Ovarian Cancer Prevention and Screening—Where Do We Stand Today?

Abstract

Widely recognized as the most deathful gynecologic malignancy affecting women worldwide, ovarian cancer has reported a significant decline in terms of prevalence and incidence in the last decades. This fact has been especially explained by to the use of menopausal hormonal therapy and of oral contraceptives in association with genetic, oncologic and gynecologic counseling. The aim of the current review is to discuss about actual ovarian cancer prevention and screening tools. For this reason, we reviewed several data related to ovarian cancer, such as: incidence and risk factors, histopathological types (epithelial with high- and low-grade serous carcinomas, clear cell carcinoma, mucinous carcinoma, germ cells ovarian cancer tumors), as well as screening, diagnosis and prevention methods (ovulation disruption, surgical prevention, etc.). Although progress has been reported in the last decades in terms of early diagnosis and treatment of ovarian cancer, this malignancy still represents a significant health problem affecting women worldwide. However, it seems that the golden key for optimizing the long-term outcomes in such patients is represented by a better understanding of the complex pathogenesis of this disease.

Introduction

Despite many attempts to improve early diagnosis and survival outcomes in ovarian cancer, it remains the leading cause of mortality among all gynecologic malignancies. Therefore, in the last decades, particular interest has been given to improve the prevention and screening tools in women worldwide, expecting therefore a decrease in the field of mortality [1,2,3].

Literature on epidemiology, risk factors, histopathological findings, prevention and screening for ovarian cancer was retrospectively reviewed by searching multiple databases: PubMed, Medline, Web of Science, Cochrane Library, Embase, Elsevier and Google Scholar. The literature that we reviewed consists mostly of studies from 2000 to present, written in English and French; from our analysis we excluded studies written in other languages than English and French as well as abstracts for which we could not access the full text sources. This paper analyzes completed studies as well as some ongoing studies with preliminary results.

Discussions

Incidence and Risk Factors

In recent years, the incidence of ovarian cancer has encountered a decline, possibly attributed to the increased utilization of oral contraceptive pills [4,5,6]. Therefore, it has been demonstrated that ovarian cancer incidence decreased by 1%-2% per year between 1990-2010 and by 3% per year after 2015 [4,5,6]. Moreover, ovarian cancer is reported to be the second most frequent malignancy in women over the age of 40, following breast cancer, especially in developed countries [7]. When analyzing all cancer types, ovarian cancer ranks the eleventh place in terms of prevalence among women while when analyzing cancer related deaths, ovarian cancer is the fifth leading cause of cancer-related fatalities in women and the most lethal one among gynecologic cancers [6].

However, ovarian cancer related death seems to be strongly influenced by racial disparities, the explanation consisting of different socioeconomic factors which seem to cause significant impact; therefore, in the study conducted by Shingala et al. the authors came to demonstrate that non-Hispanic black women and Hispanic women have a higher risk of ovarian cancer related death when compared to non-Hispanic white women [8,9].

Despite increased awareness of ovarian cancer, there hasn’t been significant progress in overall survival trends. The most important reason responsible for this gap is related to the low rate of early diagnosis due to the absence of a definitive screening tool and due to the presence of non-specific signs and symptoms that can often mimic non-malignant conditions [6,7].

Many women who experience symptoms such as abdominal distension, abdominal pain, urinary frequency, early satiety, or changes in bowel habits, may not consider them unusual or alarming [7,10,11]. Therefore, some women might delay seeking medical attention, resulting in a delayed diagnosis, or even worse, these symptoms might be wrongly considered as nonspecific, benign conditions and treated symptomatically, without proceeding to more specific diagnostic tests even by their general practicians [12,13]. In this respect, it is crucial for both women and healthcare providers to keep these non-specific symptoms in mind when assessing women at risk for ovarian cancer. A family history of ovarian and breast cancer has been demonstrated to significantly increase a woman’s risk of developing ovarian cancer. Specific mutations of BRCA1 or BRCA2 genes (which are tumor-suppressing genes), or, in scarce cases of mismatched mutation genes (MMR) are directly associated with a genetic predisposition to ovarian cancer development. These genetic mutations can amplify the risk of ovarian cancer from its baseline of 1.6% to 40%, 18%, and 10%, respectively [10,14]. This genetic connection is known as hereditary breast and ovarian cancer syndrome (HBOC) and should be taken into consideration in cases in which a first-degree family member had a prior diagnosis of ovarian or breast cancer before the age of 50. It’s important to note that carriers of these genetic mutations have a risk ranging from 10% to 40% of developing ovarian malignancies by the age of 70. Furthermore, Lynch syndrome is also associated with ovarian cancer, although it is less common in occurrence [15]. Therefore, while in cases diagnosed with Lynch syndrome a MMR deficiency is the rule, in epithelial cancers of the ovary this mutation is encountered in up to 15% of patients [14,15].

