The Obstetrician & Gynaecologist 2007;9:4:270-275
doi: 10.1576/toag.9.4.270.27358
Copyright © 2007 by the Royal College of Obstetricians and Gynaecologists.
Sentinel node mapping
Nigel Acheson, MD MRCOG, Consultant Gynaecological Oncologist1
1. Centre for Women's Health, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK Email: nigel.acheson{at}nhs.net (corresponding author)
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Abstract
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Key content:- Cancers involving the regional lymphatic system around the primary site have a poor prognosis.
- The sentinel node is understood to be the first node to which lymphatic drainage occurs from an organ or area of skin.
- The sentinel node can be identified using a blue dye or radiolabel.
- If the sentinel node does not contain metastatic tumour, the risk of involved regional nodes is small.
- The technique has the potential to reduce the morbidity associated with regional lymphadenectomy.
Learning objectives:
- To understand the sentinel node concept.
- To understand the role of sentinel node biopsy in vulval, cervical and endometrial cancer.
Ethical issues:
- Randomised controlled trials should be performed before the technique can be introduced into routine practice.
Please cite this article as: Acheson N. Sentinel node mapping. The Obstetrician & Gynaecologist 2007;9:270–275.
Keywords cervical cancer / endometrial cancer / sentinel node biopsy / vulval cancer
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Introduction
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Radical surgical techniques were introduced into gynaecological oncology more than a century ago by Wertheim, Schauta and others. Following the recent development of minimal access surgery and improvements in imaging, the safety and efficacy of more conservative techniques are now being assessed.
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The sentinel node concept
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Radical surgery for cervical and vulval cancer is based on the knowledge that involvement of the regional lymphatics carries a poor prognosis. One of the techniques being evaluated in several tumour sites, to identify lymph node status, is the concept of sentinel node mapping and biopsy. The ‘sentinel’ node is widely understood to be the first node to which lymphatic drainage occurs from an organ or area of the skin.
In the 1970s Cabenas described the sentinel node in penile carcinoma.1 It was not until the 1980s that the technique was applied to remove sentinel lymph nodes selectively. Initially carried out in patients with melanoma, the concept was then extended to surgery for breast cancer.2
More recently, sentinel node mapping has also been studied in an attempt to reduce the radicality of and, therefore, treatment-related morbidity from, surgery in women with gynaecological cancer.
If sentinel node mapping and biopsy are to become accepted in gynaecological oncology there are several points to consider:
- Can the sentinel node be identified in each case?
- If it is negative, are all other nodes negative?
- If it is positive, does this affect treatment and survival?
In patients with cutaneous melanoma or breast cancer, there is a questionable survival advantage with lymphadenectomy and, therefore, a reduction in morbidity in these conditions using the sentinel node approach has been favoured.3 In vulval cancer, the therapeutic advantage to those women with lymph node disease who have undergone lymphadenectomy led to anxiety about reducing the radicality of the surgery for fear of groin relapse.
This review describes the techniques used to identify the sentinel lymph node or nodes and explores the potential application of sentinel node mapping in vulval, cervical and endometrial cancer.
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Techniques of sentinel node identification
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Two common techniques have been studied to identify the sentinel lymph node: blue dye injection and technetium-99m (99mTc) nanocolloid. A diagrammatic representation is shown in Figure 1.
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Figure 1
Diagrammatic representation of a right-sided vulval tumour, right inguinofemoral lymph nodes and drainage of label (either 99mTc or blue dye) to the sentinel node
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Some published studies use only one technique, whereas others use a combination of the two techniques. Using vulval cancer as an example, those involving blue dyes can be used at the time of surgery alone, avoiding the need for potentially uncomfortable preoperative assessment. There have, however, been reports of anaphylaxis to the various blue dyes. The blue dye is injected into subcutaneous tissue peritumorally (or around the scar if excision of the primary lesion has taken place) immediately before node dissection begins. Typically, the injection is given in small amounts to several edges of the lesion. A groin incision is made and the blue node identified and excised. The number of sites to be injected and the effect of previous surgery/biopsies have yet to be fully evaluated.
For the 99mTc technique, subcutaneous peritumoral injections are administered before surgery in the nuclear medicine department and the sentinel node is identified with a gamma camera (Figures 2 and 3). Using this technique the position of the node can be marked before leaving the department to aid the surgeon when the woman is in the operating theatre.4,5 In our hospital the dose of 99mTc nanocolloid injected is 20 or 40 MBq, depending on the timing of surgery (whether later that day or the next).
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Figure 2
Gamma camera (Elscint SPX6). (Picture courtesy of S Farrell, Superintendent Radiographer, Royal Devon and Exeter NHS Foundation Trust)
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Figure 3
Lymphoscintographic localisation of sentinel node. (Image courtesy of S Farrell, Superintendent Radiographer, Royal Devon and Exeter NHS Foundation Trust)
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Once in the operating theatre, the sentinel node is localised using a hand-held gamma camera (Figure 4). It has become usual to use a combination of the 99mTc and blue dye techniques, as the detection rates are higher compared with single labels in several studies. Following localisation of the likely site of the sentinel node, the blue dye is injected as described above, an incision in the groin is made and the sentinel node identified and excised.
