Outcome of risk-reducing salpingo-oophorectomy in BRCA carriers and women of unknown mutation status


Prof U Menon, Gynaecological Cancer Research Centre, EGA Institute for Women’s Health, First floor, Maple House, 149 Tottenham Court Road, London W1T 7NF, UK. Email u.menon@ucl.ac.uk


Please cite this paper as: Manchanda R, Abdelraheim A, Johnson M, Rosenthal A, Benjamin E, Brunell C, Burnell M, Side L, Gessler S, Saridogan E, Oram D, Jacobs I, Menon U. Outcome of risk-reducing salpingo-oophorectomy in BRCA carriers and women of unknown mutation status. BJOG 2011;118:814–824.

Objective  To compare surgical outcomes and occult cancer rates at risk-reducing salpingo-oophorectomy in BRCA carriers and high-risk women who had not undergone genetic testing.

Design  Prospective cohort study.

Setting  Tertiary high-risk familial gynaecological cancer clinic.

Population  Women undergoing risk-reducing salpingo-oophorectomy between January 2005 and November 2009.

Methods  Women at high-risk of ovarian/tubal cancer were identified on the basis of the inclusion criteria for the UK Familial Ovarian Cancer Screening Study. Risk management options discussed with 1456 high-risk women included risk-reducing salpingo-oophorectomy. A strict histopathological protocol with serial slicing was used to assess tubes and ovaries.

Results  In total, 308 high-risk women (191 with unknown mutation status; 117 known BRCA1/BRCA2 carriers) chose risk-reducing surgery; 94.5% of procedures were performed laparoscopically. The surgical complication rate was 3.9% (95% CI 2.0–6.7). Four ovarian and ten tubal occult invasive/in situ cancers were found. The overall occult invasive cancer rate was 5.1% (95% CI 1.9–10.83) in BRCA1/BRCA2 carriers and 1.05% (95% CI 0.13–3.73) in untested women. When tubal in situ cancers were included, the overall rate was 4.55% (95% CI 2.5–7.5). Two untested women with tubal carcinoma in situ were subsequently found to be BRCA carriers. The median ages of BRCA carriers (58 years; IQR 13.4 years) and untested women (49.5 years; IQR 20.6 years) with occult invasive/in situ cancer were not significantly different (= 0.454).

Conclusions  Both high-risk women of unknown mutation status and BRCA carriers have a significant (although higher in the latter group) rate of occult invasive/in situ tubal/ovarian cancer, with a similar age distribution at detection. The data has important implications for counselling high-risk women on the likelihood of occult malignancy and perioperative complications at risk-reducing salpingo-oophorectomy. Women with occult disease should be offered genetic testing.


Inherited mutations in the BRCA1 and BRCA2 genes account for most of the known hereditary risk for breast and ovarian cancer. Published meta-analyses have found cumulative breast and ovarian cancer risks (up to an age of 70 years) to be: up to 65 and 40%, respectively, for BRCA1 carriers; and up to 49 and 18%, respectively, for BRCA2 carriers.1,2 However, higher penetrances have been documented in carriers ascertained from high-risk families with multiple cancer cases.3–6 Risk-reducing salpingo-oophorectomy (RRSO) is the most effective option for preventing ovarian/tubal cancer in women at high-risk for the disease, with a hazard ratio (HR) for ovarian cancer (OC) of 0.21 (95% CI 0.12–0.39) in BRCA1/BRCA2 carriers.7 There is a persistent 4.3% residual risk of primary peritoneal cancer.8 Oophorectomy also halves the risk of breast cancer in premenopausal women.7 Varying occult cancer rates (range 0–17%, mean 4.7%) have been documented in BRCA carriers undergoing surgery.9–14 More recently, molecular and histological changes in tubal (particularly fimbrial) epithelium not amounting to carcinoma in situ (CIS) have been reported.15,16 However, the clinical significance of these lesions and their role in ovarian carcinogenesis is yet to be established.

Clinical practice guidelines to select the threshold(s) of BRCA genetic testing and clinical intervention are based on cost-effectiveness, with BRCA gene testing within the UK’s National Health Service (NHS) being primarily available to cancer-affected individuals from high-risk families (≥20% carrier probability) or individuals from a family with a confirmed BRCA mutation. As a result, a number of high-risk women in the UK are unable to access gene testing as they have no live affected relative, and are unaware of their mutation status. With increasing awareness a number of such women are being referred to gynaecologists for management of OC risk. Options available to these high-risk women identified on the basis of their pedigree by genetic units in the UK include participation in a national screening trial and risk-reducing surgery.

