnailed cells or clear cell morphology was present. No direct communication between the two neoplasms was found. The patient did not undergo any adjunctive therapy and follow-up at 24 months revealed no residual disease.
COMMENT The histogenesis of clear cell adenocarcinoma of the urethra or of urethral diverticula is uncertain. Konnack used the term “mesonephric carcinoma” and suggested that the tumor probably arose from the mesonephric duct or intermediate mesoderaml vestiges associated with the vagina because of its location along the courses of the embryonic mesonephros and its ducts and because of the tumor’s histological resemblance to renal cell carcinoma [ 31. Schnoy and Leistenschneider found intramuscular tubular structures lined by benign epithelium adjacent to the tumor [ I l l . They interpreted these structures as mesonephric remnants and suggested that the tumor might arise from embryonic remnants although electron microscopic findings did not reveal any specific differentiation of the tumor. Tanabe et al. described abundant elongated microvilli containing internal filaments on the luminal surface of tumor cells in urethral clear cell adenocarcinoma [lo]. They interpreted this finding as suggestive of a mesonephric origin of the tumor. However, there are no other reports supporting this observation. On the contrary, the finding of short microvilli and intracytoplasmic glycogen described by a few authors [ 11,151 and seen in our cases is similar to that of clear cell carcinoma of the female genital tract [ 171. Since urethraUperiurethra1 clear cell adenocarcinoma is morphologically similar to clear cell carcinoma of the female genital tract, one might speculate that it probably arises from Muellerian derivatives. Nevertheless, association with Muellerian structures or endometriosis has not been reported. With an in situ component in periurethral glands
Fig. 6. (Case 2 . ) Psammoma bodies. H&E.
X
69
100.
described by Meis et al. [2] or abrupt transformation from benign transitional epithelium to malignant cells in a diverticulum seen in our two cases, this may indicate that the tumor originates from transitional or glandular epithelium of periurethral glands or surface transitional epithelium, albeit ultrastructural findings do not suggest the cell origin. These findings support Young and Scully’s idea that clear cell adenocarcinoma of the lower urinary tract is the result of unusual but nonspecific neoplastic differentiation of either transitional epithelium or the glandular epithelium of the periurethral glands t141. The histologic feature of urethral/periurethral clear cell adenocarcinoma is similar to that of clear cell carcinoma of the female genital tract. It is characterized by tubuloglandular and papillary structures lines by hobnailed cells with eosinophilic or clear cytoplasm. Solid sheets of clear cells are variably present. Intracytoplasmic glycogen is demonstrated in the majority of cases. In contrast to the abundance of mucin in columnarimucinous adenocarcinoma, clear cell adenocarcinoma shows scanty luminal mucin in some cases. Psammoma bodies are infrequently found [2,9]. An in situ component involving periurethral glands may be present [2]. Our cases demonstrate abrupt change from benign transitional epithelium to malignant hobnailed cells in the diverticulum. Differential diagnosis of clear cell adenocarcinoma of the lower urinary tract includes nephrogenic adenoma, clear cell carcinoma of the female genital tract, metastatic renal cell carcinoma, papillar transitional cell neoplasms, and endodermal sinus tumor. Nephrogenic adenoma or metaplasia is an uncommon lesion associated with chronic inflammation. It is most commonly found in the urinary bladder. Predilection to males and a wide age distribution including children [ 11 differ from clinical features of clear cell adenocarcinoma. It is associated
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Fig. 7. (Case 2 . ) Abundant blunt microvilli seen in the luminal surface of neoplastic cells. No internal structure is noted within the villi. The cytoplasm contains mitochondria, polyribosomes, and granular endoplasmic reticulum. Cell junctions are present between the cells. EM. x I .OOO.
