Target condition being diagnosed

Endometrial cancer (cancer of the lining of the womb (uterus)) is the fifth most common cancer in women, accounting for an estimated 320,000 new cases globally each year (Ferlay 2013). A woman’s risk of developing endometrial cancer by the age of 75 is estimated to range from 0.6% in developing countries to 1.6% in developed countries (Jemal 2008).

In the United Kingdom, the incidence of endometrial cancer has risen by 40% since 1993 (Evans 2011). Risk factors for endometrial cancer include advancing age, obesity, diabetes, nulliparity, late menopause, unopposed oestrogen replacement therapy, and Tamoxifen use (Berek 2014).

Endometrial cancer is staged surgically using the 2010 International Federation of Gynecology and Obstetrics (FIGO) system (Table 1). The cornerstone of treatment in most women with endometrial cancer is surgery, involving a total hysterectomy and bilateral salpingo‐oophorectomy, with or without a lymph node dissection. For endometrial cancers thought to be confined to the uterus at surgery, previous randomised controlled trials (RCT) have not demonstrated a survival advantage to routine systematic pelvic lymphadenectomy compared to removal of bulky nodes (Frost 2017). Systematic reviews of RCTs have concluded that minimal access surgery is the preferred approach, with reduced pain, reduced hospitalisation, and earlier resumption of daily activities, with no adverse effect on survival, when compared with open surgery (Galaal 2012; Janda 2006; Walker 2009).

At diagnosis, the majority of women will have disease confined to the womb, leading to a five‐year overall survival of over 90% (Creasman 2006). About 10% of women will have advanced disease at diagnosis, leading to a poorer overall survival (Jemal 2008).

After surgery, women may be offered adjuvant treatment, such as radiotherapy, chemotherapy, or a combination, based on risk factors for recurrence, such as stage, age, grade, lymphovascular space involvement, myometrial invasion, and lymph node status.

In a 2012 meta‐analysis of eight trials that evaluated external beam radiotherapy therapy (EBRT), the authors concluded that: “EBRT reduces the risk of locoregional recurrence, but has no significant impact on cancer‐related deaths or overall survival. It is associated with significant morbidity and a reduction in quality of life.” (Kong 2012). Avoiding over‐treatment with radiotherapy, and its potential for long‐term side effects, is important for women with endometrial cancer, most of whom will not ultimately die from their disease.

Metastatic spread to the surrounding lymph nodes is a separate, but at least partially related prognostic factor to other clinical and histopathological risk factors. Its presence is associated with an increased recurrence rate and decreased overall survival.

The benefit of adjuvant chemotherapy for women with positive lymph nodes is supported by a 2014 meta‐analysis. When compared with postoperative radiotherapy, giving combination chemotherapy resulted in significant improvement in overall survival, and significant improvement in progression free survival (Galaal 2014).

Index test(s)

Sentinel lymph node biopsy (SLNB) studies involves identifying and removing a sentinel lymph node. This is the first node that is involved in the drainage of lymph from the primary cancer to the lymph nodes. If this is negative, it is surmised that the other nodes are not involved. This is a well‐established technique in other cancers, such as breast or vulval cancer (Lawrie 2014; Lyman 2014). It involves injecting a detectable tracer into the area surrounding the tumour, which then travels along lymphatic channels to the sentinel lymph node, enabling the sentinel node to be identified at surgery, removed, and sent for histological examination to see if cancer cells have spread to the lymph node.

Ideally, a SLNB is a more targeted method of assessing the spread of apparent early stage endometrial cancer, compared with a systematic lymph node dissection, enabling appropriate selection of adjuvant therapy, such as radiotherapy or chemotherapy, and avoiding over‐treatment. SLNB is normally combined with histopathological ultrastaging to increase the chances of detecting micrometastases. This involves taking multiple fine sections of the sentinel lymph node, often combined with other histological techniques, such as immunohistochemistry (IHC). This is a much more detailed examination compared to conventional lymph node histological examination, and increases detection of lymph node metastases.

Standard histopathological assessment of lymph nodes will miss micrometastases. Hafner 2007 reported that using routine Haemotoxylin and Eosin (H&E) histology results in only a 1% chance of identifying a cluster of less than 3 cell diameters. Ultrastaging is time consuming and expensive, making it unsuitable when there are larger numbers of nodes. The contribution of IHC is particularly relevant, as between 18% and 20% of patients were upstaged after detection of micrometastases by IHC, compared to H&E staining alone (Niikura 2004; Pelosi 2003). Therefore, SLNB should involve detection of the sentinel lymph node and histopathological ultrastaging, including IHC, to maximise the detection of micrometastases.

The most commonly reported tracer(s) used for SLNB are radioactive technetium (Tc‐99m) with or without visible blue dyes, such as methylene blue or patent blue, and near infrared fluorescence tracers, such as indicyanine green (ICG; (Papadia 2017)).

There are a variety of methods described for injecting radioactive tracer or coloured dye. These include cervical injection (injection into the cervix (neck of womb), normally using a speculum to be able to see the cervix), hysteroscopic injection (injection into the inside wall of the womb using a telescope inserted through the cervix into the cavity of the womb), and subserosal myometrial injection (injection into the outside wall of the womb). Cervical injection is most convenient because of easy access to the cervix. Some studies have reported cervical injection as a single site injection (Buda 2016), and others have used cervical injection in conjunction with subserosal myometrial injection (Niikura 2013). The main concern with cervical injection alone is that there is the potential to miss metastatic spread through the ovarian drainage route to the para‐aortic region, leading to false negative results. However, data from several studies looking at endometrial cancer completely staged with both pelvic and para‐aortic node dissection suggest that isolated metastases to the high para‐aortic region are rare; a review of 18 studies suggested that only 1.5% of women will have positive para‐aortic nodes when the pelvic nodes are negative (Chiang 2011). It is likely that para‐aortic nodal dissection results in an unnecessary surgical intervention in the vast majority of women with endometrial cancer.

