Ovarian carcinoma: An overview of current status

doi: 10.18282/amor.v2.i5.143 REVIEW ARTICLE Ovarian carcinoma: An overview of current status Yogita Lugani1, Smita Asthana2*, Satyanarayana Labani2 ...
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doi: 10.18282/amor.v2.i5.143


Ovarian carcinoma: An overview of current status Yogita Lugani1, Smita Asthana2*, Satyanarayana Labani2 1 2

Department of Biotechnology, Punjabi University, Patiala, Punjab, India National Institute of Cancer Prevention and Research (NICPR-ICMR), Noida, India

Abstract: Ovarian carcinoma is one of the leading causes of morbidity and mortality associated with carcinomas affecting women. It comprises a heterogeneous group of neoplasms that represents the seventh most lethal malignancy in women worldwide, and is a major cause of death from gynecological carcinoma. Specific to different geographical locations all over the globe, there are variations in the magnitude and trends of ovarian carcinoma, and the scenario of the disease keeps changing. As such, it is necessary to update and review the existing study on ovarian carcinoma. Reviews on ovarian carcinoma from 2000 to 2015 were extracted from PubMed and Google Scholar, and a few selected landmark studies that incorporated old data were also included. The focus of the present study is to consolidate an updated global view on epithelial ovarian carcinoma, the most prevalent type of ovarian carcinoma. This article covers the epidemiology, types, diagnosis, prognosis, and treatment of epithelial ovarian carcinoma. Keywords: ovarian carcinoma; epidemiology; diagnosis; prognosis; treatment Citation: Lugani Y, Asthana S, Labani S. Ovarian carcinoma: An overview of current status. Adv Mod Oncol Res 2016; 2(5): 261–270; http://dx.doi.org/10.18282/amor.v2.i5.143. *Correspondence to: Smita Asthana, National Institute of Cancer Prevention and Research (NICPR-ICMR), Noida, Uttar Pradesh 201 301, India; [email protected]

Received: 06th June 2016; Accepted: 21st July 2016; Published Online: 17th October 2016

Introduction Ovarian carcinoma comprises a heterogeneous group of neoplasms that represents the seventh most lethal malignancy affecting women worldwide (and eighteenth most common carcinoma overall) and is a major cause of gynecological carcinoma-related death in the western world. Previously, it has been suggested that the origin of most ovarian carcinomas is from the ovarian surface epithelium or postovulatory inclusion cysts formed after follicular rupture and repair[1,2]. There are many hypotheses on the occurrence of ovarian carcinoma among women. According to the “incessant ovulation” hypothesis, a wound is created during every ovulation, which results in increased cell proliferation to repair the epithelial cells. This may result in the increased likelihood of DNA damage and carcinogenic mutation[3,4]. In another hypothesis regarding gonadotropin-based stimulation, the incidence rate of ovarian carcinoma increases after

menopause with increased levels of gonadotropin[5-8]. According to the inflammation hypothesis, inflammation may be involved during the process of ovulation, which is associated significantly with ovarian carcinoma [9]. Meanwhile, the hormonal hypothesis proposes that the ovarian surface epithelium is stimulated by excess androgen and hence, increases the risk of ovarian carcinoma; however, progesterone stimulation has demonstrated protective effect and reduces the chances of carcinoma[6]. Approximately 75% of women present with the disease are diagnosed in advanced stages[10]. On the basis of histology, ovarian carcinoma is classified into three main categories based on the ovarian tissues that cause carcinoma: epithelial ovarian tumor (which covers the ovary and its subtypes that include serous, mucinous, endometrioid, and clear cell), germ cell tumor (cells that become ova and its subtypes including dysgerminoma, immature teratoma, and yolk sac tumor), and sex cord-stromal cell tumor (which produces hormones with subtypes of malignant granulose cell tumor and Sertoli-Leydig cell tu-

Copyright © 2016 Lugani Y, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Ovarian carcinoma: An overview of current status

mor)[11]. The relative frequencies of the subtypes of ovarian carcinoma are shown in Figure 1. The maximum frequency (approximately 85%) of ovarian carcinoma is found within the epithelial cells[12]. Serous tubal intraepithelial carcinoma is a relatively recent finding in understanding the development of ovarian carcinoma and it represents the precursor lesion in high-grade serous ovarian carcinoma[13].

Figure 1. Relative frequencies sub-types[6]




The cause of ovarian carcinoma is unknown; however, a positive family history of breast and ovarian carcinoma is found to be the strongest risk factor based on epidemiologic studies[14]. There are many factors that contribute to the poor prognosis of ovarian carcinoma patients such as localization within the peritoneal cavity, absence of early symptoms, difficulty in complete eradication by surgery, and chemotherapy resistance among patients, resulting in a five-year survival rate of 45%[15]. Antibody therapy, immune checkpoint inhibitors, vaccine strategies, adoptive cell therapy, and combinatorial immunotherapy are all used for the treatment of the disease[16]. There are numerous review papers discussing ovarian carcinoma’s origin and its development [17], types and subtypes[13,18], diagnosis[19,20], prognosis[21], and treatment[16,22-24]. As such, there is a need to review and update existing information on ovarian carcinoma. The focus of the present study is to consolidate the updated global view on epithelial ovarian carcinoma (EOC) as it is one of the most prominent gynecological carcinomas. This review covers the epidemiology, diagnosis, prognosis, and treatment of epithelial ovarian carcinoma.

