cancers Review Rare Distant Metastatic Disease of Ovarian and Peritoneal Carcinomatosis: A Review of the Literature Nikolaos Thomakos 1, Michail Diakosavvas 1 , Nikolaos Machairiotis 2,*, Zacharias Fasoulakis 1 , Paul Zarogoulidis 3 and Alexandros Rodolakis 1 1 1st Department of Obstetrics and Gynecology, Alexandra Hospital, Gynecologic Oncology Unit, University of Athens, Athens 115 28, Greece 2 Department of Obstetrics & Gynecology, Department of Obstetrics-Gynaecology, Royal Oldham Hospital, Pennine Accute Trust, Oldham OL12JH, UK 3 3rd Department of Surgery, “AHEPA” University Hospital, Aristotle University of Thessaloniki, Thessaloniki 546 36, Greece * Correspondence: [email protected] Received: 9 June 2019; Accepted: 22 July 2019; Published: 24 July 2019 Abstract: Background: Although metastases of ovarian and peritoneal carcinomatosis are most commonly found within the peritoneal cavity, there is a number of other rare distant sites that have been reported. Our goal is to provide an evidence-based summary of the available literature considering the rare distant metastatic sites of ovarian and peritoneal carcinomatosis. Methods: A comprehensive search of the literature was conducted, with Medline/PubMed being searched for cases of rare metastatic disease originated from primary ovarian and peritoneal cancer with related articles up to 2019 including terms such as “ovarian cancer”, “metastases”, “peritoneal” and others. Results: The most common mechanism of ovarian cancer metastases consists of primarily dissemination within the peritoneal cavity, while, rare and distant sites can either occur at the beginning or during the course of the disease and they are usually associated with hematogenous route and lymphatic invasion, having poor prognosis, with the least common sites being skin, bone, CNS, eye, placenta, central airways, rare lymph nodes, intra-abdominal organs, heart and breast. Conclusions: The occurrence of metastatic sites described in this review represents the most common rare distant metastatic sites, and even though their patterns of metastases are still not fully clarified due to the rarity of the reports, they offer valuable information considering the pathophysiology of the disease. Keywords: Ovarian cancer; distant; metastases; peritoneal cancer 1. Introduction Ovarian cancer is the seventh most common malignancy in women in developed countries, the second most common gynecologic cancer (9.4/100,000), but most importantly, the leading cause of cancer-related deaths in women (5.1/100,000), as the five-year survival rates are below 50%. The mean age of diagnosis is between 55 to 65 years, but it can affect a wide spectrum of ages, with the lifetime risk of developing ovarian cancer being 1.5%. The incidence increases with advanced age and family history of ovarian and breast cancer, which also represent the major risk factors [1,2]. The high mortality rates can be explained by the delayed diagnosis with that vast majority—more than 75%—of affected women being diagnosed at advanced stages of the disease due to lack or non-specific symptoms, and only 15% is confined to the primary site at the time of diagnosis. The most important prognostic factor, besides the histologic type, is the stage of cancer, as more than 60% has already metastasized to other tissues at the time of diagnosis [3]. Cancers 2019, 11, 1044; doi:10.3390/cancers11081044 www.mdpi.com/journal/cancers Cancers 2019, 11, 1044 2 of 17 Cancers 2019, 11, x FOR PEER REVIEW 2 of 17 Ovarian carcinoma usually remains locoregionally confined and metastasizes by direct extension from theOvarian ovarian tumorcarcinoma to neighbor usually pelvic remains organs, locoregionally such as the bladderconfined (17%) and andmetastasizes colon, or byby detachment direct of cancerextension cells from that the spread ovarian via tumor transperitoneal to neighbor pelvic dissemination. organs, such Exfoliatedas the bladder cells (17%) are and transported colon, or by peritonealby detachment fluid and of cancancer metastasize cells that inspread every via intraperitoneal transperitoneal structure, dissemination. such asExfoliated the peritoneum cells are and omentumtransported (86%), by bowel peritoneal (50%), fluid and and spleen can (20%).metastasize Metastases in every through intraperitoneal the vasculature structure, are such less as common the in ovarianperitoneum cancer and (16%), omentum with the(86%), most bowel common (50%), sitesand sp beingleen pleura(20%). Metastases (33%), liver through (26%), the and vasculature lung (15%) [4]. On theare contraryless common lymphatic in ovarian metastases cancer (16%), both with inovarian the most and common peritoneal sites being cancer, pleura is quite (33%), common liver (26%), as 70% of ovarianand