Here, we report on the surgical and histopathological outcomes including occult cancer rates following risk-reducing surgery in high-risk women attending a tertiary multidisciplinary familial gynaecological cancer clinic. Our cohort is unique because it includes a large number of women from high-risk families whose mutation status was unknown, in addition to women who were confirmed BRCA carriers. Comparison of outcomes between these two groups provide further insight into the risk of ovarian and tubal cancer in breast and/or ovarian cancer families.


The familial gynaecological cancer clinic at University College London Hospital (UCLH) is a tertiary level clinic for managing women at ‘high-risk’ for such malignancies. The majority of the referrals are from clinical genetics teams following a family history-based assessment. The multidisciplinary team includes gynaecological oncologists, a clinical geneticist, a clinical psychologist, a radiologist, a clinical nurse specialist, a minimal-access gynaecologist, a pathologist and a clinical fellow. All women attending the clinic undergo detailed pedigree-based clinical risk assessment and counselling. Women fulfilling the inclusion criteria of the UK Familial Ovarian Cancer Screening Study (UK FOCSS) (Figure 1) were deemed to be at high risk, and received comprehensive advice on the advantages and disadvantages of risk-reducing salpingo-oophorectomy and screening for OC, as well as advice on reproductive and life-style issues. The primary recommendation is risk-reducing salpingo-oophorectomy, with a detailed discussion of the advantages and disadvantages. Women over 35 years of age also had the option of participating in the national OC screening study (UK FOCSS).

Figure 1.

 Criteria for women at high-risk of ovarian cancer, based on the inclusion criteria of the UK Familial Ovarian Cancer Screening Study (UK FOCSS).

Between January 2005 and November 2009, 1888 women with a family history of breast and/or ovarian cancer were seen in the clinic. We have excluded women whose family history fulfils Amsterdam criteria II, and those with known mismatch repair gene mutations (suggestive of Lynch syndrome), from this analysis. On assessment, 37 (2%) women were at low risk (≤2% lifetime risk or population-based risk), 217 (11.5%) were at intermediate risk (greater than population-based risk, but not fulfilling the high-risk criteria listed in Figure 1) and 1624 (76.7%) were at high risk for OC. In ten (0.53%) cases data on risk status were missing. Of 1624 high-risk women, 168 (10.3%) were younger than 35 years of age, and deferred their decision making, 1148 (70%) preferred screening and 308 (19%) opted for preventative surgery. Forty per cent of BRCA carriers and 18% of women with unknown mutation status underwent prophylactic salpingo-oophorectomy over this period.

All women underwent a pre-operative CA125 and transvaginal ultrasound scan (TVS). Surgery involved the removal of both tubes and ovaries (or all remaining adnexae in women who had undergone previous partial removal), peritoneal washings for cytological examination and endometrial sampling. Specimens were processed by a dedicated senior pathologist (EB) with a special interest in familial gynaecological cancer. A strict surgicopathological protocol was adopted: both tubes and ovaries were transversely sectioned at 2–3-mm intervals and processed in their entirety to exclude occult carcinoma. Histological assessment of dysplasia/atypia was based on dysplastic changes, degree of nuclear stratification, mitotic index, nuclear:cytoplasmic ratio, prominent nucleoli and loss of ciliated cells. Cases with histological abnormalities not amounting to CIS, but showing some nuclear enlargement, prominent nucleoli, pseudostratification, incomplete replacement of the adjacent normal ciliated cells, less than full-thickness mucosal involvement or preserved epithelial polarity were graded as mild to moderate epithelial atypia, depending on the degree of abnormality.

Demographic, clinical and histopathological data were collected for each patient using a standardised proforma, and were then entered prospectively in a bespoke database. These were used for the current analysis. Where necessary, case notes as well as TVS, histopathology, cytology and biochemistry reports were reviewed. Women who had amenorrhea for 12 months or longer [excluding those with a medical or physiological explanation, such as a Mirena intrauterine system (IUS), hormonal therapy or breast feeding] were considered to be postmenopausal for the purpose of this analysis. Outcomes were compared between BRCA carriers and women of unknown mutation status. Statistical analysis was undertaken using spss 18. The Mann–Whitney nonparametric test was used to compare age distributions between groups after reviewing histograms. A chi-square test with Yate’s continuity correction (n > 30) and Fisher’s test (n < 30) were used to calculate the difference between proportions. Two sided P values are reported for all statistical tests. Confidence intervals for a single proportion were calculated using the measuring usability statistics package (Measuring Usability LLC, Denver, CO, USA).


