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Abstract
Purpose: It is still debatable whether surgical staging of endometrial cancer (EC) should include sampling of peritoneal cytology (PC) and for what purpose this should be done. The aim of our study was to determine the significance of peritoneal cytology in EC and its association with other histological and clinical parameters. Methods: This is a retrospective study that comprises of results from 357 patients with EC that were operated in our center in the previous nine years. Patients were divided into two groups: the first group with a positive and the second group with a negative PC. Results: Malignant cells were found in the peritoneal cytology of 23 patients (6.4%), while 334 patients (93.6%) had negative PC. There was no significant difference in patients' age between the two groups (p = 0.20). Peritoneal cytology was more prevalent in the non-endometrioid than the endometrioid subtype of EC (p = 0.00). There was a significant statistical difference (p = 0.00) in malignant PC in stages where cancer is confined to the uterus (International Federation of Gynecologists and Obstetricians (FIGO) stages I and II) compared with those where cancer has metastasized outside the uterus (stages III and IV). Most of the patients with malignant PC (69.6%) had high-grade disease (G3). Conclusion: Malignant peritoneal cytology is associated with other negative prognostic factors in endometrial cancer (histological grade, FIGO stage, and non-endometrioid histological subtypes). Based on these findings, we encourage sampling of peritoneal washing in all EC patients and consider it mandatory in patients with non-endometrioid subtype, high-grade histology, and in advanced FIGO stage.
Keywords: Cytodiagnosis, endometrial neoplasms, peritoneum, risk factors
How to cite this article: Introduction 
Endometrial cancer (EC) is the second most common gynecological cancer in low-income countries and the most common gynecological cancer in high-income countries.[1] Unlike most other cancers, both incidence and mortality associated with endometrial cancer are rising. The incidence peaks between 60 and 70 years of age, but up to 5% of cases present before the age of 40.[2]
Surgery is the cornerstone of the initial management of endometrial cancer (EC). Surgery aims to remove all macroscopic diseases comprising total hysterectomy and bilateral salpingo-oophorectomy in most cases. Another important role of surgery is to obtain tissue samples for disease staging and prognostic assessment. Surgical staging is done through lymph node sampling (either by systemic pelvic with/without paraaortic lymphadenectomy or sentinel lymph node biopsy) and omentectomy in serous and undifferentiated histological subtypes.
It is still debatable whether surgical staging should include sampling of a peritoneal washing destined for a cytological examination (peritoneal cytology; PC) and for what purpose this should be done. Malignant cells can be found in the peritoneal cavity as a result of dissemination from their origin in the uterine cavity via transtubal or transmyometrial way or the other metastatic sites within the abdominal cavity. The prognostic and predictive role of peritoneal cytology (PC) were of scientific and clinical interest in recent decades. Peritoneal cytology was considered an important histological risk factor in EC and was included in 1988. International Federation of Gynecologists and Obstetricians (FIGO) staging system for endometrial cancer as a criterion for stage IIIa.[3] Supported by the evidence from several studies that suggested that peritoneal cytology is not an independent prognostic factor, FIGO omitted peritoneal cytology as a staging criterion in its latest revision of the endometrial cancer staging system done in 2009.[4–6] Besides this change, FIGO still recommends the collection of peritoneal cytology as a part of surgical staging. Both European Society for Medical Oncology (ESMO), European Society for Radiotherapy and Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) guidelines guidelines and ESGO-ESTRO-ESP guidelines for endometrial cancer do not include peritoneal cytology in its risk stratification system and adjuvant treatment planning. According to these guidelines, peritoneal cytology is no more considered mandatory in EC surgical staging.[7],[8] On the other hand, the latest National Comprehensive Cancer Network (NCCN) guideline for uterine neoplasms suggests peritoneal cytology collection, despite the fact it does not affect staging and adjuvant treatment planning.[9]
Above stated alteration is the result of conflicting and deficient evidence from the earlier studies that were examining the prognostic and predictive role of peritoneal cytology in endometrial cancer. We continued to perform peritoneal cytology as part of the surgical staging of endometrial cancer, considering it to be a fast, easy, harmless, and inexpensive procedure. Our study aimed to determine the significance of peritoneal cytology in EC and its association with other histological and clinical parameters.