Epidemiology The incidence of ovarian carcinoma is greater in high income countries compared to middle and low income countries. In 2012, approximately 239,000 cases were recorded, which account for nearly 4% of all new cases

of carcinoma in women (2% overall). Around the world, the incidence rate of ovarian carcinoma is 11 per 100,000 in Central and Eastern Europe, 5 per 100,000 in Africa, 11.7 per 100,000 in the US, 5.2 per 100,000 in Brazil, and 4.1 per 100,000 in China[25]. In Europe, approximately 65,697 new cases are estimated every year with 41,448 deaths[26]. It has been reported by the US Center for Disease Control and Prevention that about 20,000 women are diagnosed with ovarian carcinoma every year and 14,500 die every year from the disease[27]. In the past five decades, although the mortality rate for many solid tumors has decreased, the mortality rate for ovarian carcinoma remained static with an overall five-year survival rate of 44.2%[28]. A woman’s lifetime risk of developing invasive ovarian carcinoma is 1 in 75, and the lifetime risk of dying from it is 1 in 102[29]. In Germany, approximately 9,600 women develop malignant ovarian tumors every year and 5,500 women died from ovarian carcinoma[30]. Epithelial ovarian carcinoma (EOC) is responsible for the death of 14,030 out of 22,240 diagnosed cases in the US, and the cure rate of this disease was found to be less than 40% owing to the advanced stage of the disease at the time of diagnosis[15]. The aforementioned data succinctly illustrate ovarian carcinoma as one of the most serious gynecologic malignancies, responsible for the highest number of fatality. Different morphological subtypes of ovarian carcinoma possess different pathogenesis with distinct molecular alterations, different natural history, and prognosis[31-33]. In India, the ovarian cancer incidence (age-adjusted rate per 100,000) in different population-based cancer registries is reported to range from 1.7 to 15.2 for the year 2012 to 2014. An increasing trend of this cancer has been observed since 1982 to date. The projected number of cases for this cancer in India for 2015 and 2020 are 45,231 and 59,276, respectively[34].

Risk factors Multiple factors are involved in the prevalence of ovarian carcinoma; among these factors, a positive family history of breast and ovarian carcinomas is one of the strongest risk factor proven by epidemiologic studies[14,35]. Age and other environmental factors could also be associated with the risk of getting the disease. Nonetheless, there is no clear evidence to date on the association between industrial exposure of carcinogens or therapeutic radiations and ovarian carcinoma [36]. In contrast, various reproductive factors, e.g. (multi) parity and oral contraceptive use, breast feeding, tubal ligation, and hysterectomy are involved in the decreased risk of ovarian carcinoma[37-40]. Ovarian carcinoma appears to be part of the family’s phenotype of germ line mutations in

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BRCA genes (BRCA1 and BRCA2) and it is responsible for 30% lifetime risk of developing ovarian carcinoma in women up to the age of 70 years old[41]. A significant reduction in the occurrence of ovarian carcinoma owing to the use of oral contraceptives has been reported previously and this reduction is related to the alteration of the BRCA1 and BRCA2 genes. The overall benefits and harm of oral contraceptives depend on the duration of use and time[42,43]. The gene expression profile involves genetic instability with the mutation of genes (PTEN, AR1D1A, CTNNB1, KRAS, BRAF, ERBB2, TP53), over expression of genes (HNF-1 beta, HER2/neu, AKT, HLA-G, APO-E), or microsatellite instability that is associated with type I and type II ovarian tumors[18]. Women being treated for infertility are highly prone to experiencing ovarian carcinoma due to the increased levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH)[44,45].

Types of epithelial ovarian carcinoma The dualistic model categorizes EOC into two groups, designated as type I and type II[14,28]. A better model of two broad categories, namely type I and type II of ovarian carcinogenesis, has provided the basis of new histopathological, molecular, and genetic studies[18]. Type I tumors are slow-growing indolent neoplasms, and arise from a well-defined precursor, atypical hyperplasia. These tumors are confined to the ovary at the time of diagnosis and do not show TP53 mutations within a stable genome. However, in the case of type I tumor, somatic mutations are frequently found to be associated with certain genes[46]. Type I tumor includes low-grade serous carcinoma, mucinous carcinoma, clear cell carcinoma, and endometrioid adenocarcinoma. Type II tumors are high-grade clinically with more aggressive neoplasms, genetically highly unstable, with a majority of them exhibiting TP53 mutations and diagnosed at an advanced stage. It has been reported in previous studies that type II tumors (which includes high-grade serous carcinoma) may originate from the epithelium of the fimbrial portion of the fallopian tube[47-50] and/or the ovarian surface epithelium. The different types and subtypes of EOC are shown in Figure 2.

Type I tumor Low-grade serous carcinoma. The classification of serous carcinoma as low-grade and high-grade has been adapted in United Kingdom[51] and presently, many gynecological pathologists use this two-tiered grading system that was originally proposed by the MD Anderson Group (Houston, Texas, USA). Low-grade serous carcinoma is thought to arise in a well-defined adenoma-carcinoma sequence in a stepwise fashion, from a benign

Figure 2. Different types and subtypes of epithelial ovarian carcinoma

serous cystadenoma through a serous borderline tumor to an invasive low-grade serous carcinoma. In this type of tumor, there is no necrosis or multinucleation with moderate atypia, and less than or equal to 12 mitosis per 10 high power fields. Psammoma bodies are very common, with glands and papillae surrounded by clefts or nonepithelial lined space and intracytoplasmic mucin[52]. Low-grade serous carcinoma is not associated with TP53 mutations; however, two-third of its cases are found to be associated with KRAS or BRAF mutation, which are found to be mutually exclusive[53]. Low-grade serous carcinomas do not respond well to traditional chemotherapeutic agents, therefore some oncologists do not administer adjuvant chemotherapy. Mucinous carcinoma. It is relatively uncommon, affecting patients from a wide range of age including occasionally children and adolescents[54,55]. Smoking is found to be an important risk factor associated with benign, borderline, and mucinous carcinoma[56,57]. The common features favoring metastasis in ovarian mucinous carcinoma include small and bilateral tumors, nodule pattern of ovarian involvement, destructive stromal invasion, single cell infiltration with signet ring cells, cells floating in mucin, extraovarian spread, and marked lymphovascular space invasion. Most of the ovarian mucinous carcinomas are of intestinal type; however, many of these contain goblet cells and even occasionally paneth or neuroendocrine cells. Similar to low-grade serous carcinoma, ovarian mucous carcinoma commonly exhibits KRAS mutations. However, unlike low-grade serous carcinoma, BRAF mutation is not a feature of ovarian mucous carcinoma[58]. Clear cell carcinoma. Clear cell carcinoma is mainly composed of cells with abundant clear cytoplasm and prominent cell membrane, existing approximately in equal frequency to endometrioid adenocarcinoma. Clear cell carcinoma is usually negative for estrogen receptor (ER), Wilms Tumor (WT1) and p53 genes (triple nega-

