**4. Clinical implications**

The challenge is to detect a microscopic lesion during the occult period. We know also the preclinicalnaturalhistoryofHGSCwhichlastsonaverage 4years as *insitu*, stage 1 and2 cancers and approximately 1 year as stage 3 /4 cancers before they become clinically apparent [50].

To date, there is no screening test for ovarian cancer. ROCA screening (Risk of Ovarian Cancer) may be promising. It is based on a computerised Bayesian algorithm comparing each indi‐ vidual's CA125 profile to the pattern in ovarian cancer and healthy women. If the CA125 rate is closer to known cases of ovarian cancer, the risk may be greater and a specific clinical assessment with ultrasonography is performed. UKCTOCS will report on the impact on mortality in January 2015 [51, 52].

In the other non invasive methods, evaluation of DNA obtained by Papanicolaou test to detect ovarian cancers is probably encouraging: 41% (9/22) of ovarian cancers were identified using a panel of mutated genes from liquid Papanicolaou smear specimens [53].

However, none of these methods can currently be considered as a safe alternative to riskreducing surgery. It has been thoroughly demonstrated that carrying out preventive bilateral adnexectomy significantly reduces the risk of ovarian cancer (by over 98%) in at-risk groups (BRCA mutations, Lynch syndrome, family history of breast/ovarian cancer). Nevertheless, while operative morbidity can remain limited thanks to minimally invasive laparoscopic surgery, the complications of surgically induced menopause should not be minimised in women who are still young [54].

The new tubal theories in which the Fallopian tube is considered to be a conduit for EAOC (endometriosis as a precursor lesion) and as an origin for HGSC could result in a preference for exclusive bilateral salpingectomy instead of adnexectomy.

The current Canadian recommendations in British Columbia in gynaecological clinical and surgical practice are in line with this [55]:


**3. Endometrioid and clear cell cancers (see figure 1)**

1b up-regulation, MET amplification and loss of ARID1A [44].

SWI/SNF chromatin-remodelling complex.

transformation [31].

148 Contemporary Gynecologic Practice

**4. Clinical implications**

Women with CC and EC frequently present with endometriosis. In a review of 29 studies, Van Gorp *et al* [43] found a statistical association between endometriosis and endometriosisassociated ovarian cancers (EAOC): 36% of clear cell carcinoma were associated with endo‐ metriosis (11-70%), and 10% in case of endometrioid carcinoma (5-43%). A precursor lesion called atypical endometriosis was proposed. Atypical endometriosis (AE) is defined by the presence of hyperplasia or cytological atypia, increased nuclear/cytoplasmic ratio, mild hyperchromosomia, mild to moderate pleomorphism, crowded and occasionally stratified epithelial cells. AE has been identified adjacent to concomitant EAOC, with a demonstrated transition from benign endometriosis through AE to EAOC. At the molecular level, AE and EAOC share common molecular abnormalities such as PTEN and PIK3CA mutations, HNF

ARID1A (loss or mutation) and PIK3CA are early events and likely occur in precursor lesions as well as in EAOC: mutation of ARID1A gene (AT rich interactive domain 1A) was found in 41 to 57% of clear cell cancers and 30 to 48% of endometrioid cancers [31, 45-47]. ARID1A is a tumour suppressor gene and encodes BAF 250a protein that is involved in the multi-protein

It has been well established that the SWI/SNF complex is involved in DNA repair through cell cycle arrest and apoptosis, cell survival after DNA damage (particularly by promoting γH2AX induction) and genomic stability. ARID1A has recently been demonstrated to act as a negative regulator of the cell cycle through interaction with TP53 and its mutation may lead to cellular dysfunction as dysregulation of chromatin remodelling [48]. Moreover, loss of expression of this gene was recently found in benign endometriosis (20%) and AE (38.5%) adjacent to malignant lesions (57.7%), suggesting a chronological association from benign through atypical endometriosis to AEOC [44]. Samartzis et al [49] found also loss of ARID1A/ BAF 250a expression in presumably benign ovarian endometriomas (n=3/20, 15%) particularly in the form of cell clusters that could suggest a clonal loss of BAF 250a and a risk of carcinogenic

Finally tubal ligation is protective against AEOC suggesting passage of endometriosis through

The challenge is to detect a microscopic lesion during the occult period. We know also the preclinicalnaturalhistoryofHGSCwhichlastsonaverage 4years as *insitu*, stage 1 and2 cancers and approximately 1 year as stage 3 /4 cancers before they become clinically apparent [50].

To date, there is no screening test for ovarian cancer. ROCA screening (Risk of Ovarian Cancer) may be promising. It is based on a computerised Bayesian algorithm comparing each indi‐ vidual's CA125 profile to the pattern in ovarian cancer and healthy women. If the CA125 rate

the tube as a key oncogenic step with potential clinical implications (see below).

**•** genetic counseling and BRCA mutation screening in women at high genetic risk of HGSC, with risk-reducing surgery in patients with BRCA mutations

However, we believe a distinction should be drawn between HGSC and EAOC:


Finally, *ex vivo* optical imaging using reflectance and fluorescence may detect preinvasive lesions. McAlpine *et al* [58] were able to view STIC tubal lesions with 73% sensitivity, 83% specificity, 57% positive predictive value and 91% negative predictive value.

In the future, the development of real time *in vivo* high resolution imaging for STIC through falloposcopy (transcervical route) or salpingoscopy (confocal microlaparoscopy) could certainly be useful in patients with a genetic risk of ovarian cancer and who want to remain fertile, by allowing a precise histopathological diagnosis for the ovaries and tubes in real time and *in vivo* [59]*.*
