Clear cell adenocarcinoma of the lower urinary tract in association with nephrogenic adenoma, adenocarcinoma in situ, intestinal metaplasia and lymph node involvement by endosalpingiosis.
Clear cell adenocarcinoma (CCA) is a rare distinct variant of lower urinary tract carcinoma. The presenting symptoms are not specific but include typically recurrent urinary infections, dysuria, hematuria and urinary retention. The current recommended treatment is surgical excision .
Histologically, CCAs may be papillary, polypoid, or occasionally sessile solitary tumors. Reported sizes range from 0.7 cm  to 7 cm . The most frequent pattern of growth is tubulocystic, followed by papillary and solid. Hobnail configuration is frequently noted. The hallmark of the neoplastic cells is glycogen-rich clear cytoplasm with enlarged, hyperchromatic nuclei, irregular nuclear contours and coarse chromatin. Mitotic activity is frequent (2-17 per 10 high power field) .The tumor cells are positive for CK7, p53, P504S , CA125, PAX8, PAX2  with variable CK20 and CD10 staining. They are negative for ER, PR and PSA . CCA has uncertain histogenesis and the prevailing theories propose mullerian derivation , mesonephric derivation  and glandular differentiation of urothelial carcinoma [4, 5].
The main differential diagnosis of CCA includes metastatic clear cell carcinoma, mainly of renal or gynecologic origin, primary urothelial carcinoma (UCA) with clear cell features, carcinoma arising from pre-existing endometriosis and nephrogenic adenoma, mainly in small biopsy specimens.
In our case, the presence of the carcinoma in situ on the exenteration specimen and negative metastasis workup indicates that the tumor is a bladder primary rather than a metastasis. UCA with clear cell changes may resemble CCAs  with immunoreactivity for CK7, CK20 and CEA ; however, UCA lacks the typical architectural pattern of CCAs. UCA shows nuclear immunoreactivity for p63 and is negative for P504S. Of note, NA and CCA can be differentiated based on useful clinical and histological clues. NAs are usually incidental findings, superficial and small while CCAs infiltrate deep into the stroma and are associated with mass effect. Predominance of clear cytoplasm, severe cytologic atypia , frequent mitoses, and strong immunoreactivity for p53 and MIB-1 are characteristic for CCA . The possibility of malignant transformation from endometriosis was considered on the TURB specimen in this patient with a reported history of TAHBSO for likely benign disease. However; the absence of endometrial proliferation in the bladder on the exenteration specimen argues against it. Furthermore the atypical but ciliated glandular structures identified within multiple lymph nodes have morphologic and immunophenotypic features that are compatible with endosalpingiosis rather than indicative of metastasis or endometriosis. Finally, the background glandular structures with goblet cells in the urinary bladder are not malignant; they are immunophenotypically compatible with intestinal metaplasia which includes immunoreactivity with CK20 and CDX2 and a lack of PAX8 expression. In conclusion, the overall morphologic and immunophenotypic results show a clear cell adenocarcinoma involving the urinary bladder and arising in association with a nephrogenic adenoma. The lymph nodes show endosalpingiosis and are not involved by carcinoma.
Contributed by Lama Farchoukh, MD, Amin Milon, MD and Dr. Anil Parwani, MD, PhD