https://doi.org/10.1177/1066896917731862 International Journal of Surgical Pathology 1–9 © The Author(s) 2017 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896917731862 journals.sagepub.com/home/ijs Original Article Introduction The diagnostic reproducibility associated with the histo- typing of high-grade endometrial carcinomas is no more than moderate, 1,2 and the occurrence of clear cells in his- totypes other than clear-cell carcinoma (CCC) is likely to be one of the contributing factors to the phenomenon. 1,3,4 Endometrial serous carcinoma (ESC) represents approxi- mately 10% of endometrial carcinomas, 5 whereas CCCs are much more uncommon. 6 Although both are consid- ered to be high-risk histotypes, 7,8 it is recommended that they be distinguished whenever possible because there may be differences between them regarding patterns of tumor spread, prognosis, risk of subsequent malignancy, and the most optimal therapeutic approach. 7-11 For exam- ple, investigators from the Canadian high-risk endome- trial cancer consortium reported that adjuvant radiation was associated with improved overall survival for CCC, whereas adjuvant chemotherapy was associated with improved overall survival for ESC. 8 Additionally, there is evolving evidence, albeit not entirely congruent, that patients with CCC have a higher risk of thromboembolic events than their counterparts with other high-risk histo- types of endometrial carcinoma. 12-14 It is well recognized that a subset of high-grade endometrial carcinoma cannot be readily assigned a histotype. 15,16 However, cognizance of the full pathologi- cal spectrum for the established histotypes should mini- mize the erroneous classification as ambiguous those tumors that show variant morphology in one of those 731862IJS XX X 10.1177/1066896917731862International Journal of Surgical PathologyHariri et al research-article 2017 1 University of California San Diego, San Diego, CA, USA 2 University of Alabama, Birmingham, AL, USA Corresponding Author: Oluwole Fadare, Anatomic Pathology, UC San Diego Health, 9300 Campus Point Drive, Suite 1-200, MC 7723, La Jolla, CA 92037, USA. Email: oluwole.fadare@gmail.com Endometrial Serous Carcinoma With Clear-Cell Change: Frequency and Immunohistochemical Analysis Nosaibah Hariri, MBBS 1 , Morad Qarmali, MBBS 1,2 , and Oluwole Fadare, MD 1 Abstract The diagnostic distinction between endometrial serous carcinoma (ESC) and endometrial clear-cell carcinoma (CCC) may occasionally be problematic, and one potentially contributing factor is the finding of clear cells in otherwise classic cases of ESC. This study aimed to define the frequency of this finding and comparatively assessed the immunophenotype of the clear cells. A review of 56 cases of ESC identified 8 (14.28%) with clear cells, representing 1% to 20% (median 7.5) of tumoral volume in these cases. In only 3 cases were clear cells discernible at low (×20) magnification. There was no significant difference in stage distribution or age between ESC patients with and without clear cells. The immunophenotypes of ESC-associated clear cells (group 1) were compared with foci of conventional ESC on another tissue block within the same case (group 2; n = 8) as well as a randomly selected cohort of CCC cases (group 3; n = 8). Groups 1 and 2 showed no significant differences regarding p53, ER, PR, Napsin-A, p504S, and hepatocyte nuclear factor 1β (HNF1β) expression, or regarding mitotic indices or Ki67 proliferation rate. In contrast, group 1 cases showed an immunophenotypic profile that was notably different from that of group 3 cases, with the former showing statistically significantly higher/more frequent expression of ER, PR, Ki67, and p53 and lower/less frequent expression of Napsin-A, p504S, and HNF1β. We conclude that clear-cell change is seen in 14% of ESCs and is discernible at low magnification in only 5%; these areas show an immunophenotype that is essentially identical to the associated background conventional ESC and are phenotypically dissimilar to CCC. Keywords uterine serous carcinoma, endometrial serous carcinoma, clear-cell carcinoma, clear cells, uterine papillary serous carcinoma