*2.1. Nested and Large Nested Architecture*

Talbert and Young reported in 1989 three cases of a deceptively benign bladder carcinoma characterized by small packed cellular aggregates closely resembling von Brunn nests and nephrogenic adenoma [5]. Isolated cases of this histological subtype of bladder cancer had previously appeared in the literature, always being referred to as of von Brunn nest origin [6]. Now, nested UC is well recognized and fully characterized by histological, immunohistochemical, and molecular perspectives [7,8]. Under the microscope, nested UC appears as a non-papillary neoplastic growth of bland cells with scarce atypia arranged in small nests (Figure 1a) showing an evident infiltrating growth pattern at different levels of the bladder wall. Typically, the tumor does not induce a stromal reaction nor

is accompanied by inflammatory infiltrates. Problems to recognize nested UC may arise in small superficial biopsies if crushing artifacts are present or if the infiltrative nature is not seen.

**Figure 1.** Architectural changes in bladder cancer (with original magnifications included). (**a**) Nested pattern (×100), (**b**) large nested pattern (×100), (**c**) micropapillary pattern (×250), (**d**) vascular invasion in the micropapillary pattern (×100), (**e**) myxoid basophilic stroma (×400), (**f**) small tubules (×100), (**g**) microcystic pattern (×100), (**h**) verrucous pattern (×40), and (**i**) lymphoepithelioma-like pattern (×250).

Cox and Epstein described in 2011 the large nested variant of UC reporting the characteristic histology of a tumor resembling large von Brunn nests with inverted growth in 23 patients [9]. Some isolated cases of this UC variant have been reported since then, and only two more series of cases have been published so far [10,11]. The large nested UC shares with the nested UC the same morphologic characteristics and clinical aggressiveness but the nests are larger (Figure 1b), with a growth pattern mimicking conventional inverted UC. These similarities have been advised to merge them into the same group in the last WHO classification of UC [12]. Interestingly, large nested UC displays a luminal phenotype, positive with FOXA1, GATA3, and CK 20 [12]. *FGFR3* and *TERT* genes are frequently mutated in this UC subtype [12].
