Identification of pre-malignancies in the endometrium as possible precursor lesions of serous epithelial ovarian carcinoma.

Ovarian cancer is the second most frequent cancer and has the highest death
rate among gynaecologic cancers in the western world, with a lifetime risk of
1-2%. Serous epithelial ovarian cancer (EOC) is the most common type of ovarian
carcinoma and comprises approximately 50% of malignant ovarian neoplasm*s. It
is mostly high-grade and accounts for a highly aggressive and rapidly
progressive disease. The high mortality to incidence ratio associated with EOC
accounts for more deaths than all other gynaecologic malignancies combined.
Unlike many cancers, there is no easily clinical identifiable pre-malignant
phase of this malignancy making early identification difficult. Although
extensive research has focused on this topic for the last 35 years, the
aetiology of this cancer remains uncertain.

The hypothesis on the development of ovarian cancer with the endometrium as
origin is emerging. It is thought that a precursor lesion of serous ovarian
carcinoma originates in the uterus and spreads into the peritoneal cavity via a
mechanism as is accepted for endometriosis. However, the endometrial tissue has
never been extensively screened in order to reveal a putative precursor lesion
in women with serous EOC.

This new hypothesis on the endometrium as possible origin of serous EOC is
based on the following observations.
1) Previously, a precursor lesion called endometrial intraepithelial carcinoma
(EIC) was identified in the endometrium of women with serous uterus carcinoma.
Importantly, the premalignant cells of EIC have a loosely cohesive nature and
are able to spread to intraperitoneal surfaces easily. EIC is identified with
peritoneal metastasis without evidence of concordant endometrial carcinoma. It
is thought that this precursor lesion could also be responsible for a
proportion of the serous EOC.
2) Another interesting observation is that hysterectomy and/or tubal ligation
decreases the ovarian cancer risk by 43-46%, suggesting that the origin of
ovarian cancer could very well be located within the uterus.
3) The pathologist cannot morphologically differentiate between serous
carcinomas from different origins (uterus, fallopian tube, ovaries and
peritoneum). Histologically, immuno-histologically and genetically there are
many similarities among these tumours. This suggests the possibility of similar
pathways of carcinogenesis for these tumours.

To investigate this hypothesis of the endometrium as possible origin for serous
EOC, the endometrial tissue should be extensively screened in women with serous
EOC. As serous ovarian carcinoma is rapidly progressive, disease is most often
already extensively spread at diagnosis and neoadjuvant chemotherapy is needed
in the majority of these women before complete debulking surgery is attempted.
However, the influence of neoadjuvant chemotherapy on the presence of a
putative precursor lesion in the endometrium is not yet known. It is a
possibility that these putative precursor lesions disappear because of the
chemotherapy and will be overlooked when diagnosis is only based on the
endometrial tissue retrieved from debulking surgery after chemotherapy.
Therefore, a curettage is suggested in these women in order to retrieve
endometrial tissue before the start of the chemotherapy. Since diagnosis of
ovarian carcinoma is verified with a diagnostic laparoscopy or explorative
laparotomy before treatment is started, this procedure will be preceded with a
curettage.

Concluding, conformation of this new hypothesis in a prospective setting would
change the current view on the aetiology of ovarian cancer, which could have
dramatic implications for diagnosing, treatment and prognosis of patients with
this type of cancer. As holds true for other cancer types, early identification
and treatment of (pre-) malignant lesions of ovarian cancer could positively
influence the prognosis of these women.

To identify pre-malignant lesions within the endometrium as precursor lesions
of serous epithelial ovarian carcinoma.

A diagnostic laparoscopy or explorative laparotomy is planned for each patient
suspected for serous epithelial ovarian carcinoma. Preceding this diagnostic
laparoscopy or explorative laparotomy, a curettage will be performed to
retrieve endometrial tissue from these women before chemotherapy will be
started. Namely, this diagnostic operation is mostly followed by neoadjuvant
chemotherapy before complete debulking surgery is attempted.

The additional burden for the patient is minimal, since the additional duration
of the anaesthesia is only 10 minutes. There is a small chance of uterus
perforation (0.12-0.14%, Aydeniz et al., 2002). Therefore, in this study the
curettage will precede the planned diagnostic laparoscopy or explorative
laparotomy to enable screening of the uterus after the performed curettage. In
this study the additional risk will be minimal since only experienced
gynaecologists will perform this intevention. Afterwards, the patient could
have some complaints of pelvic pain or some vaginal bleeding for a maximum of
three days.