Ovarian colorectal metastases: peritoneal or hematogeneous metastatic disease?

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M. Leimkühler, P.H.J. Hemmer, N. Werner, I.H.J.T. de Hingh, M.J.E. Mourit, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1684313/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose There is an ongoing discussion whether ovarian colorectal metastases are the result of peritoneal or hematogeneous dissemination. The metastatic route has implications on the choice of treatment. This study aims to evaluate and discuss the factors indicating peritoneal or hematogenic dissemination and aims to evaluate and discuss the factors indicating peritoneal or haematogenic spread Methods A retrospective consecutive series of patients from two tertiary referral centers, who were treated for ovarian metastases from colorectal cancer between 2000 and 2018, was described. Clinical and histopathological characteristics of the primary tumor and the ovarian metastases were collected from patient files, the surgery reports and the pathology files. Statistical analysis included descriptive statistics, whereas binominal testing was used to compare the likelihood of two categories. Results Data of 141 patients were included. In most cases the ovarian capsule (73.6%) was broken and 120 patients (85.1%) had peritoneal metastases at the time of diagnosis of the ovarian metastases. Most metastatic cells were found deep in the ovarian stroma (80.0%) and 26.2% of patients developed metachronous hematogeneous (distant and/or liver) metastases. Conclusions In this study we found characteristics that support a peritoneal as well as a hematogenous dissemination. Therefore, an undoubted conclusion regarding the metastatic route cannot be drawn. Future studies should focus on the biological behavior as well as on the outcome of patients with ovarian metastases after CRS+HIPEC to evaluate its added value in this patient group. Ovarian metastases colorectal carcinoma hyperthermic intraperitoneal chemotherapy Figures Figure 1 1. Introduction Ovarian metastases occur in 1–9% of female patients suffering from colorectal carcinoma [ 1 – 4 ]. In patients presenting with peritoneal metastases, this incidence rises up to 60% [ 5 , 6 ]. Patients with ovarian metastases have a poor prognosis with a median survival of 18 to 30 months [ 7 – 9 ]. Whether this poor outcome could be explained by rapid progression of ovarian metastases or of the peritoneal metastases, or to chemoresistance of the ovarian metastases is still under debate [ 4 , 10 , 11 ]. It is essential to understand the route of metastatic dissemination in order to find possible treatment (or preventive) approaches. There are three possible metastatic routes from colorectal carcinoma to the ovaries that can be considered: lymphatic, direct peritoneal or hematogeneous [ 7 , 9 , 12 ]. There is no possibility to distinguish the three routes by histopathological staining, so other, clinical factors have to be taken into consideration. Because there is no direct lymphatic drainage from the colon to the ovaries, lymphatic dissemination is rather unlikely [ 7 ]. This leaves the other two metastatic routes as most probable potential explanations. In case of peritoneal dissemination of the colorectal tumor, the tumor cells would desquamate from the primary tumor into the fluid of the peritoneal cavity to be distributed through the peristaltic motion of the bowel [ 7 ]. This peritoneal dissemination would be supported by the frequent simultaneous occurrence of peritoneal metastases in case of ovarian metastases [ 4 , 7 ]. In case of hematogeneous dissemination the tumor cells would be distributed through the vascular system. The ovaries are highly vascularized organs, especially in premenopausal women that are twice as likely to have ovarian metastases, and could therefore be prone to hematogeneous metastases [ 3 , 9 , 13 ]. Furthermore, an overexpression of vascular endothelial growth factor (VEGF) stimulates angiogenesis [ 14 ]. A hematogeneous dissemination might be supported by the intact capsule that is often covering the ovarian metastases [ 7 ]. The metastatic route of ovarian metastases, may have implications for the treatment of patients. If ovarian metastases are the result of peritoneal dissemination, a treatment with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is rational, similar to the treatment of patients with peritoneal metastases [ 15 ]. Furthermore, it can be debatable whether the ovaries should be removed prophylactically in case of peritoneal metastases. In case of haematogeneous metastases, systemic treatment would more logical. More insight into the metastatic route of ovarian metastases from colorectal cancer is needed to make an informed treatment choice. Therefore, we collected clinical and histopathological data from patients with ovarian metastases to evaluate characteristics that might give us insight into the most likely metastatic route. 2. Materials And Methods We conducted a retrospective cohort study including patients from two large referral centers for colorectal cancer: the University Medical Center Groningen (UMCG) and the Catharina Hospital in Eindhoven. Due to the retrospective nature of the study and its use of anonymized patient data, the Medical Ethical Committee provided us a waiver and the Local Ethical Committee of both participating hospitals approved the study. All patient data were analyzed anonymously. 2.1 Patients For the inclusion of patients the Dutch nationwide pathology database (PALGA) was searched. In PALGA, histo- and cytopathological results from patients in the Netherlands are registered since 1987 [ 16 ]. The database was searched for patients who were diagnosed from 2000 to 2018 in the participating centers. The search terms “colon carcinoma” or “rectal carcinoma” or “mucinous” and “ovarian metastases” or “adnex” were used. Patients were included in the study if they had been diagnosed for colorectal cancer and had pathologically proven ovarian metastases from colorectal cancer. Patients were excluded if the location of the primary tumor was unknown or if the patient had more than one primary tumor at the same time. 2.2 Data collection and statistical analysis All patient and tumor characteristics were retrieved from each patient’s file. Patients and tumor characteristics were analyzed using descriptive statistics and displayed with total number (n) and percentage. In case of two categories (e.g. presence of peritoneal metastases versus absence of peritoneal metastases), binominal testing was used to test the null hypothesis that the two categories are equally likely to be found. Statistical analysis was performed using IBM SPSS 23. 