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Figure 4
Neoprobe used for intraoperative localisation of sentinel node. (Picture courtesy of S Farrell, Superintendent Radiographer, Royal Devon and Exeter NHS Foundation Trust)
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With regard to the processing of the sentinel node biopsy histologically, there is increasing evidence that ‘micrometastases’ within a lymph node are clinically significant; they have been identified in women with groin node recurrence following a ‘negative’ sentinel node biopsy. The presence of such micrometastases may not be detected with the haematoxylin and eosin stains routinely used. Specific immunohistochemical stains and multiple sections through the node are required to detect these micrometastases in clinically important nodes.
When using the sentinel node technique, consideration must be given as to why the sentinel node may contain tumour yet not take up the blue dye or 99mTc labels. This false negative result can arise if the sentinel node is completely replaced by tumour, thus interfering with the normal flow of lymph through the node. Careful exclusion of cases where enlarged nodes are detected clinically or on scanning can reduce the chance of such false negatives.
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Vulval cancer
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The belief that radical surgery to the vulva and regional lymph nodes was associated with good survival persisted through the 20th century. Along with other authors, Taussig and Way continued to publish good survival data for women undergoing radical surgery for vulval cancer. Despite the fact that much of this work was performed in the 1940s and 1950s, such radical surgery remained the ‘gold standard’ until the latter part of the century.
The triple incision approach was introduced in an attempt to reduce the radicality and morbidity of surgical treatment. The risk of groin lymph node metastases remained a problem, not least because it was demonstrated that such metastases could occur with depths of invasion >1 mm.
Following inguinofemoral lymphadenectomy, significant morbidity is common. This can take the form of wound breakdown and delayed wound healing, lymphocyst formation (collections of lymph under the scar), deep vein thrombosis and lymphoedema. Lymphoedema is estimated to occur in up to 30% of women and in some it can lead to permanent limitation of mobility, to say nothing of the psychological aspects of this permanent reminder of surgery.
The significant morbidity following vulval surgery led to further interest in assessing the groin nodes without performing inguinofemoral lymphadenectomy. These have included the use of ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and sentinel node identification.
Most experience of sentinel node biopsy in gynaecological oncology to date has been with vulval cancer. A consistent theme in published reports is the learning curve for each surgeon, which is longer for the blue dye than for the 99mTc technique. Most authors recommend a learning period in which at least 10 groin sentinel node biopsies are carried out and that full lymphadenectomy should be performed at the same time.
A recent systematic review6 of these tests concluded that 99mTc sentinel node biopsy had the potential to detect groin node metastases and, therefore, reduce the radicality of surgery for women with vulval cancer. (Table 1) summarises the results for sentinel node biopsy for that review and shows the sensitivity (true positive rate), specificity (true negative rate) and the likelihood ratios (the ratios of the probability of the specific test result in women who do have the disease to the probability in women who do not) for both blue dye and 99mTc. Using blue dye, sentinel node detection rates have been reported at between 58–95%, whereas for 99mTc the reported rates are between 73–100%. An RCOG working party report7 concludes that appropriate groin node dissection is important in reducing mortality from vulval cancer. The potential value of sentinel node detection is also discussed in the report, subject to the results of clinical trials.
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Table 1
Diagnostic accuracy of sentinel node biopsy in vulval cancer. (Summary of table from Selman et al. Reprinted with permission from Elsevier)6
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Although the results of the published series on sentinel node biopsy in vulval cancer look promising, the fear of false negative sentinel nodes leading to groin recurrence remains. A large study based in the Netherlands (GROINSS-V) is soon to be published, which is designed to evaluate the safety of omitting full inguinofemoral lymphadenectomy in women with early-stage vulval cancer and a negative sentinel node.
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Cervical cancer
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The management of cervical cancer has changed considerably over the last two decades. Not only has the development of cervical screening into an effective programme reduced the number of cases of cervical cancer, but also the current management for tumours greater than stage 1B1 is often chemoradiotherapy rather than Wertheim's hysterectomy. More recently, fertility-preserving treatment for cervical cancer in the form of radical trachelectomy with laparoscopic pelvic lymphadenectomy has been evolving as an alternative treatment for early-stage cervical cancer.
The potential value of sentinel node biopsy has yet to be adequately defined, as the accurate assessment of lymph node status in cervical cancer is considered critical, especially when potentially fertility-sparing surgery is planned. To date, published studies have used blue dye, 99mTc-labelling or a combination of the two techniques. Peritumoral injections of blue dye are administered at the time of surgery, or preoperatively in a nuclear medicine department if using 99mTc. The most common method of administration uses a 4-quadrant method of injection, although the amount of dye or radiolabel varies between studies.