Ovulation is directly correlated with the risk of ovarian cancer. Studies published so far indicate that the greater the number of ovulatory cycles a woman experiences, the higher her risk of developing ovarian cancer is [4]. This connection may be attributed to the proinflammatory response occurring in the distal fallopian tubes during ovulation, which can induce malignant transformations at the level of the ovaries [16]. Consequently, it is reasonable to consider that factors interrupting ovulation such as the use of oral contraceptives, pregnancy, breastfeeding, as well as early onset of menstruation and early onset of menopause respectively can contribute to reducing a woman’s risk of ovarian cancer [10,17,18].

Endometriosis has been associated with certain types of epithelial ovarian cancers such as endometroid and clear cell carcinoma. However, Scarfone et al. demonstrated the fact that endometriosis associated endometroid cancer has certain clinical features distinct from non-endometriosis associated endometroid carcinoma (such as clear cell carcinoma) such as younger age at the time of diagnostic or earlier stage; meanwhile endometriosis associated clear cell cancer is usually diagnosed as pelvic mass; even though, this tumoral subtype has a better prognosis when compared to non-endometroid associated clear cell carcinoma [19,20]. However, patients with previous history of endometriosis are usually more closely followed by their physicians and therefore are more frequently diagnosed in earlier stages of the disease [20]. When it comes to the mechanism of transformation of endometriosis in cancer, multiple mechanisms have been incriminated such as BAF250a protein upregulation, beta catenin mutation or loss of estrogen receptors. Interestingly, the iron resulted from blood metabolization at the level of the endometriotic cysts promotes oxidative stress and therefore induce genetic mutations [20,21]. A very interesting aspect is related to the response to chemotherapy of endometroid associated ovarian cancer; therefore, it has been demonstrated that greater resistance to platinum and taxanes based regimens is expected especially in clear cell carcinoma related to endometriosis; in this respect, the MD Anderson clinic recommends association of radiation therapy in such cases [22,23].

Nevertheless, it’s essential to note that there is no conclusive evidence suggesting that the removal of endometriosis lesions can reduce a woman’s risk of developing ovarian cancer [6].

Specific ethnic backgrounds have demonstrated a heightened genetic predisposition to ovarian cancer, notably among individuals of French Canadian, Icelandic, Jewish and Dutch decedents [6,10]. However, geographical differences between different population groups are not only influenced by genetics but also by the usage of oral contraceptives, healthcare system, psychological factors and financial issues [24,25].

Histology

The most commonly encountered subtypes of ovarian cancer are represented by: epithelial, germ cell, and sex-cord-stromal tumors, epithelial ovarian cancer representing up to 95% of cases [11,26]. Within the epithelial ovarian cancer category, there are four main histologic subtypes: serous, endometrioid, mucinous, and clear cell [11,17]. Serous tumors can be further classified into two categories: high-grade serous carcinomas (HGSC) and low-grade serous carcinomas (LGSC) [11,27]. HGSCs constitute the large majority of cases, representing 70% to 80% of all epithelial ovarian cancer subtypes, while LGSCs are much less common, accounting for less than 5% of cases. Endometrioid, mucinous, and clear cell subtypes make up 10%, 3%, and 10% of cases, respectively [27].

Epithelial Ovarian Cancer

Epithelial ovarian cancers, which constitute the majority of ovarian cancer cases, are categorized into two distinct types: Type I and Type II tumors [18,19,28]. The apparition of Type I tumors, known to be less aggressive than Type II tumors, is considered to be caused by continuous ovulation cycles, inflammation or by the presence of endometriosis. It is widely believed that the presence of endometriotic nodules increase a woman’s risk of ovarian cancer, endometriosis being associated with 5% to 15% of all epithelial ovarian cancer cases [11,16,29]. Many of these cancers are detected at early stages and trend to have more favorable outcomes compared to those not linked to endometriosis. In this respect, it is easy to understand the fact that in type I tumors association of anti-inflammatory treatment might have a protective role in ovarian cancer prevention.