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tive); however, it is usually negative or positive for the p16 gene. A majority of such carcinomas are endometrial in origin and are diagnosed at an early stage (stage I or II). Even though the prognosis of such carcinoma is relatively poor, the prognosis of a stage I disease is relatively good. Such neoplasms exhibit low proliferation index and they are resistant to the transitional chemotherapeutic agents used in the treatment of ovarian carcinoma[13]. Previously, no molecular events with regard to clear cell carcinoma were identified[59], but the ARID1A mutation has since been found to be involved in such cases[60]. Endometrioid adenocarcinoma. Endometrioid adenocarcinomas are low-grade tumors with a low staging (stage I); however, some of these tumors could potentially be high-grade and are usually unilateral, with 10% being bilateral. They usually arise from endometrial tissue implantation (especially an endometriosis cyst) or a pre-existing borderline adenofibroma[61,62]. In ovarian endometrioid carcinomas, mutations of the phosphatase and tensin homolog (PTEN), which are deleted from the chromosome 10 tumor suppressor, are found frequently[63]. Endometrioid adenocarcinoma of the ovary exhibits similar molecular events to that of uterine endometrioid adenocarcinoma, which include PTEN, β-catenin, KRAS, and PIK3CA mutations with microsatellite instability[64].

Type II tumor High grade serous carcinoma. High-grade serous carcinoma is more common than low-grade serous carcinoma. This type of tumor is high-grade in nature from the start, evolving quickly, and is found frequently at the advanced stage. It has been previously reported in the literature that a number of high-grade ovarian serous carcinomas actually originate from the epithelium of the distal fimbrial portion of the fallopian tube[65-68]. Necrosis and multinucleate cells are found within high-grade serous carcinoma in moderate to marked nuclear atypia, with greater than 12 mitosis per 10 high power fields. In such cases, TP53 mutation or p53 dysfunction is often implicated, and it appears to occur during early neoplastic development [69-71]. The survival rate of patients who underwent chemotherapy is significantly better with low-grade neoplasms compared to those with high-grade tumors[72].

Screening and diagnosis The diagnosis of ovarian carcinoma at an early stage is very difficult owing to the absence of specific symptoms in patients, which results in decreased survival rate among patients[20]. Imaging is an important parameter for

evaluating the extent and location of the spread of ovarian carcinoma and assessing its appropriate management, as encouraged by the International Federation of Gynecologists and Obstetricians (FIGO) committee[73]. Ultrasound, computed tomography (CT) scan, and magnetic resonance imaging(MRI) are routinely used imaging tools[19,20,74,75]. In addition, physical examination and trans-vaginal ultrasonography are used for the diagnosis of tumor and the cause of ovarian cysts is confirmed by exploratory laparotomy[74]. The screening of ovarian carcinoma can be improved using a combination of Symptom Index (SI) with a serum HE4 test or CA125 test [76]. The risk of ovarian cancer algorithm (ROCA) is a statistical algorithm used for the screening of EOC by calculating the risk of having a change-point based on a woman’s age and CA125 profile[77].

Different stages and grades The staging system for ovarian carcinoma, which has been formulated by the International Federation of Gynecologists and Obstetricians (FIGO), is surgically based after diagnosis on whether the carcinoma is limited to the ovary or has spread to other parts of the body. This staging system was revised in 2014 and different sub-stages of IC (i.e. IC1, IC2, and IC3), IIIA (i.e. IIIA1 and IIIA2), and IV (i.e. IVA and IVB) were introduced, with stage IIC removed from the previous system[78].

Prognosis Microarray studies have been used for the analysis of gene expressions in carcinoma cells[79] and seven microarray studies have been conducted for the prognosis of gene profiles in ovarian carcinoma cells [80]. In a recent study, different factors found associated with the prognosis of EOC include patient’s age, performance status, tumor stage and ascites, tumor grade, histopathologic subtype, obesity, surgical de-bulking, expression of genes (CYP4B1, CEPT1, CHMP4A), and immunological factors[21].

Treatment In most low-risk cases that are diagnosed in the early stage, surgery alone is able to cure the disease without adjuvant chemotherapy[81]. However, adjuvant chemotherapy is found to be effective in patients with a high-grade disease staging (FIGO IC)[82]. Presently, the adjuvant therapy is found to depend on the tumor’s stage and grade rather than its type[13]. However, some side effects may occur as a result of chemotherapy such as hair loss, mouth sores, hand and foot rashes, menopause,

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infertility, nausea, as well as vomiting. Sometimes, chemotherapy may also result in damages to the bone marrow, which leads to increased chances of infection. Therefore, chemotherapy is ineffective in patients who present these side effects, and other alternative treatments are needed for these patients[83]. The survival rate of 10%–30% has been observed in women with advanced ovarian carcinoma (stage III–IV) using surgical cytoreduction (total abdominal hysterectomy, bilateral salpingo-oophorectomy, pelvic and para-aortic lymph node removal, and omentectomy), followed by platinum-based chemotherapy[84]. In another study, it was concluded that bilateral oophorectomy at the time of hysterectomy resulted in increased risk of all-cause mortality, fatal and nonfatal coronary heart disease, and lung carcinoma[85]. A study conducted on platinum-sensitive patients diagnosed with ovarian carcinoma to compare the efficacy of single (platinum alone) versus combinational chemotherapies (platinum plus paclitaxel) concluded that patients administered with the combinational therapy had a significantly higher survival rate compared to those who received single chemotherapy[86]. A recent study reported that one weekly dose of paclitaxel is less toxic than three weekly doses[87]. The administration of cytotoxic drugs directly into the abdomen through intraperitoneal route increases the dose-intensity delivery to the residual tumor without any additional systemic toxicity[88]. Most molecular targeted drug therapies have been developed with the aim of blocking the receptors, ligands, or pathways. A monoclonal antibody, bevacizumab, is found to be useful in the treatment of ovarian carcinoma by inhibiting the vascular endothelial growth factor (VEGH)[22,24]. Nonetheless, bevacizumab is not a very effective treatment when used alone and hence, it is often used in combined chemotherapy in order to improve the outcome of ovarian cancer patients. Other anti-PD1-L1 monoclonal antibodies such as BMS-936559, MPDL3280A, MEDI4736, and MSB0010718C have been developed to treat ovarian carcinoma by enhancing immune function, which results in the inhibition of ligand/receptor interaction. This inhibition further reduces the response of T-lymphocyte by inhibiting the kinases involved in T-lymphocyte activation via phosphatase activity and other signaling pathways[89]. The use of biomarkers has been encouraged for the selection of ovarian carcinoma cells, but the identification of such markers has been challenging[22,90]. Currently, two markers have been identified, i.e. the mutation in BRCA gene, which is a marker for the deficiency of DNA repair through homologous recombination pathway; and folate receptor-α, which is overexpressed in this type of

