**9. Areas for future research**

## **9.1 Sentinel Lymph Node (SLN)**

From the evidence presented above, it is clear that for patients with endometrial cancer who are at risk of lymph node metastasis, the site of metastasis can be in the pelvic LNs or the para-aortic LN chain up to the renal vessels. Removal of metastatic lymph nodes has prognostic and therapeutic value. On the other hand, the addition of a systematic PLND and PaLND to a standard hysterectomy and bilateral salpingo-oophorectomy, increases the technical difficulty of the surgery, requires more operating time and increases the risk of intra-operative and postoperative complications. These problems apply even when a minimally invasive surgical approach is adopted. Therefore, the challenge is to identify a surgical technique that provides accurate staging information about nodal status, while avoiding unnecessary morbidity.

Sentinel lymph node detection might resolve this dilemma. This technique is based upon the observation that in several types of cancer, tumor cells migrate from the primary tumor to one or a few lymph nodes before metastasizing to other lymph nodes (melanoma, breast, cervix, vulva) (Altgassen et al., 2008; Hauspy et al., 2007a&b). Lymphatic mapping by sentinel lymph node (SLN) detection offers a means of assessing the lymph node status of primary tumors with respect to metastases, without having to resort to formal LND.

In a meta-analysis of various techniques to assess lymph node status in endometrial cancer, Selmanet al. (2008) showed that SLN biopsy was more accurate than MRI and CT scan. In endometrial cancer, several approaches have been attempted: serosal injection during surgery, cervical injection or peri-tumoral injection using hysteroscopic assistance. With cervical injection, detection rates of sentinel lymph nodes in low-risk endometrial cancer reach 85% (Abu-Rustum et al., 2009). A recent study in early invasive cancer suggested that SLN biopsy is a more sensitive procedure to detect pelvic lymph node metastasis compared to the classic PLND due to more extensive sectioning by the pathologist of this LN, its occasionally unusual location (common iliac or para-aortic) and the surgeon's thorough search for this blue or "hot" node (Gortzak-Uzan et al., 2010). Similarly, in early-stage endometrial cancer, SLN mapping appears to be a more sensitive procedure for detecting PLN metastasis compared to the classic PLND for the same reasons: the surgeon's thorough search for this sentinel node and extensive sectioning by the pathologist of the sentinel lymph node (Khoury-Collado et al., 2011).

A French multicentre study (SENTI-ENDO) prospectively evaluated the ability of cervical dual injection of technetium and patent blue to identify SLN in patients with endometrial cancer (Ballester et al 2011). One hundred thirty-three patients were enrolled at nine centers in France. At least one SLN was detected in 111 of the 125 eligible patients; 17% had pelvic lymph node metastases and 5% had an associated SLN in the para-aortic area. Three patients had false-negative results (two had metastatic nodes in the contralateral pelvic area and one in the para-aortic area), giving an NPV of 97% (95% CI 91 to 99) and sensitivity of 84% (62 to 95). All three of the patients in whom the SLN was negative in the presence of metastatic nodes had Type 2 endometrial cancer. Ultrastaging detected metastases, which were missed by conventional histology in nine of 111 (8%) patients with detected SLNs, representing nine of the 19 patients (47%) with metastases. SLN biopsy upstaged 10% of patients with low-risk and 15% of those with intermediate-risk endometrial cancer.

This study highlights the danger of omitting lymphadenectomy in patients with early-stage endometrial cancer, as suggested by the ASTEC study, as 11% of patients at low risk for lymph node metastasis (Grade 1, endometrioid cancer with no myometrial invasion), had positive lymph node metastasis. The authors conclude that SLN biopsy with cervical dual labeling could be a trade-off between systematic LND and no dissection at all in patients with low or intermediate risk endometrial cancer.

The limitations with this study are that the investigators used only cervical injection for the SLN mapping, which is not ideal to identify PaLNs. In a review of SLNs in endometrial cancer, Delpech et al 2008, reported a lower rate of para-aortic SLN detection using cervical injection alone compared with cervical and subserosal or subendometrial injection of patent blue. Additionally, in the SENTI-ENDO study, PaLND was not done if the PLND did not identify metastasis. This means that the incidence of para-aortic metastases could have been underestimated, as about 10% to 16% of lymph node metastases occur exclusively in the para-aortic region.

An experimental study on female cadavers by Lecuru et al 1997, had identified that one of the main routes of lymphatic drainage from the uterus ran along the infundibulo-pelvic ligament to the para-aortic area. Furthermore, when sentinel lymph node were identified using hysteroscopic injection to the tumor base, the para-aortic region was shown to be an important site of sentinel nodes in endometrial cancer, with 14% of SLN being exclusively in the para-aortic region and 47% of para-aortic sentinel nodes located above the inferior mesenteric artery (Nijkura et al., 2004). This method is technically more demanding. Nevertheless, if sentinel lymph node mapping is to replace surgical staging for endometrial cancer, we are obliged to investigate and adopt the most accurate rather than the most expedient method of identifying the sentinel lymph node.