with chronic bladder infection, calculus disease, trauma, or instrumentation. Histologically, the lesion is composed of papillary and tubular structures lined by a single layer of cuboidal cells. Nuclear atypia may be present; however, there is no mitotic activity. The tubules are located in the lamina propria without an infiltrating pattern. Associated histologic features include inflammatory response, squamous metaplasia, cystitis cystica or cystitis glandularis, which suggest a metaplastic origin of the lesion. Although it is considered to be a benign process, its exact natural history is uncertain and recurrences are common. Since the histologic morphology including electron microscopic findings of clear cell adenocarcinoma of the lower urinary tract is similar to that of clear cell carcinoma of the female genital tract, careful pelvic examination is necessary to rule out extension of genital tumor to urethraliperiurethral regions. History of prenatal diethylstilbestrol exposure may not be helpful because the majority of clear cell carcinomas of the genital tract occurring in women who are over 50 years of age are not associated with such exposure. Identification of in situ changes or transition from normal to neoplastic epithelium might help to differentiate the two entities. Renal cell carcinoma rarely metastasizes to the urethra or periurethral areas. Histologically, it seldom shows
hobnailed cells. Intracytoplasmic glycogen and lipid can be demonstrated by special stains and electron microscopic studies. No intracytoplasmic lipid has been described in urethraliperiurethral clear cell adenocarcinoma. Clear cell adenocarcinoma may be confused with transitional cell papilloma or papillary transitional cell carcinoma if a small biopsy is taken from the surface papillary portions without solid clear cell areas. However, identification of a tubuloglandular pattern and hobnailed epithelium will assist in distinguishing clear cell adenocarcinoma from papillary transitional cell neoplasms. Endodermal sinus tumor may arise in the vagina and involve the periurethral regions 1181. Histologically, it may mimic clear cell adenocarcinoma because of the papillary or tubuloglandular pattern. Solid areas of clear cells can be present. However, endodermal sinus tumor occurs in a younger age group, the majority being under 30 years of age. Also, identification of other histologic findings such as Schiller-Duval bodies, hyaline globules, myxomatous background, and staining for alpha-fetoprotein would help to differentiate the two entities. The clinical features of female urethraliperiurethral carcinoma are non-specific, including: urethral bleeding, irritative and/or obstructive voiding symptoms, dyspareunia, and hematuria. A marked delay in the diagnosis is common [2]. The periurethral location of the tumor in our first case probably masked her symptoms for some time, causing her to present late in her course and perhaps precluding the chance of surgical cure. The second case had more obvious urethral tumor growing from the diverticulum causing more acute symptoms that may have improved her survival, as she did not have positive nodes. Nevertheless, the features of our two cases and the cases of diverticular tumors in the literature [2,6,10,11] are similar to those of urethral clear cell carcinoma. The diagnosis of urethraUperiurethra1 carcinoma requires a high index of suspicion. A careful pelvic examination and evaluation of the inguinal nodes is essential. Based on known nodal drainage, distal urethral carcinomas metastasize to inguinal nodes and proximal urethral carcinomas metastasize to pelvic nodes. An intravenous urogram and a cystoscopy are also required. In our first case, the cystoscopy revealed some friable proximal urethral tissue, but the tumor was not as apparent as it was in the second case. Therefore, our first patient underwent a transvaginal excisional biopsy of her mass in order to confirm the diagnosis. The metastatic work-up includes chest x-ray, bone scan, pelvic CT scan to assess lymph nodes, and liver function studies. These studies were normal in both cases. The best treatment for female urethraliperiurethral carcinomas, especially those with clear cell adenocarci-
Urethral Diverticular Adenocarcinoma