Methods This study comprises results from 357 patients with the EC that were operated in our center in the previous nine years. Following data were collected in a retrospective manner from electronic health records: patient age at the time of the operation, FIGO stage, histological tumor grade, histological subtype, and peritoneal cytology.
Patients were further divided into two groups according to peritoneal cytology results: the first group with a positive and the second group with negative cytology. Other above-mentioned parameters were compared between the two groups.
In statistical analysis t-test, χ2 test, and regression analysis were used. Statistical analyses were performed using IBM SPSS Statistics 28. A P value of less than 0.05 was considered to be statistically significant.
Results In our sample of 357 patients, malignant cells were found in the peritoneal cytology of 23 patients (6.4%), while 334 patients (93.6%) had negative peritoneal cytology.
There was no significant difference in patients age at the time of the operation between the two groups (p = 0.20). In the first group with positive peritoneal cytology, mean age of the patient was 66.2 ± 7.2 (2SD) years; whereas in the second group with negative cytology, the mean age was 64.7 ± 8.5 (2SD) years [Graph 1].
The distribution of patients according to histological subtype and peritoneal cytology is shown in [Table 1]. Endometrioid histological subtype was the most prevalent in 317 (88.79%) patients, followed by serous, mixed, clear cell, mucinous, and squamous subtypes of endometrial cancer, respectively. We have detected positive peritoneal cytology in just 3.17% of cases with endometrioid subtype. On the other hand, the positive cytology rate went up to 50% in the serous subtype. Further, in our analysis, we have observed all cases with non-endometrioid histology as one variable and all cases with endometrioid histology as the other. Statistical difference was found between the groups with positive cytology being more prevalent in non-endometrioid histological types (p = 0.00).
Table 1: Distribution of patients based on histological subtype and peritoneal cytologyIn our study, endometrial cancer was most frequently diagnosed in FIGO stage I [Graph 2]. Positive peritoneal cytology was not detected in any of 150 patients with FIGO stage Ia, and was detected in only one patient with FIGO stage Ib. Positive peritoneal cytology was most commonly found in patients with FIGO stage IVb (47.8% of all positive cytology) [Table 2]. There was a significant statistical difference (p = 0.00) in malignant peritoneal cytology in stages where cancer is confined to the uterus (Figo stages I and II) compared with those where cancer has metastasized outside the uterus (FIGO stages III and IV). Positive cytology is less common when the disease is confined to the uterus, and more common if it has spread outside of the uterus.
Only one out of 104 patients with histological grade 1 cancer had positive peritoneal cytology. [Graph 3]. Contrarily, 16/68 patients (23. 5%) with histological grade 3 had positive peritoneal cytology. Most of the patients with malignant PC (69.6%) had high-grade disease (G3) [Table 3]. Significant difference between groups was observed in relation to the histological grade of the tumor (p = 0.00). Regression analysis indicated that the possibility for positive peritoneal cytology has been increasing proportionally with the histological grade.
