RMS in the urinary bladder has been well documented in children with the majority being embryonal, betryoid type [8, 9]. RMS in adult urinary bladder is rare, with only scattered case reports or small series [[2, 6, 7, 10–15]]. In the reported cases, the tumor usually occurs in older patients with the average age of 63+/-13 years. There is a predilection for men with a male to female ration roughly 2:1.
RMS in adult is composed of small round blue cells with high nuclear cytoplasm ratio, brisk mitosis and frequent apoptosis. Frequently the tumors show nuclear anaplasia, with random large anaplastic cells scattered in the tumor, similar to the nuclear anaplasia seen in the Wilm's tumor without the requirement of tripolar atypical mitosis . RMS in adult urinary bladders has been reported to be alveolar [[7, 14, 17]], embryonal [[11–13, 17]], pleomorphic [2, 6] type or unspecified .
Rhabdomyoblastic morphology may not be present in the tumor; therefore it may be confused with other primitive tumors, especially with small cell carcinoma. On the other hand, variable aberrant rhabdomyoblastic differentiation could be seen in poorly differentiated urothelial carcinoma. Typically, differential diagnosis of RMS in adults includes sarcomatoid urothelial carcinoma with extensive rhabdomyosarcomatous differentiation and other tumors with small round cell morphology including small cell carcinoma, plasmacytoid urothelial carcinoma, primitive neuroectodermal tumor and lymphoma. Immunohistochemical analysis has an important role in the differential diagnosis of these tumors. Desmin and myogenin immunoreactivity can be used to differentiate rhabdomyosarcoma from other round cell tumors without rhabdomyoblastic differentiation but not sarcomatoid carcinoma with rhabdomyoblastic differentiation. In practice, urothelial carcinoma with extensive rhabdomyosarcomatous differentiation can only be differentiated from de novo rhabdomyosarcoma based on finding of any carcinomatous (neoplastic epithelial) element and/or unequivocal cytokeratin immunoreactivity in tumor cells. Therefore, sufficient sampling and mapping of tumor to look for any carcinomatous element, in-situ or invasive, are critical for making the distinction between these two entities. The diagnostic difficulties are reflected in two of our cases. In case 2, the tumor is very large (25 cm) and only very small focus showing carcinomatous differentiation. In case 3, small focus of urothelial carcinoma was only identified in the initial TURBT specimen. In the subsequent TURBT, no carcinomatous component was identified albeit the whole specimen was entirely submitted in 15 cassettes for histologic evaluation. One can conceive that when the carcinomatous element is very small and/or dominated or replaced by rhabdomyosarcomatous element, the minor carcinomatous element might not be morphologically detectable easily in routine sampling. In addition, as seen in these two cases, the rhabdomyoblastic element could also lose their other epithelial characteristics such as cytokeratin reactivity. In such case, diagnosis of de novo rhabdomyosarcoma is basically a function of extensiveness of tissue sampling except for alveolar rhabdomyosarcoma for which molecular analysis for PAX3/7-FHKR translocation can be used to confirm the diagnosis. As illustrated in our cases, majority of the rhabdomyoblastic tumors of the bladder are likely rhabdomyosarcomatous carcinoma as small foci of carcinomatous element are only detectable through extensive sampling of the single or multiple specimens and pure rhabdomyoblastic tumor (a.k.a de novo rhabdomyosarcoma) is very rare and the diagnosis should be made with extreme caution.
The other challenge is differentiating rhabdomyosarcoma and rhabdomyoblastic carcinoma from small cell carcinoma. As some previous studies showed , we also find that there is significant overlapping of morphologic features between small cell carcinoma, rhabdomyosarcoma and carcinoma with extensive rhabdomyoblastic differentiation in urinary bladder. Small cell carcinoma of bladder is a rare tumor with incidence reported between 0.5% and 1% of the bladder cancers in retrospective studies [[18–20]]. It can coexist with urothelial carcinoma. It has been shown that similar patterns of allelic loss in the small cell carcinoma component coexisting with urothelial carcinoma. The similar patterns of allelic loss leads to the hypothesis that these cells have common clonal origin . The prognosis for small cell carcinoma of the urinary bladder is poor, with overall 1-year and 5-year disease-specific survival rates of 56% and 16% respectively . The treatment for bladder small cell carcinoma is not standardized. However, chemotherapy played a prominent role in the management of these tumors . Recent development includes the use of adjuvant platinum-based chemotherapy for advanced disease. For adult bladder RMS, treatments are variable, including surgical resection, radiotherapy, chemotherapy or combined therapy. Prognostic markers with a worse prognosis included nonembryonal histology, tumor invasion and tumor size > 5 cm in children' RMS . Management of carcinoma with extensive rhabdomyosarcomatous differentiation is not well defined. The preferred treatment appears to be cystectomy followed by radiation therapy or chemotherapy .
