Systematically Prognostic Analyses of Gastric Cancer Patients with Ovarian Metastasis

Ovarian metastasis of gastric cancer indicates that the disease has reached the late stage and the opportunity for radical surgery is restricted. However, the clinical characteristics and prognosis of patients with gastric cancer ovarian metastasis (GCOM) remain to be illustrated. Here, we retrieved the information of 780 GCOM cases from the Surveillance, Epidemiology, and End Results (SEERs) database and analyzed their clinicopathological characteristics as well as their survival. According to our data, most GCOM patients showed poor pathological differentiation, advanced T and N stages. The prognostic factors include patients' age, tumor size, surgical resection, and chemotherapy treatment. Of note, the marriage status was also identified as an independent prognostic factor. Besides the identification of prognostic factors, we established nomograms to help predict the overall survival and cancer-specific survival of GCOM, respectively.


Introduction
Gastric cancer represents a common malignancy worldwide [1]. Because the clinical symptoms of early gastric cancer are not typical, many patients are already in the middle and late stages when they seek treatment and have lost the opportunity for radical surgery. Currently, the main ways of gastric cancer metastasis include lymphatic metastasis, hematologic metastasis, and peritoneal implantation [2,3]. Among them, ovarian metastasis of gastric cancer is mostly caused by peritoneal implantation metastasis. After the cancer tissue invades the serosa, it falls of to the peritoneal cavity to cause implantation metastasis [4,5].
Ovarian metastases from gastric cancer are clinically known as Krukenberg tumor, which can be mucinous cell carcinoma, poorly diferentiated adenocarcinoma, or tubular adenocarcinoma [6]. Once gastric cancer has ovarian metastasis, it means that the disease has reached the late stages and the opportunity for radical surgery is restricted. Only if the patients were characterized without other distant metastasis or peritoneal metastasis, they can be treated with surgical resection by the combination of gastrectomy, hysterectomy, and adnexectomy [7]. Most patients can only accept chemotherapy and targeted therapy. However, the clinical characteristics and prognosis of patients with gastric cancer ovarian metastasis (GCOM) remain to be illustrated.
Here, we retrospectively retrieved the GCOM patients' information from the SEER database and analyzed their clinicopathologic characteristics as well as their survival.

Data Extraction.
Patients in the SEER datasets from 2000 to 2016 were extracted and selected. Te including criteria were as follows: (i) ovarian cancer was marked as secondary tumor and (ii) gastric cancer was marked as primary tumor. Te exclusion criteria were as follows: (i) the survival time was 0 months and (ii) patients without clarifed tumor T stage or N stage.

Data Analysis.
Prognosis was evaluated according to both overall survival (OS) and cancer-specifc survival (CSS). Survival information was analyzed using the Cox hazard regression model using SPSS Software (version 22.0). Survival nomogram was plotted according to the multivariate survival analysis results.

Nomogram Formulation.
Nomograms including clinical features such as age, T, N, and chemotherapy were established to predict GCOM patients' survival possibility at 1-, 3-, and 5year according to the enrolled cohort.

Patients' Characteristics.
After exclusion, there were 780 cases enrolled in the fnal cohort (Table 1)
In addition, we conducted multivariate analysis by subjecting all the signifcant factors mentioned above (Table 2). Accordingly, younger diagnostic age, married status, Genetics Research undergoing surgical resection, and accepting chemotherapy treatment were identifed as four independent prognostic factors. Considering that several variables may have clinical signifcance although showed no statistical signifcance in our study, we enrolled all the variables for another multivariate analysis (Figure 2(a)) and established a predicting nomogram for CSS ( Figure 2(b)).

Overall Survival Analysis.
Besides CSS, we also analyzed the overall survival (OS) of the enrolled patients (Table 3). Till the end of the follow-up, 678 (86.9%) cases died. Univariate analysis revealed the patient's age at diagnosis as a signifcant prognostic factor. Comparing with patients elder than 65 -years-old, patients with 46-65 -years-old and ≤45 -years-old showed a hazard ratio of 0.674 (95% CI 0.576-0.788, P < 0.001) and 0.538 (95% CI 0.372-0.777, P < 0.001), respectively (Figure 3 (Figure 3(f )). As expected, patients with the advanced N stage, namely the N2 stage, exhibited signifcantly worse OS comparing to those with earlier N stages ( Figure 3(g), HR � 1.500, 95% CI 1.199-1.875, and P < 0.001). Survival analyses also revealed that the patients who underwent surgical treatment (Figure 3(h), HR � 0.514,  In addition, we conducted multivariate analysis by subjecting all the signifcant factors abovementioned. Consistent with the CSS data, younger diagnostic age, married status, underwent surgical resection, and accepted chemotherapy treatment were identifed as four independent overall survival factors. In addition, the patients' tumor size was an independent overall survival predictor (Table 3). Similar with the CSS analyses, we enrolled all the variables for another multivariate analysis (Figure 4(a)) and established a predicting nomogram for OS (Figure 4(b)).

