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Introduction

Transitional cell carcinoma (TCC) of the urinary bladder is the ninth most common cancer in women in the USA. The American Cancer Society estimated that ~4,410 women succumbed to TCC in 2014 (1). The incidence of the disease in women is increasing, but remains 3–4 times lower compared with the incidence in men (2). However, the bladder cancer-associated mortality rate is greater in women (2). The greater mortality rate is partially attributable to delays in the diagnosis of TCC, which leads to an increased stage at presentation (2). In addition, the association and effect of gender on bladder TTC incidence, staging, prognosis and survival are poorly understood (3). The involvement of the female genital tract by TCC is another unsolved problem, and is usually associated with a poor prognosis (3). The vagina is considered to be the most commonly affected gynecological organ, with a TCC incidence of ~4% of the total TCC cases (4,5). The pathogenesis of vaginal TCC is challenging to determine. In the present study, a case of bladder TCC with metachronous vaginal TCC was discussed. The differences between local vaginal invasion and the metastatic spread from a primary bladder TCC, the occurrence of a second primary vaginal tumor and the direct implantation of TCC via urine that contains transitional cancer cells were reviewed and analyzed.

Case report

A 62-year-old female patient presented to the Department of Urology (Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium) in February 2013. The patient possessed a previous medical history of non-muscle invasive transitional bladder carcinoma, which was diagnosed in September 2009 and treated by a complete transurethral resection, and 3 years of maintenance therapy by endovesical Bacille Calmette-Guerin (BCG) instillation. The initial pathology demonstrated a diffuse carcinoma in situ (CIS). A follow-up cystoscopy in 2013 revealed recurrent CIS and no evidence of muscle invasion. The attendees of a multidisciplinary oncological meeting decided to administer a novel cycle of BCG instead of a radical cystectomy and bilateral pelvic lymph node dissection. A thoraco-abdominopelvic computed tomography scan revealed irregular thickening of the bladder wall and no evidence of regional or distant metastasis. The patient opted to be treated with a novel cycle of BCG. Following the induction therapy (6 weekly instillations), a flexible cystoscopy revealed the persistence of bladder CIS and a palpable mass through the anterior vaginal wall. A radical anterior pelvectomy and bilateral pelvic and inguinal lymph node dissection was performed. A definitive pathological examination confirmed the diagnosis of TCC of the bladder neck and the invasion into the anterior vaginal wall, and diffuse bladder CIS. The malignant infiltration of pelvic and inguinal lymph nodes was also evident. The surgical margins were negative. Adjuvant chemotherapy, consisting of gemcitabine and cisplatin, was initiated. The patient presented 6 months later with a vaginal mass and the absence of distant metastasis. A biopsy of the mass demonstrated atypical cells that expressed cytokeratin 34bE12, GATA 3 and protein P16, which are consistent with a high-grade invasive urothelial carcinoma.

All procedures used were in accordance with the ethical standards of the Institute Jules Bordet Ethics Review Committee (Brussels, Belgium) and the Declaration of Helsinki, as revised in 2000 (6). Informed consent for inclusion in the present study was obtained from the patient.

Discussion

The presence of TCC in the vaginal wall is an uncommon heterogeneous entity (3). Due to the location of the anterior wall of the vagina, the direct spread from a muscle-invasive transitional bladder cancer is not unusual in advanced and metastatic bladder cancer (4,7). The direct spread confers a poor prognosis due to the advanced stage of the disease (8). However, few cases of vaginal TCC that occur synchronously or metachronously with non-muscle invasive TCC of the urinary tract have been described (9,10). In addition, the extremely rare entity of primary vaginal TCC in the absence of a urinary tract tumor has also been reported (11–13). The pathogeneses of these variable clinical scenarios appear to be varied; however, the small number of cases in each group renders establishing the pathogenesis challenging. Recognizing and differentiating these entities is therefore critical in order to stratify the malignant behavior and distinguish the treatment and prognosis for the diseases.