2.3 Outcome measures The primary outcomes were the characteristics of the ovarian metastases, being the state of the ovarian capsule as determined during clinical and pathological inspection (example in picture 1), the laterality of ovarian metastases and whether the metastatic cells were superficial in the surface epithelium or deep in the ovarian stroma. The secondary outcomes were characteristics of the primary tumor and other metastases, namely the location of the primary tumor, the TN classification, type of the primary tumor, the presence of vascular invasion in the primary tumor, the presence of ascites, the presence of peritoneal metastases, the presence and type of hematogeneous and the time between the diagnosis of the primary tumor and the diagnosis of ovarian or other metastases ( 6months). 3. Results 3.1 Patients and primary tumor characteristics The study included 141 female colorectal cancer patients with ovarian metastases (Table 1 ). Our data showed that the most frequent location of the primary tumor was the sigmoid (25.5%) followed by appendix (17.0%), ascending colon (16.33%), coecum (14.9%), rectum (12.1%), colon transversum (6.4%), colon descendens (5.0%) and rectosigmoid (2.8%). In 74.4% of the patients the pathological report described that there was no lymph vascular space invasion in the primary tumor. In 23 patients (16.3%) synchronous non-ovarian hematogeneous metastases were diagnosed. Ascites was found in 29.8% (95% CI 22.4% − 38.1%) of the patients and 35 (83.3%) women with ascites also had peritoneal metastases. Table 1 Patient, primary tumor characteristics and treatment of the primary tumor Characteristics Frequency* % Age at diagnosis: median (range) 59 (29-88) years Location of primary tumor Sigmoid 36 25.5 Appendix 24 17.0 Colon ascendens 23 16.3 Coecum 21 14.9 Rectum 17 12.1 Colon transversum 9 6.4 Colon descendens 7 5.0 Rectosigmoid 4 2.8 T status T1 3 2.3 T2 5 3.9 T3 40 31.0 T4 71 55.0 T4 with direct extension 10 7.8 Unknown T status 12 N status N0 36 30.3 N1 35 29.4 N2 48 40.3 Unknown N status 22 Mucinous tumor 49 34.8 Vascular invasion No vascular invasion 91 74.4 Angiovascular or lymphatic invasion 30 25.6 Unknown 20 Ascites 42 29.8 Synchronous metastases (except ovarian metastases) None 89 63.1 Abdominal 34 24.1 Hematogenous 23 16.3 Liver 18 Peritoneal metastases Synchronous ( 6 months) 44 31.2 None 21 14.9 Primary treatment Cytoreductive Surgery 119 84.4 HIPEC 87 61.7 Adjuvant chemotherapy 60 42.6 Palliative chemotherapy 50 35.5 3.2 Characteristics of ovarian metastases In 73.6% of the patients with ovarian metastases the ovarian capsule was broken at pathological examination (73.6%, 95%CI 56.8%-73.1%; p < 0.001). Metastatic cells were most often found in the ovarian stroma (80%; 95%CI 71.8%-85.8%), significantly more often than (only) on the surface of the ovaries (p < 0.001) (Table 2 ). Table 2 Characteristics of ovarian metastases Frequency (n) Percentage (%) Ovarian metastases Synchronous ( 6 months) 62 44.0 Laterality of ovarian metastases Bilateral 67 48.2 Unilateral 72 51.8 Ipsilateral 42 Contralateral 30 Unknown 2 Median diameter (range) in cm at pathological assessment 8.8 (1.5–36.0) Location of metastases in ovaries Deep 112 80.0 Superficial 28 20.0 Unknown 1 Capsule Broken 92 73.6 Intact 33 26.4 Unknown 16 Necrosis Not present 91 64.5 Present 50 35.5 Peritoneal metastases Simultaneous with ovarian metastases 107 89.2 Non-simultaneous with ovarian metastases 13 10.8 3.3 Other metastases Most synchronous and metachronous metastases were located inside the abdominal cavity (24.1% and 22.0% respectively), namely on the uterus, urinary bladder, small bowel, spleen or gallbladder, and 120 patients showed other peritoneal metastases in addition to ovarian metastases (85.1%; 95%CI 74.9%-88.2%). Peritoneal metastases were diagnosed synchronous to ovarian metastases in 107/120 (89.2%) patients and metachronous in 13/120 (10.8%) patients (Table 2 ). Furthermore 79 out of 92 (75.9%) patients with a broken ovarian capsule also were diagnosed with peritoneal metastases. Patients with ovarian metastases showed metachronous hematogeneous (distant and/or liver) metastases in 37 patients (26.2% of patients). In 23 patients (62.2%) with hematogeneous metastases these metastases were detected at the same time as the ovarian metastases. 4. Discussion This study provided some insight into the clinical characteristics of ovarian colorectal metastases, and provides arguments for peritoneal as well as hematogeneous dissemination as etiology. Several characteristics are arguments for a peritoneal dissemination: the majority of patients had ascites and synchronous peritoneal metastases. Additionally, most ovaries showed a broken capsule, most primary tumors were stage 3 or 4 and mucinous and were in close proximity to the ovaries. In our study the vast majority of ovarian metastases showed a broken capsule (73.6%; 95%CI 56.8%-73.1%), making an infiltrative growth of colorectal cancer cells from the outside more likely. An earlier study, including 23 patients, reported 48% (95%CI 26.8% -69.4%) of broken ovarian capsules [ 17 ], being comparable to the proportion found in our study. Furthermore, the primary tumor showed several characteristics that are arguments for a peritoneal dissemination. First, most primary tumors were stage 3 or 4, which are known risk factors for dissemination directly into the peritoneal cavity [ 18 ]. We even observed a direct growth into the ovaries in 8% of patients. Second, the close proximity of the primary tumor to the ovaries (sigmoid, appendix , ascending colon or caecum) makes implantation of tumor cells on the ovaries by direct seeding more likely. In the literature a comparable distribution of locations of primary tumors has been described [ 4 , 21 ]. Third the majority of primary tumors showed absence of vascular invasion, making a hematogeneous dissemination less likely[ 22 ]. Fourth, in a third of the patients the primary tumor was mucinous, which is more than the 14% described in the general colorectal patient group [ 19 ]. Mucinous tumors are more likely to disseminate through the abdominal cavity by means of mucine discarded from the primary tumor [ 20 ]. Moreover, ascites was present in a third of patients