In sentinel lymph node studies, the main endpoints are detection rates, sensitivity, and the false negative rate. The detection rate is the percentage of the patients where a sentinel lymph node was identified by the technique, regardless of whether the lymph node was positive or negative. It is not clear whether unilateral pelvic detection of a sentinel lymph node should be viewed as a failure of the technique, because lymph drainage may not flow to both sides of the pelvis in every patient. Ideally, a pelvic sentinel lymph node should be identified on both sides of the pelvis. False negatives are important results, as this represents a true failure of the technique. In this case, metastatic disease is undetected, which could lead to under‐treatment. Although there is no standard for an acceptable level of false negative results of a test in endometrial carcinoma, for SLNB in breast cancer, it is agreed that false negatives should not exceed 5%.

Clinical pathway

A patient with endometrial cancer will typically present with abnormal menstrual bleeding, or more commonly, post‐menopausal bleeding. An endometrial biopsy is taken to make a diagnosis, either by blind pipelle biopsy or hysteroscopically guided.

Following diagnosis, further imaging (with computer tomography (CT), magnetic resonance imaging (MRI), or both) may be indicated, although patients with grade 1 endometrial cancer on biopsy may only have a chest x‐ray performed, rather than cross‐sectional imaging.

Patients with endometrial cancer who are fit for surgery would then have a hysterectomy and bilateral salpingo‐oophorectomy performed, with or without sampling or excision of pelvic lymph nodes. Presence or absence of pelvic lymph node disease may affect recommendations for adjuvant pelvic radiotherapy, chemotherapy, or both. Others may recommend adjuvant treatment, based on histological and clinical risk factors. If SLNB is planned, injection of the tracer into the cervix, body of the womb, or both can be performed either shortly before or at the time of the hysterectomy. In those who have Tc‐99m tracers used, specialised imaging techniques, such as planar scintigraphy or single photon emission computed tomography (SPECT/CT; which overlays radioactive 'hot spots' onto conventional CT images) may be used to aid anatomical localisation of highlighted lymph nodes.

A SLNB could replace a full removal of lymph nodes at time of hysterectomy, if CT or MRI do not demonstrate markedly abnormal lymph nodes. Alternatively, SLNB could be performed instead of no pelvic lymph node sampling, since previous studies have demonstrated no therapeutic benefit of pelvic lymph node excision in endometrial cancer (Frost 2017). Presence of absence of a positive sentinel lymph node would then guide subsequent treatment strategies.

Rationale

A recently updated Cochrane Review found that there was no therapeutic benefit to systematic pelvic lymphadenectomy in endometrial cancer (Frost 2017). In addition, there was a four‐fold increase in surgical‐related morbidity and an eight‐fold increase in lymphoedema and lymphocyst formation (a retroperitoneal collection of lymph) in the group who underwent the surgery. This can cause serious long‐term morbidity in women, many of whom would have an otherwise excellent prognosis. Despite these data, lymphadenectomy is still widely practiced world‐wide, supported by a number of factors, including the belief that ‘doing something’ is better than ‘doing nothing’. Many women continue to be subjected to the short‐ and long‐term risks of over‐treatment.

A pelvic lymph node dissection becomes difficult with increased obesity, and carries a risk of vascular or nerve injury (Agar 2015). The risk of leg lymphoedema following a node dissection is commonly under‐reported (or not reported at all in results of surgical studies), with rates up to 38% (Biglia 2015), and lymphocyst formation in around 20% (Zikan 2015). The debilitating effects of lower limb lymphoedema cannot however, be underestimated, and have a marked effect on the quality of life of long‐term survivors (van de Poll 2015). Substitution of a SLNB instead of a lymph node dissection reduces both acute and chronic morbidity in other cancers (Ashikaga 2010). Therefore, it is highly likely that this is also the case in endometrial cancer, although there are no data available to support this. There are no published RCTs evaluating the accuracy of SLNB in endometrial cancer.

There is considerable disagreement among the UK cancer centres regarding the value of lymph node dissection in endometrial cancer, because a systematic review of RCTs of full pelvic lymph node dissection found no overall survival advantage (Frost 2017). Some centres do not perform any form of node dissection, while other centres will perform a node dissection in aggressive endometrial cancers, such as grade 3 endometrial, or serous cancer of the uterus (so‐called type II endometrial cancers). While it would seem unlikely that a lymph node dissection removing micrometastases may offer any therapeutic benefit, it could identify more aggressive cancers that require loco‐regional, systemic adjuvant therapy, or both. However, whether there is any advantage to treating, based on lymph node status, rather than other known risk factors, such as age, histological type, myometrial invasion, and lymphovascular space invasion, remains controversial (and will not be answered by a study on diagnostic test accuracy).

The clinical implication of a false negative test, if full lymphadenectomy was not performed after sentinel lymph node biopsy, would be an increased risk of recurrence or residual disease following surgery, compared with a full lymphadenectomy. This could potentially lead to under treatment, depending on what risk factors are used to determine the administration of adjuvant treatment. However, if full lymphadenectomy was not otherwise planned, decisions about adjuvant treatment would normally be based on other histological and patient‐specific risk factors, rather than knowledge of lymph node status.