The Significance of Peritoneal Washing as a Prognostic Indicator for Ovarian Cancer Patients

Ovarian cancer (OC) is considered one of the most common tumor malignancies, affecting approximately 200,000 women each year (1-4). As less than 50% of the patients appear to reach a 5-year survival, it is considered as the eighth most frequent cause of death among cancer patients and the leading cause of death among gynecological cancers (2-3,5-8). Actually, due to the absence of primary symptoms and the lack of proper and efficient screening procedures, ovarian cancer is usually diagnosed in advance stages (III-IV), contributing to cancer fatality (9-12). The most common histological type is serous carcinoma, which appears in approximately 1/3 of the cases (1,13). The standard treatment for advanced ovarian cancer patients is primary debulking surgery (PDS), followed by platinum – based chemotherapy (9,10,14,15). If an optimal cytoreduction is not feasible with this procedure, neo-adjuvant chemotherapy, followed by interval debulking surgery (IDS) is preferred (9-10,14,16-18). The latter may provoke less surgical complications, but both are considered similarly effective regarding survival (19-23). Peritoneal washing (PW) has been included in gynecological cancer surgical procedures, as an easy, simple, cheap, and safe technique (24-26). This technique consists of the installation of fluid in the peritoneal cavity, followed by its extraction and cytological examination (27). The aim is to detect malignant cells found in the peritoneum indicating a possible metastasis of an ovarian tumor and/or an incomplete cytoreduction (1-2,5,27-30). Thus, PW can provide valuable information and is considered to have a prognostic value (1,25-26,31). When PW appears positive, it can upstage a T1a/T1b and a T2a/T2b cancer to a T1c and T2c, respectively (25). Therefore, it is included in the FIGO staging and the TNM system, in cases of early-stage ovarian neoplasms (25,30,32). Patients and Methods The main goal of our review was to study and analyze PW’s utility in the gynecologic cancer surgeries and consider its prognostic impact on patient survival. We collected information about the main factors that influence the technique’s results and the principal parameters that affect patient outcome. For preparing this review, we collected information from published articles in the PubMed platform. Our main purpose was to prioritize studies published during the last decade to reassure their credibility. However, studies from former decades were not excluded from our study to expand the information evaluated.

Likewise, in Zuna’s study, 86.6% of positive PW was correspondent with peritoneal histology (33). In the same study, 6.8% of the negative cytological results were histologically positive, whereas 1.1% of the positive ones were histologically negative. OC directly spreads in the peritoneal cavity and assisted by the peritoneal circulation results in tumor implantation (34). Peritoneal metastasis is correlated with a worse prognosis, since it increases the possibility of tumor recurrence and mortality (33,34). Sehouli Hou However, Giordano In Iura’s Conclusively, the correspondence of PW with tumor invasion indicates its usefulness in the management of ovarian cancers (1). The differentiation of the ovarian cancer into invasive and non-invasive tumors seems to be of great prognostic significance (39). Invasive primary tumors tend to provoke a poorer prognosis compared to the non-invasive ones (44). Sneige Another study showed that not only stage I borderline tumors presented with a high 5-year survival rate (95%-97%), but also stage II and III, which appeared with a survival rate of 65%-87%, proving the great outcome of non-invasive tumors. Similarly, another study highlighted that most borderline tumors reveal great survival outcomes (45). Jeffrey Tumor stage is also proved to be a significantly important prognostic factor influencing patient survival (2,40). Sehouli A different study revealed that 17%-36% of patients with advanced ovarian cancer had a 5-year survival, confirming the previous results (46). Furthermore, Wang Sehouli Iura In Kojima’s study, the median OS and PFS for PWC positive patients was 32 and 18 months, respectively, whereas for the negative cases was 31 and 29 months, respectively. Therefore, they noticed a significant relation only between PFS and PW (5). In Iura’s study, the median OS and PFS in PW positive cases was 18 and 13, while in negative PW cases was 47 and 17, respectively. Both OS and PFS were significantly correlated with PW (28). Additionally, Binesh