in our study, comparable to findings by Miller er al[ 17 ]. Ascites is often a sign of the presence of cancer cells in the peritoneum, confirmed by the fact that 83% of patients with ascites also had peritoneal metastases. In addition, around 85% of patients with ovarian metastases in our series showed peritoneal metastases, which indicates the presence of cancer cells inside the peritoneal cavity. This is in accordance with earlier studies, which found an incidence of peritoneal metastases up to 80% in the presence of ovarian metastases [ 4 , 9 ]. Other characteristics are arguments for a hematogeneous dissemination to the ovaries, such as ovarian metastases were found deep in the ovarian stroma, there is a frequent bilateral occurrence of ovarian metastases and some patients were diagnosed with metachronous hematogeneous non-ovarian metastases. In our study the majority of metastases were located deep inside the ovarian stroma, with a few ovaries even showing an intact capsule, making a hematogenous dissemination more likely. There was frequent bilateral occurrence of ovarian metastases, comparable to literature describing bilateral occurrence of ovarian metastases in 46–71% of patients [ 6 , 9 , 21 ]. Most metachronous metastases were found in either the liver or other distant locations, indicating the presence of circulating tumor cells. In broader perspective the ovary is already well vascularized and an overexpression of vascular endothelial growth factor (VEGF) stimulates angiogenesis [ 14 ]. It therefore offers an ideal environment for cancer cells to grow and is considered prone to hematogeneous metastases, but also provides an ideal environment for peritoneal metastases [ 1 , 3 , 9 , 25 , 26 ]. Also it was recently shown that the high grade serous primary ovarian carcinomas often develop in the distal end of the Fallopian tube and then disseminate to the ovaries, while the ovarian capsule remains intact. High-grade serous ovarian carcinoma is therefore most often a metastasis of a primary tubal carcinoma [ 27 – 30 ]. This direct implantation and extensive growth of peritoneal metastasis on the ovary might also occur in case of CRC (Fig. 1 ). It might therefore be reasonable to prophylactically remove the ovaries. Several studies found that survival rates were similar in patients with peritoneal metastases with or without ovarian involvement [ 4 , 23 , 24 ]. Selected patient treated with CRS + HIPEC showed significantly better survival in a recent population based study [ 1 ]. This makes clinical decision in favor of CRS + HIPEC comprehensible. However, as there is no randomized controlled trial yet, patients that did not receive CRS + HIPEC might have presented with a higher tumor load or substantial comorbidities at baseline, favoring the CRS + HIPEC group. The most important limitation of our study is its retrospective and cross-sectional nature; therefore not all described items were systematically reported in the patient’s file. Besides, we did not analyze data of patients without ovarian metastases. Although we analyzed the surgical as well as the pathological reports it cannot be ruled out that an important outcome parameter – a broken ovarian capsule- has been the result of iatrogenous damage during surgery. Furthermore, the lack of a control group makes it impossible to draw conclusions about the true impact of ovarian metastases on survival. However, this is the largest study so far documenting the characteristics of ovarian colorectal metastases and primary colorectal tumors. Considering all arguments it is not possible to answer the question whether ovarian metastases are the result of direct intraperitoneal or hematogeneous dissemination or a combination of both. This question, remains highly relevant as it has implications for clinical decision making and treatment. The patient has to be informed that it is not known yet, whether CRS + HIPEC or systemic treatment is the most beneficial in case of colorectal ovarian metastases. Nor do we know whether prophylactic removal of the ovaries in case of primary surgery would be of benefit for the prognosis. Further research is needed to find out the prognostic value of ovarian metastases in CRC. Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing interests The authors declare that there were no competing interest during the preparation of this manuscript. Author Contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.Leimkuhler, B.L. van Leeuwen and G.H. de Bock. The first draft of the manuscript was written by M.Leimkuhler, B.L. van Leeuwen and G.H. de Bock and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript Data Availability The datasets analysed during the current study are available from the corresponding author on reasonable request. Ethics approval This is cross-sectional study. The Research Ethics Committee of the University Medical Center Groningen has confirmed that no ethical approval is required. Consent to participate Due to the nature of the study informed consent was not required. References Bakkers C, van der Meer R, Roumen RM, Lurvink RJ, Lemmens VE, van Erning FN, de Hingh IH. Incidence, risk factors, treatment, and survival of ovarian metastases of colorectal origin: a Dutch population-based study. Int J Colorectal Dis 2020: 35:1035–1044. Eveno C, Goere D, Dartigues P et. al. 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Supplementary Files Picture1Ovary.docx a) Ovary of 15 cm and 1650g with ruptured capsule and b) Immunohistochemical examination reveals cytokeratine 20 tumor marker positive Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1684313","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":108346364,"identity":"2ea0e6ac-11a4-45b9-aa1b-9179e42cdf80","order_by":0,"name":"M. 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Colon carcinoma might disseminate through the direct peritoneal route or through a hematogeneous route through the hepatic portal system, ovarian carcinomas often result from direct implantation of cancer cells that originate in the tuba\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1684313/v1/30f6557fc78a26ba8c20b10d.png"},{"id":22386012,"identity":"815362a6-3d2c-4457-ade6-c4371456fbe4","added_by":"auto","created_at":"2022-06-08 01:29:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":521143,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1684313/v1/f87bd756-e9a0-42a9-93f0-c167f975e204.pdf"},{"id":21926409,"identity":"824e3105-3c73-410e-9a5c-b3f9d9e75e4c","added_by":"auto","created_at":"2022-05-26 15:59:57","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":143404,"visible":true,"origin":"","legend":"\u003cp\u003ea) Ovary of 15 cm and 1650g\u0026nbsp;with ruptured capsule and b) Immunohistochemical examination reveals cytokeratine 20 tumor marker positive\u003c/p\u003e","description":"","filename":"Picture1Ovary.docx","url":"https://assets-eu.researchsquare.com/files/rs-1684313/v1/9f7a85d3c95bae26445ce8c2.