PAX2 distinguishes benign mesonephric and mullerian glandular lesions of the cervix from endocervical adenocarcinoma, including minimal deviation adenocarcinoma

Abstract

Mesonephric remnants of the cervix are vestiges of the embryonic mesonephric system which typically regresses during female development. Uncommonly, hyperplasia of the mesonephric remnants may occur. The differential diagnosis of exuberant mesonephric hyperplasia includes minimal deviation adenocarcinoma of the cervix, a tumor with deceptively bland morphology for which no reliable diagnostic biomarkers currently exist. PAX2 encodes a transcription factor necessary in the development of the Wolffian duct system, and the protein is expressed in several tumors of mesonephric origin, including renal cell carcinoma, Wilm tumor, and nephrogenic adenoma. We hypothesized that PAX2 may also be expressed in mesonephric lesions of the cervix and may distinguish mesonephric hyperplasia from minimal deviation adenocarcinoma of the cervix. We demonstrated that PAX2 was strongly and diffusely expressed in mesonephric remnants (6 of 6) and in mesonephric hyperplasia (18 of 18); however, no expression was noted in mesonephric adenocarcinoma (0 of 1). PAX2 was expressed in normal endocervical glands (including tunnel clusters and Nabothian cysts) (86 of 86), lobular endocervical glandular hyperplasia (5 of 5), tubal/tuboendometrioid metaplasia (8 of 8), and cervical endometriosis (13 of 14). In contrast, only 2 cases of endocervical adenocarcinoma were positive for PAX2 [invasive adenocarcinoma of the minimal deviation type (0 of 5), usual type (1 of 22), and endometrioid type (1 of 1)]. Adjacent adenocarcinoma in situ, as well as cases of pure adenocarcinoma in situ (0 of 6), were also PAX2 negative. PAX2 expression in the 2 positive endocervical adenocarcinomas was patchy and weak. Most (11 of 15) stage II endometrial endometrioid adenocarcinomas lacked PAX2 expression but 1 of 10 grade 1 tumors and 3 of 5 grade 2 tumors did express PAX2. These results suggest that PAX2 immunoreactivity may be useful to (1) distinguish mesonephric hyperplasia from minimal deviation adenocarcinoma, (2) to distinguish lobular endocervical glandular hyperplasia from minimal deviation adenocarcinoma, and (3) to distinguish endocervical tubal metaplasia or cervical endometriosis from endocervical adenocarcinoma in situ. Overall, a strong, diffuse nuclear PAX2 expression pattern in a cervical glandular proliferation predicts a benign diagnosis (positive predictive value 90%, negative predictive value 98%; P<0.001); however, PAX2 should not be interpreted in isolation from the architectural and cytologic features of the lesion as it may be expressed in some stage II endometrial adenocarcinomas involving the cervix.