Morphologic and other clinicopathologic features of endometrial clear cell carcinoma: a comprehensive analysis of 50 rigorously classified cases.

Clear cell carcinoma of the endometrium (CCC) is an uncommon histotype whose analyses have generally been hampered by its rarity and issues of interobserver diagnostic variability. In this study, we analyzed the clinicopathologic features of 50 CCCs that were assembled from multiple institutions and which we considered to be morphologically unambiguous after a rigorous review process for diagnostic accuracy. Forty-four (88%) of the 50 CCC cases showed an admixture of the classic architectural patterns (glandular, papillary, solid and cystic in decreasing order of prevalence). Mitotic indices were variable but were generally low: 60% of cases had a mitotic index of 3 or lower. The predominant cell type lining glands and papillae was invariably hobnail and/or cuboidal. Stratification of nuclei (greater than 3 cells) or columnar cells on glands and papillae were uncommon and never diffusely present. 82% of cases showed an admixture of polygonal cells with clear and eosinophilic cytoplasm; only clear cells were present in 4% and only eosinophilic cells were present in 10%. Hobnail cells were common, being identifiable in 86% of cases, and being diffuse in 60%. Only 2 cases had a predominance of nuclear grade 3 cells. Psammoma, hyaline and targetoid bodies were identified in 32%, 52% and 20% of cases respectively. Clear cell endometrial intraepithelial carcinoma was identified in 41.7% of cases with evaluable background endometrium. The 5-year progression free survival (PFS) for the entire cohort was 61%, and was 88%, 75%, 22% and 28.6% for stages I to IV respectively. On univariate analyses, age >65 years, advanced FIGO stage, and the presence of any lymph node metastases were associated with reduced PFS (p=0.02, 0.002, and 0.002 respectively). On multivariate analyses, the only variable associated with reduced PFS was age >65 years. The 5-year overall survival (OS) for the entire cohort was 78%, and was 94%, 87.5%, 66.7%, and 42.8% for stages I to IV respectively. On univariate analyses, the following factors were associated with reduced OS: age >65 years (p=0.04), advanced FIGO stage (p=0.003), distant metastases (p=0.003), myometrial invasion >30% (p=0.01), a mitotic index >4 (p=0.014), and a specific architectural pattern (at least 10% of the tumor composed of solid masses or individual infiltrating tumor cells, p=0.02). On multivariate analyses, only age >65 years and advanced stage were associated with reduced OS (p=0.023 and 0.022 respectively). In summary, endometrial CCC has a wide morphologic spectrum that is detailed and illustrated herein, but also has core cytoarchitectural features that are of high diagnostic utility. Morphologically unambiguous CCC apparently have patient outcomes that are more favorable than has previously been reported, indicating that ambiguous tumors should be classified separately. The existence of morphologically ambiguous clear-cell rich carcinomas that do not fit the conventional histotypic groupings, is a likely reflection of the biologic complexity of endometrial carcinomas in general; these cases should be reported descriptively, and studied separately from conventional CCC.