2021-10/ March 8
Contributor: Leili Mirsadraei

A woman in her 80s presented with gross hematuria. She was found to have a large palpable and non-mobile abdominal mass. Cystoscopy revealed a 5.5 cm hemorrhagic tumor in the right bladder dome. A transurethral biopsy was performed and based on the histologic diagnosis; the patient subsequently underwent radical cystectomy.


1. What is the correct diagnosis?

a. Invasive high grade urothelial carcinoma, NOS

b. Invasive urothelial carcinoma, micropapillary variant

c. Clear cell adenocarcinoma, Mullerian type

d. Uterine papillary serous carcinoma secondarily involving urinary bladder

1. Clear cell adenocarcinoma, Mullerian type

The tumor shows a predominantly tubulopapillary architecture, with the tubules and papillae lined by cuboidal cells with pleomorohic nuclei and prominent nucleoli. Occasionally tumor cells show prominent hobnail morphology. Solid sheets of tumor cells with clear cytoplasm are focally present. Mitotic figures are readily identifiable. The background bladder is notable for endometriosis. Immunohistochemical staining showed expression of PAX8, CK7, NapsinA, HNF1beta, wild-type p53 and high proliferation index by Ki67 in the neoplastic cells, while p63, CK20, GATA3, ER, and PR were negative. Based on the morphology and immunophenotype, the tumor was classified as Clear cell adenocarcinoma, Mullerian type, in a background of endometriosis.

The main differential diagnosis is nephrogenic adenoma, and especially on a limited biopsy material, it can be difficult to differentiate the two entities. In addition, there is a subset of clear cell adenocarcinomas, which can have relatively bland cytology closely mimicking nephrogenic adenoma. In contrast to clear cell adenocarcinomas, nephrogenic adenomas typically do not have solid areas and clear cytoplasm, and although they may focally have hobnail cells with degenerative atypia, they lack the diffuse nuclear pleomorphism, hyperchromasia, and high mitotic activity seen in clear cell adenocarcinoma. Nephrogenic adenomas are relatively small, often just a few millimeters in size; while clear cell adenocarcinomas are typically large and obviously malignant masses. Both nephrogenic adenoma and clear cell adenocarcinoma express PAX-8 and PAX-2, however, Ki-67 immunohistochemistry may be of assistance as it shows only 1-2% positivity in typical nephrogenic adenoma and 20-30% or higher in clear cell adenocarcinoma. Clear cell adenocarcinomas of the bladder are aggressive tumors with most patients dying of this disease.

1. Tong GX et al: Expression of PAX8 nephrogenic adenoma and clear cell adenocarcinoma the lower urinary tract: evidence of related histogenesis? Am J Surg Pathol. 32 (9): 1380-7, 2008.

2. Oliva E et al: Clear cell carcinoma of the urinary bladder: And report and comparison of for tumor is of mullerian origin benign probable urothelial origin with discussion of histogenesis nondiagnostic problems. Am J Surg Pathol. 26 (2): 190-7, 2002.

Leili Mirsadraei
NYU Langone Hospital- Long Island


bladder; Clear cell adenocarcinoma, Mullerian