A total of 308 women from breast and/or ovarian cancer families opted for risk-reducing salpingo-oophorectomy between January 2005 and November 2009. Of these, 65 (21.1%) were BRCA1 carriers, 52 (16.9%) were BRCA2 carriers and 191 (62%) had an unknown mutation status. The characteristics of the cohort are described in Table 1. In 26 of the 191 women of unknown mutation status, an affected member of the family was not found to carry a pathogenic mutation on BRCA1/BRCA2 testing.

Table 1.   Characteristics of high-risk women undergoing risk-reducing salpingo-oophorectomy
Cohort characteristic (n = 308)n
  1. BSO, bilateral salpingo-oophorectomy; B/L, bilateral; C/L, contralateral; FDR, first-degree relative; IQR, interquartile range; LAVH, laparoscopic-assisted vaginal hysterectomy; SO, salpingo-oophorectomy; TAH, total abdominal hysterectomy; TLH, total laparoscopic hysterectomy; U/L, unilateral.

  2. *Requiring resuscitation and admission to an intensive care unit for 1 day.

  3. **Treated with appropriate antibiotics (one showed methicillin-resistant Staphylococcus aureus on culture).

  4. ***Bowel was viable and did not require resection: it was reduced and the rectus sheath defect sutured.

Age distribution: median (IQR) years50.7 (45.5, 57.6)
Confirmed BRCA mutation117/308 (38%)
BRCA165 (21.1%)
BRCA252 (16.9%)
Unknown mutation status191/308 (62%)
FDR breast cancer147/297 (49.5%)
FDR ovarian cancer155/297 (52.2%)
Family history of ovarian cancer <50 years78/295 (26.4%)
Family history of breast cancer <45 years165/297 (55.6%)
Personal history of breast cancer101/299 (33.8%)
Parity P037/254 (14.6%)
Parity P136/254 (14.2%)
Parity P2116/254 (45.7%)
Parity P350/254 (19.7%)
Parity ≥P415/254 (5.9%)
Postmenopausal157/308 (51%)
Jewish ancestry46/259 (17.8%)
Laparoscopic BSO277 (89.9%)
TAH + BSO8 (2.6%)
Subtotal hysterectomy + BSO1 (0.3%)
Laparotomy + BSO6 (1.95%)
LAVH + BSO5 (1.6%)
TLH BSO1 (0.3%)
Laparoscopic U/L SO4 (1.3%)
Laparoscopic B/L oophorectomy 3 (0.97%)
Laparoscopic U/L salpingectomy + C/L SO1 (0.3%)
Laparoscopy converted to laparotomy + BSO2 (0.65%)
Intraoperative complications
Difficult intubation (short neck)1 (0.3%)
Cardiorespiratory arrest during peritoneal insufflation*1 (0.3%)
Serosal bowel injury (dense adhesions between bowel and anterior abdominal wall)1 (0.3%)
Uterine perforation (sutured during procedure)1 (0.3%)
Postoperative complications
Superficial wound infection**2 (0.65%)
Postlaparotomy pelvic haematoma (managed conservatively)1 (0.3%)
Pulmonary embolism (treated with anticoagulation)1 (0.3%)
Bowel obstruction with herniation of small bowel through the rectus sheath***1 (0.3%)
Urinary retention (managed conservatively)1 (0.3%)
Clostridium difficile diarrhoea1 (0.3%)
Anaemia needing blood transfusion1 (0.3%)

A detailed comparison of the characteristics of women in the BRCA1/BRCA2 and unknown mutation status groups is presented in Table 2. The median age of BRCA carriers opting for risk-reducing surgery (48.9 years; IQR 13.1 years) was significantly lower than that of women of unknown mutation status (52.1 years; IQR 11.7 years) undergoing surgery (= 0.016; Table 2). The groups did not differ with respect to parity or menopausal status, but did differ significantly with regards to family history of cancer: breast cancer families and personal history of breast cancer were over-represented in BRCA carriers, whereas breast and/or ovarian cancer families or a close relative with OC were more common in women of unknown mutation status (< 0.0005; Table 2).

Table 2.   Comparison of demographics in BRCA carriers and women of unknown mutation status undergoing risk-reducing salpingo-oophorectomy
CharacteristicBRCA1/BRCA2 (n = 117)Unknown mutation status (n = 191)PTest statistic
  1. FDR, first-degree relative; HBC, high-risk breast cancer only family; HBOC, high-risk breast and ovarian cancer family; HOC, high-risk ovarian cancer only family; IQR, interquartile range.