carcinoma[22,92]. A new therapeutic concept for ovarian carcinoma involves optimal cytoreductive therapy, followed by molecular targeting therapy, intraperitoneal chemotherapy, and dose-dense chemotherapy[93]. Recently, the investigation of immune checkpoints (the immune system being turned off by carcinoma cells) represents a potent therapy against ovarian carcinoma[16,90]. Hormonal replacement therapy for carcinoma treatment has been reported by Lipkowitz and Kohn[94]. Fertility Sparing Surgery (FSS) is another promising,and safe approach used to treat ovarian carcinoma. FSS therapy has been successfully used recently for the treatment of borderline ovarian tumors and early stage epithelial ovarian cancer[95,96]. Although the use of FSS is very effective in preserving childbearing capacity, its application is controversial owing to the use of in vitro fertilization after surgery[97]. The use of BRAF inhibitors (vemurafenib and dabrafenib) and MEK inhibitor (trametinib) offers a more hopeful option for ovarian carcinoma patients and these inhibitors are also used in rational pathway-targeted therapeutic combinations such as co-targeting PI3-kinase signaling, as well as dosing strategies to prevent or delay drug resistance and achieve long-term survival benefit [98]. Poly(ADP-ribose) polymerase (PARP) inhibitors have been approved by the US Food and Drug Administration (FDA) as a monotherapy in patients previously treated with chemotherapy, and the inhibitors have also shown synergistic action with anti-angiogenic agents due to oxygenation changes. The use of these inhibitors has opened up a whole new treatment option for BRCA-deficient ovarian cancer patients in the US and Europe[99,100]. The suppression of PTTG1 (pituitary tumor transforming gene) expression and the activation of p53 expression were shown by DNA-damaging drugs (doxorubicin and bleomycin), which induce cell cycle arrest to repair the damaged DNA. In addition, p53 also promotes programmed cell death by regulating cellular transcription[101]. The first human trial of p53-targeting modified vaccinia Ankara (p53MVA) vaccine in patients with advanced refractory gastrointestinal cancers demonstrated enhanced T-cell recognition of p53 following vaccination[102]. Anti-PD-1 immunotherapy drug nivolumab was found to be effective in a previous study conducted on patients of advanced platinum-resistant ovarian cancer[103].

Conclusion Ovarian cancer is the most lethal malignancy in women, being the major cause of death with a high incidence rate to the extent of 15/100,000. The frequency of EOC is high among all types of ovarian cancer. EOC is divid-

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ed into two different types (i.e., Type I versus II) based on the risk factors involved, along with the stage and genes implicated during carcinogenesis. Ultrasound, CT, and MRI are the most commonly used techniques for the screening and diagnosis of ovarian cancer. Meanwhile, surgery, chemotherapy, or a combination of both is used for treatment purposes. Many newer therapies have also been introduced for the treatment of the disease. Currently, there is on-going research focusing on the development of new effective screening methods to detect the disease at an early stage.



Author contributions SA and LS conceptualized the review and finalized the manuscript preparation. YL performed the literature search and drafted the manuscript.


Acknowledgments We thank Dr Priti Aggarwal, Professor at Era Medical College, Lucknow for reviewing and improving the manuscript.



Conflict of interest The authors declare no potential conflict of interest with respect to the research, authorship, and/or publication of this article.


References 1.







Mok SC, Kwong J, Welch WR, Samimi G, Ozbun L, et al. Etiology and pathogenesis of epithelial ovarian cancer. Dis Markers 2007; 23(5–6): 367–376. doi: 10.1155/2007/ 474320. Landen CN Jr, Birrer MJ, Sood AK. Early events in the pathogenesis of epithelial ovarian cancer. J Clin Oncol 2008; 26(6): 995–1005. doi: 10.1200/JCO.2006.07.9970. Fathalla MF. Incessant ovulation – A factor in ovarian neoplasia? Lancet 1971; 2(7716): 163. doi: 10.1016/ S0140-6736(71)92335-X. Tortolero-Luna G, Mitchell MF. The epidemiology of ovarian cancer. J Cell Biochem 1995; 59(Suppl 23): 200–207. doi: 10.1002/jcb.240590927. Rao BR, Slotman BJ. Endocrine factors in common epithelial ovarian cancer. Endocr Rev 1991; 12(1): 14–26. doi: 10.1210/edrv-12-1-14. Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Carcinoma Inst 1998; 90(23): 1774– 1786. doi: 10.1093/jnci/90.23.1774. Kuroda H, Mandai M, Konishi I, Tsuruta Y, Kusakari T, et al. Human ovarian surface epithelial (OSE) cells ex-







