Borderline Mucinous Tumor With Granulosa Cell Proliferation
We read with great interest the articles describing the intriguing association of adult granulosa cell tumor (AGCT) with ovarian mucinous tumors 1–5. We describe a recently diagnosed case of borderline mucinous tumor demonstrating focal proliferation of granulosa cells.
A 24-year-old female complained of abdominal pain for 2 months. Radiologic investigations revealed a complex cystic mass measuring 11×9×7 cm. The CA125 level was 17.7 IU/mL. Grossly the tumor was multiloculated with cystic areas containing mucoid material. No well-defined mural nodule was identified. Microscopically the tumor was composed of cystic spaces lined by intestinal-type mucinous epithelium showing epithelial proliferation, nuclear stratification, and mild nuclear atypia (Fig. 1A). However, there was no evidence of stromal invasion in multiple sections studied. Focal areas showed mucin percolating in the stroma with associated sheets of muciphages. In 2/20 sections, the septae and papillary cores of the mucinous epithelium were mildly thickened by proliferation of cells that were different from the more fibrous stroma seen elsewhere (Figs. 1B–D). Focally there was a close intermingling of mucinous epithelium and these cells (Fig. 1E), which had round to oval nuclei, fine chromatin, inconspicuous nucleoli, and scant to moderate cytoplasm (Fig. 1F). Some of the cells showed longitudinal nuclear grooves, whereas an occasional mitotic figure was also seen. No Call-Exner bodies were seen. The inhibin immunostain showed positivity (Figs. 1G, H) in these cells, thus the morphologic and immunohistochemistry features were those of granulosa cell proliferations within the septae of a borderline mucinous neoplasm.
The exact nature of AGCT-like areas associated with mucinous tumors can only be confirmed by molecular studies. In a recent study, the authors have conclusively demonstrated the heterogenous nature of AGCT-like components in mucinous neoplasms, as relatively specific FOXL2 mutation was identified in only a subset of cases 6. One of the FOXL2-mutated cases was a collision tumor with macroscopically and microscopically nodular mass displaying features of AGCT, which abutted the borderline mucinous neoplasm 5,6. In the other mutation-positive case, authors hypothesized evolution of diffuse AGCT-like areas from cellular thecomatous stroma in the septae of a borderline mucinous neoplasm 3,6. Similar to the second case, a prominent fibrothecomatous component was seen in 2 FOXL2 mutation-positive AGCT cases in the study of Shah et al 7. This might indicate that in a subset of cases, AGCT evolves from the prominent fibrothecomatous background probably due to acquisition of somatic FOXL2 mutation. Therefore, mucinous neoplasms associated with prominent thecomatous background and/or AGCT-like areas should be tested for FOXL2 mutation to ascertain the neoplastic nature of AGCT component, which may be important for long-term follow-up of these patients.
Around 20% of ovarian mucinous neoplasms show elevated serum inhibin levels, the source of which was localized to luteinized stromal cells 8. Some unknown factors secreted by mucinous epithelium might be inducing the proliferation of luteinized stromal cells, which are not uncommonly present in mucinous neoplasms. A similar mechanism has been postulated for occurrence of ovarian-type stroma in biliary cystadenomas and pancreatic mucinous cystic neoplasms. In our case, the subepithelial stromal cells were not luteinized and nuclear grooves were present in some of the cells suggesting granulosa cell differentiation. The extent of granulosa cell proliferation in our case was very limited and was not of sufficient degree to label it as AGCT. Therefore, similar to proliferation of luteinized stromal cells, the granulosa cell proliferation might be induced by the mucinous neoplasm that might act as precursors for the development of AGCT.
Heterologous mucinous differentiation is seen in a subset of Sertoli-Leydig cell tumors, which can occasionally show prominent borderline to malignant change in the mucinous component 9.