Median age years (IQR)48.9.0 (13.1)52.1 (11.7)0.016Mann–Whitney
Parity P014 (14.7%)23 (14.5%)0.789Chi-square
Parity P113 (13.7%)23 (14.5%)
Parity P242 (44.2%)74 (46.5%)
Parity P318 (18.9%)32 (20.1%)
Parity > P38 (8.4%)7 (4.4%)
Postmenopausal55 (47%)102 (53.4%)0.292Chi-square
HBC63/115 (54.8%)16/185 (8.6%)< 0.0005Fisher’s
HBOC50/114 (43.9%)124/185 (67%)< 0.0005Chi-square
HOC2/114 (1.8%)43/185 (23.2%)< 0.0005Fisher’s
Self breast cancer63/114 (55.3%)38/185 (20.5%)< 0.0005Chi-square
Breast cancer < 45 years in family83/112 (74.1%)82/185 (44.3%)< 0.0005Chi-square
FDR breast cancer67/112 (59.8%)80/185 (43.2%)0.006Fisher’s
FDR ovarian cancer26/112 (23.2%)129/185 (69.7%)< 0.0005Fisher’s
Ovarian cancer < 50 years in family21/111 (18.9%)57/184 (31%)0.029Fisher’s
Occult neoplasia10 (8.55%; 95% CI 4.17–15.16)4 (2.1%; 95% CI 0.57–5.28)0.011Fisher’s

Of the 308 surgical procedures undertaken, 74% (228) were performed at UCLH, seven were performed at other NHS gynaecological oncology centres, six were performed in the private sector and the remaining procedures were performed at local referring NHS hospitals. A total of 291 were completed laparoscopically (Table 1). In all cases where the ovary was not removed at surgery, previous oophorectomy had been undertaken for benign pathology. Three patients who were operated on outside of our institution only underwent laparoscopic bilateral oophorectomy at initial surgery. One of them subsequently underwent completion bilateral salpingectomy at our hospital. Fifteen patients underwent primary laparotomy: six because of multiple previous abdominal surgeries and nine for concomitant hysterectomy. In total, hysterectomy was undertaken in 15 (4.9%) patients for benign pathology such as fibroid uterus, heavy periods and uterovaginal prolapse (Table 1). In two women laparoscopic surgery was converted to laparotomy because of serosal bowel injury (one) and poor visualisation as a result of dense adhesions (one). Four patients had intraoperative complications and eight had postoperative complications (Table 1), giving an overall complication rate of 3.9% (95% CI 2.0–6.7).

Histological examination revealed 14 occult invasive/in situ cancers: four were ovarian (three primary ovarian, one recurrent breast) and ten were primary tubal in origin (one invasive, nine CIS) (Table 3). The overall occult cancer rate was 4.55% (95% CI 2.51–7.51). The occult ovarian/tubal cancer (invasive cancers and in situ cancers with positive cytology) rate was 2.6% (95% CI 1.13–5.05): 5.13% (95% CI 1.9–10.83) for BRCA carriers and 1.05% (95% CI 0.13–3.73) for women of unknown mutation status. When in situ tubal cancer was included, the rate was 4.55% (95% CI 2.51–7.51). Six of these 14 occurred in BRCA1 carriers (occult rate 9.23%; 95% CI 3.46–19.02), four in BRCA2 carriers (occult rate 7.69%; 95% CI 2.14–18.54) and four in women of unknown mutation status (occult rate 2.1%; 95% CI 0.57–5.28). The occult invasive/in situ cancer rate for both BRCA1/BRCA2 carriers (8.55%; 95% CI 4.17–15.16) was significantly higher than that of women with unknown mutation status (= 0.016) (Table 2).

Table 3.   Detailed findings in the 14 occult cancers detected at risk-reducing salpingo-oophorectomy
Study IDAge at surgeryFHLocationHistologyCytologyFIGO stageFT atypia (additional)Description of lesionCarrier status
  1. b/l, bilateral; c/l, contralateral; CIS, carcinoma in situ; FH, family history; FT, fallopian tube; HBC, high-risk breast cancer only family; HBOC, high-risk breast and ovarian cancer family; i/l, ipsilateral; u/l, unilateral.