Discussion
Gastrointestinal cancer metastases to the ovary are a type of ovarian metastases. Ovarian metastatic tumors are most commonly metastasized from gastric cancer to the ovary, accounting for 67% of ovarian metastatic tumors, 5.4% of ovarian malignant tumors, and 1.3% of all ovarian tumors [8,9]. Among them, Krukenberg tumor caused by the metastasis of signet ring cell carcinoma is an important type of ovarian metastases, and its prognosis is extremely poor [10,11]. However, few studies reported the clinicopathological characteristics and evaluated the survival of this specifc patient group due to the limited sample size. According to our data, most GCOM patients showed poor pathological diferentiation, advanced T stage and N stage. Prognostic variables include the patients' age, tumor size, surgical resection, and chemotherapy treatment. In this specifc cohort, several conventional prognostic factors were not signifcant because the patients were already within the TNM stage IV. Tis means that several prognostic factors (such as the tumor size) may lose their signifcant efect on the survival of those patients with very late stage. Liu et al.'s data described the entire younger gastric cancer patients and concluded that early-onset gastric cancer cases showed worse survival compared with late-onset gastric cancers [12], while our data only compared patients with ovarian metastasis. Terefore, the conclusions are completely diferent. Liu's conclusion was reasonable considering younger patients may have more genetic mutations and more quickly tumor progression. But it is also reasonable in our study that elder patients with distant metastasis exhibited worse prognosis compared than younger advanced-staged patients because elder patients had worse basic health and lower immune capacity to prevent tumor progression. Of note, the marriage status was also identifed as an independent prognostic variable for the frst time, although the possible underlying mechanisms require further investigation.
In our opinion, surgical resection is suitable for those who are in good general condition, whose primary tumor is resectable or has been resected, and who can tolerate surgery  Genetics Research 7 [13,14]. Tere are several advantages of surgical treatment. First, diagnosis can be confrmed after operation, so as to prevent patients with primary disease from losing the chance of treatment. Second, surgical resection can reduce compression, inhibit the production of peritoneal efusion, and relieve symptoms. Tird, the location and nature of the primary tumor can be clarifed and whether it can be resected can be estimated. Lastly, the primary tumor may be resected at the same time and therefore achieve radical treatment and improve patients' survival [15,16]. Terefore, we suggested that women with gastrointestinal diseases which are considered to be tumors should ask for gynecological consultation or routine pelvic examination. In addition, the pelvis of women patients who are  8 Genetics Research accepting gastrectomy should be routinely explored by surgeons. Besides, women with a history of gastrointestinal tumor surgery should have a regular gynecological followup. For patients with limited pelvic metastases, total hysterectomy and bilateral adnexectomy can be performed to remove pelvic metastases as much as possible [17]. Our study has several limitations. First, the SEER dataset includes data from a limited number of geographic regions and may not be the representative of the overall US population. Tis could result in an overrepresentation or underrepresentation of certain races, which could afect the accuracy of survival analyses based on race. Second, while the SEER dataset contains a large amount of data, some subgroups of interest may have relatively small sample sizes such as our specifc cohort, and the limited sample size request us to validate the major conclusion in more cohorts worldwide in the future. Consistently, to make our data more precise, we selected a strict data exclusion strategy and may thus missed information on important variables. Finally, here we did not analyze the survival efect of comorbidities, which cannot be obtained from the SEER dataset. However, comorbidities afect patients' survival and treatment outcomes. Without this information, it can be difcult to account for the impact of comorbidities on survival and accurately assess the efectiveness of diferent treatments.

Conclusion
Taken together, our data suggested that the diagnostic age, marriage status, surgical resection, and chemotherapy treatment were signifcant prognostic factors for gastric cancer patients with ovarian metastasis.

Data Availability
Data used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.