*2.2. Micropapillary Architecture*

UC may sometimes display a micropapillary architecture. Delicate, thin, and fragile papillae without stromal axis are the hallmark of this morphological variant of UC (Figure 1c). To note, the invasive component of micropapillary UC shows nests with cells detached from the basal membrane, a typical artifact in this tumor that mimics lymphatic invasion and is associated with biological aggressiveness [13]. The vascular invasion is a very frequent histological finding (Figure 1d). Aside from rare pure examples, the majority of cases are mixed with a conventional transitional

cell carcinoma, usually high grade. Like the rest of micropapillary carcinomas across the body [14], this histological subtype of UC has a dismal prognosis, even worse than conventional high-grade UC at the same stage [15], and typically presents with advanced stages at diagnosis. Although exceptional, micropapillary carcinomas from other sites may metastasize to the urinary bladder [16], making the correct diagnosis more difficult.

The first description of this variant of UC was made in 1994 by Amin et al. [17], where they stressed the histological similarities of this bladder tumor with the classic papillary serous carcinoma of the ovary. After that, many series have been published all along the urinary tract, including the renal pelvis and ureter [18,19].

Abundant immunohistochemical and molecular analyses have been performed in micropapillary UC [20–22] all confirming its aggressive potential. Although initially thought to be a variant of adenocarcinoma by some authors [23], Yang et al. have very recently reported that the micropapillary UC is not a variant of adenocarcinoma [22].

#### *2.3. Myxoid Stromal Change*

UC may display focal myxoid changes in the stroma (Figure 1e) mimicking the colloid adenocarcinomas seen in other sites. This change has been previously reported [24,25] and when observed in transurethral resection specimens, may lead to an erroneous interpretation of colonic adenocarcinoma invading the bladder wall. Solid cell nests immersed in a basophilic edematous stroma are the hallmark of this histological change, which is usually focal but can be generalized in some isolated cases. Again, immunohistochemistry is of much help in cases in which the transitional phenotype of the tumor is not evident on hematoxylin-eosin slides. GATA3 positivity, co-expression of CK7 and CK20, and CDX-2 negativity should resolve the diagnostic dilemma in doubtful cases [24]. Attention must be paid, however, to the occasional CK7 positivity of some colorectal adenocarcinomas, a finding that is a sign of dismal prognosis [26].
