Endometrial Tumors with “Shadow Cells” Intimate a Neoplastic Potential for Morules or Their Progenitors in β-Catenin Mutated Endometrial Adenocarcinomas.

Background : Several features are shared by endometrial morules and pilomatrixoma-like endometrial carcinomas including CDX-2 and β-catenin nuclear staining, absence of p63 and p40 nuclear staining, and a unique form of endepithelial differentiation that produces so-called shadow cells. Both endometrial morules and pilomatrixoma-like endometrial carcinomas may be associated with low-grade endometrioid adenocarcinoma. Methods : We present 11 fully staged endometrioid endometrial adenocarcinomas that showed extrauterine metastases (Stages III and IV), morules, shadow cell differentiation, and nuclear β-catenin positive immunohistochemical staining (both in morules and in adjacent malignant glandular cells). Results : All intrauterine adenocarcinomas had at least focal components of grade 1 endometrial adenocarcinoma and morules and showed nuclear β-catenin immunostaining in morules and in adjacent malignant glandular cells. 10 cases were stages III and IV endometrial cancers, and one, initially diagnosed as grade 1 stage II endometrioid endometrial adenocarcinoma, rapidly recurred in the retroperitoneum as a nuclear β-catenin positive pilomatrixoma-like tumor without an obvious glandular component. Two positive lymph node dissections showed metastatic adenocarcinoma with malignant glands, morules and shadow cells. Five cases showed at least focal components of morphologically divergent high-grade tumor with foci resembling malignant pilomatrixoma. Extrauterine “shadow cell granulomas” were detected in 8 cases. Conclusion : Metastatic nuclear β-catenin positive endometrial adenocarcinomas with morules can metastasize and show pilomatrixoma-like tumor foci. This highlights the ability of these cancers to evolve into “other-than-glandular” carcinomas. Furthermore, because of their shadow cell features, we speculate that endometrial morules are not simply inert “epitumoral” elements; but that either they or the population of progenitor cells from which they eventuate harbors an abnormal β-catenin gene that may endow endometrial adenocarcinomas with morules the capacity for progressive, divergent differentiation into a higher-grade matrix-producing tumor.