​Uterine cancer is the fourth most common cancer affecting women in Singapore, and its incidence has been increasing steadily over the last decade. Approximately 380 women are diagnosed with uterine cancer in Singapore every year, of which 60 per cent are seen and managed by the Department of Gynaecological Oncology at KK Women’s and Children’s Hospital (KKH).

Endometrial cancers account for 80 to 90 per cent of all uterine cancers globally, and more than two thirds of patients are found to have early-stage cancers. In KKH, about 180 patients are diagnosed with Stage I to Stage II endometrial cancers annually, according to the International Federation of Gynecology and Obstetrics (FIGO) 2009 criteria.

The current standard treatment for women in Singapore with early-stage endometrial cancers is a total hysterectomy (removal of the uterus), bilateral salpingooophorectomy (removal of both ovaries and fallopian tubes) and a systematic bilateral pelvic lymphadenectomy (complete removal of lymph nodes from the pelvis). Surgical staging is also carried out to guide adjuvant treatment decisions, define recurrence risk and facilitate assessment of prognosis.

Approximately 10 per cent of women with cancer that is clinically confined to the uterus (i.e. no evidence of distant spread on computed tomography or magnetic resonance imaging scans) are found to have pelvic lymph nodes metastases – where cancer cells are found to have spread to the pelvic lymph nodes.

Where the pelvic lymph nodes are found to be positive for cancer, this has been shown to confer a less ideal prognosis. Such patients are upstaged to a diagnosis of Stage IIIC cancer, and would need to undergo adjuvant treatment such as chemotherapy and radiotherapy. Systematic bilateral pelvic lymphadenectomy has been associated with significant morbidity such as lower limb lymphoedema, pelvic lymphocyst formation and transient neuralgias in up to 20 per cent of patients.

 

AN ENHANCED MODALITY OF SURGICAL STAGING

The sentinel lymph node (SLN) is the first node in a regional lymphatic basin that receives the lymph flow from the primary tumour, and its histological status may accurately predict the status of the regional lymphatic basin. Hence, SLN mapping and biopsy has been mooted as a useful modality for assessing lymph node involvement and triaging patients who would benefit from adjuvant treatment. This can help to prevent a complete pelvic lymphadenectomy and its associated morbidity in a significant number of patients – particularly those with early-stage cancer.

 

 

The traditional method for SLN mapping involves the use of a blue dye (patent blue or methylene blue) as well as radioactive tracers such as technetium-99 (Tc-99). However, using radioactive tracers necessitates a pre-operative nuclear medicine injection and lymphoscintigram, which are associated with additional costs and patient discomfort.

In recent years, SLN mapping using ICG-NIR (indo-cyanine green and near-infrared imaging) has emerged as an attractive alternative, and has been found to have similar rates of mapping success to that of radiocolloid Tc-99 combined with blue dye in many studies1, 2.

Indo-cyanine green (ICG) dye is very safe, with a one in 42,000 risk of anaphylactic reaction. The fluorescent dye, which is injected into the cervix during the SLN mapping process, relies on a flourimetry-capable camera and appears blue when excited by a light source in the near-infrared (NIR) range.

As light in the NIR range has a wavelength range of 700 to 900 nanometres and is invisible to naked eye, it does not alter the surgical field when used. Laparoscopic systems are available where the fluorescence in the dye can be activated by a button on the NIR camera head. This turns the lymphatic channels and lymph nodes bright blue during the surgical staging of cancer (Figure 1), enabling a lymph node to be quickly and accurately identified (Figure 2) and a biopsy to be performed – where the lymph node is retrieved to examine its histological status (Figure 3).

 

 

It was found that two patients (5.7%) had positive bilateral pelvic lymph nodes, two patients (5.7%) had positive SLNs and no patients had false-negative SLNs. Four patients (11.4%) were upstaged to Stage II or Stage IIIC1 endometrial cancer. The results obtained from the evaluation were similar to that in recently published international data, and showed that SLN biopsy is a feasible alternative to systematic pelvic lymphadenectomy for surgical staging of endometrial cancer.

 

     

Following the pilot, the Department of Gynaecological Oncology at KKH officially introduced SLN mapping and biopsy using ICG-NIR to all patients diagnosed with endometrial cancer in August 2017.

KKH is the first cancer centre in Singapore to offer this new modality of cancer staging for endometrial cancer and, to date, has conducted this procedure in more than 100 patients blaparoscopically and more than 16 patients via open surgery.

Since 2014, the United States National Comprehensive Cancer Network (NCCN) guidelines have reflected emerging data regarding the role of SLN mapping in endometrial cancer management. The guidelines now include SLN biopsy using ICG-NIR as a consideration in the surgical staging of apparent uterine-confined malignancy, and the cervical injection technique is considered useful and validated.

Since May 2017, the Society of Gynaecologic Oncology in the United States has also endorsed the use of SLN mapping using ICG-NIR in patients with low grade (Grade 1 or 2) endometrial cancer following the NCCN SLN mapping algorithm guidelines; however, patients should be counselled regarding the potential risk for missed occult disease using SLN biopsy for cancer staging.

Based on international data, the risk of missing occult disease is less than five per cent; this is lower than the risk associated with indirect methods such as radiological imaging. In our pilot evaluation, the risk approaches zero per cent if performed in carefully selected patients.

 

​Associate Professor Timothy Lim, Head and Senior Consultant, Department of Gynaecological Oncology, KK Women’s and Children’s Hospital

Associate Professor Timothy Lim is the Deputy Chairman of the Division of Obstetrics and Gynaecology at KKH. Heading the Department of Gynaecological Oncology, A/Prof Lim holds a strong interest in cervical cancer prevention, sentinel lymph node techniques, fertility sparing cancer surgery as well as advanced laparoscopic cancer surgery. A/Prof Lim is also the Academic Deputy Vice Chairman of Research for the SingHealth Obstetrics and Gynaecology Academic Clinical Programme.

 

​References:

  1. Holloway RW, Abu-Rustum NR, Backes FJ, Boggess JF, Gotlieb WH, Jeffrey Lowery W, Rossi EC, Tanner EJ, Wolsky RJ. Sentinel lymph node mapping and staging in endometrial cancer: A Society of Gynecologic Oncology literature review with consensus recommendations. Gynecol Oncol. 2017 Aug;146(2):405-415.
  2. Anna Jo Bodurtha Smith et al. Sentinel lymph node assessment in endometrial cancer: a systematic review and meta-analysis. Am J Obstet Gynecol May 2017;456-79
  3. Rossi EC, Kowalski LD, Scalici J, Cantrell L, Schuler K, Hanna RK, Method M, Ade M, Ivanova A, Boggess JF. A comparison of sentinel lymph node biopsy to lymphadenectomy for endometrial cancer staging (FIRES trial): a multicentre, prospective, cohort study. Lancet Oncol. 2017 Mar;18(3):384-392.
  4. Jennifer A Ducie et al. Comparison of a sentinel lymph node mapping algorithm and comprehensive lymphadenectomy in the detection of stage 3C endometrial varcinoms at higher risk for nodal disease. Gyn Oncol 147(2017);541-48
  5. Geppert B, Lönnerfors C, Bollino M, Persson J. Sentinel lymph node biopsy in endometrial cancer-Feasibility, safety and lymphatic complications. Gynecol Oncol. 2017 Dec 20.