noma, is controversial because of their rarity [2-161. The treatment is based on the location of the tumor and the presence of metastases. Localized distal urethral cancer may be amenable to radiation therapy, or radiation therapy combined with partial or total urethrectomy . Whether inguinal lymphadenectomy should be done is controversial [ 191. Careful examination of the inguinal nodes may suffice unless the nodes are palpable, in which case, a node dissection is generally performed. When the tumor involves the proximal and/or entire urethra or periurethral area, the treatment is more extensive, including anterior exenteration. Whether preoperative or postoperative radiation therapy should be added is a debatable issue [2-16,191. Radiation therapy alone has been employed with some success, but a combination approach seems to be more appropriate [2-161. Pelvic lymphadenectomy during the anterior exenteration will more accurately stage the patient. Since there are only a few reported cases of clear cell adenocarcinoma of urethral diverticula and the urethra, follow-up information is limited. In most of the cases, the diagnosis was made at advanced stages of disease. The prognosis appears to correlate with the clinical stage of the disease. Meis et al. suggested in their study that survival time was shorter in the columnar/mucinous carcinoma than in the clear cell adenocarcinoma although it was not statistically significant [2]. They reported the largest experience with clear cell female urethral carcinoma, with nine cases reported [2]. The patients had similar features to those with urethral adenocarcinoma. However, their treatments varied: three patients had preoperative radiation and exenteration, five patients had radiation therapy alone, and one patient had only chemotherapy. The 2 year survival rate was 55%. Incidence of metastases at the time of presentation was 44% with spread to lymph nodes, lung, skin, vulva, and liver. Few of the cases were periurethral in location [2]. Review of the literature disclosed that 14 of 23 female patients with urethraUperiurethra1 clear cell adenocarcinoma were alive without disease after treatment, the follow-up period ranging from 20 months to 24 years with a mean follow-up period of 93 months. Seven patients died of disease. Metastases to abdominal or
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pelvic lymph nodes, regional skin, lung, liver, and peritoneum were found in these cases. Although the majority of surviving patients were treated with a combination of radical surgery and radiation, more data need to be accumulated to evaluate the best modality of treatment.
REFERENCES 1. Petersen RO: “Urologic Pathology.” Philadelphia: Lippincott, 1986, pp 435437. 2. Meis JM, Ayala AG, Johnson DE: Adenocarcinoma of the urethra in women. A clinicopathologic study. Cancer 60: 1038-1052, 1987. 3. Konnack JW: Mesonephric carcinoma involving the urethra. J Urol 110:76-78, 1973. 4. Altwein J , Schafer R, Hohenfellner R: Mesonephric carcinoma of the female urethra. Eur Urol 1:248-250, 1975. 5. Tiltman AJ: Primary adenocarcinoma of the female urethra. J Pathol 117:97-99, 1975. 6. Cea PC, Ward JN, Lavengood RW, et al.: Mesonephric adenocarcinomas in urethral diverticula. Urology 10:58-61, 1977. 7. Murayama T , Komatsu H, Asano M, et al.: Mesonephric adenocarcinoma of the urethra in a woman. Report of a case. J Urol 120:50O-S01, 1978. 8. Philipson BM, Himmelman A, Johansson S , et al.: Clear cell adenocarcinoma of the urethra. Scand J Urol Nephrol 15:327329, 1981. 9. Cantrell BB, Leifer G, DeKlerk DP, et al.: Papillary adenocarcinoma of the prostatic urethra with clear-cell appearance. Cancer 48:2661-2667, 1981. 10. Tanabe ET, Mazur MT, Schaeffer AJ: Clear cell adenocarcinoma of the female urethra. Cancer 49:372-378, 1982. 11. Schnoy N, Leistenschneider W: Tumor of mesonephric origin in a diverticulum of the urethra. Virchows Arch 397:335-345, 1982. 12. Assimos DG, O’Connor VJ: Clear cell adenocarcinoma of the urethra. J Urol 131540-541, 1984. 13. Ingram EA, DePauw P: Adenocarcinoma of the male urethra with associated nephrogenic metaplasia. Case report and review of the literature. Cancer 55:160-164, 1985. 14. Young RH, Scully RE: Clear cell adenocarcinoma of the bladder and urethra. Am J Surg Pathol 9:816-826, 1985. 15. Peven DR, Hidvegi DR: Clear cell adenocarcinoma of the female urethra. Acta Cytol 29:142-146, 1985. 16. Rivard DJ, Waisman SS: Primary mesonephric carcinoma of the female urethra. J Urol 134:756-757, 1985. 17. Dikersin GR, Welch WR, Erlandson R, et al.: Ultrastructure of 16 cases of clear cell adenocarcinoma of the vagina and cervix in young women. Cancer 45:1615-1624, 1980. 18. Copeland LJ, Sneige N , Ordonez NG, et al.: Endodermal sinus tumor of the vagina and cervix. Cancer 55:2558-2565, 1985. 19. Ray B, Guinan PD: Primary carcinoma of the urethra. In Javadpour N (ed): “Principles and Management of Urologic Cancer.” Baltimore: Williams and Wilkins, 1979, p 445473.