004348.0HBOCFT (u/l)CIS0i/lCIS and atypia in one tube. c/l tube normalBRCA1
095640.4HBCFT (b/l)CIS0b/lCIS at fimbrial end of one tube with mild-to-moderate atypia; focal mild atypia of c/l tubeBRCA1
008653.4HBOCFT (u/l)Serous (grade 2)1ai/lInvasive serous carcinoma FT, incidental benign serous cystadenoma c/l ovaryBRCA1
023367.4HBCFT (u/l)CIS0I/lCIS and atypia in same FTBRCA1
021360.4HBCOvarySerous carcinoma (grade 2)+2cb/l2.8 mm, subcapsular serous carcinoma ovary, extension into serosal connective tissue and 0.8-mm submucosal deposit in one tubeBRCA1
092442.5HBOCFT (u/l)CIS+1cb/lCIS in one and atypia in b/l FTBRCA1
087458.7HBCOvarySerous carcinoma (grade 3)1aNone5 × 5-mm invasive lesion in lining of inclusion cystBRCA2
085357.4HBCOvaryPapillary serous carcinoma (grade 2)1cc/l9-mm lesion in ovary with 4-mm invasion with extracapsular extensionBRCA2
212959.5HBCFT (u/l) and Ovary (u/l)CIS FT & CIS ovarySuspicious for malignancy?1c ?0NoneCIS in one tube and focus of CIS involving ovarian surface adjacent to this tubeBRCA2
220859.9HBOCFT (u/l)CIS0NoneFocal CIS in one tubeBRCA2
036636.2HBCOvarySecondary carcinoma (previous breast)+N/ANoneMetastatic adenocarcinoma consistent with breast primaryUnknown mutation status
199354.6HBCFT (u/l)CIS+1cb/lCIS in one and atypia in b/l FTUnknown mutation status
181860.3HBOCFT (u/l)CIS0c/lCIS in one FT and atypia in c/l FTUnknown mutation status
201044.4HBOCFT (b/l)CIS0b/lCIS in one FT and atypia in b/l FTUnknown mutation status

Of the four women of unknown mutation status with occult in situ/invasive cancers, two women with tubal CIS were subsequently found to carry a BRCA1 and a BRCA2 mutation, respectively, upon genetic testing following histology, and in two others, an affected relative had previously tested negative for BRCA1/BRCA2 mutations. Of the latter two women, the first had a strong family history of breast and ovarian cancer: epithelial OC in her mother age 62 years and maternal aunt age 49 years; breast cancer in three maternal aunts aged 43, 46 and 50 years; colorectal cancer in a maternal aunt age 47 years; breast cancer in her grand aunt age 60 years). The second had a strong family history of breast cancer: breast cancer herself age 30 years, breast cancer in her paternal grandmother age 60 years and paternal aunt age 45 years. None of the four women of unknown mutation status had a primary invasive OC, although a metastatic OC consistent with a primary breast cancer was found in one of them.

Of the primary invasive cancers, four were stage 1 (three fallopian tube, one OC) and one was stage 2 (OC) (Table 3). Of the ten tubal lesions, nine were CIS and one was a stage-1a invasive cancer. Of the nine CIS cases, two with tubal CIS had adenocarcinoma on peritoneal cytology, and one had cytology suspicious of malignancy. However, no focus of primary cancer was identifiable, even after full staging surgery and completion hysterectomy in these patients. The median age of patients with occult primary in situ/invasive cancer (56 years; IQR 16.1 years) was not statistically significantly different from the rest of the cohort (50.4 years; IQR 11.8 years) (= 0.433). No statistically significant difference was found between the median ages of women of unknown mutation status (49.5 years; IQR 20.6 years) and BRCA carriers (58 years; IQR 13.4 years) with occult invasive/in situ cancer (= 0.454).

We also found mild to moderate tubal atypia not amounting to CIS/serous tubal intraepithelial carcinoma (STIC) in one/both tubes of ten other women, of whom three were BRCA1 carriers, two were BRCA2 carriers and five had unknown mutation status (Table 4). The overall mild to moderate tubal atypia rate was 3.57% (95% CI 1.8–6.3). This was not statistically significantly different (= 0.768) for BRCA1/BRCA2 carriers (4.27%; 95% CI 1.4–9.69) or those with unknown mutation status (3.14%; 95% CI 1.16–6.71). Thirty-seven women (12%) had other incidental benign pathology (without atypia) of the tubes/ovaries. There was no difference in benign pathology rates between BRCA1/BRCA2 carriers and patients of unknown mutation status.

Table 4.   Mild-to-moderate atypia not amounting to carcinoma in situ
Study IDAge at surgery (years)Mutation statusFamily historySite of atypiaCytologyHistology
  1. b/l, bilateral; c/l, contralateral; CIS, carcinoma in situ; FT, fallopian tube; HBC, high-risk breast cancer only family; HBOC, high-risk breast and ovarian cancer family; i/l, ipsilateral; u/l, unilateral.