press LH/hCG receptors, and hCG inhibits apoptosis of OSE cells via up-regulation of insulin-like growth factor-1. Int J Cancer 2001; 91(3): 309–315. doi: 10.1002/ 1097-0215(200002)9999:99993.0.CO;2-0. Mandai M, Konishi I, Kuroda H, Fujii S. LH/hCG action and development of ovarian cancer – A short review on biological and clinical/epidemiological aspects. Mol Cell Endocrinol 2007; 269(1–2): 61–64. doi: 10.1016/ j.mce.2006.11.014. Bonello N, McKie K, Jasper M, Andrew L, Ross N, et al. Inhibition of nitric oxide: Effects on interleukin-1 beta-enhanced ovulation rate, steroid hormones, and ovarian leukocyte distribution at ovulation in the rat. Biol Reprod 1996; 54(2): 436–445. doi: 10.1095/biolreprod54.2.436. The oncology committee of the International Federation of Gynecology and Obstetrics. FIGO news: Changes to the 1985 FIGO report on the result of treatment in gynaecological cancer. Int J Gynecol Obstet 1987; 25(1): 87–88. doi: 10.1016/0020-7292(87)90233-5. National Ovarian Cancer Coalition [Internet]. Dallas, Texas [cited 2015 Oct 17]. Available from: http://www. ovarian.org/types_and_stages.php. McCluggage WG. Morphological subtypes of ovarian carcinoma: A review with emphasis on new developments and pathogenesis. Pathol 2011; 43(5): 420–432. doi: 10.1097/PAT.0b013e328348a6e7. Kuhn E, Kurman RJ, Vang R, Sehdev AS, Han G, et al. TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma — Evidence supporting the clonal relationship of the two lesions. J Pathol 2012; 226(3): 421–426. doi: 10.1002/ path.3023. Amos CI, Struewing JP. Genetic epidemiology of epithelial ovarian cancer. Cancer 1993; 71(Suppl S2): 566– 572. doi: 10.1002/cncr.2820710212. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011. CA: Cancer J Clin 2011; 61(4): 212–236. doi: 10.3 322/caac.20121. Chester C, Dorigo O, Berek JS, Kohrt H. Immunotherapeutic approaches to ovarian cancer treatment. J Immunother Cancer 2015; 3(7): 1–10. doi: 10.1186/s40425-01 5- 0051-7. Kurman RJ, Shih IM. The origin and pathogenesis of epithelial ovarian cancer: A proposed unifying theory. Am J Surg Pathol 2010; 34(3): 433–443. doi: 10.1097/PAS. 0b013e3181cf3d79. Koshiyama M, Matsumura N, Konishi I. Recent concepts of ovarian carcinogenesis: Type I and Type II. BioMed Res Int 2014; 2014: 1–11. doi: 10.1155/2014/934261. Iyer VR, Lee SI. MRI, CT, and PET/CT for ovarian cancer detection and adnexal lesion characterization. Am J Roentgenol 2010; 194(2): 311–321. doi: 10.2214/ AJR.09.3522.

266 doi: 10.18282/amor.v2.i5.143

Lugani Y, et al.













Burges A, Schmalfeldt B. Ovarian cancer: Diagnosis and treatment. Dtsch Arztebl Int 2011; 108(38): 635–641. doi: 10.3238/arztebl.2011.0635. Ezzati M, Abdullah A, Shariftabrizi A, Hou J, Kopf M, et al. Recent advancements in prognostic factors of epithelial ovarian carcinoma. Int Sch Res Notices 2014; 2014: 1–10. doi: 10.1155/2014/953509. Raja FA, Chopra N, Ledermann JA. Optimal first-line treatment in ovarian cancer. Ann Oncol 2012; 23 (Suppl 10): 118–127. doi: 10.1093/annonc/mds315. Kim J, Coffey DM, Creighton CJ, Yu Z, Hawkins SM, et al. High-grade serous ovarian cancer arises from fallopian tube in a mouse model. Proc Natl Acad Sci USA 2012; 109(10): 3921–3926. doi: 10.1073/pnas.1117135109. Garcia A, Singh H. Bevacizumab and ovarian cancer. Ther Adv Med Oncol 2013; 5(2): 133–141. doi: 10.1177/ 1758834012467661. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, et al. GLOBOCAN 2012 v1.0, Cancer incidence and mortality worldwide: IARC Cancer Base No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013 [cited 2015 Nov 25]. Available from: http://globocan.iarc.fr. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, et al. GLOBOCAN 2008 v1.2, Cancer incidence and mortality worldwide: IARC Cancer Base No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer; 2010 [cited 2015 Nov 22]. Available from: http://globocan.iarc.fr. Angelina Jolie's effect: Risk factors for ovarian cancer! [Internet]. India: Zee Media Corporation Ltd. [cited 2015 Oct 17]. Available from: http://zeenews.india.com/news/ health/diseases-conditions/angelina-jolies-effect-risk-facto rs-for-ovarian-carcinoma_1566989.html. SEER Cancer Statistics Review 1975–2013. [Internet]. USA: National Cancer Institute; 2010 [cited 2015 Nov 20]. Available from: http://seer.cancer.gov/archive/ csr/1975_2013/results_merged/topic_survival.pdf. Ovarian cancer statistics. [Internet]. Washington, DC: Ovarian Cancer National Alliance; 2015 [cited 2015 Nov 20]. Available from: http://www.ovariancancer.org/wpcontent/uploads/2015/06/Statistics-2015_final.pdf. Husmann G, Kaatsch P, Katalinic A, Bertz J, Haberland J, et al. (German) [Krebs in Deutschland: 2005/2006; Häufigkeiten und trends; Eine gemeinsame Veröffentlichung des Robert Koch-Instituts und der Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V.]. Berlin: Robert Koch-Institut; 2010. Available from: http: //www.rki.de/DE/Content/Gesundheitsmonitoring/Gesundheitsberichterstattung/GBEDownloadsB/KID2010.pdf? _blob=publicationFile. Shih IM, Kurman RJ. Ovarian tumorigenesis: A proposed model based on morphological and molecular genetic






37. 38.





