Clear Cell Carcinoma of Bladder Esther Oliva MD Massachusetts General Hospital Boston, MA, U.S.A.

Clinical History: A 78 year-old woman presented with hematuria of 2 months duration. A cystoscopic exam revealed a large polypoid broad based lesion located at the trigone growing up into the bladder. Vaginal examination was unremarkable. The patient underwent a transurethral resection of the mass. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis : Clear cell carcinoma of the bladder Pathological Findings and Discussion: Clear cell carcinoma (CCC) is a rare tumor of the bladder characterized by a microscopic appearance similar to that of a CCC of mullerian origin seen in the female genital tract. In the past these tumors were designated as mesonephric carcinomas despite the lack of convincing evidence for a mesonephric origin. No etiologic factors have been associated with bladder CCCs to date. Whether such neoplasms arise from mullerian elements in the bladder and are histogenetically identical to the female genital tract cancer; or represent a peculiar variant of vesical adenocarcinoma of non-mullerian derivation, or may denote a peculiar morphologic expression of transitional cell (urothelial) carcinoma with gland differentiation is often uncertain. Clinical Features Patients are typically females that range in age from 22 to 83 (mean 57 years), commonly presenting with hematuria and/or dysuria or other clinical symptoms. The tumors often form a visible mass. One case has been reported in association with a diverticulum, an association much more commonly seen in the urethra. Gross Features Although the gross appearance is non-specific, frequently they grow as polypoid to papillary masses that range in size from 1 to 8 cm, and more often involve the trigone, posterior or lateral walls of the bladder. Sometimes gross invasion into the bladder wall may be seen. Microscopic Features Architecture: CCCs have a characteristic morphology, showing one or more of the three typical patterns of CCC of the female genital tract, namely tubulo-cystic, complex papillary and diffuse. The most common pattern is tubulo-cystic, which is seen in most neoplasms, and typically predominates. The tubules range in size and may contain either basophilic or eosinophilic secretion or both, but rarely the tubules may be solid. The papillae are generally small and rounded but often show complex architecture and their fibrovascular cores may be may be edematous or extensively hyalinized, the latter being a clue for the diagnosis of CCC. When present, the diffuse pattern is typically a minor component in most tumors. Cells: The tumor cells lining the tubules, cysts and papillae range from flat to cuboidal to columnar and they may have either clear or eosinophilic cytoplasm and not infrequently an admixture of thereof. Hobnail cells are frequently seen but they are only rarely conspicuous. In the diffuse areas the cells tend to be round to polygonal and have abundant cytoplasm.Nuclear pleomorphism is typically moderate to severe but exceptions may occur. For example, in one of the13 cases reported by Oliva and colleagues the papillary areas of the tumor focally had very bland cytology and were reminiscent of nephrogenic adenoma. There is associated brisk mitotic activity and necrosis is frequently seen. Associated findings: As it is seen in CCC of the female genital tract, the inflammatory infiltrate associated with bladder CCC is most often composed of plasma cells. In some cases, CCCs may be associated with endometriosis or transitional cell carcinoma or even rarely with adenocarcinoma, NOS. Histochemical And Immunohistochemical Profile CCC of the bladder has abundant intracytoplasmic glycogen which is positive for PAS but negative for mucin stain. This tumor is typically positive for CK7. It is also positive for CK20, CEA, CA125, LeuM-1 and negative for prostate specific antigen, prostate-specific acid phosphatase, estrogen and progesterone receptors. These tumors show high MIB-1 and Ki-67 activity, and are positive for p53. Differential Diagnosis Nephrogenic adenoma (NA) is a benign reactive process related to some type of urothelial injury that most often causes problems with CCC especially in biopsy specimens. In contrast to CCC, NA has a male predilection and it is usually a small lesion but rarely may simulate a malignant neoplasm grossly. Histologically it is most commonly composed of small hollow tubules that are accompanied frequently by cysts and papillae and uncommonly by a diffuse growth of cells. Most frequently the cells lining the tubules are flat or cuboidal, clear cells being present in 15 and 35% of the cases in two studies, however, they were conspicuous in only two cases in one series. In the same studies hobnail cells were seen in 53 and 70 % of the cases but were numerous in only 5 cases in one study. Prominent nucleoli was seen in 20% of NAs in one series and mild to moderate nuclear atypia has been noted in several series including all cases in a recent study of 18 NAs conducted by Cheng and colleagues characterized also by the presence of nuclear enlargement and hyperchromasia. The cytologic atypia, nonetheless, falls well short of that shown by CCCs and mitotic activity is £1/10 high power fields. There is no established distinguishing immunohistochemical profile between NA and CCC. As expected, NA has low MIB-1 activity and is negative for p53 in contrast to CCC. PAX 2, a promising recently described antibody that shows nuclear staining in all NA, has not been yet studied in CCCs. A particular clinical scenario that merits discussion is that both NA and CCC have a propensity to arise within urethral (and rarely bladder) diverticula. It is helpful to keep in mind that NA involving a diverticulum typically occupies a relatively superficial portion of the diverticular wall with a well-demarcated margin in contrast to the irregular, infiltrative margin of CCC. It has been postulated by some investigators that NA may be a precursor lesion of