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Squamous differentiation (SD) and morular metaplasia (MM) are frequently present in uterine endometrioid adenocarcinoma (EAC) and can mimic areas of solid tumor. We used immunohistochemical stains to further characterize these lesions, and to determine which markers would help to distinguish these metaplasias from areas of solid growth in EAC. The pathology database was searched for diagnoses of EAC from 1997 to 2007, the hematoxylin and eosin-stained slides were reviewed, and 143 cases with SD, MM, or both (SD+MM) were identified. A panel of immunohistochemical stains was performed. In particular, we were interested in PAX2 and PAX8, recently studied markers of Müllerian tissue as potential markers for differentiation of metaplasias and tumor. In addition, estrogen receptor and progesterone receptor, and Her-2/neu, were examined to determine whether there was a differential expression between the metaplasias and solid tumor that may be diagnostically useful. In addition, to further characterize MM and SD, bcl-2 as a marker of cell regulation and inhibition of apoptosis, p16 as a surrogate marker for human papillomavirus, and p63 as a marker of mature SD were studied. Adjacent normal endometrium (NEM), when present, and 20 EAC cases (FIGO Grades 1–3) without SD or MM served as controls. PAX2 was positive in NEM (58/61, 95%) and was lost in SD (15/136, 11%), MM (1/25, 4%), and EAC (57/163, 35%), whereas PAX8 was positive in all NEM (61/61, 100%) and in the majority of SD (125/136, 92%), MM (19/25, 73%), and EAC (162/163, 99%). The estrogen receptor and the progesterone receptor were expressed by the majority of EAC (148/163, 91% and 144/163, 88%, respectively), whereas both were markedly diminished in SD (56/136, 41% and 58/136, 43%) and MM (4/25, 16% and 2/25, 8%). Approximately half of the MM was positive for bcl-2 (12/25, 48%), making it an unreliable marker. Her-2/neu was negative in all cases (0%). p16 was patchy in SD (111/136, 82%), MM (22/25, 88%), and EAC (154/163, 94%), whereas p63 was predominantly positive only in SD (96/136, 71%). Estrogen receptor and progesterone receptor, PAX2, and PAX8 were helpful in differentiating MM from SD, EAC, or NEM (P<0.05). In addition, p63 distinguished between SD and MM, supporting the theory that morules do not show characteristic mature SD.