Female Urethral Diverticula With Clear Cell Adenocarcinoma JOHN 5. WHEELER,
ROBERT C. FLANIGAN, MD, HI YOUNG HONG, MD, ANU JAM1L. WALLOCH, MD From the Departments of Urology ( I S . W., R.C.F.1 and Pathology (H.Y.H., j.L.W.I, Loyola University Medical Center, Maywood, and Hines Veterans Administration Hospital, Hines, lllinois JR., MD,
Clear cell adenocarcinoma in a urethral diverticulum in the female is a very rare and unusual tumor. We recently treated two patients with this tumor. Their presentation, histologic evaluation, and management are reviewed in light of the limited experience in the literature. KEYWORDS:urethral carcinoma. exenteration, histologic evaluation and management
INTRODUCTION The differential diagnosis of urethral and periurethral masses in females includes caruncles, diverticula, fibrous polyps, condylomas, abscesses, and rarely mesenchymal tumors and urethral carcinomas. Primary urethral carcinoma is prone to occur in females with a peak incidence in the sixth and seventh decades of life. Histologic types include squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, undifferentiated carcinoma, and melanoma. Squamous cell carcinoma comprises 53%, while adenocarcinoma constitutes 14% of the neoplasms [ I ] . Adenocarcinoma of the urethra is divided into two groups based on morphology: columnar/mucinous type and clear cell type [ 2 ] . Clear cell adenocarcinoma is a histologically distinct tumor, which has been also called “mesonephric carcinoma” because of its morphologic resemblance to clear cell carcinoma of the kidney. Since Konnack reported the first case in 1973 [3], 25 cases have been described to date [2-161. Two cases occurred in men 19,131. The age range was 27 to 73 years with the majority being in the sixth and seventh decades of life. Frequent clinical manifestations were hematuria, bloody discharge, recurrent urinary tract infection, pain or discomfort, and a vaginal mass or swelling. Associated diverticula were found in only 6 cases [2,6,10,11]. Nevertheless, these six tumors behaved clinically and pathologically in a manner similar to those from the urethra alone. Herein we describe two female patients who presented with periurethral masses initially suspected to be urethral diverticula. In each case cystoscopy revealed a mass in the diverticulum. The biopsy proved to be clear cell 0 1992 Wiley-Liss, Inc.
adenocarcinoma. The differential diagnosis, histogenesis, therapeutic management, and prognosis are reviewed.
CASE #1 A 56 year-old white female sought medical attention for intermittent gross hematuria and dyspareunia of 5 month duration. She also had decreased urinary flow, incomplete emptying, and straining to void for 20 years. She denied any urinary infections. Twenty years ago, she had a total abdominal hysterectomy and salpingooophorectomy for uterine leiomyomata. She was hypertensive and smoked one pack per day. General physical examination was unremarkable. Pelvic examination showed normal vaginal mucosa and an absent uterus. A cytologic cervico-vaginal smear was negative. A tender, firm, poorly mobile mass 3 cm in diameter was noted distal to the level of the bladder neck. Pressure upon the mass caused no drainage per urethra. No inguinal adenopathy was noted. Urinalysis revealed microhematuria. Urine culture was normal. An intravenous urogram showed normal upper tracts and a large filling defect at the base of the bladder with a thickened bladder wall (Fig. 1). A retrograde urethrogram showed a solid mass associated with a small cystic space, the diverticulum, communicating with the urethra at the bladder neck (Fig. 2). During cystoscopy, Accepted for publication March 12. 199I . Address reprint requests to John S. Wheeler, Jr., MD, Dept. of Urology, Loyola University Medical Center, 2160 S . First Ave., Maywood, IL 60153.
