In theory there are some cytologic features that may be helpful in differentiating neoplastic epithelial cells from various ovarian tumors (benign, borderline and carcinomas). Since serous tumors are the most common subtypes, most of the cytomorphologic studies have been done in these tumors7-9. Tumor cells from benign epithelial ovarian tumors (cystadenoma, cystadenofibroma) tend to form simple, non-branching papillary structures, composed of uniform cells with minimal to no cytologic atypia. Cellularity of peritoneal washing cytology (PWC) is usually less than seen in serous borderline oarian tumors (SBOT) or carcinomas. PWC in SBOT is often cellular (especially if the tumor ruptured intraoperatively or if there is ovarian surface involvement) and the papillae tend to be larger, three dimensional and branching with smooth borders. The tumor cells are small; the nuclear to cytoplasmic ratio is high when compared to those from benign tumors. Surface cilia may be present. Moderate cytologic atypia, including coarse chromatin and prominent nucleoli may be seen, as well as single neoplastic cells in the background. Psammoma bodies can be seen8. PWC from malignant epithelial ovarian tumors show irregular papillae, composed of obviously malignant tumor cells and numerous single cells in the background. While distinguishing high grade carcinoma from a borderline tumor are usually not difficult, differentiating borderline tumors from low grade carcinoma on cytomorphology alone cannot be done. The most helpful findings that may suggest an underlying frankly malignant process include: small irregular papillae, numerous large, pleomorphic single cells, mitotic figures and cytoplasmic vacuoles.
The most common genetic alterations in SBOT are somatic mutations of BRAF and KRAS, which are which are mutually exclusive and are seen in more than 50% of SBOT. Studies have shown that SBOT and low grade serous carcinomas represent a continuum and that approximately 5% of SBOT progress to low grade carcinomas10. Recent morphologic studies by Ardighieri et al11 and Zeppernick et al6 described a unique population of tumor cells associated with SBOT harboring V600E BRAF mutation. These neoplastic cells exfoliate of the papillae and are characterized by cytoplasmic eosinophilia, discrete cell borders, round prominent nuclei and faintly staining chromatin. Additionally these cells exhibit characteristic IHC profile and strongly express p16, decreased ER, PR and WT-1 expression and low to virtually zero Ki67 index. Molecular studies suggest that BRAF mutation in these tumor cells leads to cellular senescence, which is manifested in characteristic cytologic and morphologic changes described above. This case report illustrates several potential pitfalls one can encounter when looking at ascitic fluid or PWC associated with this subtype of SBOT. Mainly ascites and PWC from SBOT can be alarming at first glance due to hypercellularity (with predominance of single cells) of the specimen, as illustrated in this case. Secondly, a subset of BSOT harboring BRAF mutation exfoliates numerous single cells with unique and somewhat unusual characteristics, that may be worrisome; and potentially one can misinterpret as sign of malignancy (specifically high grade carcinoma).
Careful selection of IHC stains and correlation of resection specimen (if available) can avoid over interpretation of the cytologic findings as malignant, and save the patient from unnecessary neoadjuvant therapy.
The final pathologic stage of this ovarian borderline tumor was pT1c (due to surface involvement and the presence of neoplastic cells in the PWC). All lymph nodes, peritoneal biopsies and the omentum were uninvolved by tumor. The patient is undergoing regular surveillance without further treatment.