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ovarian colorectal metastases: peritoneal or hematogeneous metastatic disease?","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOvarian metastases occur in 1\u0026ndash;9% of female patients suffering from colorectal carcinoma [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In patients presenting with peritoneal metastases, this incidence rises up to 60% [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Patients with ovarian metastases have a poor prognosis with a median survival of 18 to 30 months [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Whether this poor outcome could be explained by rapid progression of ovarian metastases or of the peritoneal metastases, or to chemoresistance of the ovarian metastases is still under debate [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIt is essential to understand the route of metastatic dissemination in order to find possible treatment (or preventive) approaches. There are three possible metastatic routes from colorectal carcinoma to the ovaries that can be considered: lymphatic, direct peritoneal or hematogeneous [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. There is no possibility to distinguish the three routes by histopathological staining, so other, clinical factors have to be taken into consideration. Because there is no direct lymphatic drainage from the colon to the ovaries, lymphatic dissemination is rather unlikely [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This leaves the other two metastatic routes as most probable potential explanations. In case of peritoneal dissemination of the colorectal tumor, the tumor cells would desquamate from the primary tumor into the fluid of the peritoneal cavity to be distributed through the peristaltic motion of the bowel [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This peritoneal dissemination would be supported by the frequent simultaneous occurrence of peritoneal metastases in case of ovarian metastases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In case of hematogeneous dissemination the tumor cells would be distributed through the vascular system. The ovaries are highly vascularized organs, especially in premenopausal women that are twice as likely to have ovarian metastases, and could therefore be prone to hematogeneous metastases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Furthermore, an overexpression of vascular endothelial growth factor (VEGF) stimulates angiogenesis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A hematogeneous dissemination might be supported by the intact capsule that is often covering the ovarian metastases [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe metastatic route of ovarian metastases, may have implications for the treatment of patients. If ovarian metastases are the result of peritoneal dissemination, a treatment with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is rational, similar to the treatment of patients with peritoneal metastases [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Furthermore, it can be debatable whether the ovaries should be removed prophylactically in case of peritoneal metastases. In case of haematogeneous metastases, systemic treatment would more logical. More insight into the metastatic route of ovarian metastases from colorectal cancer is needed to make an informed treatment choice. Therefore, we collected clinical and histopathological data from patients with ovarian metastases to evaluate characteristics that might give us insight into the most likely metastatic route.\u003c/p\u003e"},{"header":"2. Materials And Methods","content":"\u003cp\u003eWe conducted a retrospective cohort study including patients from two large referral centers for colorectal cancer: the University Medical Center Groningen (UMCG) and the Catharina Hospital in Eindhoven. Due to the retrospective nature of the study and its use of anonymized patient data, the Medical Ethical Committee provided us a waiver and the Local Ethical Committee of both participating hospitals approved the study. All patient data were analyzed anonymously.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patients\u003c/h2\u003e \u003cp\u003eFor the inclusion of patients the Dutch nationwide pathology database (PALGA) was searched. In PALGA, histo- and cytopathological results from patients in the Netherlands are registered since 1987 [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The database was searched for patients who were diagnosed from 2000 to 2018 in the participating centers. The search terms \u0026ldquo;colon carcinoma\u0026rdquo; or \u0026ldquo;rectal carcinoma\u0026rdquo; or \u0026ldquo;mucinous\u0026rdquo; and \u0026ldquo;ovarian metastases\u0026rdquo; or \u0026ldquo;adnex\u0026rdquo; were used. Patients were included in the study if they had been diagnosed for colorectal cancer and had pathologically proven ovarian metastases from colorectal cancer. Patients were excluded if the location of the primary tumor was unknown or if the patient had more than one primary tumor at the same time.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data collection and statistical analysis\u003c/h2\u003e \u003cp\u003eAll patient and tumor characteristics were retrieved from each patient\u0026rsquo;s file. Patients and tumor characteristics were analyzed using descriptive statistics and displayed with total number (n) and percentage. In case of two categories (e.g. presence of peritoneal metastases versus absence of peritoneal metastases), binominal testing was used to test the null hypothesis that the two categories are equally likely to be found. Statistical analysis was performed using IBM SPSS 23.