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.

FIGURE 1

Gross findings of UB-MNAC. A and B, The tumor protrudes into the endometrial cavity, without grossly definite myometrial invasion. C, The tumor deeply infiltrates into the myometrium (lower panel). The cut surface of the tumor closely resembles that of intramural leiomyoma (upper panel). D, The tumor infiltrates the entire uterine wall.

FIGURE 2

Histopathologic findings of UB-MNAC: architectural patterns. A, Tubular pattern. The tubules are lined by a single layer of cuboidal cells and possess intraluminal eosinophilic material (inset). B, Glandular pattern. The endometrioid-like glands are lined by several layers of columnar epithelium. C, Glandular pattern. Some glands are cystically dilated and irregular in shape. D, Papillary pattern. Note the intraluminal papillary projections and floating micropapillary tufts (inset). E, Glomeruloid pattern. Dilated glands contain intraluminal cribriform structures with 2 points of attachment, resembling a renal glomerulus. F, Comedonecrosis-like pattern showing necrotic debris centrally located in the dilated glandular lumina and surrounded by tumor cells arranged in a papillary, cribriform, or solid pattern. G, Retiform pattern showing elongated, slit-like branching tubules. H, Sex cord-like pattern showing anastomosing trabeculae and cords of tumor cells with background of edematous or myxoid stroma.

FIGURE 3

Histopathologic findings of UB-MNAC: adverse pathologic characteristics and metastasis. A, High mitotic activity. Blue circles indicate mitotic figures. B, Coagulative tumor cell necrosis. C, Sarcomatous component resembling nonspecific spindle cell sarcoma. D, Sarcomatous component showing severe nuclear pleomorphism. Note large, bizarre nuclei with intranuclear vacuoles (right upper and lower corners). E, Lymphovascular invasion. F, Histopathologic examination of pulmonary metastatic lesion reveals the carcinomatous component in the glandular pattern only.

FIGURE 4

Immunostaining results of UB-MNAC. A, Uniform nuclear GATA3 expression. B, Diffuse and strong nuclear PAX2 immunoreactivity. C, Preserved PTEN expression. D, Lack of ER expression. E, Lack of PR expression. F, Wild-type p53 immunostaining pattern. G, Focal p16 expression. H, Uniform CD10 immunoreactivity along the luminal surface. I, Focal calretinin expression.

FIGURE 5

Summary of SNVs identified in 12 UB-MNACs by NGS. Each column represents a case, and each row represents a gene.

FIGURE 6

Summary of CNVs identified in 12 UB-MNACs by NGS. Each column represents a case, and each row represents a chromosome.