203949.1BRCA1HBOCFT b/lMild-to-moderate tubal atypia
144645.6BRCA1HBOCFT b/lMild atypia b/l FT
203063.9BRCA1HBOCFT u/lMild atypia
219557.3BRCA2HBCFT b/lMild atypia b/l FT
048862.7BRCA2HBCFT b/lMild atypia b/l FT
113050.5Unknown mutation statusHBCFT b/lMild atypia b/l FT; benign serous cystadenoma left ovary
136153.3Unknown mutation statusHBOCFT u/lMild atypia i/l FT; c/l FT hyperplastic changes but no atypia
082467.1Unknown mutation statusHBCFT b/lMild to moderate tubal atypia
052039.6Unknown mutation statusHBOCFT u/lMild atypia one FT; i/l fimbrial cyst
018838.9Unknown mutation statusHBOCFT u/lMild atypia one FT
044040.5Unknown mutation statusHBOCEndometriumComplex atypical endometrial hyperplasia (AEH); adenomyosis and uterine serosal endometriosis


Our study shows that at risk-reducing salpingo-oophorectomy, high-risk women from breast and/or ovarian cancer families without a confirmed BRCA mutation have a 1.05% (95% CI 0.13–3.73) risk of occult cancer, whereas those with confirmed BRCA1/BRCA2 mutations have a 5.13% risk (95% CI 1.9–10.83). When tubal carcinoma in situ lesions were included, the rates were higher: 2.1% (95% CI 0.57–5.28) in women of unknown mutation status and 8.55% (95% CI 4.2–15.2) in BRCA carriers. The latter is consistent with other reports in the literature.9,11,12,17

On reviewing the literature, we found six small series (Table 5) that included outcomes of preventative surgery using a strict histopathological protocol in women from high-risk families where the BRCA mutation status was not known prior to surgery.11,17–22 Occult neoplasia was reported in five of 68 women of unknown mutation status undergoing risk-reducing salpingo-oophorectomy (Table 5). This includes three women with occult cancers, reported by Lu et al., where BRCA1/BRCA2 mutations were found at testing following surgery.21 Combining our data (four occult cases, 191 cases) with these reports, the overall occult invasive/in situ cancer rate for those with unknown mutation status was 3.1% (95% CI 1.30–6.0). If we include two studies that did not follow a strict pathological protocol,23,24 the occult rate falls to 2.6% (95% CI 1.1–5.1). Overall, these data suggest that women from high-risk families where genetic testing has not been undertaken may also have high occult cancer rates. This is an important issue that affects a significant proportion of the women seen in our clinics (who have not undergone BRCA testing), and our findings will facilitate more informed counselling and decision making in these cases.

Table 5.   Risk-reducing salpingo-oophorectomy series, including outcomes in high-risk women not known to carry BRCA1/BRCA2 mutations*
AuthorTotal HR cohortBRCA1/BRCA2BRCAUnknown mutation statusStrict protocolUMS occult neoplaisa
  1. adenoca, adenocarcinoma; b/l, bilateral; BO, bilateral oophorectomy; BOT, borderline ovarian tumour; BSO, bilateral salpingo-oophorectomy; CIS, carcinoma in situ; FT, fallopian tube; HR, high risk; inv, invasive; NA, not applicable; pap, papillary; u/l, unilateral; VUS, variant of uncertain significance.

  2. *Includes series following a strict histopathological protocol.

  3. **All three cancers were found to be in BRCA1/BRCA2 carriers on testing postoperatively, and ten remained untested.

  4. ***May include some data from Leeper et al.20

Olivier et al.171289434 (9 BO, 25 BSO)0YesNA
Lu et al.2133   19**1 VUS    13**Yes1 pap serous adenoca FT and ovary; 1 u/l serous BL ovarian tumor; 1 b/l serous BOT
Salazar et al.22207112Yes1 pap serous adenoca ovary + pap serous BOT (same case)
Colgan et al.1960391011Yes0
Leeper et al.20301758Yes (in 23)1 BOT adenofibroma ovary
Lamb et al.11***1136222, 5 VUS24Yes0
Total38433510468 5
This study (UCLH)308117191Yes3 FT CIS, 1 secondary ovarian (breast recurrence)
Sum692451104259 8