Table 3: Distribution of patients based on histological grade and peritoneal cytology Discussion Positive peritoneal cytology was found in 6.4% of subjects that were included in this study. Incidence of positive PC largely varies in the literature from 5.6% to 17%.[6],[10],[11],[12] These variations may be explained by the possibility that reactive mesothelial cells were mistaken with malignant cells in studies with a high rate of positive PC, and conversely, with sampling error if a malignant PC rate was too low.[6] Our positive PC rate corresponds better with the results of more recent studies with numerous patients.[10],[12]
Older age is an independent negative prognostic factor in endometrial cancer.[10],[13] In the present study, the patients' age was not significantly different between groups with positive and negative PC. This is in accordance with some other studies on this topic.[10],[13] On the contrary, Matsuo et al. observed a higher incidence of positive PC in patients older than 78 years (14,4%) compared with those younger than 57 years (7%) in a large observational study of 4506 patients with non-endometrioid EC.[14]
We have found a large difference in positive PC between endometrioid and non-endometrioid types. A statistically significant difference in positive PC rate between endometrioid and non-endometrioid types was confirmed in other studies.[10],[13],[14] Malignant peritoneal cytology is more prevalent in serous histological type than any other. This can be explained by its aggressive behavior and frequent peritoneal spread where peritoneal implants can be a source of malignant cells in the peritoneal cavity. According to Garg et al., positive peritoneal cytology is an independent prognostic factor associated with worse survival of patients with all histological types even in absence of distant spread in FIGO stages I and II.[13]
In our study, positive PC was rarely found in stage I disease. A significant difference in malignant PC was observed between cases with disease outside of the uterus compared with those where the cancer was confined to the uterus. Most of the patients with stage IV disease had positive PC – 78.6%. In the publication of Takenaka et al., 60% of patients with FIGO stage IV had positive PC.[15] High rate of positive PC in stage IV is due to the fact that most of the patients in this stage have intraperitoneal spread. Positive PC increases the risk of nodal involvement, thus increasing the stage.[12],[16] Several newly published papers concluded that positive peritoneal cytology has a negative impact on survival even in the early stages of EC.[10],[13],[14],[15] The risk of death was 4.7 times higher in FIGO stage Ia when peritoneal cytology was positive, 2.0 times increased in stage IB and 1.7 times more in stage II disease.[12] It can be concluded that positive peritoneal cytology is not only an indicator of intra-abdominal disease spread but can also suggest aggressive biological behavior of the tumor in any stage.
The positive peritoneal cytology rate in this study has been increasing proportionally with the histological grade of the tumor. Most of the patients with malignant PC (69.6%) had high-grade disease (G3). Our results are similar to those of some other publications.[13],[15],[16],[17] However, separate studies on this topic failed to prove a significant association between the histological grade and peritoneal cytology.[6],[10],[14] Histological grade is a well-known and proven independent prognostic factor in endometrial cancer. Patients with grade 1 disease are usually in the low-risk prognostic group and are not candidates for adjuvant treatment. It is questionable if low-risk patients with positive PC have a worse outcome and if they benefit from adjuvant treatment.[10],[15]
Due to the small number of patients with positive peritoneal cytology and its possible negative implications on reliable results of survival, we did not perform a survival analysis. In our opinion, the results of the studies with a small number of subjects like this one, but where survival analysis was done, influenced objective conclusions about the prognostic significance of peritoneal cytology in endometrial cancer. Most of the earlier studies that were done until 2009 concluded that peritoneal cytology is not an independent prognostic factor. These studies were with a small number of subjects with malignant PC, lacked stratification and in some, multivariate analysis was not done.[5],[6] These results led to the mentioned change in the FIGO staging system of endometrial cancer. More recent studies with larger cohorts concluded that peritoneal cytology is an independent negative prognostic factor in endometrial cancer.[10],[13],[14],[15] Are these emerging results enough evidence for another shift in endometrial cancer guidelines or FIGO staging system? For now, prospective randomized trials are encouraged to determine if adjuvant therapy in early-stage disease should be indicated based on malignant peritoneal cytology among other prognostic factors. In high-grade, advanced, and metastatic disease, treatment decision is already dominated by other risk factors and the addition of peritoneal cytology results will not play a crucial role in decision-making.
In conclusion, this study demonstrates that malignant peritoneal cytology is associated with other negative prognostic factors in endometrial cancer (histological grade, FIGO stage and non-endometrioid histological subtypes). Based on these findings, we encourage sampling of peritoneal washing in all EC patients and consider it mandatory in patients with non-endometrioid subtype, high-grade histology, and in advanced FIGO stages.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
Correspondence Address:
Dr. Slobodan Maricic
Veselina Maslese 76/38 21000 Novi Sad
Serbia
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/joc.joc_53_22
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