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcome measures\u003c/h2\u003e \u003cp\u003eThe primary outcomes were the characteristics of the ovarian metastases, being the state of the ovarian capsule as determined during clinical and pathological inspection (example in picture 1), the laterality of ovarian metastases and whether the metastatic cells were superficial in the surface epithelium or deep in the ovarian stroma. The secondary outcomes were characteristics of the primary tumor and other metastases, namely the location of the primary tumor, the TN classification, type of the primary tumor, the presence of vascular invasion in the primary tumor, the presence of ascites, the presence of peritoneal metastases, the presence and type of hematogeneous and the time between the diagnosis of the primary tumor and the diagnosis of ovarian or other metastases (\u0026lt;\u0026thinsp;6 months or \u0026gt;\u0026thinsp;6months).\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003e3.1 Patients and primary tumor characteristics\u003c/h2\u003e\n \u003cp\u003eThe study included 141 female colorectal cancer patients with ovarian metastases (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Our data showed that the most frequent location of the primary tumor was the sigmoid (25.5%) followed by \u003cspan class=\"InternalRef\"\u003eappendix\u003c/span\u003e (17.0%), ascending colon (16.33%), coecum (14.9%), rectum (12.1%), colon transversum (6.4%), colon descendens (5.0%) and rectosigmoid (2.8%). In 74.4% of the patients the pathological report described that there was no lymph vascular space invasion in the primary tumor. In 23 patients (16.3%) synchronous non-ovarian hematogeneous metastases were diagnosed. Ascites was found in 29.8% (95% CI 22.4% \u0026minus;\u0026thinsp;38.1%) of the patients and 35 (83.3%) women with ascites also had peritoneal metastases.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cp\u003eTable 1 Patient, primary tumor characteristics and treatment of the primary tumor\u003c/p\u003e\n \u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" width=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eCharacteristics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003eFrequency*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eAge at diagnosis: median (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e59 (29-88) years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eLocation of primary tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eSigmoid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e25.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eAppendix\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e17.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eColon ascendens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e16.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eCoecum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e14.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eRectum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e12.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eColon transversum\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e6.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eColon descendens\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e5.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eRectosigmoid\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eT status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eT1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e2.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eT2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e3.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eT3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e31.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eT4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e55.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eT4 with direct extension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e7.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eUnknown T status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eN status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eN0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e30.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eN1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e29.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eN2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e40.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eUnknown N status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eMucinous tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e34.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eVascular invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;No vascular invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e74.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Angiovascular or lymphatic invasion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e25.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Unknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eAscites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e29.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eSynchronous metastases (except ovarian metastases)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;None\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e63.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Abdominal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e24.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Hematogenous\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e16.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003ePeritoneal metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Synchronous (\u0026lt; 6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e53.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Metachronous (\u0026gt; 6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e31.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;None\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e14.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003ePrimary treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; Cytoreductive Surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e119\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e84.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; HIPEC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e61.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; Adjuvant chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e42.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" width=\"51.559633027522935%\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;Palliative chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"31.192660550458715%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" width=\"17.24770642201835%\"\u003e\n \u003cp\u003e35.