analysis. Am J Pathol 2004; 164(5): 1511–1518. doi: 10.1016/S0002-9440(10)63708-X. McCluggage WG. My approach to and thoughts on the typing of ovarian carcinomas. J Clin Pathol 2008; 61(2): 152–163. doi: 10.1136/jcp.2007.049478. Soslow RA. Histologic subtypes of ovarian carcinoma: An overview. Int J Gynecol Pathol 2008; 27(2): 161–174. doi: 10.1097/PGP.0b013e31815ea812. Three year report of population based cancer registries 2012-2014: Incidence, distribution, trends in incidence rates and projections of burden of cancer. [Internet]. Bengaluru, India: National Centre for Disease Informatics and Research, National Cancer Registry Programme, and Indian Council Medical Research [cited 2016 May 2016]. Available from: http://www.ncrpindia.org/ALL_NCRP_ REPORTS/PBCR_REPORT_2012_2014/ALL_CONTEN T/Printed_Version.htm. Lagos VI, Perez MA, Ricker CN, Blazer KR, Santiago NM, et al. Social-cognitive aspects of underserved Latinas preparing to undergo genetic cancer risk assessment for hereditary breast and ovarian cancer. Psychooncology 2008; 17(8): 774–782. doi: 10.1002/pon.1358. Ricciardelli C, Oehler MK. Diverse molecular pathways in ovarian cancer and their clinical significance. Maturitas 2009; 62(3): 270–275. doi: 10.1016/j.maturitas.2009. 01. 001. Schuijer M, Berns EMJJ. TP53 and ovarian cancer. Hum Mutat 2003; 21(3): 285–291. doi: 10.1002/humu.10181. Negri E, Franceschi S, Tzonou A, Booth M, La Vecchia C, et al. Pooled analysis of 3 European case-control studies: I. Reproductive factors and risk of epithelial ovarian cancer. Int J Cancer 1991; 49(1): 50–56. doi: 10.1002/ijc. 29 10490110. Franceschi S, La Vecchia C, Booth M, Tzonou A, Negri E, et al. Pooled analysis of 3 European case-control studies of ovarian cancer: II. Age at menarche and at menopause. Int J Cancer 1991; 49(1): 57–60. doi: 10.1002/ijc. 2910490111. Franceschi S, Parazzini F, Negri E, Booth M, La Vecchia C, et al. Pooled analysis of 3 European case-control studies of epithelial ovarian cancer: III. Oral contraceptive use. Int J Cancer 1991; 49(1): 61–65. doi: 10.1002/ijc. 2910490112. Ford D, Easton DF, Bishop DT, Narod SA, Goldgar DE. Risks of cancer in BRCA1-mutation carriers. Lancet 1994; 343(8899): 692–695. doi: 10.1016/S0140-6736(94)91578-4. Havrilesky LJ, Gierisch JM, Moorman PG, Coeytaux RR, Peragallo Urrutia R, et al. Oral contraceptive use for the primary prevention of ovarian cancer. Evidence Report/Technology Assessment No. 212. (Prepared by the Duke Evidence-based Practice Center under Contract No. 290-2007-10066-I.) AHRQ Publication No. 13-EHC033EF [Internet]. Rockville, MD: Agency for Healthcare Re-

267 doi: 10.18282/amor.v2.i5.143

Ovarian carcinoma: An overview of current status













search and Quality [cited 2015 Oct 20]. Available from: https://effectivehealthcare.ahrq.gov/ehc/products/416/1530/ cancer-ovarian-contraceptives-executive-130611.pdf. Havrilesky LJ, Moorman PG, Lowery WJ, Gierisch JM, Coeytaux RR, et al. Oral contraceptive pills as primary prevention for ovarian cancer: A systematic review and meta-analysis. Obstet Gynecol 2013; 122(1): 139–147. doi: 10.1097/AOG.0b013e318291c235. Tomao F, Russo GL, Spinelli GP, Stati V, Prete AA, et al. Fertility drugs, reproductive strategies and ovarian cancer risk J Ovarian Res 2014; 7(51): 1–18. doi: 10.1186/17572215-7-51. Risch HA, Marrett LD, Howe GR. Parity, contraception, infertility, and the risk of epithelial ovarian cancer. Am J Epidemiol 1994; 140(7): 585–597. Kurman RJ, Shih IM. Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—Shifting the paradigm. Hum Pathol 2011; 42(7): 918–931. doi: 10.1016/j.humpath.2011.03.003. Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJJ, et al. Dysplastic changes in prophylactically removed fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001; 195(4): 451– 456. doi: 10.1002/path.1000. Piek JMJ, Kenemans, P, Verheijen RHM. Intraperitoneal serous adenocarcinoma: A critical appraisal of three hypotheses on its cause. Am J Obstet Gynecol 2004; 191(3): 718–732. doi: 10.1016/j.ajog.2004.02.067. Maeda D, Takazawa Y, Ota S, Takeuchi Y, Seta A, et al. Bilateral microscopic adenocarcinoma of the fallopian tubes detected by an endometrial cytologic smear. Int J Gynecol Pathol 2010; 29(3): 273–277. doi: 10.1097/PGP. 0b013e3181c30301. Przybycin CG, Kurman RJ, Ronnett BM, Shih IM, Vang R. Are all pelvic (nonuterine) serous carcinomas of tubal origin? Am J Surg Pathol 2010; 34(10): 1407–1416. doi: 10.1097/PAS.0b013e3181ef7b16. Royal College of Pathologists. Datasets for the histopathological reporting of neoplasms of the ovaries and fallopian tubes and primary carcinomas of the peritoneum. London: Royal College of Pathologists; 2008. Silva EG, Deavers MT, Malpica A. Patterns of low-grade serous carcinoma with emphasis on the nonepitheliallined spaces pattern of invasion and the disorganised orphan papillae. Int J Gynecol Pathol 2010; 29(6): 507– 512. doi: 10.1097/PGP.0b013e3181e31f74. Vang R, Shih IM, Kurman RJ. Ovarian low-grade and high-grade serous carcinoma: Pathogenesis, clinicopathologic and molecular biologic features, and diagnostic problems. Adv Anat Pathol 2009; 16(5): 267–282. doi: 10.1097/PAP.0b013e3181b4fffa. Seidman JD, Horkayne-Szakaly I, Haiba M, Boice CR, Kurman RJ, et al. The histologic type and stage distribu-












