Clear cell carcinoma of the lower urinary tract in a male patient. Presentation and update on histogenesis and management

To the Editor: Clear cell carcinoma (CCC) of the lower urinary tract is a rare condition, especially in men. Only 11 cases have been reported worldwide since then. The differential diagnosis of the disease is problematic for the pathologist. We encountered such a case of invasive CCC of the bladder in a middleaged man with lymph node metastasis, in which clinical information and immunohistochemistry provided significant assistance. Differential diagnosis of CCC includes (i) vesical adenocarcinoma of Müllerian origin; (ii) tubular cystic clear cell adenocarcinoma of the prostate or the seminal vesicles, probably of Müllerian origin; (iii) small papillary urothelial carcinoma of the bladder; (iv) clear cell adenocarcinoma of the urethra; (v) hepatic adenocarcinoma of the bladder with clear cell pattern; (vi) metastatic CCC, such as renal cell carcinoma with coexistence of urothelial carcinoma; and (vii) nephrogenic adenoma, a benign process that may cause a significant diagnostic confusion. In the present case the nephrogenic adenoma was excluded due to the large size of the lesion and the absence of some form of mucosal irritation such as infection, urinary calculi, immunosuppressive treatment, genitourinary trauma or genitourinary tract procedures. Cells were cuboid or flat, in contrast to the CCC, occasionally with a mild to moderate nuclear atypia and a rare mitotic figure. The possibility of a metastatic renal CCC was also ruled out because no renal involvement was evident (Fig. 1). The tumor was identified as a high-grade CCC (Fig. 2), which fully infiltrated the bladder wall, extending into the perivesical fat, the prostate, the spermatic vesicles and four of the resected pelvic lymph nodes. Focal areas with typical characters of high-grade urothelial carcinoma were present. The clear cell element of the malignancy was characterized by a solid, pseudopapillae pattern without a clear vascular axis. The tumor cells were medium sized with an almost spherical and open colored nucleus, clearly visible nucleolus and abundant clear cytoplasm. The tumor infiltrated a great number of blood and lymphatic vessels. No signs of endometriosis or Müllerian duct remnants were recognized. Furthermore, no typical glandular configuration was observed in the outer layer of cells, which had a characteristic hobnail nuclear pattern. The immunohistological phenotype of the CCC is focally or diffusely positive for CA125, which is not a specific marker for this tumor. Moreover, the tumor is positive for cytokeratin 7 (CK7), a keratin that is sensitive but not specific for the urothelial origin of the tumor. CK20 is present in adenocarcinomas and urothelial carcinomas, but is negative or weakly positive in CCC. Positive immunostaining for uroplakin III is also demonstrated in approximately 50% of cases. In the present patient’s mass, neoplastic cells were strongly positively stained for CK7, CK20 (Fig. 3), p53, PAS, weakly positive for CA125, and negative for prostate-specific antigen, CD10, AFP, and hepatocyte, while Ki 67 was highly expressed. The histological origin of these tumors is uncertain, but interesting. A theory of a Müllerian origin was initially proposed. In men the prostatic utricle is considered to be a remnant of the Müllerian duct, while there is also the possibility of remnant elements in the bladder or the urethra. Another theory describes a glandular differentiation of the urothelial carcinoma. A third hypothesis is that CCC are probably adenocarcinomas of non-Müllerian origin, which have a clear cell pattern for unknown reasons. Very recently, compelling evidence was reported for a urothelial origin of CCC of the lower urinary tract, in which urothelial and CCC share common chromosomal mutations. CCC seems to be a particularly aggressive tumor and radical surgery with adjuvant chemotherapy is considered to be the treatment of choice. In contrast, the accumulated experience confirms that despite high stage at diagnosis, a favorable prognosis is maintained regardless of length of follow up. Figure 1 CT of the bladder. Pathology International 2009; 59: 595–597 doi:10.1111/j.1440-1827.2009.02413.x