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003e3.2 Characteristics of ovarian metastases\u003c/h2\u003e\n \u003cp\u003eIn 73.6% of the patients with ovarian metastases the ovarian capsule was broken at pathological examination (73.6%, 95%CI 56.8%-73.1%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Metastatic cells were most often found in the ovarian stroma (80%; 95%CI 71.8%-85.8%), significantly more often than (only) on the surface of the ovaries (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable border=\"1\" id=\"Tab2\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of ovarian metastases\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFrequency (n)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePercentage (%)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOvarian metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSynchronous (\u0026lt;\u0026thinsp;6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMetachronous (\u0026gt;\u0026thinsp;6 months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLaterality of ovarian metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e48.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e51.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIpsilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eContralateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMedian diameter (range) in cm at pathological assessment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.8 (1.5\u0026ndash;36.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLocation of metastases in ovaries\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSuperficial\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCapsule\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBroken\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e73.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e26.4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNecrosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNot present\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e64.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePresent\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e35.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePeritoneal metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSimultaneous with ovarian metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNon-simultaneous with ovarian metastases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec9\"\u003e\n \u003ch2\u003e3.3 Other metastases\u003c/h2\u003e\n \u003cp\u003eMost synchronous and metachronous metastases were located inside the abdominal cavity (24.1% and 22.0% respectively), namely on the uterus, urinary bladder, small bowel, spleen or gallbladder, and 120 patients showed other peritoneal metastases in addition to ovarian metastases (85.1%; 95%CI 74.9%-88.2%). Peritoneal metastases were diagnosed synchronous to ovarian metastases in 107/120 (89.2%) patients and metachronous in 13/120 (10.8%) patients (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Furthermore 79 out of 92 (75.9%) patients with a broken ovarian capsule also were diagnosed with peritoneal metastases. Patients with ovarian metastases showed metachronous hematogeneous (distant and/or liver) metastases in 37 patients (26.2% of patients). In 23 patients (62.2%) with hematogeneous metastases these metastases were detected at the same time as the ovarian metastases.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study provided some insight into the clinical characteristics of ovarian colorectal metastases, and provides arguments for peritoneal as well as hematogeneous dissemination as etiology.\u003c/p\u003e \u003cp\u003eSeveral characteristics are arguments for a peritoneal dissemination: the majority of patients had ascites and synchronous peritoneal metastases. Additionally, most ovaries showed a broken capsule, most primary tumors were stage 3 or 4 and mucinous and were in close proximity to the ovaries.\u003c/p\u003e \u003cp\u003eIn our study the vast majority of ovarian metastases showed a broken capsule (73.6%; 95%CI 56.8%-73.1%), making an infiltrative growth of colorectal cancer cells from the outside more likely. An earlier study, including 23 patients, reported 48% (95%CI 26.8% -69.4%) of broken ovarian capsules [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], being comparable to the proportion found in our study. Furthermore, the primary tumor showed several characteristics that are arguments for a peritoneal dissemination. First, most primary tumors were stage 3 or 4, which are known risk factors for dissemination directly into the peritoneal cavity [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. We even observed a direct growth into the ovaries in 8% of patients. Second, the close proximity of the primary tumor to the ovaries (sigmoid, \u003cspan refid=\"Sec8\" class=\"InternalRef\"\u003eappendix\u003c/span\u003e, ascending colon or caecum) makes implantation of tumor cells on the ovaries by direct seeding more likely. In the literature a comparable distribution of locations of primary tumors has been described [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Third the majority of primary tumors showed absence of vascular invasion, making a hematogeneous dissemination less likely[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Fourth, in a third of the patients the primary tumor was mucinous, which is more than the 14% described in the general colorectal patient group [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Mucinous tumors are more likely to disseminate through the abdominal cavity by means of mucine discarded from the primary tumor [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Moreover, ascites was present in a third of patients in our study, comparable to findings by Miller er al[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Ascites is often a sign of the presence of cancer cells in the peritoneum, confirmed by the fact that 83% of patients with ascites also had peritoneal metastases. In addition, around 85% of patients with ovarian metastases in our series showed peritoneal metastases, which indicates the presence of cancer cells inside the peritoneal cavity. This is in accordance with earlier studies, which found an incidence of peritoneal metastases up to 80% in the presence of ovarian metastases [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOther characteristics are arguments for a hematogeneous dissemination to the ovaries, such as ovarian metastases were found deep in the ovarian stroma, there is a frequent bilateral occurrence of ovarian metastases and some patients were diagnosed with metachronous hematogeneous non-ovarian metastases. In our study the majority of metastases were located deep inside the ovarian stroma, with a few ovaries even showing an intact capsule, making a hematogenous dissemination more likely. There was frequent bilateral occurrence of ovarian metastases, comparable to literature describing bilateral occurrence of ovarian metastases in 46\u0026ndash;71% of patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Most metachronous metastases were found in either the liver or other distant locations, indicating the presence of circulating tumor cells.