Large nested variant of urothelial carcinoma: 23 cases mimicking von Brunn nests and inverted growth pattern of noninvasive papillary urothelial carcinoma.

We describe a rare pattern of urothelial carcinoma (UC) invasion consisting of large, irregular to regular nests, with bland cytology. We prospectively retrieved 23 cases of large nested UC from one of the author's consult files (2001 to 2010). The mean patient age was 63.7 years (39 to 89 y), and 86% were men. There were 18 cases with transurethral resection of the bladder, 2 nephroureterectomy specimens, and 3 radical cystectomy (RCs) specimens. A surface component was present in 19 of 23 cases, with 16 low-grade papillary UCs, 2 low-grade papillary UCs with <5% high-grade UC, and 1 high-grade papillary UC. Twenty of 23 cases invaded into the muscularis propria (MP), 2 into lamina propria with no MP present, and 1 into smooth muscle indeterminate between muscularis mucosae and MP. In 21 cases, the invasive component was composed of medium to large nests that varied from rounded circumscribed borders to a stromal-tumor interface with a more irregular ragged appearance. Two showed a verruciform, pushing border into the MP with the nests having central cyst formation. Cytologically, the nuclei lacked significant nuclear atypia, where at most occasional scattered slightly enlarged, hyperchromatic nuclei with small-indistinct nucleoli were noted. Four cases had focal necrosis and 3 cases had more extensive necrosis. The median mitotic count was 1.5 per 10 high-power fields. The stroma surrounding the large nests typically had a mild-to-moderate fibrous and/or inflammatory reaction; 4 cases exhibited no stromal reaction, whereas 2 cases had a moderate-to-marked stromal response. In 7 of 23 cases, conventional patterns of urothelial invasion were identified, 5 of which composed ≤5% of the neoplasm. One case had angiolymphatic invasion. Four cases had subsequent RC specimens available for review. Two of 4 RC specimens had no residual carcinoma (1 with neoadjuvant radiotherapy), 1 had large nested UC in MP, and 1 had mixed large nested UC and focal conventional UC invading through the MP into perivesicle tissue. Clinical follow-up was available for 17 of 23 patients [mean follow-up, 43 mo (5 mo to 9 y)]. Three of 17 patients developed metastatic disease (2 lung, 1 unknown) with 2 of these dead of disease; another patient was dead of disease with no known details. Of these 3 patients that died of disease, 2 had no and 1 had focal (<5%) conventional invasive UC on transurethral resection. These cases, which posed great diagnostic difficulty both for contributing pathologists and for the consultant, represent the first formal description of a large nested pattern of UC. This pattern is distinguished from an inverted growth pattern of noninvasive UC and from von Brunn nests by either MP invasion, irregularly infiltrating nests, or a stromal reaction. Despite the bland cytologic features of these neoplasms, they have well-documented metastatic potential.