The term "high grade serous carcinoma" (HGSC) describes a group of ovarian, tubal and
peritoneal cancers with an aggressive biological behavior. HGSC is the leading cause of death
from gynecologic malignancy in western civilized countries. Women affected, usually have
advanced stage disease with metastatic spread throughout the abdominal cavity at time of
diagnosis. Five-year survival rates are in the range of 10 to 30 percent. The specificity of
current diagnostic tools (CA-125 and transvaginal ultrasonography) is low and ineffective at
detecting HGSC early enough to improve clinical outcomes. Definitive diagnosis of HGSC mostly
relies on surgical confirmation. These findings underline the need for an effective test for
early detection of HGSC. In the general population, the lifetime risk is 1.5 percent.
Women with germ line mutations in the BRCA1 and BRCA2 gene or a strong family history of
epithelial ovarian cancer carry a high risk for breast cancer and/or HGSC development.
Familial or inherited syndromes account for approximately 13 percent of cases of invasive
epithelial ovarian and fallopian tube cancer. The lifetime risk of ovarian cancer is 35 to 46
percent in women with BRCA1 gene mutations and 13 to 23 percent in those with BRCA2
mutations. Again, even in this population with high-risk for HGSC, the specificity of CA-125
and transvaginal ultrasonography is still too low and ineffective to improve clinical
outcomes.
Over the last years, increasing scientific evidence conglomerated that a large proportion of
not only familial HGSC develop primarily in the lining of the fallopian tube, that resembles
Müllerian epithelium. These precursor lesions are called "serous tubal intraepithelial
carcinomas" (STICs) and are characterized by p53 overexpression on immunohistochemistry and
high Ki-67 labelling index indicating a high proliferation index. In over 90 percent, STICs
carry mutations in the TP53 tumor suppressor gene.
As for today, risk reducing bilateral salpingo-oophorectomy (rrBSO) is the most effective
approach to reducing the risk of HGSC in high risk women. Among women with an increased risk
of HGSC (most with BRCA mutations) who underwent rrBSO, 4 to 17 percent are found to have a
STIC or even invasive neoplasm, and approximately 80 percent of these neoplasms are in the
ampullar part of the fallopian tube.
Recent findings highlighted the malignant potential of STICs. On histopathological specimen,
intraluminal shedding of tumor cells from STICs can be frequently demonstrated in the
fallopian tube. This shedding of tumor cells from STICs appears to be a risk factor for early
transperitoneal metastasis frequently found in HGSC. There is a strong clinical need for
screening for STICs, since they are the precursor lesion of HGSC. These facts underline the
importance of an effective - non-invasive - test for early detection of STICs.
The ovarian surface, the fallopian tubes, the uterine cavity and the peritoneal cavity all
together form a communicating compartment. The physiological function of the ciliated lining
of the tubes is to transport the egg into the uterine cavity after ovulation thus making it
likely that exfoliated cells from STICs can be found in the uterine cavity.
A promising approach for the detection of STICs has been established by Paul Speiser and
Robert Zeillinger (Molecular Oncology Group, Department of General Gynaecology and
Gynaecologic Oncology, Medical University of Vienna, Austria). This approach is called the
ALPINE technique (Austrian Lavage Procedure for the Detection of tubal Intraepithelial
Neoplasms) (manuscript under preparation). To facilitate an quick and easy lavage of the
uterine cavity and proximal tubes, a special catheter was developed (MEDICOPLAST, MF 13005,
catheter for uterine and tubal lavage). The ALPINE technique includes a lavage of the uterine
cavity and proximal fallopian tubes and subsequent analysis of this lavage fluid for the
presence of pre-malignant and malignant cells.
For the proof of principle that tumor cells from ovarian cancer are shed and can be found in
the lavages of the uterine cavity, uterine lavages were collected before a surgical
intervention for suspected ovarian malignancy at our institution and at the Catholic
University Leuven, Division Gynaecological Oncology, Belgium. After malignancy was confirmed,
genetic changes in the TP53 and KRAS genes were determined in tumor tissue. In a set of 9
epithelial ovarian cancer patients (EOC) and 1 ovarian metastases of a signet ring carcinoma,
the presence of these genetic changes was examined in lavage samples, using digital droplet
PCR (ddPCR). 10 genetic changes were identified in tumor tissue of these patients and 9/10
(90%) of these changes were detected in the corresponding lavage specimen too.
Furthermore, a filter approach, followed by p53 immunofluorescence staining was established,
confirming the presence of tumor cells in the lavage sample of one additional patient.
In a next step, lavage samples of 23 ovarian carcinoma patients, and if applicable
corresponding tumor tissue, were analysed through deep sequencing by the group of Bert
Vogelstein (Johns Hopkins University, Baltimore, USA). The presence of genetic changes,
indicative for ovarian cancer, could be confirmed in 18/23 (78.3%) lavage specimen including
both, early and advanced stages.
These results are proof that ovarian cancer cells are shed into the fallopian tubes and
uterine cavity, and can be collected through our ALPINE technique. The fact that ovarian
cancer cells were detected with high sensitivity in the lavage of the uterine cavity and
proximal tubes shows that this approach has potential in early diagnosis. Therefore, the
investigators are confident that this method could be applied in detection of premalignant
changes in high risk patients, as well.
Aim of the study:
The current study aims at answering the scientific question, whether exfoliated cells from
STICs get transported into the uterine cavity via the fallopian tube, and whether it is
possible to detect those cells in the lavage fluid from the uterine cavity and proximal
fallopian tubes.
Methods:
To address this question, the investigators will study 20 lavage samples and their 20
corresponding STIC-positive tissue samples in women who opt for rrBSO because of increased
risk of HGSC (mostly carrying a BRCA mutation), without a history of tubal occlusion for
sterilization. Women who opt to have the fallopian tubes removed but the ovaries preserved
are eligible for the study too, as are women who opt for rrBSO plus hysterectomy.