Due to the difference in management, proper classification of the rhabdomyoblastic tumors in bladder and differentiate these tumors from morphologic mimics such as small cell carcinoma are important. In this study, we compared the expression of cytokeratin, myogenin, synaptophysin and chromogranin in rhabdomyosarcomatous tumor and small cell carcinoma of the bladder. As shown in Table 4, areas of rhabdomyosarcomatous differentiation were positive for desmin and myogenin, negative for cytokeratin and chromogranin in all cases. In this study, we reported strong positivity for synaptophysin detected in the RMS component of one of the sarcomatoid carcinomas, which was not reported previously. As reported , positivity for synaptophysin can also be detected in pure RMS, and hence has little utility to differentiate rhabdomyosarcomatous tumors from other mimics with neuroendocrine differentiation such as small cell carcinoma. In contrast, small cell carcinoma components, whether it is pure or admixed with urothelial carcinoma, were positive for cytokeratin and largely positive for chromogranin, and negative for myogenin. FISH analysis was performed on paraffin-embedded formalin-fixed tissue in three cases of rhabdomyosarcomatous tumor of the bladder tumors to detect rearrangement of the FKHR (13q14) region which is hallmark of alveolar rhabdomyosarcoma. No FKHR rearrangement was detected in any of these three cases. The negativity for such arrangements does not support the diagnosis of alveolar type of rhabdomyosarcoma. Primary de novo rhabdomyosarcoma of any type is very rare in adult bladder. In this setting, only alveolar rhabdomyosarcoma can be reliably diagnosed by molecular test for PAX3 or 7-FKHR translocation. If the tumor is negative for PAX3 or 7-FKHR translocation and lack of morphologic pleomorphism, most of rhabdomyosarcomatous tumors arising from adult bladder are likely of rhabdomyosarcomatous carcinoma, a form of sarcomatoid carcinoma. Embryonal rhabdomyosarcomas can arise in bladder wall in pediatric patient but are extremely rare in adult patient. Clear morphologic differential separation of de novo embryonal rhabdomyosarcoma from those rhabdomyosarcomatous carcinomas would be a challenge and depend upon one's will to search for evidence of carcinoma in specimen. Unless a molecular test reveals evidence of alveolar rhabdomyosarcoma, tumors with extensive rhabdomyosarcomatous differentiation of the adult bladder should be either classified as rhabdomyosarcomatous sarcomatoid carcinoma when epithelial differentiation is identified or rhabdomyosarcomatous tumor of the bladder when no epithelial differentiation can be detected after reasonable effort to search such evidence in a caveat that there is no standard for what is considered reasonable effort in evaluating such specimen. Such diagnostic approach acknowledges the difficulty in making morphologic differentiation between rare occurring de novo soft tissue rhabdomyosarcoma and rhabdomyosarcomatous sarcomatoid carcinoma in adult patients.
In summary, pure RMS is very rare in adult urinary bladder while rhabdomyosarcomatous sarcomatoid carcinoma is more common. Adequate sampling, search for admixed in-situ or invasive urothelial carcinoma and use of cytokeratin stain may help to reach a correct diagnosis. A descriptive diagnosis of rhabdomyosarcomatous tumor of the bladder is preferred in difficult cases. Rhabdomyosarcoma and rhabdomyosarcomatous sarcomatoid carcinoma can be differentiated from small cell carcinoma of the bladder by immunohistochemical evaluation of cytokeratin and chromogranin and myogenin.