Clinicopathologic and Molecular Characteristics of Mesonephric Adenocarcinoma Arising From the Uterine Body

Abstract

Mesonephric adenocarcinoma (MNAC) is a rare tumor of the female genital tract mainly occurring in the uterine cervix. To date, only a few cases of MNAC arising from of the uterine body (UB-MNAC) have been reported. The clinicopathologic and molecular characteristics of UB-MNAC remain unknown. In this study, we investigated the clinical, histopathologic, immunohistochemical, and genetic features of UB-MNAC. In total, 11 cases were included. Six patients developed metastatic disease, most commonly in lungs (5/6). Histopathologically, UB-MNAC was characterized by an admixture of tubular, glandular, papillary, retiform, glomeruloid, sex cord-like, and comedonecrosis-like architectural patterns. Three adverse pathologic characteristics, including advanced International Federation of Gynecology and Obstetrics stage, high mitotic activity, and presence of lymphovascular the invasion, were independent factors predicting the development of metastasis. All cases were positive for GATA-binding protein 3 and paired box 2 expression and showed wild-type p53, patchy p16, and preserved PTEN expression, as indicated by immunohistochemistry. Next-generation sequencing using 12 samples (11 primary tumors and 1 metastatic tumor) revealed 42 single nucleotide variations in 16 genes, mostly in KRAS (10/12) and ARID1A (9/12). Copy number variation was found in 16 genomic regions, and consisted of 57 gains and 10 losses, with 1q gain (11/12) being the most prevalent. In conclusion, UB-MNAC displays an aggressive biological behavior, with a tendency to metastasize to the lungs. Adverse pathologic characteristics reflect the aggressive nature of UB-MNAC. Distinct molecular features of UB-MNAC include frequent somatic mutations of KRAS and ARID1A and gain of 1q.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Cytologic features of upper gynecologic tract adenocarcinomas exhibiting mesonephric‐like differentiation

“…Nuclear molding and hyaline globules were identified in 50% and 38% of cases, respectively. Although not all cases were subjected to a full panel of immunohistochemical stains, the tumors frequently were positive for PAX8 and GATA3; less often were found to express TTF‐1, CD10, and calretinin; and largely were negative for ER, PR, and WT1, as is typical of the immunoprofile of AMDs reported in the literature …”

“…Eosinophilic material frequently is encountered within tubular lumens. Nuclei tend to be uniform and hyperchromatic, with coarse to vesicular chromatin . These tumors frequently express cytokeratins (AE1/AE3, CAM 5.2, and CK7), epithelial membrane antigen, CD10, GATA3, PAX8, HMGA2, vimentin, calretinin, and CA 125, and are negative for hormone receptors and WT1 .…”

“…Nuclei tend to be uniform and hyperchromatic, with coarse to vesicular chromatin . These tumors frequently express cytokeratins (AE1/AE3, CAM 5.2, and CK7), epithelial membrane antigen, CD10, GATA3, PAX8, HMGA2, vimentin, calretinin, and CA 125, and are negative for hormone receptors and WT1 . Frequent mutations in KRAS , as well as mutations in NRAS , ARID1A , ARID1B , and SMARCA4 , have been reported in patients with mesonephric‐like adenocarcinomas …”

Pulmonary metastasis of mesonephric‐like adenocarcinoma arising from the uterine body: a striking mimic of follicular thyroid carcinoma

“…However, the majority of the reported UB‐MNACs were predominantly located in the endometrium rather than in the deeper myometrium, and were not associated with mesonephric remnants . In addition to the frequent somatic KRAS mutations identifiable in the MNACs regardless of the tumour sites, UB‐MNACs show characteristic alterations such as frequent PIK3CA mutations and nearly universal immunopositivity for TTF‐1 . McFarland et al .…”

“…have proposed that UB‐MNAC could originate from Müllerian tissue and obtain the morphological and immunohistochemical phenotype characteristic of mesonephric differentiation; thus, this uterine corpus tumour has recently been described as a ‘mesonephric‐like adenocarcinoma’ rather than MNAC . Although the clinical course of mesonephric‐like adenocarcinomas arising from the uterine body is not yet well established, approximately half of the reported cases have shown aggressive biological behaviour of the tumour, with a tendency to metastasise to the lungs …”