The majority (71.4%; 10/14) of occult invasive/in situ cancers in our series occurred in the fallopian tubes. In line with other series,11 five of these were found in BRCA1 carriers, two were found in BRCA2 carriers and three were found in women of unknown mutation status. In addition, we found adenocarcinoma on peritoneal washings in two women (BRCA1 carrier, untested) with tubal CIS, and suspicious cytology in one woman (BRCA2 carrier), with no evidence of invasion. Subsequent full staging surgery did not reveal any additional pathology. Our findings along with that of other similar reports in the literature serve to emphasise the importance of peritoneal washings in all high-risk women undergoing risk-reducing surgery.19,25

For many years the most durable hypothesis has been that epithelial OC arises from the ovarian surface epithelium. More recent research, largely driven by such findings in the high-risk population, has led to the fallopian tube being considered an integral part of new models proposed for ovarian carcinogenesis.16,26,27 Carcinoma in situ has been described as a precursor lesion, and is found to be present as a continuum with early tubal carcinomas, supporting transition from one to another.28 It has been postulated that genotoxic injury is more likely to lead to a progression of these lesions to cancer in women at high risk for disease.26 Nevertheless, the clinical significance of these early precursor lesions and details of any putative molecular pathway have yet to be established. Our findings support the hypothesis that a number of OCs in BRCA carriers may arise in the fallopian tube/extrauterine mullerian epithelium. They also suggest that the same holds true for high-risk women with unknown mutation status, and women with occult invasive/in situ cancer in this group should be offered mutation testing.

The age distribution of women of unknown mutation status with occult invasive/in situ cancer was similar to that of mutation carriers. However, the former group may delay surgery till an older age. The median age of BRCA carriers undergoing RRSO was 48.9 years, which is consistent with other reports in the literature,17,19 and is in keeping with a positive BRCA genetic test result being a predictor of risk-reducing surgery.29,30 However, women with unknown mutation status underwent surgery at a significantly older median age of 52.1 years (= 0.016), which has important implications for counselling.

To the best of our knowledge, this is the largest series to date reporting outcomes in high-risk women from breast/ovarian or OC families who have not undergone BRCA testing (Table 5). Previous series have focused largely on BRCA carriers,8,10,13,31 with only limited outcome data available on women from high-risk families where genetic testing has not been undertaken.11,17,19–24 Other strengths of our study include prospective data collection using a standardised proforma, strict histopathological assessment of removed tubes and ovaries, and a strict definition of high risk using accepted definitions adopted in the UK high-risk screening trial (UK FOCSS). A limitation of our study is that the BRCA status of women in the unknown mutation status group is not obtainable given the current testing guidelines in the UK. The availability of these data would have enabled us to comment on histopathological outcomes of BRCA-negative high-risk women.

Overall, 94.5% of the preventative surgeries were completed laparoscopically, and included six of the 15 women who had a concomitant planned hysterectomy. The laparoscopic bowel injury rate of 0.32% (95% CI 0.01–1.8) is consistent with the incidence of bowel injury reported by others.32 The laparotomy conversion rate (0.65%; 95% CI 0.08–2.33) and overall complication rate (3.9%; 95% CI 2.03–6.71) is similar to other reports in the literature.23,31 Of the 12 patients who had surgical complications, seven were major (2.27%; 95% CI 0.92–4.63). Meeuwissen described a major complication rate of 1.5% and minor complication rate of 10% in 133 high-risk women undergoing RRSO, whereas Kauff reported a major complication rate of 5% in 80 cases.23,31 Although RRSO is well established as the most affective means of preventing ovarian/tubal cancer in high-risk women,7,33 it is important that patients are counselled about the not insignificant risk of complications prior to surgery.

Uptake rates for risk-reducing salpingo-oophorectomy vary between different populations.34,35 Whereas a number of studies report higher uptake rates,36 in others, similar rates to ours have been reported.29,30 Our lower RRSO uptake rates reflect our referral pattern. As we have a longstanding interest in OC screening, women who specifically wish to participate in screening are more likely to be referred from the regional genetic centres, with a proportion of those who choose RRSO having surgery at their local hospital.

