**3. Tumour markers**

Screening for any disease is aimed at detection of premalignant conditions or early stage disease. Cervical cancer screening is a successful programme as the progression from premalignant to malignant disease is well understood. However, until recently, precursor lesions were not recognised for ovarian cancer. Now, there is evidence to suggest that some of the high-grade serous cancers start as premalignant lesions in the fimbrial end of the fallopian tube as serous tubal intraepithelial carcinoma (STIC) [3]. Strategies to detect these premalig-

Ultrasound has been used as a screening tool to detect early malignant lesions in the ovary and fallopian tube. Features such as presence of septa, papillary projections and solid areas are used to distinguish possible malignant lesions from benign ones. The use of colour flow Doppler to detect altered blood flow as a result of neo-vascularisation has also been explored

Transvaginal ultrasonography (TVS) has long been considered a useful modality for estimating morphological factors of carcinogenesis. Non-invasiveness and ease of implementation are amongst its benefits for screening, and women generally find TVS an acceptable modality for detection [4]. Factors often used for the assessment of ovarian masses include morphology and volume analysis, but more advanced methods such as Doppler and neuronal network

There are many challenges to overcome in the utilisation of TVS as a screening modality. Variation in operator competence is one such challenge. The United Kingdom Collaborative Trial for Ovarian Cancer Screening (UKCTOCS) trial overcame this challenge by providing standardised training regimes to all sonographers. Although this could be a viable solution, there will always be variation in competence based on operator experience. For example, more experienced sonographers may be better at detecting borderline cysts than less experienced sonographers. The lack of standardised terms to describe ovarian sonographic features is another issue. The International Ovarian Tumour Analysis (IOTA) Group have created a set of recommendations to address this by setting definitions for morphological features such as

Patient acceptability of screening modality is also an essential factor to consider. In a recent study, 72.7% of women (n = 651) reported no discomfort during TVS, 23.3% of women reported some pain or discomfort and 3.5% documented moderate to severe pain during the TVS procedure. Increasing pain was attributed to history of hysterectomy and a prolonged scanning time. Interestingly, those who experienced pain were noted less likely to return for

Visualisation of the ovary is a further quality assurance factor to overcome in ovarian cancer screening. Decreasing follicular activity and ovarian shrinkage in postmenopausal women makes visualisation problematic. In a study involving TVS of 43,867 women (median age 60.6 years), factors affecting visualisation of ovaries in postmenopausal women included

nant lesions are likely to change the approach to ovarian cancer screening.

**2. Role of pelvic ultrasound in ovarian cancer screening**

in diagnosing ovarian neoplasms.

216 Ovarian Cancer - From Pathogenesis to Treatment

analyses are being investigated for their efficacy.

'septum, solid, smooth, irregular', and so on. [5].

a subsequent scan 1 year later [4].

Tumour markers are substances, mostly proteins produced by the tumour cells, which can be detected in the blood and other bodily secretions of the affected individual. These markers can be produced by normal tissue as well but their levels are usually significantly elevated during a malignant process. Tumour markers are used for the early detection, to guide management and to assess treatment response in cancer.

sporadic of which 90% occur in postmenopausal women, and for this reason, screening trials in the general population have been aimed at this cohort. In the high-risk population, however, even premenopausal women are at increased risk and are therefore included in screening studies.

Screening for Ovarian Cancer

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Approximately, 5–10% of ovarian cancers are attributed to genetic mutations. Mutations in the BRCA1 and BRCA 2 genes increase the risk of developing both breast and ovarian cancer. The life time risk of developing ovarian cancer (up to the age of 70 years) is 40% (95% CI, 35–46%) for carriers of BRCA1 mutation and 18% (95% CI, 13–23%) for BRCA2 mutation carriers [27]. A strong family history of breast and ovarian cancers could be an indicator of the presence of mutations in BRCA genes given their high penetrance [28]. The age of onset of ovarian cancer tends to be younger in BRCA carriers when compared to the general population. Median age at diagnosis is 63 years in the general population [29], 51.2 years for BRCA 1

Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome secondary to mutations in the mismatch repair genes (MMR)—MLH1, MSH2, MSH6 and PMS2, which not only increases the risk of developing colorectal cancer but also ovarian and endometrial cancer in female carriers. The estimated cumulative risks of ovarian cancer by age

Traditionally, testing for gene mutations has been undertaken in individuals with a strong family history of ovarian cancer. Earlier studies looking at family history alone have shown that women with a first degree relative with ovarian cancer have a 4–5% life time risk of developing ovarian cancer. With two affected close relatives, the risk increases to around 10% and

More recently there has been a different approach to screening for gene mutations. A randomised controlled trial looking at testing of the population regardless of family history in the Ashkenazi Jewish population reported a slightly higher incidence of BRCA mutations in the population screening group when compared with the family history group [33]. Such studies suggest that unselected testing of the population identifies 50% more carriers of genetic muta-

Other than genetic factors, risk of ovarian cancer has also been found to increase with nulliparity, early menarche and late menopause, hormone replacement therapy and endometriosis. Factors suppressing ovulation such as use of the oral contraceptive pill, multiparity,

Symptoms of ovarian cancer occur insidiously, with many patients presenting with non-gynaecological symptoms such as indigestion, abdominal bloating and early satiety,

70 years for women with Lynch Syndrome is around 10% (range 6–14%) [31].

can become higher with even more relatives affected by ovarian cancer [32].

tions than the traditional approach to screening based on family history alone.

longer periods of lactation have been associated with a decreased risk [34].

**6. Symptom-based screening**

**5. Genetic predisposition to ovarian cancer**

and 57.5 years for BRCA2 mutation carriers [30].

CA125 is the most commonly used tumour marker for the detection of ovarian cancer. In 1981, Bast et al. developed OC125, a murine monoclonal antibody, which was found to react with ovarian carcinoma cells [16]. An immunoassay was then developed to detect the antigen CA125 in the serum of patients affected by non-mucinous ovarian cancer. CA125 levels were found to be elevated in 82% of women affected by non-mucinous epithelial ovarian cancer, and it was useful in monitoring the treatment response [17].

Elevated CA125 levels are seen in 50% of stage I and >90% of stage II–IV serous ovarian cancers [18]. However, the levels are usually not elevated with mucinous and borderline ovarian tumours. CA125 is also not very specific to ovarian cancer as the levels are increased in other malignancies such that of the gastrointestinal tract, breast and lung; and in benign gynaecological (e.g. endometriosis, fibroids, adenomyosis, benign masses and pregnancy) [18] and non-gynaecological conditions (e.g. heart failure, pancreatitis, hepatitis) [19].

A cut-off value of 35 U/ml is accepted as the upper limit of normal [17]. This cut-off value is acceptable in postmenopausal women, whereas, in premenopausal women, the cut-off value tends to be significantly higher at 50 U/ml [20]. Other factors have also been found to affect the CA125 level. A study on CA125 levels in healthy postmenopausal women observed varying levels with race (highest in Caucasian and lowest in African women), lower levels with previous hysterectomy, regular smoking and caffeine intake, and, higher levels with a previous (non-ovarian) cancer diagnosis. Age of the individual, age at menarche and menopause and previous ovarian cysts were also predictive of baseline levels in postmenopausal women [21].

The CA125 level can be elevated for up to 5 years prior to the diagnosis of ovarian cancer. This finding has been crucial for its application in screening asymptomatic women [22]. Given its low sensitivity and specificity, interpretation of CA125 level using a cut-off value has not been very useful in screening. However, sequential measurements of CA125 as a first-line test and transvaginal ultrasound as a second-line test in multimodal screening have been found to significantly improve its sensitivity and specificity [23].

Human epididymis protein 4 or HE4 is another tumour marker which is elevated in ovarian cancer but not with benign ovarian masses. It can therefore be used to distinguish between the two [24]. In a study using an algorithm combining both HE4 and CA125, 93.8% of epithelial ovarian cancers were accurately classified as high risk [25]. Other markers that have been tested include prolactin, transthyretin, CA72-4 and CA15-3. Combining these markers with CA125 has not shown to improve its efficacy in screening for ovarian cancer [26].
