Development of Peritoneal Carcinoma in women diagnosed with Serous Tubal Intraepithelial Carcinoma (STIC) following Risk-Reducing Salpingo-Oophorectomy (RRSO)

In the last few decades a growing number of women are being diagnosed with genetic mutations that increase their lifetime risk of developing ovarian cancer. The main ovarian cancer subtype is high grade serous carcinoma (HGSC) and almost 20% of these are associated with germline mutations of BRCA 1 and 2, but more than 40% of the patients do not have a family history of cancer and are not routinely tested [1]. Overall, women with BRCA 1 and 2 germline mutations have a higher risk of developing ovarian cancer (44 and 17%, respectively) compared with the 1 to 5% baseline risk of the general population [2]. With high grade serous being a major histological subtype, this population has also an increased risk for serous uterine and peritoneal cancers [3].

HGSC of the ovary usually present as advanced stage, progress rapidly and have a poor prognosis. There is increased evidence that the distal part of the fallopian tube is the site of origin of most ovarian and peritoneal HGSC and Serous Tubal Intraepithelial Carcinoma (STIC) represents the precursor lesion, although it is believed that STIC itself is likely to have metastatic potential [4, 5]. A large spectrum of fallopian tube lesions have been described ranging from p53 signatures with normal-appearing tubal epithelium, no atypia and low proliferation index based on Ki-67 immunostaining but with mutant p53 expression pattern [6] to serous tubal intraepithelial lesions (STIL) with cytological atypia but falling short of STIC [7]. p53 immunohistochemistry is one of the most efficient markers for STICs and a predictor for TP53 mutation. More than 90% of STICs have p53 signatures and share identical TP53 mutations with invasive ovarian or peritoneal cancers suggesting that STICs are the site of origin for high grade serous carcinomas [8]. Germline TP53 mutations are considered to have a significant role in the oncogenesis of several human cancers [9] and are found in more than 95% of ovarian high grade serous carcinomas [10]. These mutations represent the initial event in the development of high grade serous carcinomas and are documented in the majority of STICs [11, 12].

For women at increased risk, management options include ovarian screening and prophylactic surgery. Currently there is no widely accepted screening strategy for ovarian cancer, [13] but several studies have proven the effectiveness of Risk-Reducing Salpingo-Oophorectomy (RRSO), showing a reduction of approximately 80% in the risk for developing ovarian or fallopian tube cancer after prophylactic surgery [14–16]. Apart from reducing ovarian cancer risk, RRSO has been proven to reduce overall mortality up to 60% and is strongly recommended for prevention of ovarian cancers in BRCA 1/2 mutation carriers [14, 17].

As removal of the ovaries in pre-menopausal patients increases the risk for osteoporosis, coronary disease, stroke and total mortality, RRSO is not recommended in the general population [18]. For BRCA1 carriers RRSO is recommended before the age of 40 and for BRCA 2 carriers RRSO is recommended before the age of 45 or in any case when their family is complete [19]. Even with this strategy, the risk for development of subsequent peritoneal carcinomas has been reported to be 1 to 4.3% [14, 20].

The incidence of occult high grade serous carcinomas in the distal fallopian tube at the time of RRSO varies from 5 to 15% [21, 22] and the incidence of STIC varies from 0.6 to 7% in women with BRCA1 and BRCA2 mutations [23].

The aim of this study is to review the histological findings of 300 consecutive RRSOs, to analyse the association of STIC with subsequent diagnosed peritoneal carcinomas and to discuss the possible change in the management and follow up of these patients.

This is a retrospective study of 300 consecutive RRSOs performed at the Royal Marsden Hospital (RMH) in London, between January 2008 and January 2017.

All patients underwent pelvic ultrasound imaging prior to surgery, with additional CT and MRI when indicated. Suspicious features were detected in 4 cases (1.3%). The first case was an asymptomatic 62 years old female, BRCA 1 carrier, with a large echogenic cyst measuring 9 × 6.5 cm on the left ovary, containing debris suggesting previous haemorrhage. There was no abnormal vascularity seen on colour Doppler and in view of the elevated CA 125 of 100 it was labelled as suspicious and excision was advised. Intraoperative findings were not suggestive of malignancy and a BSO was performed with the specimen extracted in a bag without spillage. The final histology showed high grade serous carcinoma of the left tube (pT1a) with negative cytology and no p53 signatures. In the second case (42 years old female, BRCA 2 carrier), pelvic ultrasound demonstrated two cystic structures within the right ovary and minimal free fluid in the pouch of Douglas. CA 125 was 85 and intraoperatively, suspicious deposits seen in the pouch of Douglas were biopsied and sent for histology along with the BSO specimen. The final histology revealed high grade serous carcinoma of the ovary (with mutant p53 staining pattern) with peritoneal deposits and cytology positive. Bilateral coincidental benign Brenner tumours were seen. Following staging surgery the final FIGO stage was 3A2 due to microscopic high grade serous carcinoma disseminated within the omentum. The third patient was a 53 years old woman who declined BRCA testing, but with a strong family history of ovarian and breast cancer (first and second degree relatives) and a CA 125 of 36. Following an abnormal pelvic ultrasound, she underwent a MRI which demonstrated a small 2.1 × 3 cm right ovarian cyst with enhancing papillary soft tissue suspicious for malignancy. Suspicious peritoneal deposits were biopsied intraoperatively and final histology report confirmed high grade serous carcinoma of both fallopian tubes with a background of serous tubal intraepithelial carcinoma of the left tube (with mutant, over-expressed p53 staining) and infiltration of both ovaries. Peritoneal cytology was positive for malignant cells. Bladder and pelvic peritoneal biopsies showed high grade serous carcinoma and tumour was initially staged as 2B, but upstaged after final surgery to 3A1 due to left external iliac lymph node involvement. For the fourth woman, abnormal pelvic ultrasound demonstrated a bulky left ovarian thin walled cyst, but the final pathology returned benign findings.

All the procedures were performed laparoscopically and there were four conversions to laparotomy (1.3%). Morbid adhesions and frozen pelvis were responsible to conversion to laparotomy in three cases and external iliac vein injury resulted in conversion of the fourth case.

In our single centre series, STIC was associated with a significantly higher risk of subsequent peritoneal high grade serous carcinoma, therefore we now recommend all these patients should be considered for long term surveillance for up to 10 years.