The finding of occult cancer found in two of 26 women whose relative tested negative for BRCA1/BRCA2 mutations lends support to the importance of offering preventative surgery to high-risk BRCA1/BRCA2 mutation-negative breast and ovarian/OC only families. It is consistent with the presence of phenocopies and the possibility of other unidentified genetic variants contributing to cancer risk in these families. The differences found in BRCA and unknown mutation status groups with respect to family history (Table 2) reflect rules governing genetic testing in the UK in the last decade, which require initial testing in a live cancer-affected individual in the family, and the different survival rates for breast and ovarian cancer. Unlike breast cancer, OC usually presents at a late stage, with an overall 5-year survival rate of 30–40%.37 Women from hereditary breast cancer alone (HBC) families are therefore more likely to have living affected relatives who can undergo genetic testing under NHS rules, and hence, are significantly over-represented in the BRCA group. However, in hereditary ovarian cancer only (HOC) or hereditary breast and ovarian cancer (HBOC) families, there are likely to be fewer living affected relatives who can undergo genetic testing. Hence, women from HOC/HBOC families are more likely to belong to the unknown mutation status group. The same reasons are likely to explain: (a) the over-representation of individuals with a personal history of breast cancer (< 0.0005), a first degree relative (FDR) with breast cancer (= 0.006) and a history of early breast cancer in the family (< 0.0005) in the BRCA group; as well as (b) the higher prevalence of women with an FDR with OC (< 0.0005) and early onset OC in the family (= 0.029) in the unknown mutation status group. We also analysed whether the over-representation of HOC/HBOC families in the unknown mutation status group could result from an increased uptake rate of risk-reducing surgery by women from these families in the entire cohort (data not shown). However, the presence of a family history of OC (HBOC/HOC family) was not associated with an increased uptake of RRSO in the cohort.

A number of guidelines suggest genetic testing may be of value at a BRCA probability of >10%.38,39 The current threshold of 20%BRCA probability for genetic testing set by the National Institute for Clinical Excellence (NICE)40 may be too high, and there is a need for this to be revisited. Two women in our series with unknown mutation status were subsequently found to have a BRCA mutation when tested after being found to have tubal CIS. Our findings raise the issue of giving serious consideration to the possibility of offering genetic testing to individuals in the UK from HBOC/HOC families who do not have living affected relatives and have been unable to access genetic testing.


In this paper, we have reported on surgical outcomes and compared occult ovarian/tubal cancer rates in BRCA carriers as well as high-risk women of unknown mutation status. Our study represents the largest such series to date of women who have not undergone BRCA testing. Both BRCA carriers and women of unknown mutation status were found to have a significant occult in situ/invasive cancer rate, consistent with what has been previously reported in the literature. However, the occult rate was significantly higher in the former group. The ages at which these cancers occurred were similar in both groups, although the latter group were found to have surgery at an older age compared with the former. High-risk women found to have occult in situ/invasive cancer should be offered genetic testing. Women undergoing risk-reducing surgery have a not insignificant complication rate of 3.9%. It is important that clinicians are made aware of these issues, as it has implications for counselling high-risk women.

Disclosure of interests

IJ has consultancy arrangements with Becton Dickinson in the field of OC. ANR has received honoraria from Fujirebio Diagnostics for giving lectures and attending meetings on the use of biomarkers in OC management, but none were directly related to this work. The other authors declare no conflict of interest.

Contribution to authorship

RM, AA and MJ were involved in the initial data collection. RM, UM and IJ were involved in analysis, drafting and writing the article. ANR, LS, ES, AA, DO, SG, MJ, CB, EB and MB contributed to writing the article. UM, IJ, ANR, RM, CB, LS, SG, ES and DO were responsible for the clinical care of the patients. EB reviewed the histological specimens and contributed to the histopathological sections of the article. RM and MB performed the statistical analysis and contributed to writing the statistical sections of the article. The final draft was prepared by RM, UM and IJ, and approved by the others. IJ and UM made equal contributions.

Details of ethics approval

The project was referred to the Chair of the Research Ethics committee (National Hospital for Neurology and Neurosurgery & Institute of Neurology Joint REC, reference number 07L 173). Under the Research Governance Framework the project was deemed to be a clinical audit, and permission for data analysis and submission for publication was given.


This work has not been directly funded by any commercial organisation, charity or other sources. A large portion of this work was performed at UCLH/UCL within the ‘women’s health theme’ of the NIHR UCLH/UCL comprehensive biomedical research centre (CBRC), supported by the Department of Health.


We are particularly grateful to all of our patients. We acknowledge the support and help provided by The Eve Appeal and Ms S. Chamberlain (clinic secretary). We are grateful to all the surgeons involved in the care of our patients (T. Mould, M. Widschwendter, A. Olaitan, N. MacDonald, A. Cutner, A. Vashisht, N. Aslam, D. Jurkovic, R. Salim and R. Hadwin). A large portion of this work was performed at UCLH/UCL within the ‘women’s health theme’ of the NIHR UCLH/UCL CBRC, supported by the Department of Health.