- Journal Details
- Format
- Journal
- eISSN
- 1581-3207
- First Published
- 30 Apr 2007
- Publication timeframe
- 4 times per year
- Languages
- English
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
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.
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
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
All consecutively operated women (asymptomatic carriers of pathogenic or likely pathogenic
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
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
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).
Statistical analysis was performed using SPSS 22.0 for Windows. Descriptive statistics was used to describe the basic features of the data in the study. Differences between the groups were investigated with Student-t test. P-values <0.05 were considered to be statistically significant.
In the period of our study (January 2009 – December 2015), 155 women underwent RRSO due to high ovarian cancer risk.
In our cohort, there were 110/155 (71.0%)
Mean age at RRSO among our patients was 48.3 (29–72); 47.6 (29–72) for
Before RRSO was performed, 110/155 (71.0%) women had already been diagnosed with breast cancer, 4/155 (2.6%) women had the first breast cancer diagnosis before and the second breast cancer diagnosis after RRSO and 1/155 (0.6%) woman was diagnosed with breast cancer after RRSO.
Among women where RRSO was performed, the mean age at breast cancer diagnosis was 54.0 (33–64) among women with STIC and 49.3 (38–61) among women with invasive cancer. The mean age of breast cancer diagnosis in
Of all the RRSO procedures (N = 155), there were 141 (91.0%) bilateral laparoscopic salpingo– oophorectomies, 5 (3.2%) unilateral laparoscopic salpingo-oophorectomies and 7 (4.5%) laparoscopic salpingectomies. One patient (0.6%) had a bilateral and one had (0.6%) a unilateral laparoscopic salpingo-oophorectomy.
Non-invasive or invasive serous high-grade cancer was diagnosed in 9 out of 155 (5.8%) operated women (Table 1). There were five (3.2%) occult ovarian cancers and 4 (2.6%) STICs. All cancers were detected among
Clinical characteristics of occult findings after RRSO
| Patient Number | Age at RRSO (years) | Occult finding | Type of pathogenic variant | FIGO STAGE | Cytology | Treatment | Vital status | |
|---|---|---|---|---|---|---|---|---|
| 1 | 53 | STIC | deletion exons 4–9 | STIC | NEG | Surgery | NED | |
| 2 | 69 | STIC | c.3018_3021delTTCA | STIC | NEG | Surgery | NED | |
| 3 | 64 | STIC | negative/high risk | STIC | NEG | Surgery | NED | |
| 4 | 45 | STIC | BRCA1 | deletion exons 4–9 | (Staging NEG) procedure I C | PC | Surgery+ACT | NED |
| 5 | 56 | HGSC | c.181T>G | III B | PC | Surgery+ACT | DOOD | |
| 6 | 39 | HGSC | c.5266dup.C | III B | PC | Surgery+ACT | OT | |
| 7 | 57 | HGSC | c.5266dup.C | I C | PC | Surgery+ACT | NED | |
| 8 | 39 | HGSC | c.1687C>T | III A | PC | Surgery+ACT | NED | |
| 9 | 61 | HGSC | deletion exons 4–9 | III A | PC | Surgery+ACT | OT |
ACT = adjuvant chemotherapy; DOOD = died of other disease; FIGO = International Federation of Gynecology and Obstetrics; HGSC = high grade serous cancer; NED = no evidence of disease; NEG = negative; OT = on treatment; PC = peritoneal carcinomatosis; RRSO = risk reducing oophorectomy; STIC = serous intraepithelial tubal cancer
Among patients with occult invasive cancers, two were 39 years of age, all the other were older, mean age being 50.4 years. Mean age of patients with STICs was 57.8 years. The difference was not statistically significant. There were no occult cancers diagnosed among
Three of four women with STIC underwent surgical staging procedure (Table 1). In three cases with STIC, staging procedure did not find any additional neoplastic cells and observation with no adjuvant treatment was recommended. In one case, the malignant cells were detected in the peritoneal cavity by cytological examination only. Stage was assessed to be I C. This patient received adjuvant chemotherapy with paclitaxel and carboplatin.
Among patients with occult cancers, one was assessed as stage I C, two as stage III A and two as stage III B. All received the adjuvant treatment with six courses of paclitaxel and carboplatin (Table 1).
Two STICs were found at the fimbrial part of fallopian tube and in the other two STICs, fallopian tube only was reported as a localisation. In invasive cancer patients, cancer cells were found in (i) two cases at the fimbrial part of the Fallopian tube and in one ovary, (ii) in one case the disease was present in both ovaries and in both Fallopian tubes, (iii) in one case cancer cells were present on the surface of both ovaries with normal Fallopian tubes and, (iv) in one case cancer cells were present on the surface of one ovary and in the Fallopian tube. Pathohistological findings included one patient with focally atypical epithelium of the fallopian tube with the addition of transitional cell metaplasia, one patient with adenomatoid hyperplasia with bilateral proliferation of Sertoli cells in both hiluses of ovaries that represented embryonal remnants and one patient with transitional cell metaplasia.
All except one patient with STIC had a negative cytology result; on the other hand, all occult cancers had positive cytological findings.
Before the RRSO CA-125 measurement was performed in 83.9% of women. It was negative in all occult cancers and STICs except in one occult cancer, where it was slightly elevated, being 48 kU/L (normal value being ≤ 35 kU/L). When considering CA-125 specificity in premenopausal years and normal vaginal ultrasound, patient was considered screen negative.
In our study the follow-up period was 23 to 73 months. Until December 2018 one woman with occult cancer died of gastric cancer which was diagnosed after adjuvant treatment for ovarian cancer. Two out of nine (22.2%) are being treated for their third recurrence of disease, the rest (6/9, 66.7%) are alive with no signs of disease. Mean follow-up of patients with occult invasive and non-invasive ovarian cancer was 29 months (15–51). After RRSO, no woman developed peritoneal cancer.
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
Among high-risk
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
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
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
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
Clinical characteristics of occult findings after RRSO
| Patient Number | Age at RRSO (years) | Occult finding | Type of pathogenic variant | FIGO STAGE | Cytology | Treatment | Vital status | |
|---|---|---|---|---|---|---|---|---|
| 1 | 53 | STIC | deletion exons 4–9 | STIC | NEG | Surgery | NED | |
| 2 | 69 | STIC | c.3018_3021delTTCA | STIC | NEG | Surgery | NED | |
| 3 | 64 | STIC | negative/high risk | STIC | NEG | Surgery | NED | |
| 4 | 45 | STIC | BRCA1 | deletion exons 4–9 | (Staging NEG) procedure I C | PC | Surgery+ACT | NED |
| 5 | 56 | HGSC | c.181T>G | III B | PC | Surgery+ACT | DOOD | |
| 6 | 39 | HGSC | c.5266dup.C | III B | PC | Surgery+ACT | OT | |
| 7 | 57 | HGSC | c.5266dup.C | I C | PC | Surgery+ACT | NED | |
| 8 | 39 | HGSC | c.1687C>T | III A | PC | Surgery+ACT | NED | |
| 9 | 61 | HGSC | deletion exons 4–9 | III A | PC | Surgery+ACT | OT |