tion of ovarian carcinomas of surface epithelial origin. Int J Gynecol Pathol 2004; 23(1): 41–44. doi: 10.1097/01. pgp.0000101080.35393.16. Köbel M, Kalloger SE, Santos JL, Huntsman DG, Blake Gilks C, et al. Tumor type and substage predict survival in stage I and II ovarian carcinoma: Insights and implications. Gynecol Oncol 2010; 116(1): 50–56. doi: 10.1016/ j.ygyno.2009.09.029. Jordan SJ, Whiteman DC, Purdie DM, Green AC, Webb PM. Does smoking increase risk of ovarian cancer? A systematic review. Gynecol Oncol 2006; 103(3): 1122– 1129. doi: 10.1016/j.ygyno.2006.08.012. Benito V, Lubrano A, Arencibia O, Medina N, Eva EA, et al. Serous and mucinous borderline ovarian tumors: Are there real differences between these two entities? Eur J Obstet Gynecol Reprod Biol 2010; 153(2): 188–192. doi: 10.1016/j.ejogrb.2010.07.024. Singer G, Oldt R III, Cohen Y, Wang BG, Sidransky D, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 2003; 95(6): 484–486. doi: 10.1093/jnci/ 95.6.484. Tan DSP, Kaye S. Ovarian clear cell adenocarcinoma: A continuing enigma. J Clin Pathol 2007; 60(4): 355–360. doi:10.1136/jcp.2006.040030. Wiegand KC, Shah SP, Al-Agha OM, Zhao Y, Tse K, et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N Engl J Med 2010; 363(16): 1532–1543. doi: 10.1056/NEJMoa1008433. Bell KA, Kurman RJ. A clinicopathologic analysis of atypical proliferative (borderline) tumors and well-differentiated endometrioid adenocarcinomas of the ovary. Am J Surg Pathol 2000; 24(11): 1465–1479. doi: 10.1097/ 00000478-200011000-00002. Stern RC, Dash R, Bentley RC, Snyder MJ, Haney AF, et al. Malignancy in endometriosis: Frequency and comparison of ovarian and extraovarian types. Int J Gynecol Pathol 2001; 20(2): 133–139. doi: 10.1097/00004347-200 104000-00004. Obata K, Morland SJ, Watson RH, Hitchcock A, Chenevix-Trench G, et al. Frequent PTEN/MMAC1 mutations in endometrioid but not serous or mucinous epithelial ovarian tumors. Cancer Res 1998; 58(10): 2095–2097. Catasús L, Bussaglia E, Rodríguez I, Gallardo A, Pons C, et al. Molecular genetic alterations in endometrioid carcinomas of the ovary: Similar frequency of beta-catenin abnormalities but lower rate of microsatellite instability and PTEN alterations than in uterine endometrioid carcinomas. Hum Pathol 2004; 35(11): 1360–1368. doi: 10. 1016/j.humpath.2004.07.019. Lee Y, Medeiros F, Kindelberger D, Callahan MJ, Muto MG, et al. Advances in the recognition of tubal intra-epithelial carcinoma: Applications to cancer screening

268 doi: 10.18282/amor.v2.i5.143

Lugani Y, et al.










75. 76.


and the pathogenesis of ovarian carcinoma. Adv Anat Pathol 2006; 13(1): 1–7. doi: 10.1097/01.pap.000020182 6.46978.e5. Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, et al. A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol 2007; 211(1): 26–35. doi: 10.1002/path.2091. Kindelberger DW, Lee Y, Miron A, Hirsch MS, Feltmate C, et al. Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 2007; 31(2): 161–169. doi: 10.10 97/01.pas. 0000213335.40358.47. Herrington CS, McCluggage WG. The emerging role of the distal fallopian tube and p53 in pelvic serous carcinogenesis. J Pathol 2010; 220(1): 5–6. doi: 10.1002/ path.2630. Ho CL, Kurman RJ, Dehari R, Wang TL, Shih IM. Mutations of BRAF and KRAS precede the development of ovarian serous borderline tumors. Cancer Res 2004; 64(19): 6915–6918. doi: 10.1158/0008-5472.CAN-04-2067. Sieben NLG, Macropoulos P, Roemen GMJM, Kolkman-Uljee SM, Jan Fleuren G, et al. In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours. J Pathol 2004; 202(3): 336– 340. doi: 10.1002/path.1521. Singer G, Stöhr R, Cope L, Dehari R, Hartmann A, et al. Patterns of p53 mutations separate ovarian serous borderline tumors and low- and high-grade carcinomas and provide support for a new model of ovarian carcinogenesis: A mutational analysis with immunohistochemical correlation. Am J Surg Pathol 2005; 29(2): 218–224. doi: 10.1097/01.pas.0000146025.91953.8d. Malpica A, Deavers MT, Lu K, Bodurka DC, Atkinson EN, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol 2004; 28(4): 496–504. doi: 10.1097/00000478-200404000-00009. Sala E. Ovarian cancer: imaging in treatment selection and planning with FIGO update. Cancer Imaging 2014; 14(Suppl 1): 1–2. doi: 10.1186/1470-7330-14-S1-O18. Pectasides D, Gaglia A, Arapantoni-Dadioti P, Bobota A, Valavanis C, et al. HER-2/neu status of primary breast cancer and corresponding metastatic sites in patients with advanced breast cancer treated with trastuzumab-based therapy. Anticancer Res 2006; 26(1): 647–653. Cannistra SA. Cancer of the ovary. N Engl J Med 2004; 351(24): 2519–2529. doi: 10.1056/NEJMra041842. Andersen MR, Goff BA, Lowe KA, Scholler N, Bergan L, et al. Use of a Symptom Index, CA125, and HE4 to predict ovarian cancer. Gynecol Oncol 2010; 116(3): 378– 383. doi: 10.1016/j.ygyno.2009.10.087. Skates, SJ. Ovarian cancer screening: Development of the Risk of Ovarian Cancer Algorithm (ROCA) and ROCA screening trials. Int J Gynecol Cancer 2012; 22(Suppl 1):













