HMGA2 is commonly expressed in uterine serous carcinomas and is a useful adjunct to diagnosis

Abstract

Serous carcinoma is the prototype of type 2 uterine carcinoma. In many cases, establishing a diagnosis is straightforward, but problems can arise in that papillary variants of endometrioid carcinoma may be mistaken for serous carcinoma, and glandular variants of serous carcinoma may be misdiagnosed as endometrioid carcinoma. Markers such as p53, oestrogen receptor and p16 may be of use in problematic cases, but there is overlap and these may not therefore be of value in an individual case. It has been shown recently that high-mobility group AT-hook 2 (HMGA2) is expressed by most ovarian serous carcinomas, and our aim was to ascertain whether it is also expressed in uterine serous carcinoma and of value in its distinction from endometrioid carcinoma. Whole tissue sections of uterine serous (n = 33) and endometrioid (n = 38) carcinoma were immunostained using HMGA2 antibody. As many of the diagnostic problems relate to the distinction between serous carcinoma and grade 3 endometrioid carcinoma, tissue microarrays (TMAs) containing uterine serous (n = 71) and uterine grade 3 endometrioid (n = 68) carcinomas were also stained. Staining was classified as negative (totally negative or occasional nuclei positive), 1+ (<10% of nuclei positive), 2+ (10-49% of nuclei positive), 3+ (50-74% of nuclei positive), or 4+ (≥75% of nuclei positive). On the whole tissue sections, positive staining was also classified as weak, moderate, or strong, and an immunohistochemical composite score, taking into account both extent and intensity of staining, was calculated. On whole tissue sections, there was a statistically significant difference between HMGA2 staining in serous and endometrioid carcinomas with regard to both extent and composite score, with higher expression in serous carcinomas (P < 0.0001). Thirty of 33 (91%) serous carcinomas were positive, usually with diffuse (3+ or 4+) staining. All five cases of serous endometrial intraepithelial carcinoma (EIC) (the postulated precursor of uterine serous carcinoma) were positive, as were 14 of 38 (37%) endometrioid carcinomas, usually with 1+ or 2+ staining. There was a statistically significant difference in HMGA2 staining in the TMAs between the serous and grade 3 endometrioid carcinomas, with higher expression in the former (P < 0.0001). Immunoreactivity for HMGA2 is diffusely positive in whole tissue sections in most uterine serous carcinomas and negative in most endometrioid carcinomas, although, as with other markers, there is overlap in individual cases. In conjunction with other markers, HMGA2 may be of value in problematic uterine carcinomas where the differential diagnosis includes serous and endometrioid carcinoma. As HMGA2 is expressed in serous EIC, this suggests that it may be implicated in the early development of uterine serous carcinoma.