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      The pathogenesis, diagnosis, and management of metastatic tumors to the ovary: a comprehensive review

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          Abstract

          Secondary tumors of the ovary account for 10–25% of all ovarian malignancies. The most common tumors that give rise to ovarian metastases include breast, colorectal, endometrial, stomach, and appendix cancer. The correct diagnosis of secondary ovarian tumors may be challenging as they are not infrequently misdiagnosed as primary ovarian cancer, particularly in the case of mucinous adenocarcinomas. The distinction from the latter is essential, as it requires different treatment. Immunohistochemistry plays an important role in distinguishing primary ovarian tumors from extra-ovarian metastases and, furthermore, may suggest the primary tumor site. Despite extensive study, some cases remain equivocal even after assessing a broad spectrum of antigens. Therefore, gene expression profiling represents an approach able to further discriminate equivocal findings, and one that has been proven effective in determining the origin of cancer of unknown primary site. The available data concerning secondary ovarian tumors is rather limited owing to the relative heterogeneity of this group and the practical absence of any prospective trials. However, several intriguing questions are encountered in daily practice, including rational diagnostic workup, the role of cytoreductive surgery, and consequent adjuvant chemotherapy. This review seeks to address these issues comprehensively and summarize current knowledge on the epidemiology, pathogenesis, and management of secondary ovarian tumors, including further discussion on the different pathways of metastatisation, metastatic organotropism, and their possible molecular mechanisms.

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          Mechanisms of transcoelomic metastasis in ovarian cancer.

          Metastasis from epithelial ovarian cancer can occur via the transcoelomic, haematogeneous, or lymphatic route. Of these, transcoelomic metastasis is the most common, and is responsible for the greatest morbidity and mortality in women with this disease. Unfortunately, very little is known about the mechanisms behind this process. This review assesses the current evidence and ideas about the biology of transcoelomic dissemination. The mechanisms of cell detachment, migration, and implantation in transcoelomic metastasis are placed within the context of clinical observations of ovarian cancer to derive a stepwise hypothesis of this process. Evidence for transcoelomic dissemination versus transcoelomic metaplasia in ovarian cancer is presented. Future high throughput microarray studies that compare changes at a genomic and gene expression level between primary ovarian tumours and their peritoneal metastases are hoped to lead to a more conclusive picture of transcoelomic metastasis, and to delineate the key molecular players in this process. These studies might also result in the identification of potential new therapeutic targets in ovarian cancer.
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            Cancer of unknown primary site.

            Cancer of unknown primary site (CUP) is a well recognised clinical disorder, accounting for 3-5% of all malignant epithelial tumours. CUP is clinically characterised as an aggressive disease with early dissemination. Diagnostic approaches to identify the primary site include detailed histopathological examination with specific immunohistochemistry and radiological assessment. Gene-profiling microarray diagnosis has high sensitivity, but further prospective study is necessary to establish whether patients' outcomes are improved by its clinical use. Metastatic adenocarcinoma is the most common CUP histopathology (80%). CUP patients are divided into subsets of favourable (20%) and unfavourable (80%) prognosis. Favourable subsets are mostly given locoregional treatment or systemic platinum-based chemotherapy. Responses and survival are similar to those of patients with relevant known primary tumours. Patients in unfavourable subsets are treated with empirical chemotherapy based on combination regimens of platinum or taxane, but responses and survival are generally poor. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients with carcinoma of unknown primary site: a prospective trial of the Sarah Cannon research institute.

              Molecular tumor profiling is a promising diagnostic technique to determine the tissue of origin in patients with carcinoma of unknown primary site (CUP). However, the clinical value of these molecular predictions is unknown. We used tumor profiling results to direct site-specific therapy for patients with CUP. Tumor biopsy specimens from previously untreated patients with CUP were tested with a 92-gene reverse transcriptase polymerase chain reaction cancer classification assay. When a tissue of origin was predicted, patients who were treatment candidates received standard site-specific first-line therapy. Of 289 patients enrolled, 252 had successful assays performed, and 247 (98%) had a tissue of origin predicted. Sites most commonly predicted were biliary tract (18%), urothelium (11%), colorectal (10%), and non-small-cell lung (7%). Two hundred twenty-three patients were treatment candidates, and 194 patients received assay-directed site-specific treatment. In these 194 patients, the median survival time was 12.5 months (95% CI, 9.1 to 15.4 months). When the assay predicted tumor types that were clinically more responsive, the median survival was significantly improved when compared with predictions of more resistant tumors (13.4 v 7.6 months, respectively; P = .04). In this large prospective trial, molecular tumor profiling predicted a tissue of origin in most patients with CUP. The median survival time of 12.5 months for patients who received assay-directed site-specific therapy compares favorably with previous results using empiric CUP regimens. Patients with CUP predicted to have more responsive tumor types had longer survival compared with patients with less responsive tumor types. Molecular tumor profiling contributes to the management of patients with CUP and should be a part of their standard evaluation.
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                Author and article information

                Contributors
                +420 495 832 176 , okubec@gmail.com
                Journal
                Clin Exp Metastasis
                Clin. Exp. Metastasis
                Clinical & Experimental Metastasis
                Springer Netherlands (Dordrecht )
                0262-0898
                1573-7276
                20 July 2017
                20 July 2017
                2017
                : 34
                : 5
                : 295-307
                Affiliations
                [1 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, Department of Oncology and Radiotherapy, , Faculty of Medicine and University Hospital in Hradec Králové, Charles University, ; Sokolská 581, 500 05 Hradec Králové, Czech Republic
                [2 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, Department of Obstetrics and Gynecology, , Faculty of Medicine and University Hospital in Hradec Králové, Charles University, ; Hradec Králové, Czech Republic
                [3 ]ISNI 0000 0004 1937 116X, GRID grid.4491.8, The Fingerland Department of Pathology, , Faculty of Medicine and University Hospital in Hradec Králové, Charles University, ; Hradec Králové, Czech Republic
                Author information
                http://orcid.org/0000-0003-2105-625X
                http://orcid.org/0000-0002-9602-7501
                http://orcid.org/0000-0003-4887-3196
                http://orcid.org/0000-0002-4126-0410
                http://orcid.org/0000-0002-8567-0745
                Article
                9856
                10.1007/s10585-017-9856-8
                5561159
                28730323
                c1c49e07-8083-448d-885d-41ca56c91f57
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 2 April 2017
                : 12 July 2017
                Funding
                Funded by: Progres Q40/06
                Funded by: BBMRI_CZ LM2015089
                Categories
                Review Article
                Custom metadata
                © Springer Science+Business Media B.V. 2017

                Oncology & Radiotherapy
                ovary,neoplasm,tumor,ovarian cancer,krukenberg tumor,metastasis
                Oncology & Radiotherapy
                ovary, neoplasm, tumor, ovarian cancer, krukenberg tumor, metastasis

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