The prevalence of occult ovarian cancer in the series of 155 consequently operated high risk asymptomatic patients – Slovenian population based study

Worldwide, ovarian cancer is the seventh most common cancer and the eighth cause of death from cancer in women.1 According to the Slovenian cancer registry, the median age at the time of diagnosis for ovarian cancer patients is 62 years.2 Epithelial ovarian cancer (EOC), being the commonest, is thought to be hereditary in at least 10% of cases, mostly due to BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants. Ovarian cancer risk in BRCA carriers ranges from 36%–53% in BRCA1 and 11%–25% in BRCA2 carriers by the age of 80 years, compared to 1–2% in the general population.3 In addition, it presents at a younger age than in patients without a genetic predisposition. Genetic counselling, testing and appropriate screening and preventive strategies can highly reduce the risk.3, 4, 5, 6

In more than 70%, EOC is diagnosed in advanced stages (III/IV). This is mainly due to vague and non-specific symptoms, and because of an ineffective ovarian cancer screening. BRCA carriers are therefore recommended to undergo salpingo-oophorectomy or salpingectomy as a risk-reducing strategy for ovarian cancer.3,7,8 A new paradigm of high grade pelvic serous cancer carcinogenesis puts fallopian tubes as an anatomic origin of the primary lesion. Salpingectomy with delayed oophorectomy might therefore be offered to BRCA carriers younger than 40 (after given informed consent in a research setting) who have completed their reproduction.9, 10

So far, no precancerous lesions, like intraepithelial carcinoma, have ever been found in the ovaries. Precancerous lesions were found only in fallopian tubes. The first report of precancerous lesions in fallopian tubes after risk-reducing salpingo-oophorectomy (RRSO) was as a non-invasive serous tubal intraepithelial carcinoma (STIC).11,12 Occult ovarian and tubal cancers where also found in specimens of BRCA carriers after RRSO. Occult cancers have been reported to occur between 2% and 17% and STICs between 3% and 12%, respectively.13, 14, 15, 16, 17, 18, 19, 20, 21, 22 The occult cancer detection is probably influenced by the age at RRSO, gynaecological screening prior to RRSO, extent of the surgical removal of specimens and the accuracy of tubal pathohistological assessment. It is known that the protocol for sectioning and extensively examining the fimbriated end of the Fallopian tube (SEE-FIM) enables a more exact histopathological examination of the distal tube with its fimbrial part.23

Ovarian cancer risk reduction after RRSO is reported to be between 80%–96%. The risk of primary peritoneal cancer after RRSO is between 1%–4%.24, 25 Recurrence rate of ovarian cancer after the diagnosis of an occult invasive carcinoma at RRSO is relatively high (16%–47%), despite predominantly early stage, and small volume disease.17, 25 On the other hand, the STICs rarely recur as carcinoma (5.8%–9%), and therefore chemotherapy may not be needed.24, 26 Recommendations about the optimal treatment of STICs lesions remain unclear. Opinions for treatment of STIC lean toward staging procedures and observations, if no other lesions are found.

Our study aimed to assess the prevalence, localization, type and outcome of occult cancer at RRSO in asymptomatic carriers of pathogenic or likely pathogenic BRCA1/2 variants and high-risk BRCA1/2 negative women.

All consecutively operated women (asymptomatic carriers of pathogenic or likely pathogenic BRCA1/2 variants and high-risk BRCA1/2 negative) who underwent RRSO or salpingectomy from January 2009 to December 2015 at the Institute of Oncology Ljubljana, Slovenia, were included in our study.

From 1999 genetic counselling and testing is offered at the Institute for women with positive family history of ovarian and breast cancer. Women with confirmed BRCA pathogenic or likely pathogenic variants and BRCA negative women with high ovarian cancer risk (at least two first or second-degree relatives with ovarian cancer) are assessed in a multidisciplinary setting by an onco–genetic team. In accordance with the guidelines high risk women are advised to perform risk reducing procedures (RRSO).7, 8, 27 Until 2014, RRSO was offered only after women turned 40 years of age. From 2014 tubectomy with delayed oophorectomy is offered in a research setting to women younger than 40 years who have completed their reproduction.