A recent systematic review9 of sentinel node detection in early uterine cervix carcinoma identified 23 studies for inclusion, with a total of 842 women. Twelve of the studies used the combined technique, five used 99mTc alone and four used blue dye alone. Two studies used different techniques for the detection of sentinel nodes and women from these studies were divided into the appropriate analysis of sentinel node detection rates by technique. In this systematic review, the combined technique of blue dye and 99mTc had a sensitivity of 92% and a sentinel node detection rate of 97%. Using a single technique, both the sentinel node detection rates were lower: 88% with 99mTc and 84% with blue dye alone. The authors recommend a combined technique of blue dye and 99mTc as a reliable way to detect sentinel nodes in cervical cancer. They, and other researchers, feel that the hypothesis that full lymphadenectomy could be avoided in women with a negative sentinel node should now be tested. Other authors point to the technique's ability to identify sentinel nodes at sites other than those routinely removed at pelvic lymphadenectomy.
In summary, the sentinel node technique in cervical cancer has a high detection rate when blue dye and 99mTc techniques are used in combination. The exact role of the technique in managing women with cervical cancer will need to be assessed by further clinical studies.
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Endometrial cancer
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The current management of endometrial cancer is evolving with regard to the surgical approach to the disease and the role of adjuvant radiotherapy in cases considered to be at high risk of local disease relapse following surgery. One of the proposed benefits of sentinel node biopsy in endometrial cancer is a potential reduction in morbidity related to pelvic lymphadenectomy; however, early results from the ASTEC study question the role of lymphadenectomy in the surgical management of endometrial cancer.
There are also many prognostic variables, such as tumour grade and depth of invasion, that have been used to predict the likelihood of nodal metastases (and, therefore, the decision to give adjuvant radiotherapy). In addition, endometrial cancer can metastasise via a haematogenous route rather than exclusively via the lymphatic system.
The sentinel node concept has only been explored in a small number of women so far. The technique is more complicated technically as it involves injection of the dye/radiolabel into the uterus, usually at the time of hysteroscopy.
In the small series reported, sentinel node detection rates of 62–100% have been achieved but questions remain about the optimal sites of injection of the marker and about the reliability of the technique, given the complexity of the uterine lymphatic network.8,10
The current situation regarding sentinel node biopsy is that there is evidence that the technique is feasible but the efficacy and role of the technique as applied to endometrial cancer are still unproven.
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Conclusion
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Sentinel node mapping, like many new techniques, has generated great interest in gynaecological oncology. The possible reduction of morbidity and utilisation in minimal access surgery has led to evaluation of the technique in a variety of tumour types. It is, perhaps, most promising in reducing the morbidity from inguinofemoral lymphadenectomy in vulval cancer. However, the safety and efficacy of the technique must be confirmed before it is introduced into routine practice.
Furthermore, it is clear from experience in all tumour types that those who use sentinel node mapping must be aware of the learning curve for the technique if false negative results are to be minimised.
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References
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- Cabenas RM. An approach for the treatment of penile cancer. Cancer 1977;39:456–66. [PubMed 837331][Medline]
- Thompson JH, Uren RF, Scolyer RA, Stretch JR. Selective sentinel lymphadenectomy: progress to date and prospects for the future. Cancer Treat Res 2005;127:269–87. [PubMed 16209088][Medline]
- Wong JH. The development of lymphatic mapping and selective lymphadenectomy. Cancer Treat Res 2005;127:1–14. [PubMed 16209075][Medline]
- Frumovitz M, Ramirez PT, Levenback C. Lymphatic mapping and sentinel node detection in gynaecologic malignancies of the lower genital tract. Curr Oncol Rep 2005;7:435–44. [PubMed 16221380][Medline]
- Robison K, Steinhoff MM, Granai CO, Brard L, Gajewski W, Moore RG. Inguinal sentinel node dissection versus standard inguinal node dissection in patients with vulvar cancer: a comparison of the size of metastasis detected in inguinal lymph nodes. Gynecol Oncol 2006;101:24–7. doi:10.1016/j.ygyno.2005.08.052[Medline]
- Selman TJ, Luesley DM, Acheson N, Khan KS, Mann CH. A systematic review of the accuracy of diagnostic tests for inguinal lymph node status in vulvar cancer. Gynecol Oncol 2005;99:206–14. doi:10.1016/j.ygyno.2005.05.029[Medline]
- Royal College of Obstetricians and Gynaecologists. Management of Vulval Cancer. Working Party Report. London: RCOG Press; 2006. [www.rcog.org.uk/resources/Public/pdf/vulval_cancer.pdf].
- Torné A, Puig-Tintoré LM. The use of sentinel lymph nodes in gynaecological malignancies. Curr Opin Obstet Gynecol 2004;16:57–64. [PubMed 15128009][Medline]
- van de Lande J, Torrenga B, Raijmakers PGHM, Hoekstra OS, van Baal MW, Brölmann HAM, et al. Sentinel lymph node detection in early stage uterine cervix carcinoma: a systematic review. Gynecol Oncol 2007;106:604–13. doi:10.1016/j.ygyno.2007.05.010[Medline]
- Oehler MK, Fung A, Jobling TW. Advances in the treatment of endometrial cancer. In: J Br Menopause Soc 2005; (11):18–22.[PubMed 15814058].[Medline]
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Abstract
Introduction