In contrast, Type II tumors are often associated with more adverse outcomes. These cancers are typically diagnosed at later stages and are frequently linked to genetic mutations in the BRCA genes and p53 mutations, which are tumor-suppressing genes [29]. Therefore, in cases in which a type II tumor is expected, BRCA testing is mandatory, followed by genetic counseling in order to decrease the risk of apparition of ovarian cancer in patient herself as well as in grade I relatives.

LGSC Versus HGSC

When it comes to epithelial ovarian cancers, it’s possible to further subdivide this category into High-Grade Serous Carcinomas (HGSC) and Low-Grade Serous Carcinomas (LGSC). HGSCs constitute the majority, making up 90% of all serous tumor types, while LGSCs account for the remaining 10% [30]. These two subtypes exhibit distinct molecular profiles, clinical presentations, and overall prognostic [27,30]. LGSCs generally have a more favorable prognosis, with significantly longer expected survival times when compared to those with HGSCs, as well as clear cell or mucinous types [30,31].

Moreover, individuals diagnosed with LGSCs are typically younger when compared to those diagnosed with HGSCs [31]. LGSCs often originate within the ovaries, while HGSCs tend to initiate in the fallopian tubes, subsequently spreading to the ovaries or peritoneum [32]. HGSCs are associated with a scarcer prognosis, with more than 85% of women presenting with advanced-stage disease, resulting in a 10-year mortality rate of 70% [32]. Once demonstrated the fact that fallopian tube epithelium represents the origin of high grade serous ovarian cancer, it is evident that the most cited method of prevention remains salpingectomy, a procedure which in certain cases is standard recommended in BRCA1/2 carriers after completion of childbearing process [17,21]. When it comes to general population (with no known genetic mutation) it is estimated that the lifetime risk of developing ovarian cancer is about 1,3%, low enough to contraindicate routine salpingectomy for ovarian cancer prevention [33].

Clear Cell Carcinoma

Clear cell carcinomas represent up to 10% of epithelial ovarian cancers and share similarities with endometrioid cancers, as they generally exhibit a relatively favorable prognosis. This positive trend is related to their frequent diagnosis at earlier stages [28]. However, if the diagnosis occurs late or the disease has progressed significantly, the prognosis becomes comparable to that of serous or endometrioid types. This is mainly related to a poorer response to platinum-based chemotherapy and to a higher risk of associated paraneoplastic syndromes such as coagulation disorders or paraneoplastic hypercalcemia [7,28]. Due to the fact that a certain number of cases diagnosed with clear cell carcinoma originate from endometrial cysts, it is well understood the fact that a correct approach of endometrial cysts might have a protective role against clear cell carcinoma development.

Mucinous Carcinoma

Mucinous carcinomas, the least prevalent among epithelial cancers, are typically diagnosed in early stages of the disease [28]. However, when it comes to mucinous ovarian carcinoma, attention should be focused on differentiating primary versus metastatic lesions; therefore, it is well recognized the fact that digestive cancers usually metastasize at the level of the ovary, conducting to the apparition of Krukenberg tumors, with frequent histology of mucinous neoplasia [34]. As expected, in such cases the prognosis and therapy are related to the primary digestive tumor conducting to the apparition of the ovarian mucinous metastasis. Therefore, it is highly advised for women to undergo a gastrointestinal evaluation to exclude the possibility of mucinous carcinoma [7,28]. Whenever the digestive origin is excluded, a primary mucinous ovarian cancer is incriminated. Interestingly, in certain cases diagnosed with mucinous ovarian cancer also has a history of endometriosis; in this respect, we should underline the fact that a proper diagnosis, treatment and follow up of patients with endometriosis is expected to have a protective role against mucinous carcinoma development.

Germ Cells Ovarian Cancer Tumors

Germ cell tumors, represent scarce eventualities, with an estimated incidence of 5% among all types of ovarian malignant tumors; they are typically diagnosed at a young age, with the peak of incidence between 10 and 30 years [35,36]. Ovarian germ cell tumors are known to produce specific tumor markers, such as LDH, AFP, beta HCG, CA19-9 and SCC antigen, therefore offering valuable information for diagnostic and therapeutic strategy [37,38]. Given that this type of malignancy is frequently encountered in younger women, it is crucial for the patient to benefit from a multidisciplinary approach including gynecologist, obstetrician, genetic counsellor and surgeon in order to formulate a comprehensive plan with particular interest on fertility wishes and oncological outcomes. Interestingly, the histologic types of ovarian germ cell tumors bear similarities to those of germ cell tumors arising in the testes of men [37]. Notably, germ cell tumors present with similar generally vague symptoms as other ovarian cancer types, such as abdominal swelling and irregular vaginal bleeding [36,37].