Clinical data were retrospectively collected from women with occult ovarian/tube/peritoneal cancer or non-invasive high-grade serous intraepithelial tube carcinoma diagnosed at the time of RRSO. Collected data included age at RRSO, mutation status, type of mutation, preoperative cancer antigen 125 (CA-125) level, histopathology result, staging, treatment (surgery and adjuvant chemotherapy), recurrence rate, prior history or development of breast cancer after RRSO, disease status and vital status. Asymptomatic women with negative ovarian cancer screening test (normal CA-125 and gynaecological ultrasound) 6 months prior to RRSO were included. Patients with ovarian or tubal cancer diagnosis prior to RRSO and those whose RRSO was a part of breast cancer treatment were excluded from the analysis.

All RRSOs had the same surgical and pathological protocol. During surgery, before the salpingo-oophorectomy took place, peritoneal washing was performed and the material was sent for cytological examination. If there was no free fluid in the cavum Douglasi, we eluted the pelvis with 10 mL of physiologic solution and the material was sent for cytological examination. At our institution SEE-FIM protocol is used for RRSO specimens.23 When occult cancer and STIC are diagnosed, staging procedure is offered. After staging procedure is performed, cancers are managed according to the national guidelines.7 In women with STIC, when no other lesion is found at staging procedure, only observation with regular follow up is offered. When malignant cells are found at cytological examination of peritoneal cavity washing with no other lesion at staging procedure, chemotherapy with carboplatin and paclitaxel is offered.

The start of follow-up after RRSO was defined as the date of RRSO, where no other treatment was required. After cancer treatment with chemotherapy, the start of follow-up was defined as the date of the last given chemotherapy. The end of follow-up was defined as the last outpatient visit at our institution.

The study was approved by the Ethical Committee of the Institute of Oncology Ljubljana (Number ERID–EK/15).

In the period of our study (January 2009 – December 2015), 155 women underwent RRSO due to high ovarian cancer risk.

We are presenting a population based study which aimed to address the prevalence, localization, type and outcome of occult cancer at RRSO in asymptomatic carriers of pathogenic or likely pathogenic BRCA1/2 variants and high-risk BRCA1/2 negative women.

Our main outcome was the detection of pathologic serous changes in tubes and ovaries in 5.8% of all operated women.

At RRSO we found occult serous cancer in 5.5% of BRCA carriers, with 3.4% (5/145) having high-grade cancers and 2.1% (3/145) STICs; all were found in BRCA1 positive women. The prevalence of occult cancers in BRCA1 positive women in our study was 7.3% (8/110). According to the available literature, the prevalence of occult cancer found after RRSO varies from 2% to 17%.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 28 In our study, the prevalence of occult cancer in BRCA1/2 positive women was 5.5%, which is similar to what Conner et al. have found.29 We detected fewer occult cancers than Powell et al. who reported a rate of 7.9% and more than Reitsma et al. (2.2%) and Finch et al. (4.2%).14,16,24 It would be expected that studies that reported lower prevalence of occult cancers also had a lower median age at RRSO. Reitsma et al. reported the median age at RRSO to be 44 years of age, which is less than in our study where the median age at RRSO was 47.14 Since only asymptomatic women and screen negative women were included, the age at RRSO seems to be the most important factor which determines the higher prevalence of pathologic findings. When considering BRCA1/2 carriers, all pathological changes in our study were detected among the BRCA1 positive patients. In contrast, there were no pathological changes in 35 BRCA2 positive women. The speculative reason for this might be lower ovarian cancer penetrance and the later age of onset in BRCA2 carriers in comparison with BRCA1 carriers and therefore critical number of cases for one case to be found was probably not achieved until the end of this evaluation.