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Fig. 1. (Case 1 .) Cystogram showing a large filling defect at the base of the bladder.
a small edematous bleb with friable urethral mucosa was noted at the proximal urethra and the diverticulum was not well appreciated. The bladder was trabeculated. Transvaginal excision revealed a firm, irregular mass associated with the diverticulum. Subsequent metastatic work-up was negative. The patient then received 15 Gy of radiation in five fractions to the lower pelvis followed by a radical cystourethrectomy , excising the entire urethra and anterior vagina, leaving the posterior vaginal wall for vaginal closure. The transvaginal biopsy consisted of a 1 X 0.5 X 0.1 cm elliptical portion of the urethral diverticulum wall and multiple firm tan-yellow polypoid fragments of tissue, 2.1 X 1 X 0.8 cm in toto. The radical cystourethrectomy specimen contained a 1.5 x 1.0 x 1.0 cm polypoid grey-white gritty mass in the septum between the proximal urethra and vagina. The vaginal and urethral mucosa and urinary bladder were unremarkable. Microscopic examination of the periurethral mass revealed a urothelial lined diverticulum and a polypoid mass composed of branched and closely packed glands with open lumina and rare papillary fronds lined by cuboidal and hobnailed cells with granular easinophilic cytoplasm (Fig. 3 ) . Solid areas of clear cells with well-demarcated cell borders were evident (Fig. 4). The nuclei had a vesicular chromatin pattern with nuclear membrane clumping and conspicuous nucleoli. The mucicarmine and diastase-resistant periodic acid-Schiff (D-PAS) stains were negative, while periodic acid-Schiff (PAS) was positive in the cytoplasm of occasional hobnail cells. The mitotic rate was one per ten highpower fields. The bladder showed chronic cystitis, while the urethral and vaginal mucosa were unremarkable. Two deep hypogastric lymph nodes embedded in the perivesicular fibroadipose tissue were positive for metastatic clear cell adenocarcinoma.
Fig. 2. (Case 1.) Urethrogram showing a small cystic connection to bladder neck, a diverticulum (see arrow).
The patient subsequently received post-operative radiation of 45 Gy in 27 fractions to the pelvis, beginning 6 weeks after surgery, without complication. The followup at 30 months revealed no residual disease.
CASE #2 A 75 year-old white female sought medical attention for vaginal spotting, urgency, incontinence, and dysuria of recent onset. She denied any previous urologic problems. She was an insulin-dependent diabetic. The general physical examination and pelvic examination were unremarkable. Urinalysis showed many white and red blood cells per high-powered field. The urine culture was negative. Intravenous urography revealed an elevated floor of the bladder and a urethral diverticulum. Cystoscopy showed edematous and erythematous mucosa of the trigone and bladder neck, with a 1.5 cm mobile polypoid mass within
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Fig. 3. (Case 1 . ) Closely packed glands lined by hobnailed cells.
Fig. 4. (Case 1.) Solid areas containing clear cells.
the urethra and associated with the diverticulum. A biopsy was taken. Metastatic work-up was unremarkable. The patient then underwent anterior exenteration and pelvic node dissection. The anterior exenteration included the urinary bladder, urethra, anterior portion of the vagina, cervix, uterus, and bilateral adnexal structures. A 2.5 X 1.5 X 1.O cm soft tan-yellow polypoid mass was present extending from the proximal urethral to the bladder neck. Longitudinal sections showed a 1.5 X 1.O cm posterior urethral diverticulum with the anterior and lateral wall involved with the tumor which was continuous with the polypoid mass (Fig. 5 ) . The tumor deeply invaded the urethrovaginal septum. There were several small satellite nodules in the bladder mucosa adjacent to the main mass. The vaginal mucosa, fallopian tubes, and ovaries were unremarkable. The uterus was not enlarged but the endometrium was lush, 0.3 cm thick.
