Does endometrial morular metaplasia represent odontogenic differentiation?

The nature of endometrial morular metaplasia (MorM) is still unknown. The nuclear ß-catenin accumulation and the not rare ghost cell keratinization suggest a similarity with hard keratin-producing odontogenic and hair matrix tumors rather than with squamous differentiation. We aimed to compare MorM to hard keratin-producing tumors. Forty-one hard keratin-producing tumors, including 26 hair matrix tumors (20 pilomatrixomas and 6 pilomatrix carcinomas) and 15 odontogenic tumors (adamantinomatous craniopharyngiomas), were compared to 15 endometrioid carcinomas with MorM with or without squamous/keratinizing features. Immunohistochemistry for ß-catenin, CD10, CDX2, ki67, p63, CK5/6, CK7, CK8/18, CK19, and pan-hard keratin was performed; 10 cases of endometrioid carcinomas with conventional squamous differentiation were used as controls. In adamantinomatous craniopharyngiomas, the ß-catenin-accumulating cell clusters (whorl-like structures) were morphologically similar to MorM (round syncytial aggregates of bland cells with round-to-spindled nuclei and profuse cytoplasm), with overlapping squamous/keratinizing features (clear cells with prominent membrane, rounded squamous formations, ghost cells). Both MorM and whorl-like structures consistently showed positivity for CD10 and CDX2, with low ki67; cytokeratins pattern was also overlapping, although more variable. Hard keratin was focally/multifocally positive in 8 MorM cases and focally in one conventional squamous differentiation case. Hair matrix tumors showed no morphological or immunophenotypical overlap with MorM. MorM shows wide morphological and immunophenotypical overlap with the whorl-like structures of adamantinomatous craniopharyngiomas, which are analogous to enamel knots of tooth development. This suggests that MorM might be an aberrant mimic of odontogenic differentiation.

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 ß-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 ß-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 ß-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.

Impact of endometrial carcinoma histotype on the prognostic value of the TCGA molecular subgroups.

BACKGROUND: The Cancer Genome Atlas (TCGA) identified four prognostic subgroups of endometrial carcinoma: copy-number-low/p53-wild-type (p53wt), POLE-mutated/ultramutated (POLEmt), microsatellite-instability/hypermutated (MSI), and copy-number-high/p53-mutated (p53mt). However, it is still unclear if they may be integrated with the current histopathological prognostic factors, such as histotype. OBJECTIVE: To assess the impact of histotype on the prognostic value of the TCGA molecular subgroups of endometrial carcinoma. METHODS: A systematic review and meta-analysis was performed by searching 7 electronic databases from their inception to April 2019 for studies assessing prognosis in all TCGA subgroups of endometrial carcinoma. Pooled hazard ratio (HR) for overall survival (OS) was calculated in two different groups ("all-histotypes" and "endometrioid"), using p53wt subgroup as reference standard; HR for non-endometrioid histotypes was calculated indirectly. Disease-specific survival and progression-free survival were assessed as additional analyses. RESULTS: Six studies with 2818 patients were included. In the p53mt subgroup, pooled HRs for OS were 4.322 (all-histotypes), 2.505 (endometrioid), and 4.937 (non-endometrioid). In the MSI subgroup, pooled HRs were 1.965 (all-histotypes), 1.287 (endometrioid), and 6.361 (non-endometrioid). In the POLEmt subgroup, pooled HRs were 0.763 (all-histotypes), 0.481 (endometrioid), and 2.634 (non-endometrioid). Results of additional analyses were consistent for all subgroups except for non-endometrioid POLEmt carcinomas. CONCLUSION: Histotype of endometrial carcinoma shows a crucial prognostic value independently of the TCGA molecular subgroup, with non-endometrioid carcinomas having a worse prognosis in each TCGA subgroup. Histotype should be integrated with molecular characterization for the risk stratification of patients in the future.