The common embryological origin of the vagina and the urinary tract may explain the metaplasia of the vaginal squamous epithelium to TCC (14,15). Two hypotheses exist to explain the pathogenesis of primary vaginal TCC. The first hypothesis, ‘true multifocality’, was suggested by Jendresen et al (14) and postulates that transitional cell neoplasms are derived from a common vaginal stem cell line with pluripotent capacity. This hypothesis involves the presence of various foci of cancer in the urogenital tract, and may explain primary transitional carcinoma of the vagina and its association with TCC in the urinary tract (14). The second hypothesis, proposed by Singer et al (15), emphasizes the seeding phenomenon that involves the pagetoid spread of cancer cells to distant mucosa. The majority of these tumors occur in the cervix (12). Histologically, these tumors are composed of mixed squamous and TCC cells (12). At present, only 3 reported cases were diagnosed with TCC of the vagina without a prior history of TCC in the urinary tract (12,13). Pure TCC, similar to TCC of the urinary system, is extremely rare. Immunohistochemistry and the cytokeratin profile may aid the differentiation between TCC of the vagina and TCC of the urinary system, since vaginal TCC is CK7+/CK20− while bladder TCC is CK7+/CK20+ (16). Certain TCC patients are recommended for close follow-up examinations due to the increased risk of other urinary tract tumors (17).

Synchronous or metachronous vaginal metastasis of bladder TCC has been previously reported. However, the vagina is an uncommon site of metastasis for bladder cancer and other common malignancies (18,19). Bladder TCC may metastasize to the vagina through various mechanisms, including through the lymphatic system or blood vessels, in ways that are similar to the metastasis of bladder cancer to the liver, lungs, brain, adrenals and bone (20). Another metastasis mechanism is associated with the retrograde venous blood flow from the bladder to the vagina, which is similar to the mechanism of penile metastases from bladder cancers (21,22). However, vaginal metastasis may occur via another mechanism that involves the implantation of shed tumor cells into the vagina during micturition or transurethral resection, and probably possesses a better prognosis (23). This hypothesis is consistent with the hypothesis that metastases occurs on the sites of trocar placement, surgery scars, supra pubic catheter orifices and nephrostomy tracts, and emphasizes the importance of respecting surgical oncology principles (24–30). This hypothesis is based on the association of non-muscle invasive bladder and vaginal TCC with the same immunohistochemistry profile (10,14,15,18,19,23,31–38). At present, 15 cases of vaginal TCC have been described in the literature, occurring at an average of 4.3 years subsequent to the initial diagnosis of bladder TCC. These patients are treated with a local excision of the metastases or a total hysterovaginectomy. The prognosis is good and recurrence is rare (39). However, another mechanism of pathogenesis may be responsible for the occurrence of vaginal tumors, which involves the direct invasion of a muscle-invasive bladder cancer that is misdiagnosed as a superficial tumor, and has progressed into the bladder wall with intact or minimal changes to the urothelium (40). The misdiagnosis may be partially due to 40% of non-muscle invasive tumors being understaged by an initial transurethral resection, which may be demonstrated by analyzing cystectomy specimens (41,42). This highlights the importance of physical examinations and bimanual vaginal palpations in order to detect tumors in patients with non-muscle invasive bladder cancer. Second-look transurethral resection may also improve tumor staging, and is recommended for any patient with a T1 or high-grade tumor at the initial resection and in non-containing muscle specimens at pathology (43). Second-look transurethral resection may also be considered in cases where the urologist is unsure that the initial resection was complete, particularly in cases demonstrating extensive and multiple tumors (44). Inaccurate diagnosis and staging may lead to invasion of the vaginal wall by the direct extension of the tumor, and may adversely affect the survival of the patient.

Determining the pathogenesis of vaginal TCC that is associated with bladder TCC may affect the treatment and the prognosis of patients. Vaginal metastasis via the bloodstream is evidence of systemic disease that requires treatment with systemic therapy, and the prognosis is generally poor (19). Direct local invasion by a muscle-invasive bladder cancer may be surgically removed with the intent to cure. The role of adjuvant radiotherapy or chemotherapy in vaginal TCC is not clear. However, early diagnosis and accurate staging is mandatory in order to avoid vaginal invasion. The association between vaginal and non-muscle invasive TCC is complex. Primary vaginal TCC is an aggressive lesion that is usually invasive at the time of diagnosis. The therapy used for these lesions is similar to that used for conventional squamous cell carcinoma, and the prognosis is challenging to establish (19). Avoiding contamination of the vagina by irrigating fluid and urine during a transurethral resection is important in order to avoid malignant cells of the bladder seeding into the vaginal wall (23).

References