\u003c/p\u003e \u003cp\u003eIn broader perspective the ovary is already well vascularized and an overexpression of vascular endothelial growth factor (VEGF) stimulates angiogenesis [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It therefore offers an ideal environment for cancer cells to grow and is considered prone to hematogeneous metastases, but also provides an ideal environment for peritoneal metastases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Also it was recently shown that the high grade serous primary ovarian carcinomas often develop in the distal end of the Fallopian tube and then disseminate to the ovaries, while the ovarian capsule remains intact. High-grade serous ovarian carcinoma is therefore most often a metastasis of a primary tubal carcinoma [\u003cspan additionalcitationids=\"CR28 CR29\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. This direct implantation and extensive growth of peritoneal metastasis on the ovary might also occur in case of CRC (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). It might therefore be reasonable to prophylactically remove the ovaries.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSeveral studies found that survival rates were similar in patients with peritoneal metastases with or without ovarian involvement [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Selected patient treated with CRS\u0026thinsp;+\u0026thinsp;HIPEC showed significantly better survival in a recent population based study [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This makes clinical decision in favor of CRS\u0026thinsp;+\u0026thinsp;HIPEC comprehensible. However, as there is no randomized controlled trial yet, patients that did not receive CRS\u0026thinsp;+\u0026thinsp;HIPEC might have presented with a higher tumor load or substantial comorbidities at baseline, favoring the CRS\u0026thinsp;+\u0026thinsp;HIPEC group.\u003c/p\u003e \u003cp\u003eThe most important limitation of our study is its retrospective and cross-sectional nature; therefore not all described items were systematically reported in the patient\u0026rsquo;s file. Besides, we did not analyze data of patients without ovarian metastases. Although we analyzed the surgical as well as the pathological reports it cannot be ruled out that an important outcome parameter \u0026ndash; a broken ovarian capsule- has been the result of iatrogenous damage during surgery. Furthermore, the lack of a control group makes it impossible to draw conclusions about the true impact of ovarian metastases on survival. However, this is the largest study so far documenting the characteristics of ovarian colorectal metastases and primary colorectal tumors.\u003c/p\u003e \u003cp\u003eConsidering all arguments it is not possible to answer the question whether ovarian metastases are the result of direct intraperitoneal or hematogeneous dissemination or a combination of both. This question, remains highly relevant as it has implications for clinical decision making and treatment. The patient has to be informed that it is not known yet, whether CRS\u0026thinsp;+\u0026thinsp;HIPEC or systemic treatment is the most beneficial in case of colorectal ovarian metastases. Nor do we know whether prophylactic removal of the ovaries in case of primary surgery would be of benefit for the prognosis. Further research is needed to find out the prognostic value of ovarian metastases in CRC.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there were no competing interest during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthor Contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by M.Leimkuhler, B.L. van Leeuwen and G.H. de Bock. The first draft of the manuscript was written by M.Leimkuhler, B.L. van Leeuwen and G.H. de Bock and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData Availability\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eEthics approval\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis is cross-sectional study. The Research Ethics Committee of the University Medical Center Groningen has confirmed that no ethical approval is required.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent to participate\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eDue to the nature of the study informed consent was not required.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eBakkers C, van der Meer R, Roumen RM, Lurvink RJ, Lemmens VE, van Erning FN, de Hingh IH. Incidence, risk factors, treatment, and survival of ovarian metastases of colorectal origin: a Dutch population-based study. Int J Colorectal Dis 2020: 35:1035\u0026ndash;1044.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eEveno C, Goere D, Dartigues P et. al. Ovarian metastasis is associated with retroperitoneal lymph node relapses in women treated for colorectal peritoneal carcinomatosis. Ann Surg Oncol 2013: 20:491\u0026ndash;496.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eErroi F, Scarpa M, Angriman I et. al. Ovarian metastasis from colorectal cancer: prognostic value of radical oophorectomy. J Surg Oncol 2007: 96:113\u0026ndash;117.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKuijpers AM, Mehta AM, Aalbers AG, van Driel WJ, Boot H, Verwaal VJ. Treatment of ovarian metastases of colorectal and appendiceal carcinoma in the era of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. 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Eur J Surg Oncol 2009: 35:92\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWright JD, Powell MA, Mutch DG, Rader JS, Gibb RK, Huettner PC, Herzog TJ. Synchronous ovarian metastases at the time of laparotomy for colon cancer. Gynecol Oncol 2004: 92:851\u0026ndash;855.