Positive PW usually reflects omental metastasis. However, Hou As stated above, tumor type may relate with both PW and prognosis. Clear cell carcinomas usually present as large lesions, localized in the ovary and compressing the surrounding organs (52). Thus, clear cell carcinomas may delay spreading in the peritoneum and provide a positive PW, explaining why some studies have found clear cell tumors with a low detection rate (27). However, since approximately 70-75% of OC cases are discovered in advanced stages (11-12,39,53), we assume there is a higher possibility for omental metastasis occurrence. This, combined with clear cell tumor’s resistance to chemotherapy that may be responsible for a residual disease, provide positive PW results in the favorable detection rate of 100% and indicate the aggressiveness of clear cell carcinomas. Contrastingly, serous carcinomas metastasize earlier, resulting in an increased possibility of a positive PW result, but still have a prognosis better than the other tumor types (1,28,52,54). Therefore, the relation between histological tumor type, PW and cancer prognosis is not clear and additional studies are needed to prove PW’s significance. Invasive carcinomas are correlated with worse prognosis than non-invasive ones. This is most probably due to the more aggressive character that invasive tumors are expected to have. Therefore, they metastasize more frequently and thus, have a higher tendency to appear positive in PWC. Additionally, non-invasive cancers are more likely to be discovered in an earlier stage. A study revealed that 75% of borderline tumors presented with FIGO stage I at diagnosis, whereas only 20% of invasive cancers were at the same stage. Most of the invasive tumors (60%) had reached stage III at the time of diagnosis (55). The advanced stage during the diagnosis of invasive cancers, enhances their correlation with a positive PW and dismal prognosis. We assumed there is a relation connecting invasive tumors, with positive PW and hence a poorer prognosis. According to the information given above, tumor stage is considered to be related with the cancer’s forecast. It is also worth mentioning that more advanced stages appear with a higher detection rate in PW, as they give noticeable metastasis more frequently. Thus, tumor stage may be associated with PW and prognosis. However, PW appears to have a more powerful significance in prognosis than tumor staging. As Iura In agreement with this study, Zuna As mentioned, residual disease indicates that microscopic cancer cells have remained in the peritoneum. This may be due to their chemo-resistant character. As a result, they have a higher chance of progressing and developing into a recurrent tumor (33,56,57). Thus, residual tumor is associated with a tumor recurrence and a poorer prognosis. Therefore, it is more preferable to aim for a complete cytoreduction, which should be the ultimate purpose (19,35). Residual tumors and the possibility of a tumor recurrence are usually associated with a positive PW result, which indicates a poorer prognosis. Kojima We can assume PW’s prognostic significance through its correlation with the factors mentioned above. Since most of these parameters seem to relate with a positive PW result and a more dismal prognosis, we suggest PW to be used as a prognostic factor. PW appears to have a direct relation to patient’s survival. According to the results presented, a positive PW result is usually associated with reduced patient OS and PFS. This proves PW’s significance as an independent prognostic factor. We hypothesize that the dismal prognosis of positive PW is most probably due to the existence of at least one of the above factors, which provoke a positive result and thus cause a negative outcome. However, it is worth mentioning that when studying each parameter individually, their prognostic significance may be minor compared to that of PW. As described above, a positive PW result associates with a dismal prognosis, despite the existence of an early grade tumor or a complete cytoreduction. We suppose this may be possibly due to a different prognostic factor intervening with patient outcome. Therefore, PW is presented to be a stronger indicator of prognosis, than each of the above parameters independently.

The outcome of patients with OC is determined by several factors that provoke a positive result in PW. i) Omental metastasis usually appears positive in PW and has a dismal outcome; ii) Serous carcinomas, as the most common ovarian tumor, appear more frequently in positive peritoneal results, than other histological tumor types. However, they usually have a good prognosis, in contrast to clear cell tumors, which usually have a bad outcome; iii) Invasive carcinomas tend to provoke a positive PW result and poorer prognosis; iv) Smaller tumors of less than 10 cm usually metastasize easier compared to the larger ones, and thus result in a positive PW; v) Higher grade and higher stage tumors, as more aggressive, tend to spread in the peritoneal cavity, resulting in positive PW and worse outcomes; vi) Incomplete cytoreduction, frequently appears positive in PW and increases the chance of tumor recurrence and diminished survival. Through this correlation we concluded that PW can be used as an independent prognostic tool when examining and treating patients with OC. When comparing the prognostic value of PW to each parameter independently, PW appears to be a more determinant indicator. No absolute result can be conducted from this review and additional research is needed to prove the significance of PW. Conflicts of Interest The Authors declare that there are no conflicts of interest in relation to this study. Authors’ Contributions K.A, F.Z, T.N, C.C and K.SE; Contributed to conception and design. K.NE; Were responsible for overall supervision. V.A, P.V, D.G and P.A; Drafted the manuscript, which was revised by K.K, S.S, C.C, A.S, A.C, D.G and K.NE. All Authors read and approved the final manuscript.