Fig. 5. (Case 2 . ) Anterior exenteration specimen; anterior-posterior longitudinal section. A: 1.5 cm lobulated tumor within a urethral diverticulum. B: Posterior urethra. C: Anterior vagina. D: Uterine corpus. E: Posterior wall of bladder.
Microscopic examination of the periurethral mass and satellite nodules revealed papillary fronds and closely packed glands lined by cuboidal cells. Occasional glands and papillae showed hobnailed epithelium with eosinophilic cytoplasm. Solid areas of clear cells with welldemarcated cytoplasmic borders were also present. The nuclei were vesicular with a clumped chromatin pattern. Small nucleoli were seen in a few cells. The cytoplasm contained PAS-positive and diastase-sensitive material. Intraluminal mucin was demonstrated by mucicarmine stain. The intracytoplasmic mucin was, however, not identified. The mitotic rate was two per ten high-power fields. Abrupt transition from normal transitional epithe-
Urethral Diverticular Adenocarcinoma
hum to neoplastic cells was noted in the diverticulum. Psammoma bodies were occasionally seen (Fig. 6). There was focal necrosis. Electron microscopic examination disclosed polygonal cells encompassed by a well-formed basal lamina. Junctional complexes were present between the cells. The luminal surface showed abundant short microvilli without internal structures. The cytoplasm contained numerous mitochondria, polyribosomes, and stacks of granular endoplasmic reticulum (Fig. 7). Glycogen was not prominent, which might be due to prolonged fixation of the tissue. No lipid droplets were identified. The uninvolved bladder showed follicular cystitis. The uterine corpus contained an endometrial adenocarcinoma. It was composed of glands and papillary fronds lined by columnar cells with fusiform nuclei. There was squamous metaplasia. No hobnailed cells or clear cell morphology was present. No direct communication between the two neoplasms was found. The patient did not undergo any adjunctive therapy and follow-up at 24 months revealed no residual disease.
COMMENT The histogenesis of clear cell adenocarcinoma of the urethra or of urethral diverticula is uncertain. Konnack used the term “mesonephric carcinoma” and suggested that the tumor probably arose from the mesonephric duct or intermediate mesoderaml vestiges associated with the vagina because of its location along the courses of the embryonic mesonephros and its ducts and because of the tumor’s histological resemblance to renal cell carcinoma [ 31. Schnoy and Leistenschneider found intramuscular tubular structures lined by benign epithelium adjacent to the tumor [ I l l . They interpreted these structures as mesonephric remnants and suggested that the tumor might arise from embryonic remnants although electron microscopic findings did not reveal any specific differentiation of the tumor. Tanabe et al. described abundant elongated microvilli containing internal filaments on the luminal surface of tumor cells in urethral clear cell adenocarcinoma [lo]. They interpreted this finding as suggestive of a mesonephric origin of the tumor. However, there are no other reports supporting this observation. On the contrary, the finding of short microvilli and intracytoplasmic glycogen described by a few authors [ 11,151 and seen in our cases is similar to that of clear cell carcinoma of the female genital tract [ 171. Since urethraUperiurethra1 clear cell adenocarcinoma is morphologically similar to clear cell carcinoma of the female genital tract, one might speculate that it probably arises from Muellerian derivatives. Nevertheless, association with Muellerian structures or endometriosis has not been reported. With an in situ component in periurethral glands
Fig. 6. (Case 2 . ) Psammoma bodies. H&E.