Among high-risk BRCA negative women, the prevalence of occult serous disease was 10% (1/10). Limited data is available for the comparison of prevalence of occult cancers after RRSO in BRCA negative women. Only Reitsma’s study from Netherlands found one (1/57) case of STIC and one (1/57) case of atypical hyperplasia in RRSO specimens of BRCA-negative women with VUS.14 Our finding suggests the benefit and the importance of preventive surgeries in these women as well, though the number of our patients was very small.

An interesting and counterintuitive finding is the comparison of mean age among invasive and noninvasive cancers found at RRSO. Surprisingly, women diagnosed with STIC were older than women diagnosed with cancer. Mean age was 57.8 (45–69) and 50.4 (39–61) years, respectively. The difference was not statistically significant, most probably due to relatively small sample size. Furthermore, there was also insignificant trend of noninvasive cancer patients having breast cancer at an older age than those with invasive cancer. Similar findings were mentioned also in study from Powell et al.16

The localization of occult serous pelvic disease was coherent with the literature. Occult cancers were found in the tubal epithelium in 60% (3/5) and only in 40% (2/5) in the ovaries. In two cases the ovary was infiltrated only on the surface epithelium, in all other cases the cortex and stroma were also infiltrated. Intraepithelial serous lesions were found only in the tubal epithelium. In 50% (2/4) of cases, STICs were found at the fimbrial part of tubes. In other two cases exact localization was not defined and is being revised.17

International Federation of Gynaecology and Obstetrics (FIGO) stage distribution among occult cancers diagnosed after RRSO was undoubtedly different and much more favourable than among population that presents with symptoms. There were 55.6% (4/9) of cancers staged I, II or in situ. There were no cancers staged higher than III B, two were III B and two were III A. The long term outcome is therefore expectedly better among patients diagnosed with ovarian/fallopian/peritoneal cancer after RRSO.

Cytological examination of peritoneal cavity washing was found to be very important. When all pathologic findings are negative, positive cytology finding is the only one that may determine further treatment. Women with positive cytology with all other specimens being negative are advised systemic chemotherapy based on cytology findings.26

Screening for ovarian cancer in the general population with CA-125 (and possibly transvaginal ultrasound) is generally not recommended due to its low sensitivity and specificity. It is, however, seen as a reasonable temporary alternative for women at high risk, who wish to delay RRSO.30 In our study, only one patient with an occult cancer had serum CA-125 levels above the cut-off value. CA-125 assay did not prove to be an effective screening tool for early cancer detection in our patients.

Genotype-phenotype correlations in BRCA carriers are not well defined and it is therefore difficult to estimate the exact risk of ovarian cancer associated with specific pathogenic variants.31 The mutational spectrum in patients with occult carcinoma in our study is in line with what is otherwise known about Slovenian BRCA carriers. Three of the detected variants are very common in Slovenian BRCA1 carriers, i.e. c.181T>G p.(Cys61Ser), c.1687C>T p.(Gln563*) and c.5266dupC p.(Gln1756Profs*74).32 In contrast, the deletion of exons 4–9 is only seen in 3.4% of our BRCA positive families but appears to be associated with a particularly high ovarian cancer risk. In this study, three out of eight (37.5%) BRCA positive patients with occult cancer carried this variant, which further supports the hypothesis that deletion 4–9 is highly penetrant with regards to ovarian cancer.

The main limitation of our study is already mentioned relatively small sample size that limits statistical evaluation. On the other hand, we were able to obtain an accurate clinical data for the sample studied. All studied women were tested and operated in our centre, where genetic testing and preventive follow up is performed on a national level.

In conclusion, a 5.8% prevalence of occult invasive and noninvasive serous cancer after RRSO was found in high risk asymptomatic and screen negative BRCA1/2 carriers. Most of occult invasive and noninvasive serous cancers were detected in BRCA1 positive patients, yet the RRSO should also be considered as a preventive method for BRCA negative high risk women. Age at preventive gynaecologic surgery should be carefully considered, taking into account the completion of childbearing age, and ideally, performed soon after 35, at least in BRCA1 patients. Cytology examination of peritoneal cavity washing should be performed in all cases of RRSO. And finally, our results favour the hypothesis of tubal origin of high-grade serous ovarian and peritoneal cancer.