Epithelial ovarian cancer (EOC) remains the tumor with the most unfavorable prognosis within the field of the gynecological oncology. The incidence of ovarian cancer in the Netherlands in 2008 was 14.5 per 100,000 with 12.3 deaths per 100,000 . In the United States in 2007 the incidence was 13.0 per 100,000 and there were 8.2 deaths per 100,000 . The high mortality rate is partially due to the fact that approximately 75% of patients are diagnosed with advanced stage EOC.
EOC can metastasize through three different ways: intraperitoneal (in the abdominal cavity), lymphogenous and hematogenous [3, 4]. Concerning the lymphogenous spread, it is clear that lymphatic metastases of EOC mainly occur in the para-aortic lymph nodes . It is believed that the tumor cells follow the lymph vessels that accompany the ovarian artery and vein in the infundibulopelvic ligament up to the high para-aortic region and renal vein. Nevertheless, pelvic lymph node metastases are also frequently found [6–16]. These tumor cells probably follow a different route, following the para-uterine vessels in the broad ligament towards the uterine artery and vein and further on to the iliac vessels. In some case reports, isolated inguinal node metastases are also described [17–20]. The exact mechanism of this route of metastasis is still unclear, but the metastatic cells might follow the course of the round ligament towards the inguinal lymph nodes, or might follow the iliac vessels towards the femoral vessels. The incidence of lymph node metastasis in clinical stage I to II ovarian carcinoma is reported between 6.1 - 29.6% (mean 14.2%) .
In case of a clinical early stage ovarian cancer, the Dutch guideline  recommends a staging laparotomy with adequate lymph node sampling, with an absolute minimum of ten lymph nodes removed. In the same guideline, a footnote is made stating that a larger number of removed lymph nodes will increase the chance of finding metastases. These lymph nodes also need to be sampled from different anatomical regions, of which the most important are the para-aortic and paracaval region between the renal vein and inferior mesenteric artery, the common, internal and external iliac vessels and the obturator fossa.
According to the International Federation of Gynecology and Obstetrics (FIGO), EOC with lymph node metastases is classified as FIGO stage IIIC disease, even in the absence of peritoneal metastases . In contrast to patients with FIGO stage I ovarian cancer after a comprehensive staging procedure, patients with a FIGO stage III ovarian cancer are obliged to receive adjuvant chemotherapy. Therefore, the recognition of lymph node metastases is of utmost importance.
Surgical staging of EOC and the extent of lymph node dissection differs greatly from center to center .
A recent review, published in 2011, showed an incidence of 14.2% for lymph node metastasis in early EOC . The incidence is higher in grade 3 tumors (20.0%) and the serous histological subtype (23.3%), whereas in grade 1 and mucinous tumors the incidence is 4.0% and 2.6%, respectively.
The assessment of lymph nodes with the aid of radiological techniques (computed tomography (CT) scan, magnetic resonance imaging (MRI), positron emission tomography (PET)) alone in EOC is insufficient; the sensitivity and specificity for detection of lymph node metastases with PET scan is 73.2% and 96.7%, with CT scan 42.6% and 95.0%, and with MRI 54.7% and 88.3%, respectively .
To identify the involved lymph nodes different surgical approaches exist, ranging from taking random lymph nodes in different anatomical regions (lymph node sampling) to a systematic lymphadenectomy . A systematic lymphadenectomy can be considered as the gold standard. However, such a radical procedure gives more morbidity than lymph node sampling. These include the formation of lymphocysts (up to 13.5%), nerve and vessel injury (up to 4%), increased blood loss and increased operating time .
With a sentinel node procedure the first node that receives primary lymphatic flow can be identified (the so-called sentinel node). The pathological examination is an indication of the nodal status of the remaining nodes; when the sentinel node is negative, one can presume that the remaining nodes are also not involved. As a consequence, the patient may be spared a radical lymphadenectomy, and thus the associated morbidity .
The sentinel node technique has been proven effective in different cancers such as breast cancer and malignant melanoma. In gynecological tumors it has been shown to be effective in vulvar cancer . Currently, sentinel node studies are being performed for cervical and uterine cancer, and some cancer centers already routinely perform sentinel node procedures for these gynecological cancers. Sentinel node studies in ovarian cancer are scarce. Nyberg et al. performed a study in 16 patients with high-risk uterine cancer in whom technetium and blue dye were injected into the right or left ovary . Since patients with a high-risk uterine cancer undergo a staging procedure similar to that of patients with early stage ovarian cancer (namely, a total abdominal hysterectomy (TAH) with bilateral salpingo-oophorectomy (BSO) and a pelvic and para-aortic lymphadenectomy), these patients were selected to investigate whether injecting tracers in the ovary would render sentinel nodes. After an incubation time of 15 minutes, a sentinel node was detected in 15 out of 16 patients. Negishi et al. used activated charcoal solution to identify ovarian lymphatics in 11 patients . The charcoal was injected into the cortex of the ovary. The charcoal was deposited in (sentinel) lymph nodes of all patients. In both studies the tracer was injected into the ovary. Some authors claim that injecting in the ovary can be difficult when bulky ovarian masses are present. Furthermore, it is claimed that there is a risk of tumor dissemination when tracers are injected into the ovarian capsule . In the current feasibility study, the injection of the tracer is performed in the ovarian ligaments, not in the ovarian cortex. This is to avoid spillage and to be as close as possible to the draining lymph vessels in the ovarian ligaments, irrespective of the size of the ovarian masses. Therefore, in addition to including patients with high-risk endometrial cancer, we also can include patients with an enlarged ovary without risk of tumor dissemination.
Lymphatic mapping can be performed with blue dyes as well as with radioactive isotopes; both can be injected into the ovarian ligaments, which contain the main routes of lymph drainage. After the incubation time the sentinel nodes can be visualized by either colorization (blue lymph nodes can be identified) and/or with a gamma probe that detects the radioactive tracer . In breast cancer it has been shown that the detection rate is highest when both radioactive isotope and blue dye are combined [28, 29].
The blue dyes can cause an allergic reaction, exhibited with urticaria, erythema, hypotension and even cardiovascular collapse with bronchospasm . However, the incidence of allergic reactions is very low and varies between 0.07 and 2.7% [30–32].
The radioactive isotope is safe for patient and health care workers . No allergic reactions have been described due to the radioactive isotope.
Since lymph node metastases are found in 14.2% of patients with clinical early stage ovarian cancer, this is a clinically relevant study. Indeed, a sentinel node procedure can prevent unnecessary radical lymph node dissection with the associated morbidity. It could also be more accurate than at-random lymph node sampling which is the current standard care in ovarian cancer in the Netherlands.
This study is scientifically relevant since injecting tracers in the ovarian ligaments can enhance our knowledge on the lymphatic routes and dissemination sites of ovarian cancer, that is, the anatomical locations of the lymph nodes most likely to be involved in ovarian cancer. Injection of tracer in the ovarian ligaments has, to our knowledge, never been published.