*3.8. Giant Cells*

Giant cells are rarely observed in UC and only single case reports and a few short series have been published so far [72–74]. Two morphological variants have been described: osteoclast-like and giant pleomorphic cells, both of them associated with high-grade neoplasms. For practical purposes, these cells must be distinguished from trophoblastic and syncytiotrophoblastic cells appearing in some UC (see above). The presence of these giant cells in UC may be focal in the context of a high-grade UC or diffuse across the tumor, making difficult the correct diagnosis. A dedifferentiated sarcomatoid UC (see below) diagnosis can be considered in some of these cases.

Pleomorphic giant cell carcinoma have been described in many sites of the body and is a tumor subtype with dismal prognosis everywhere. Giant cell tumor areas in UC show a diffuse growth of cells with extreme pleomorphism and high mitotic count (Figure 2f). Cytoplasmic vacuolization and emperipolesis can be detected. Unusually, these tumors are at advanced stages at diagnosis, with deep infiltration in the bladder wall and frequent lymphatic dissemination [72]. Fifty percent of the patients reported in the series of Samaratunga et al. died of disease within the first year of follow-up [73]. By immunohistochemistry, the co-expression of CK7/20 and GATA3 positivity are retained in these tumors.

Osteoclast-like giant cells can be rarely observed in tumors originating in many sites of the body. In the bladder, they appear very occasionally in the context of high-grade UC. Contrary to the observed in pleomorphic giant cells, osteoclastic-like giant cells devoid of atypia and mitosis and show a reactive, non-neoplastic appearance. Whether these cells are truly neoplastic or reactive in the context of the tumor is a classical controversy that has been recently elucidated [74]. In this study, osteoclast-like giant cells are negative for GATA3, thrombomodulin, uroplakin II, and cytokeratin AE1/AE3, thus confirming their non-epithelial differentiation [74].
