Relationship between morular metaplasia and squamous differentiation in endometrial carcinoma

Morular metaplasia (MM) is a peculiar type of metaplastic change commonly observed in endometrial lesions, which is defined by the absence of overt squamous features and a characteristic immunophenotype. The nature of MM and its relationship with conventional squamous differentiation (SD) is still undefined. Here, we present a morphological and immunophenotypical study of cases with mixed MM/SD and conventional SD, providing new insights on this field. Twenty cases of endometrioid carcinoma (10 with mixed MM and SD and 10 with conventional SD) were assessed by immunohistochemistry for β-catenin, CD10, CDX2, ki67, p63, p40, estrogen receptor (ER), progesterone receptor (PR) and cytokeratins (CK) 5/6, 7, 8/18 and 19. In mixed MM/SD cases, SD was mostly located within the MM areas; several degrees of SD development were observed within MM, from cells with larger cytoplasm and prominent membrane, to overt SD with morular shape and ghost cell keratinization. In the MM→SD transition, there was progressive loss of nuclear β-catenin, CD10, CDX2 and CK8/18 expression, increase of CK5/6 and CK7 expression, and stable CK19 positivity. ER, PR and ki67/MIB1 expression was low-to-negative in both MM and SD. The squamous cell markers p63 and p40 were mostly expressed at the interfaces between MM and SD. Conventional SD cases showed direct transition from glandular epithelium to SD with a surface growth and no ghost cell keratinization; immunohistochemistry showed strong positivity for ER, PR and all CKs, basal positivity for p63, p40 and ki67/MIB1, negativity for nuclear β-catenin, CD10 and CDX2. In conclusion, MM appears as the precursor of a peculiar form of SD, which differs morphologically and immunophenotypically from conventional SD. Defining MM based on the absence of overt squamous might not be meaningful. Further studies are necessary to clarify the nature of MM.