Ovarian cancer is the eighth most common cancer among women with a lifetime risk of about 1 in 70 . It accounts for approximately 30% of all cancer deaths within the female genital tract and is the most aggressive cancer compared with its incidence rate .
The peritoneal cavity is a common site of involvement for various reactive, inflammatory, and neoplastic processes. Metastases from primary ovarian malignancies are particularly common in this location. Approximately 70% of OEC, the most common form of ovarian cancers, are not diagnosed until the disease has involved the upper abdomen or spread beyond the abdominal cavity . Traditional strategy for the management of advanced ovarian cancer is primary cytoreductive surgery with intraoperative peritoneal washing cytology followed by adjuvant chemotherapy. However, it seems that such strategy does not increase overall patient survival significantly. Neoadjuvant chemotherapy (NACT) is emerging as an effective treatment modality in many locally advanced solid tumors, including breast, gastrointestinal and bone and soft tissue malignancies these years. The rationale behind NACT protocol is to make inoperable advanced disease operable, to increase cancer resection rates, and to facilitate potential organ conservation , if applicable. Nowadays, NACT has been advocated by NCCN guideline for patients with advanced ovarian cancer with an aim to improve tumor debulking and overall survival.
Approximately 70-80% advanced ovarian cancers could be accurately diagnosed based on clinicopathological and imaging studies. However, the remaining 20-30% of ovarian cancers may cause clinical management problem due to a similar clinicopathological presentations. Therefore, it is important to have cytologic or pathologic diagnosis for those patients with probable ovarian cancers prior to NACT. But concerns have been raised about the reliability of using cytology to diagnose ovarian cancer since non-gynecologic cancer cells can not be reliably differentiated under microscope. In 2003, Schwartz and Zheng reported the role of cytology in pretreatment diagnosis of ovarian cancer followed by NACT and recommended that it was essential for the clinician and the cytologist or pathologist to communicate with each other to make a better diagnosis by using cytological material . The bottleneck limiting the efficient application of pre-neoadjuvant cytology is lack of sensitive and effective biomarkers for ovarian cancer in this setting.
Recent proposals about the tubal origin of ovarian cancer challenged the traditional theory [11, 19, 20]. Large numbers of biomarkers have been used on the way to testify the new creation. PAX8 is a member of the PAX gene family, which includes nine well-characterized transcription factors (PAX1-9). Each member is directly implicated in the transcription of various genes, involved in organogenesis, morphogenesis, thyroid, renal and Müllerian cell differentiation . This marker, initially identified in normal cells originating in Müllerian ducts, is also present in ovarian tumors and is characteristic for the epithelial phenotypes (serous, clear cell, and endometrioid) [5, 21–23]. Moreover, PAX8 allows the differentiation between Müllerian and non-Müllerian origin in the case of an ovarian metastatic carcinoma that could derive from a primary tumor in pancreas, colon or mammary gland [24, 25]. Due to its relatively specific for Müllerian epithelial cells, this marker is useful for the differentiation of the ovarian carcinomas, especially in the advanced stages, from breast carcinomas or malignant mesotheliomas exhibiting similar histologic features. Moreover, PAX8 has a diagnostic value as Müllerian differentiation marker in peritoneal effusions demonstrating the origin in high- and low-grade serous carcinomas .
In the present study, we examined the utility of PAX8 antibody combining with Calretinin in differential diagnosis of cancer cells within the ascites from patients with advanced “ovarian” cancer. All ascitic samples showing PAX8+/Calretinin- from patients who might receive NACT were 100% correlated to the final diagnosis of ovarian cancer. Even among the 20 cases with uncertain primary organ sites based on cytology diagnosis, 13 samples with PAX8+/Calretinin- were confirmed with ovarian cancer both immunohistochemically and clinicopathologically. The rest of the samples with PAX8-/Calretinin + or Calretinin- were not of ovarian origin. These results were further confirmed by examining the metastatic cancer and benign control groups. However, one thing we would like to emphasize here is that PAX8 can be also positive in renal cell carcinoma and benign Müllerian epithelia. This was demonstrated in one renal cancer case and 5 benign Müllerianosis samples. Fortunately, renal cell metastasis to ovary or clinically mimicking advanced ovarian cancer is extremely rare and benign Müllerian epithelia are easily identifiable under microscope. PAX8 staining can also be similarly applied to all peritoneal washing specimens in gynecologic malignancy when ovarian or Müllerian primay is questioned.