β-catenin (CTNNB1) S33C Mutation in Ovarian Microcystic Stromal Tumors

Abstract

Microcystic stromal tumor (MCST) is a recently described subtype of ovarian tumor characterized by prominent microcystic histologic pattern and diffuse immunoreactivity for CD10 and vimentin. However, its pathobiology, particularly its histogenesis, remains largely unclear. Here, we report 2 cases of ovarian MCST, in which we have performed extensive histologic, immunohistochemical, and genetic investigations to determine its distinct nature among ovarian neoplasms. The patients were 32 and 41 years of age. Both tumors were solid and cystic masses involving the right ovary. Microscopically, tumor cells with generally bland, round-to-ovoid nuclei grew in microcystic, macrocystic, and solid patterns. Intervening thick fibrous stroma was observed. Immunohistochemically, tumor cells were diffusely and strongly positive for CD10, vimentin, and Wilms tumor 1. Furthermore, we detected aberrant nuclear expression of β-catenin protein in both cases. Of interest, mutation analyses revealed the presence of an identical point mutation, c.98C>G, in exon 3 of β-catenin (CTNNB1) in both tumors. This is an oncogenic mutation that causes replacement of serine with cysteine at codon 33, leading to the loss of a phosphorylation site in the β-catenin protein. The results of this study strongly suggest that dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the pathogenesis of ovarian MCST. Finally, by comparing the immunophenotype of MCST with its histologic mimics and other ovarian sex cord-stromal tumors, we were able to identify unique features of MCST and a panel of markers useful in differential diagnosis.

Microcystic Stromal Tumor

“…19,20 In the study by Maeda and colleagues, investigation and subsequent detection of aberrant nuclear b-catenin staining in 2 MSTs was prompted by the morphologic and immunohistochemical similarity between MST and solid pseudopapillary neoplasm (SPN) of the pancreas and ovary. 2,21,22 We acknowledge this important finding as an impetus to study b-catenin in the current largest available series of MST, but we are of the view that MST is a distinct entity from ovarian SPN. In MST, there is an absence of features that define SPN, including a pseudopapillary pattern, cells with abundant foamy cytoplasm, and oval nuclei with nuclear grooves.…”

“…1-3 ER and PR are also usually negative. 1,2 Tumors that most often enter the differential diagnosis with MST are others within the sex cord-stromal category, including thecoma and, particularly when a solid pattern predominates, steroid cell tumor. 1,[16][17][18] Thus, it is important to be cognizant of the overlapping but distinct profiles expected with the application of sex cord-stromal markers in this setting.…”

“…1 As demonstrated in our original study, and in 4 subsequently reported cases, MSTs are uniformly positive for CD10 and vimentin. [1][2][3][4] Inhibin, calretinin, and epithelial membrane antigen are typically negative, and focal cytokeratin positivity may occasionally be observed. In 2011, Maeda et al 2 reported 2 MSTs with aberrant b-catenin nuclear accumulation and identical mutations in exon 3 of CTNNB1, implicating dysregulation of the Wnt/b-catenin pathway in the pathogenesis of this neoplasm.…”

The Utility of Immunohistochemistry in the Differential Diagnosis of Gynecologic Disorders

“…It should be noted that WT1 stains positively in 70% of granulosa cell tumors. 192,196,[202][203][204][205][206][207][208][209][210] Granulosa Cell Tumor Versus Poorly Differentiated Adenocarcinoma.-Inhibin, calretinin, FOXL2, EMA, and CK7.…”

Oncogenic Activation of the Wnt/β-Catenin Signaling Pathway in Signet Ring Stromal Cell Tumor of the Ovary

“…Ovarian MCST is typically a larger mass-forming lesion characterized by macrocystic and microcystic, often hemorrhagic, changes, a solid growth pattern, and diffuse expression of vimentin, CD10, and the Wilms tumor 1 (WT1) protein. 19 The tumor described in this report showed no macroscopic or microscopic features suggesting a relationship to ovarian MCST. 20 Also, WT1 protein expression typically seen in MCST was not detected.…”