X
69
100.
described by Meis et al. [2] or abrupt transformation from benign transitional epithelium to malignant cells in a diverticulum seen in our two cases, this may indicate that the tumor originates from transitional or glandular epithelium of periurethral glands or surface transitional epithelium, albeit ultrastructural findings do not suggest the cell origin. These findings support Young and Scully’s idea that clear cell adenocarcinoma of the lower urinary tract is the result of unusual but nonspecific neoplastic differentiation of either transitional epithelium or the glandular epithelium of the periurethral glands t141. The histologic feature of urethral/periurethral clear cell adenocarcinoma is similar to that of clear cell carcinoma of the female genital tract. It is characterized by tubuloglandular and papillary structures lines by hobnailed cells with eosinophilic or clear cytoplasm. Solid sheets of clear cells are variably present. Intracytoplasmic glycogen is demonstrated in the majority of cases. In contrast to the abundance of mucin in columnarimucinous adenocarcinoma, clear cell adenocarcinoma shows scanty luminal mucin in some cases. Psammoma bodies are infrequently found [2,9]. An in situ component involving periurethral glands may be present [2]. Our cases demonstrate abrupt change from benign transitional epithelium to malignant hobnailed cells in the diverticulum. Differential diagnosis of clear cell adenocarcinoma of the lower urinary tract includes nephrogenic adenoma, clear cell carcinoma of the female genital tract, metastatic renal cell carcinoma, papillar transitional cell neoplasms, and endodermal sinus tumor. Nephrogenic adenoma or metaplasia is an uncommon lesion associated with chronic inflammation. It is most commonly found in the urinary bladder. Predilection to males and a wide age distribution including children [ 11 differ from clinical features of clear cell adenocarcinoma. It is associated
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Wheeler et al.
Fig. 7. (Case 2 . ) Abundant blunt microvilli seen in the luminal surface of neoplastic cells. No internal structure is noted within the villi. The cytoplasm contains mitochondria, polyribosomes, and granular endoplasmic reticulum. Cell junctions are present between the cells. EM. x I .OOO.
with chronic bladder infection, calculus disease, trauma, or instrumentation. Histologically, the lesion is composed of papillary and tubular structures lined by a single layer of cuboidal cells. Nuclear atypia may be present; however, there is no mitotic activity. The tubules are located in the lamina propria without an infiltrating pattern. Associated histologic features include inflammatory response, squamous metaplasia, cystitis cystica or cystitis glandularis, which suggest a metaplastic origin of the lesion. Although it is considered to be a benign process, its exact natural history is uncertain and recurrences are common. Since the histologic morphology including electron microscopic findings of clear cell adenocarcinoma of the lower urinary tract is similar to that of clear cell carcinoma of the female genital tract, careful pelvic examination is necessary to rule out extension of genital tumor to urethraliperiurethral regions. History of prenatal diethylstilbestrol exposure may not be helpful because the majority of clear cell carcinomas of the genital tract occurring in women who are over 50 years of age are not associated with such exposure. Identification of in situ changes or transition from normal to neoplastic epithelium might help to differentiate the two entities. Renal cell carcinoma rarely metastasizes to the urethra or periurethral areas. Histologically, it seldom shows
hobnailed cells. Intracytoplasmic glycogen and lipid can be demonstrated by special stains and electron microscopic studies. No intracytoplasmic lipid has been described in urethraliperiurethral clear cell adenocarcinoma. Clear cell adenocarcinoma may be confused with transitional cell papilloma or papillary transitional cell carcinoma if a small biopsy is taken from the surface papillary portions without solid clear cell areas. However, identification of a tubuloglandular pattern and hobnailed epithelium will assist in distinguishing clear cell adenocarcinoma from papillary transitional cell neoplasms. Endodermal sinus tumor may arise in the vagina and involve the periurethral regions 1181. Histologically, it may mimic clear cell adenocarcinoma because of the papillary or tubuloglandular pattern. Solid areas of clear cells can be present. However, endodermal sinus tumor occurs in a younger age group, the majority being