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSekine K, Hamaguchi T, Shoji H et. al. Retrospective Analyses of Systemic Chemotherapy and Cytoreductive Surgery for Patients with Ovarian Metastases from Colorectal Cancer: A Single-Center Experience. Oncology 2018: 95:220\u0026ndash;228.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eGoere D, Daveau C, Elias D et. al. The differential response to chemotherapy of ovarian metastases from colorectal carcinoma. Eur J Surg Oncol 2008: 34:1335\u0026ndash;1339.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMason MH,3rd, Kovalcik PJ. Ovarian metastases from colon carcinoma. J Surg Oncol 1981: 17:33\u0026ndash;38.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAyhan A, Guvenal T, Salman MC, Ozyuncu O, Sakinci M, Basaran M. The role of cytoreductive surgery in nongenital cancers metastatic to the ovaries. Gynecol Oncol 2005: 98:235\u0026ndash;241.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eByrne AT, Ross L, Holash J et. al. Vascular endothelial growth factor-trap decreases tumor burden, inhibits ascites, and causes dramatic vascular remodeling in an ovarian cancer model. Clin Cancer Res 2003: 9:5721\u0026ndash;5728.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eEsquivel J, Elias D, Baratti D, Kusamura S, Deraco M. Consensus statement on the loco regional treatment of colorectal cancer with peritoneal dissemination. J Surg Oncol 2008: 98:263\u0026ndash;267.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCasparie M, Tiebosch AT, Burger G, Blauwgeers H, van de Pol A, van Krieken JH, Meijer GA. Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive. Cell Oncol 2007: 29:19\u0026ndash;24.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eMiller BE, Pittman B, Wan JY, Fleming M. Colon cancer with metastasis to the ovary at time of initial diagnosis. Gynecol Oncol 1997: 66:368\u0026ndash;371.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eEnblad M, Graf W, Birgisson H. Risk factors for appendiceal and colorectal peritoneal metastases. Eur J Surg Oncol 2018: 44:997\u0026ndash;1005.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLam AK, Chan SS, Leung M. Synchronous colorectal cancer: clinical, pathological and molecular implications. World J Gastroenterol 2014: 20:6815\u0026ndash;6820.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKermanshahi TR, Magge D, Choudry H et. al. Mucinous and Signet Ring Cell Differentiation Affect Patterns of Metastasis in Colorectal Carcinoma and Influence Survival. Int J Surg Pathol 2017: 25:108\u0026ndash;117.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eHuang PP, Weber TK, Mendoza C, Rodriguez-Bigas MA, Petrelli NJ. Long-term survival in patients with ovarian metastases from colorectal carcinoma. Ann Surg Oncol 1998: 5:695\u0026ndash;698.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eChoi HJ, Hyun MS, Jung GJ, Kim SS, Hong SH. Tumor angiogenesis as a prognostic predictor in colorectal carcinoma with special reference to mode of metastasis and recurrence. Oncology 1998: 55:575\u0026ndash;581.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBignell MB, Mehta AM, Alves S et. al. 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Support of the \u0026apos;fallopian tube hypothesis\u0026apos; in a prospective series of risk-reducing salpingo-oophorectomy specimens. Eur J Cancer 2013: 49:132\u0026ndash;141.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Ovarian metastases, colorectal carcinoma, hyperthermic intraperitoneal chemotherapy","lastPublishedDoi":"10.21203/rs.3.rs-1684313/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1684313/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePurpose\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThere is an ongoing discussion whether ovarian colorectal metastases are the result of peritoneal or hematogeneous dissemination. The metastatic route has implications on the choice of treatment. This study aims to evaluate and discuss the factors indicating peritoneal or hematogenic dissemination and aims to evaluate and discuss the factors indicating peritoneal or haematogenic spread\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMethods\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA retrospective consecutive series of patients from two tertiary referral centers, who were treated for ovarian metastases from colorectal cancer between 2000 and 2018, was described. Clinical and histopathological characteristics of the primary tumor and the ovarian metastases were collected from patient files, the surgery reports and the pathology files. Statistical analysis included descriptive statistics, whereas binominal testing was used to compare the likelihood of two categories.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResults\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eData of 141 patients were included. In most cases the ovarian capsule (73.6%) was broken and 120 patients (85.1%) had peritoneal metastases at the time of diagnosis of the ovarian metastases. Most metastatic cells were found deep in the ovarian stroma (80.0%) and 26.2% of patients developed metachronous hematogeneous (distant and/or liver) metastases. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConclusions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eIn this study we found characteristics that support a peritoneal as well as a hematogenous dissemination. Therefore, an undoubted conclusion \u0026nbsp;regarding the metastatic route cannot be drawn. Future studies should focus on the biological behavior as well as on the outcome of patients with ovarian metastases after CRS+HIPEC to evaluate its added value in this patient group.\u003c/p\u003e","manuscriptTitle":"Ovarian colorectal metastases: peritoneal or hematogeneous metastatic disease?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-26 15:59:55","doi":"10.21203/rs.3.rs-1684313/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2c87b77c-bf21-4407-9b00-aaf077b91223","owner":[],"postedDate":"May 26th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-06-08T01:29:09+00:00","versionOfRecord":[],"versionCreatedAt":"2022-05-26 15:59:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1684313","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1684313","identity":"rs-1684313","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}