CCC; however, this theory has never been proven conclusively. Because of the issue of sampling the differential diagnosis of NA and CCC is occasionally very difficult despite the above considerations. A benign diagnosis of nephrogenic adenoma should be made with caution if any degree of cytologic atypia or mitotic activity is present, particularly in the absence of a history of genitourinary surgery or trauma. Immunohistochemical stains are not helpful in this differential diagnosis which should be based on morphologic features. Transitional cell carcinoma of the bladder with clear cells These tumors are characterized by the presence of abundant clear cytoplasm secondary to glycogen deposits. This may be a focal finding but in some instances it is quite extensive. The pattern may be seen in carcinoma in situ, but it is relatively more common in high-grade urothelial carcinomas. However, this morphology is frequently seen in association with typical areas of transitional cell neoplasia. Clear cell renal carcinoma may rarely metastasize to the bladder but it is extremely rare that this is the only metastatic site. Approximately 20 cases have been reported in the literature and in three cases the tumors were synchronous. Histologically, renal CCC is characterized most frequently by a compact alveolar growth of tumor cells, although it may show tubules and cysts, the latter frequently containing blood or eosinophilic secretion. Hobnail cells are not a feature of renal CCC while the finding of very delicate blood vessels surrounding the nests of tumor cells is a very characteristic feature of renal CCC. This vasculature is not a feature of primary CCC of the bladder. In difficult cases immunohistochemistry may be helpful. In contrast to CCC of the bladder, renal CCC is always negative for CK7 and CK20; it is also negative for CEA but positive for CAM5.2 and vimentin. Metastatic clear cell cervical or vaginal CCC: In one study Vang and colleagues studied the immunohistochemical profile of 17 CCCs arising in the gynecologic tract (vagina (1), uterus (5) and ovary (11)) and included 2 CCCs arising in the urologic tract (bladder (1) and urethra (1)). All tumors showed a similar immunohistochemical profile, being positive for CK7, Cam 5.2, 34 bE12, CEA, Leu-M1, CA-125, and p53, showing variable positivity for vimentin, HER-2/neu and being negative for ER and PR. Thus, neither immunohistochemistry nor morphology are helpful in identifying the origin of the tumor and one should rely on the clinical history, as well as the clinical and gross findings. Clear cell carcinoma of the prostate secondarily involving the bladder. Only one CCC of the prostate has been reported in the literature with morphologic features of CCC of the bladder. In a male, secondary bladder involvement by such a tumor, or a CCC primary in a mullerian duct cyst in the seminal vesicle or prostatic utricle as described recently by Gualco and colleagues would potentially be in the differential diagnosis of primary CCC of the bladder especially if only a biopsy is available for microscopic examination but clinical findings should resolve the problem. Finally, one case of renal-type CCC occurring in the prostate has been recently reported. A 73-year-old patient presented with hematuria and underwent a transurethral resection which disclosed a CCC similar to that seen in the kidney. The tumor cells were positive for vimentin, EMA, low-molecular weight keratin and CD10 and negative for PSAP, CK7, CK20 and CA-125. Subsequently the patient underwent a cystoprostatectomy which revealed a conventional prostate carcinoma, Gleason score 3+3. Other tumors that may contain clear cells and involve the bladder include clear cell melanoma and clear cell myelomelanocytic tumor, however, these tumors typically display a solid or solid and spindle growths, they lack the other characteristic patterns of CCC and they are positive for HMB-45. Histogenesis In the past bladder CCCs were thought to be of mesonephric origin, and they used to be designated as mesonephric adenocarcinomas despite lacking of convincing evidence for a mesonephric origin. As these tumors occur more frequently in women, they are histologically very similar to CCCs of the female genital tract, and they are occasionally associated with benign mullerian epithelium, a mullerian origin is postulated for some of them. However, a different histogenetic explanation should be possible as most bladder CCCs have not been associated with endometriosis, and CCC of the urethra has no such association. It is likely that many bladder CCCs originate from peculiar glandular differentiation in transitional cell neoplasms as they have been diagnosed in patients with a previous history of transitional cell carcinoma, and their immunohistochemical profile overlaps with that of transitional cell carcinoma. The final possible explanation is that CCCs are adenocarcinomas of non-mullerian type that for unknown reasons have a CCC morphology. The fact that adenocarcinoma of the bladder in general is more common in females would support this and this explains CCCs of other non-genital sites. Genetics A very recent study conducted by Hartmann and colleagues found loss of heterozygosity at p53Alu, D9S303, and D9S304 in one CCC. Comparative genomic hybridization analysis found losses at chromosomes 9 and 17 in the CCC that matched the changes seen in the LOH analysis. Furthermore, the authors postulate that there is molecular evidence of progression from NA to CCC as they found similar changes in both lesions by comparative genomic hybridization analysis. Behavior Most patients with CCC of the bladder lack of adequate follow-up information which precludes therapeutic recommendations. However, most patients with CCC are treated by surgery with or without adjuvant therapy. As many of these tumors have an exophytic growth pattern, they may be diagnosed at an early stage and some of them may have a relative better prognosis. 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