Prevention

When discussing about risk factors for ovarian cancer and prevention, it should be clearly stated that these factors can be classified as either modifiable or non-modifiable. While non-modifiable factors usually refer to genetic factors, modifiable factors refer to the number of pregnancies, the use of oral contraceptives or breastfeeding. A crucial aspect of prevention involves initially educating both women and healthcare providers about modifiable factors, about the way in which they can be modified in order to decrease the risk of developing breast cancer as well as about signs, symptoms, and prevalence of ovarian cancers. A study indicated that, on one hand women in the general population often struggle to accurately identify the signs and symptoms of ovarian cancer, while on the other hand, there are instances where certain factors (such as abnormal pap smear results) were inaccurately associated with ovarian cancer. Merely 40% of the women in this study were considered to be at least "slightly familiar" with signs and symptoms [39].

In any healthcare setting, there exists an opportunity for education. Providing information to at-risk patients or even the general population about risk factors and symptoms can contribute to fostering self-advocacy and health awareness.

More recently, electronic programs have been successfully implemented in order to provide a better quality of life as well as increased awareness in both early and advanced stage ovarian cancer [40].

Ovulation Disruption

The utilization of oral contraceptives has demonstrated a notable reduction, ranging from 40% to 50% in the risk of ovarian cancer development among average-risk women, a direct proportionality relationship being observed between the dimensions of risk reduction and the period of oral contraceptive administration [4,18]. As previously mentioned, disrupting ovulation significantly diminishes a woman’s risk for ovarian cancer. Various approaches, including multiple pregnancies, breastfeeding, undergoing a hysterectomy, and the removal of fallopian tubes or ovaries might also contribute to this risk reduction [29]. Additionally, initiating one’s first pregnancy before the age of 25 has been demonstrated to be associated with a decreased risk of ovarian cancer [11,27].

Another frequently used method of contraception is represented by the intrauterine devices, initially proposed in 1964; nowadays, the most frequently used are the levonorgestrel releasing uterine device – which releases progestin, a molecule causing endometrial suppression as well as cervical mucus secretion and the copper intrauterine device which creates a state of local inflammation inhibiting therefore fertilization. Those devices also seem to decrease the risk of ovarian cancer development through multiple mechanisms such as ovulation suppression, modifying the local pH, inducing a foreign body inflammatory condition and by antiestrogenic effect [41]. When it comes to the efficacy of subdermal devices realizing hormones with contraceptive effect, conflicting results have been reported so far; however, the exact effect of this subdermal devices on the risk of ovarian cancer development is rather hard to be estimated due to the fact that these patients are usually long consumers of oral contraceptives. Therefore, is hard to be estimated if a potential protective effect is caused by the long history of oral contraceptives administration or due to the subdermal devices [42,43].

Surgical Prevention

Similarly to breast cancer, in ovarian cancer, surgical prevention is feasible especially in cases in which genetic mutations are present; even though, decision of surgical removal of a healthy, but at-risk tissue necessitate comprehensive education and awareness in regard to the risk of developing at a certain moment of a malignant tumor. As specified before, surgical prevention which is most appropriate in BRCA 1/2 carriers represent bilateral salpingectomy and leads toa 80% decrease of the risk of malignant transformation [17]. Once this tissue is removed, the risk of developing serous epithelial cancer decreases dramatically due to the fact that in a significant number of cases this histopathological subtype results after malignant transformation of serous cells located at Fallopian level.

Although this surgical procedure is associated with minimal risks of early postoperative complication, we should not omit the fact that in time, side effects such as diminished sexual function, vaginal dryness and potential impact on orgasmic ability might develop [4,16]. Therefore, the decision to perform prophylactic bilateral salpingectomy must be carefully analyzed considering factors such as the woman’s age, desire to procreate and preexisting health conditions.

Another issue which should be discussed in the one of salpingectomy during hysterectomy for benign conditions; therefore, although in cases in which hysterectomy is performed for benign uterine conditions such as myomatosis Fallopian tubes might be preserved, studies have shown that bilateral salpingectomy significantly decreases the risk of apparition in the next decades of high grade serous ovarian cancer [16]. In this respect, at the present time, the recommendation in patients diagnosed with benign uterine conditions is to perform total hysterectomy with bilateral salpingectomy and ovarian preservation.