under 30 years of age. Also, identification of other histologic findings such as Schiller-Duval bodies, hyaline globules, myxomatous background, and staining for alpha-fetoprotein would help to differentiate the two entities. The clinical features of female urethraliperiurethral carcinoma are non-specific, including: urethral bleeding, irritative and/or obstructive voiding symptoms, dyspareunia, and hematuria. A marked delay in the diagnosis is common [2]. The periurethral location of the tumor in our first case probably masked her symptoms for some time, causing her to present late in her course and perhaps precluding the chance of surgical cure. The second case had more obvious urethral tumor growing from the diverticulum causing more acute symptoms that may have improved her survival, as she did not have positive nodes. Nevertheless, the features of our two cases and the cases of diverticular tumors in the literature [2,6,10,11] are similar to those of urethral clear cell carcinoma. The diagnosis of urethraUperiurethra1 carcinoma requires a high index of suspicion. A careful pelvic examination and evaluation of the inguinal nodes is essential. Based on known nodal drainage, distal urethral carcinomas metastasize to inguinal nodes and proximal urethral carcinomas metastasize to pelvic nodes. An intravenous urogram and a cystoscopy are also required. In our first case, the cystoscopy revealed some friable proximal urethral tissue, but the tumor was not as apparent as it was in the second case. Therefore, our first patient underwent a transvaginal excisional biopsy of her mass in order to confirm the diagnosis. The metastatic work-up includes chest x-ray, bone scan, pelvic CT scan to assess lymph nodes, and liver function studies. These studies were normal in both cases. The best treatment for female urethraliperiurethral carcinomas, especially those with clear cell adenocarci-
Urethral Diverticular Adenocarcinoma
noma, is controversial because of their rarity [2-161. The treatment is based on the location of the tumor and the presence of metastases. Localized distal urethral cancer may be amenable to radiation therapy, or radiation therapy combined with partial or total urethrectomy . Whether inguinal lymphadenectomy should be done is controversial [ 191. Careful examination of the inguinal nodes may suffice unless the nodes are palpable, in which case, a node dissection is generally performed. When the tumor involves the proximal and/or entire urethra or periurethral area, the treatment is more extensive, including anterior exenteration. Whether preoperative or postoperative radiation therapy should be added is a debatable issue [2-16,191. Radiation therapy alone has been employed with some success, but a combination approach seems to be more appropriate [2-161. Pelvic lymphadenectomy during the anterior exenteration will more accurately stage the patient. Since there are only a few reported cases of clear cell adenocarcinoma of urethral diverticula and the urethra, follow-up information is limited. In most of the cases, the diagnosis was made at advanced stages of disease. The prognosis appears to correlate with the clinical stage of the disease. Meis et al. suggested in their study that survival time was shorter in the columnar/mucinous carcinoma than in the clear cell adenocarcinoma although it was not statistically significant [2]. They reported the largest experience with clear cell female urethral carcinoma, with nine cases reported [2]. The patients had similar features to those with urethral adenocarcinoma. However, their treatments varied: three patients had preoperative radiation and exenteration, five patients had radiation therapy alone, and one patient had only chemotherapy. The 2 year survival rate was 55%. Incidence of metastases at the time of presentation was 44% with spread to lymph nodes, lung, skin, vulva, and liver. Few of the cases were periurethral in location [2]. Review of the literature disclosed that 14 of 23 female patients with urethraUperiurethra1 clear cell adenocarcinoma were alive without disease after treatment, the follow-up period ranging from 20 months to 24 years with a mean follow-up period of 93 months. Seven patients died of disease. Metastases to abdominal or
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pelvic lymph nodes, regional skin, lung, liver, and peritoneum were found in these cases. Although the majority of surviving patients were treated with a combination of radical surgery and radiation, more data need to be accumulated to evaluate the best modality of treatment.
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