lung cancer (15%) patients [4]. On the present contrary with lymphatic pelvic and meta/orstases para-aortic both in lymphovariannode and peritoneal involvement cancer, (ovarian is andquite peritoneal common carcinomas as 70% of are ovarian indistinguishable cancer patients and present are considered with pelvic a and/or single para-aortic clinical entity lymph with node shared involvement (ovarian and peritoneal carcinomas are indistinguishable and are considered a single pathogenesis and clinical features) [2,3,5]. clinical entity with shared pathogenesis and clinical features) [2,3,5]. Although, as previously mentioned, metastases of ovarian and peritoneal carcinomatosis are Although, as previously mentioned, metastases of ovarian and peritoneal carcinomatosis are mostmost commonly commonly found found within within the the peritoneal peritoneal cavity,cavity, there is is a a number number of of other other rare rare distant distant sites sites that that havehave been been reported. reported. These These can can either either occur occur atat thethe beginning or or during during the the co courseurse of the of thedisease disease and and theythey are usuallyare usually associated associated with hematogenouswith hematogenous route route and lymphatic and lymphatic invasion, invasion, having having poor prognosis, poor withprognosis, the least with common the least sites common being sites mainly being skin, mainly bone, skin, central bone, central nervous nervous system system (CNS), (CNS), eye, eye, breast, bronchus-trachea,breast, bronchus-trachea, heart-pericardium, heart-pericardium, rare lymph rare lymph nodes nodes and extremelyand extremely rare rare intra-abdominal intra-abdominal sites (Figuresites1 ,(Figure Table1 )[1, 5Table–8]. 1) [5–8]. Ovarian cancer Lymph Rare intra- Placenta Eye CNS Bones Heart Breast Bronchus Skin and Trachea Nodes abdominal and Fetal Hematoge Hematoge- Hematog Hematoge- Direct Lymphatic Lymphatic Hematogenou Direct -nous nous Hematoge- enous nous spread invasion Spread nous spread Spread s spread invasion (unspecified) spread spread spread Lymphatic Hematoge Lymphatic Hematogen Lymphatic Direct Direct Lymphatic Lymphatic Spread Spread -nous Spread ous spread Spread invasion invasion (unspecified) Spread spread (unspecified) Direct Direct Iatrogenic Lymphatic spread invasion Spread invasion Transperitone aly Figure 1. Rare distant metastatic sites of ovarian cancer and their route of metastasis. Figure 1. Rare distant metastatic sites of ovarian cancer and their route of metastasis. Table 1. Metastatic sites, frequency and prognosis and peritoneal carcinomatosis. MetastaticTable Site 1. Metastatic sites, frequency Frequency and prognosis and Prognosis peritoneal (Median carcinomatosis. Survival) Ref. CNS 0.3–12% 8.2 monthsPrognosis [9–13] Metastatic Site Frequency Ref. Eye 9 cases reported until 2009 6.5–16(Median months Survival) [14–21] CNSSkin 0.3–12% 1.2% 12 months (1–418.2 months months) [[9–13]22–27] Eye 9 cases reported until 2009 6.5–16 months [14–21] Bones <3.74% 7.5 months [28,29] 12 months Skin Supraclavicular1.2% 4% NR [22–27] (1–41 months) Lymph nodesBones Inguinal 0.8–3%<3.74% NR7.5 months [28,29][30–39] SupraclavicularMediastinal-Cardiophrenic 2.3%4% 68.9–72.3 monthsNR Lymph Inguinal 0.8–3% NR Breast 0.03–0.6% 16 months (13 days–3.5 months)[30–39] [40–43] nodes Mediastinal- 2%–3% in epithelial Spleen 2.3% 68.9–72.3NR months Rare Cardiophrenic ovarian cancer [44–47] intra-abdominal Depends on type and stage 16 months Breast Gastrointestinal 0.03–0.6% <15 months [40–43] of diagnosis (13 days–3.5 months) Spleen 2%–3% in epithelial ovarian cancer NR Rare intra-Bronchus and Trachea 10 reports until 2018 6–24 months [5,48,49] Gastrointesti [44–47] abdominal HeartDepends on type 2.4–4% and stage of diagnosis 3–72 months<15 months [22,32,50,51] nal 3 cases reported until now BronchusPlacenta and andTrachea Fetus 10 reports until 2018 NR6–24 months [5,48,49] [52–54] to placenta 0 to fetus Heart 2.4–4% 3–72 months [22,32,50,51] CNS: Central Nervous System, NR: Not Reported. Cancers 2019, 11, 1044 3 of 17 2. Methods and Objectives A comprehensive search of the literature was conducted using the following keywords: “ovarian cancer”, “distant metastases”, “peritoneal” and others. Medline/PubMed was carried out for our primary search. The aim of this review is to provide an evidence-based summary of the available literature considering the rare distant metastatic sites of ovarian and peritoneal carcinomatosis and their early recognition based on the fact that further update of current bibliography may expand our knowledge and be essential in the improvement of the diagnostic and therapeutic approach. 3. Pathways and Metastatic Sites of Ovarian and Peritoneal Cancer 3.1.