Tubal ligation represents another option being associated with a significant reduction in the risk of development of certain histopathological subtypes of ovarian cancer [4]. An interesting study conducted on this issue was published by Gaitskell et al. in 2016; therefore, in this study the authors included 1,1 million women from UK without prior ovarian cancer or oophorectomy history who were followed on a mean period of 13,8 years. The authors came to demonstrate that tubal ligation significantly decreased the risk of high grade serous ovarian cancer development; meanwhile a certain reduction was observed for endometroid and clear cell carcinoma, demonstrating therefore that these tumors might also originate from cells at Fallopian level. Interestingly, the risk reduction was significantly lower when it comes to low grade serous ovarian cancer and almost null for mucinous ovarian cancer [44].

However, surgical prevention should not be seen as an isolated method of prevention; it should be rather considered as a part of a multidisciplinary approach which should include genetic counseling, healthcare providers, oncological and gynecological counseling.

Pharmacologic Prophylaxis

As mentioned before, in certain cases a significant mechanism responsible for ovarian carcinogenesis is represented by the inflammatory status induced during ovulation by ovarian disruption. Therefore, when discussing about pharmacological prophylaxis, two pathways should be taken in consideration: the first one consists of interruption of ovulation – by using of contraceptive pills, pregnancy or breastfeeding while the second one refers to the systemic administration of anti-inflammatory drugs in order to decrease inflammation caused by ovulation. However, studies published so far on the issue of systemic administration of low dose or standard dose of non-steroidal anti-inflammatory pills (such as aspirin) reported conflicting results, a standard recommendation not being available at this time [29]. While certain studies have not established a direct relationship between ovarian cancer risk reduction and aspirin use, other investigators have demonstrated a significant risk reduction in females taking a daily low-dose aspirin compared to those not using aspirin [29]. However, the protective role of anti-inflammatory therapy seems to be particularly justified in women with previously known lesions of endometriosis. As mentioned before, the presence of endometriotic nodules as well as the products resulting from blood catabolization at the level of endometriotic cysts (especially iron) conduct to the activation of oxidative mechanisms leading therefore to a proinflammatory condition which stimulates carcinogenesis. In this setting is perfectly justified to consider that administration of an anti-inflammatory regimen could offer positive benefits, discouraging further tumorigenesis [9].

Screening and Diagnosis

Ovarian cancer screening still represents a significant challenge for the clinician due to the notoriously vague and nonspecific symptoms associated with early stages of this disease. Historically, the cancer antigen 125 (CA125) has been considered as golden standard in order to identify ovarian cancer patients, with aspirations to become a basic “screening” tool. However, in the last decades its lack of specificity and sensitivity became evident, as CA125 was found to be elevated in benign conditions such as endometriosis, benign ovarian cysts, nongynecological conditions – cardiac failure, liver dysfunction - and even during pregnancy. Moreover, normal ranges have been observed in almost half of patients diagnosed with early stages of ovarian cancer. Consequently, the CA125 marker is no longer recommended for screening ovarian cancer [39]. However, more recent studies came to investigate the potential preventive role of triple screening – CA125, Human epididymis 4 – HE4 and transvaginal ultrasound in women with suspect ovarian lesions [10]. More recently, a study conducted in the United Kingdom came to demonstrate that not only serum concentration but also urine concentrations of HE4 and CA125 might orientate the diagnosis of ovarian cancer; however, the method is still under research [45].

Given that genetic mutations significantly increase the risk of gynecologic cancer development, genetic screening is an option for determining a patient’s risk status especially if first degree relatives have been diagnosed with breast or ovarian cancer. Therefore, as mentioned before BRCA1/2 or MMR mutations are strongly recommended to be determined in women at risk in order to identify the carriers and provide them a more proper follow up program [46]. Creation of specified clinics for BRCA mutation carriers conducted to a significant improvement in the management of such cases [47].

When it comes to the possibility of establishing a positive diagnostic of ovarian cancer through a biopsy, this method has been widely deemed due to the high risk of dissemination and inducing the apparition of distant metastases including abdominal wall metastasis; more recently transvaginal ultrasound-guided biopsies have been proposed, with low rates of punction site metastasis [48]. However, the method is still in an experimental phase, more studies still being needed before validating it as a safe screening tool [46].

Conclusions

Although progress has been reported in the last decades in terms of early diagnosis and treatment of ovarian cancer, this malignancy still represents a significant health problem affecting women worldwide. However, it seems that the golden key for optimizing the long-term outcomes in such patients is represented by a better understanding of the complex pathogenesis of this disease.