S24–S26. doi: 10.1097/IGC.0b013e318256488a. FIGO ovarian cancer staging. [Internet] [cited 2015 Aug 15]. Available from: https://www.sgo.org/wp-content/ uploads/2012/09/FIGO-Ovarian-Cancer-Staging_1.10.14.pdf. Fehrmann RSN, Li XY, van der Zee AGJ, de Jong S, te Meerman GJ, et al. Profiling studies in ovarian cancer: A review. Oncologist 2007; 12(8): 960–966. doi: 10.1634/ theoncologist.12-8-960. Dressman HK, Berchuck A, Chan G, Zhai J, Bild A, et al. An integrated genomic-based approach to individualized treatment of patients with advanced-stage ovarian cancer. J Clin Oncol 2007; 25(5): 517–525. doi: 10.1200/JCO. 20 06.06.3743. Ahmed FY, Wiltshaw E, A’Hern RP, Nicol B, Shepherd J, et al. Natural history and prognosis of untreated stage I epithelial ovarian carcinoma. J Clin Oncol 1996; 14(11): 2968–2975. Vergote I, De Brabanter J, Fyles A, Bertelsen K, Einhorn N, et al. Prognostic importance of degree of differentiation and cyst rupture in stage I invasive epithelial ovarian carcinoma. Lancet 2001; 357(9251): 176–182. doi: 10. 1016/S0140-6736(00)03590-X. Carelle N, Piotto E, Bellanger A, Germanaud J, Thuillier A, et al. Changing patient perceptions of the side effects of cancer chemotherapy. Cancer 2002; 95; 155–163. doi: 10.1056/NEJM199002083220602. Hennessy BT, Coleman RL, Markman M. Ovarian cancer. Lancet 2009; 374(9698): 1371–1382. doi: 10.1016/ S0140-6736(09)61338-6. Parker WH, Broder MS, Chang E, Feskanich DS, Farquhar C, et al. Ovarian conservation at the time of hysterectomy and long-term health outcomes in the nurses’ health study. Obstet Gynecol 2009; 113(5): 1027–1037. doi: 10.1097/AOG.0b013e3181a11c64. Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, et al. ICON and AGO collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: The ICON4/AGO-OVA R-2.2 trial. Lancet 2003; 361(9375): 2099–2106. doi: 10. 1016/ S0140-6736(03)13718-X. Huang TC, Campbell TC. Comparison of weekly versus every 3 weeks paclitaxel in the treatment of advanced solid tumors: A meta-analysis. Cancer Treat Rev 2012; 38(6): 613–617. doi: 10.1016/j.ctrv.2011.10.008. Glehen O, Cotte E, Schreiber V, Sayag-Beaujard AC, Vignal J, et al. Intraperitoneal chemohyperthermia and attempted cytoreductive surgery in patients with peritoneal carcinomatosis of colorectal origin. Br J Surg 2004; 91(6): 747–754. doi:10.1002/bjs.4473. Kuhn E, Tisato V, Rimondi E, Secchiero P. Current preclinical models of ovarian cancer. J Carcinog Mutagen 2015; 6(2): 1–9. doi: 10.4172/2157-2518.1000220.

269 doi: 10.18282/amor.v2.i5.143

Ovarian carcinoma: An overview of current status








De Felice F, Marchetti C, Palaia I, Musio D, Muzii L, et al. Immunotherapy of ovarian cancer: The role of checkpoint inhibitors. J Immunol Res 2015; 2015: 1–7. doi: 10.1155 /2015/191832. McCabe N, Turner NC, Lord CJ, Kluzek K, Białkowska A, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly (ADP-ribose) polymerase inhibition. Cancer Res 2006; 66(16): 8109–8115. doi: 10.1158/0008-5472. CAN-06-01 40. Konner JA, Bell-McGuinn KM, Sabbatini P, Hensley ML, Tew WP, et al. Farletuzumab, a humanized monoclonal antibody against folate receptor α, in epithelial ovarian carcinoma: A Phase I study. Clin Cancer Res 2010; 16(21): 5288–5295. doi: 10.1158/1078-0432.CCR-10-0700. Seoung J, Park Y, Rhim C, Kim S. Current possible drug therapies for ovarian cancer. J Cancer Ther 2014; 5: 1203–1214. doi: 10.4236/jct.2014.513122. Lipkowitz S, Kohn EC. To treat or not to treat: The use of hormone replacement therapy in patients with ovarian cancer. J Clin Oncol 2015; 33(35): 4127–4128. doi: 10.1200/JCO.2015.63.6670. Chen RF, Li J, Zhu TT, Yu HL, Lu X. Fertility-sparing surgery for young patients with borderline ovarian tumors (BOTs): Single institution experience. J Ovarian Res 2016; 9(16): 1–8. doi: 10.1186/s13048-016-0226-y. Ditto A, Martinelli F, Lorusso D, Haeusler E, Carcangiu M, et al. Fertility sparing surgery in early stage epithelial








ovarian cancer. J Gynecol Oncol 2014; 25(4): 320–327. doi: 10.3802/jgo.2014.25.4.320. Seong SJ, Kim DH, Kim MK, Song T. Controversies in borderline ovarian tumors. J Gynecol Oncol 2015; 26(4): 343–349. doi: 10.3802/jgo.2015.26.4.343. Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 2014; 14(7): 455–467. doi: 10.1038/nrc3760. Meehan RS, Chen AP. New treatment option for ovarian cancer: PARP inhibitors. Gynecol Oncol Res Pract 2016; 3: 3. doi: 10.1186/s40661-016-0024-7. Vasconcelos I, Gaspar O. Meta-analysis of the PARP inhibitor olaparib reveals therapeutic efficacy in ovarian cancer independent of BRCA1/2 mutation status. Adv Mod Oncol Res 2016; 2(1): 91–96; http://dx.doi.org/ 10.18282/amor.v2.i2.54. Panguluri SK, Yeakel C, Kakar SS. PTTG: An important target gene for ovarian cancer therapy. J Ovarian Res 2008; 1: 6. doi: 10.1186/1757-2215-1-6. Hardwick N, Chung V, Cristea M, Ellenhorn JD, Diamond DJ. Overcoming immunosuppression to enhance a p53MVA vaccine. Oncoimmunology 2014; 3(10): 1–3. doi: 10.4161/21624011.2014.958949. Azvolinsky A. Anti-PD-1 antibody nivolumab shows activity in ovarian cancer. [Internet]. US: UBM Medica, LLC; 2015 [cited 2015 Aug 15]. Available from: http:// www.cancernetwork.com/gynecologic-cancers/anti-pd-1antibody-nivolumab-shows-activity-ovarian-cancer.

270 doi: 10.18282/amor.v2.i5.143

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