Sentinel node biopsy: linchpin of melanoma management

FOR patients with high-risk primary cutaneous melanomas, the most important advances in their surgical management in recent decades followed the introduction of sentinel node biopsy (SNB) in the mid-1990s and its subsequent widespread use around the world.

These advances in surgical management have been based primarily on the results of the first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Also relevant has been the publication and implementation of the American Joint Committee on Cancer (AJCC) 8th Edition staging system for cutaneous melanoma.

With solid organ cancers, the surgeon’s aim is to completely remove the primary tumour and adjacent lymph nodes. Pathological staging is based on the pathologist’s assessment of both the primary tumour (determining T stage) and the presence or absence of tumour metastases in draining regional lymph nodes (determining N stage). The final overall stage is determined by a combination of these data.

For most solid organ cancers – eg, breast, stomach, colon, lung – the ability to do this is straightforward because the information is available from the operative specimen, or the nodes are close to the primary. For cutaneous melanoma, however, routinely removing the regional lymph nodes by performing an elective lymph node dissection (ELND) at the time of the wide excision of the primary melanoma was abandoned more than three decades ago due to its morbidity and its demonstrated lack of significant impact on the oncological outcome.

In 1992, Morton and colleagues first reported the technique of sentinel node biopsy (SNB), which permitted accurate nodal staging without ELND. The minimally invasive SNB procedure involved identification of nodes that received lymphatics draining directly from the site of a primary cutaneous melanoma.

Pre-operative injection of a radio-labelled tracer allowed mapping of the site of the lymph nodes draining the primary melanoma. Then in the operating theatre, after intradermal injection of blue dye at the primary site and using a hand-held gamma-detection probe, the surgeon identified the sentinel nodes via a localised incision at the mapped site, confirming the identity of the sentinel nodes by the presence of blue-stained afferent lymphatics, blue staining of the node itself and radioactivity in it, measured with the gamma probe. Only sentinel nodes were removed, avoiding the risk of considerable morbidity associated with ELND, but nevertheless providing accurate nodal staging and valuable prognostic information.

MSLT-I was a trial designed to definitively assess the reliability and impact of the SNB procedure by randomising patients to wide local excision only or to wide local excision and SNB. This trial showed conclusively that, for patients with cutaneous melanoma, sentinel node status provided reliable prognostic information, along with the Breslow thickness and the presence or absence of ulceration in the primary melanoma.

From a practical perspective, when the procedure was explained to patients with melanoma and the information it offered was outlined, most requested SNB so that they were better informed of their prognosis, in spite of there being no effective therapy available at that time even if they were found to be at higher risk, notably with a positive sentinel node. Also at that time, for the patient who had a clinically evident metastasis in a regional lymph node, the standard treatment recommendation was a completion lymph node dissection (CLND), removing all the nodes in that region en bloc. CLND was also the recommendation for patients who had microscopic nodal involvement identified by SNB.

MSLT-II was a subsequent trial designed to address the question of whether a CLND was actually necessary for patients who were sentinel node-positive. These patients were therefore randomised to observation, with clinical review and regular ultrasound examination of the region, or to CLND. There was no difference in the survival of the two groups, but the trial confirmed the higher morbidity from CLND in patients who had that procedure compared with those who were observed.

A study published in JAMA Surgery on 3 August 2022 by the Multicenter Selective Lymphadenectomy Trials Study Group, of which we are members, reported that, in the sentinel node-positive patients in the observation group of MSLT-II, node field recurrence was very uncommon, even though a CLND had not been performed, indicating that the SNB procedure had been therapeutic by removing all nodal disease in most patients.

The results of MSLT-II allow clinicians to provide more in-depth information about the value of performing an SNB, including a substantial reduction in the risk of node field recurrence, and with clinical trial evidence that CLND, with its associated morbidity, is not usually required.

When it had become clear that SNB provided reliable staging and prognostic information, the outcomes from a SNB were integrated into the development of the AJCC 8th Edition melanoma staging system.

In the patient cohort used to assess and validate the AJCC staging criteria, all those with a melanoma ≥ 1.0 mm in thickness were required to have had an SNB. The survival curves for each thickness grouping were much better than in the AJCC 7th Edition, where SNB had not been mandated for staging purposes. Also, in the AJCC 7th Edition, all patients who had positive microscopic (sentinel node-positive) regional lymph nodes were categorised as Stage IIIA and those with clinically or radiologically defined nodes as Stage IIIB or Stage IIIC, depending on the number of involved nodes.

The AJCC 8th Edition combined details from the primary melanoma (thickness, presence of ulceration, presence of in transit/satellite/microsatellite metastasis) with the sentinel node status, or the presence of clinically evident regional nodes. This led to better stratification of prognosis for patients with nodal disease, with Stage IIIA restricted to patients with microscopic nodal involvement and a primary melanoma classified as T1–T2a (T2a = 1–2 mm thick without ulceration). Patients with a higher risk, T2b or greater primary melanoma (1–2 mm thick with ulceration or > 2 mm thick) who were sentinel node-positive were assigned to a higher stage, depending on the primary tumour pathology and the number of positive sentinel nodes and/or in transit/satellite/microsatellite metastases.

About 5 years ago, patients with Stage IV melanoma (ie, with distant metastases) were being treated successfully, in ever-increasing numbers, with new systemic therapies (targeted therapy and immunotherapy). Studies assessing these new treatments as adjuvant therapies for patients with resected lymph node metastases (ie, Stage III disease only) were therefore designed and commenced.

These trials reported a significant improvement in disease-free survival, particularly for patients with AJCC 8th Edition Stage IIIB, IIIC and IIID disease. As previously explained, this included patients with primary melanomas 1–2 mm in thickness with ulceration (T2b) and greater thickness (T3–T4) who were sentinel node-positive.

Today, the SNB procedure informs the patient and their treating clinician of the relevance of a treatment that may have an impact on the patient’s cancer outcome, as seen in other solid organ cancers where Stage III disease is typically treated with adjuvant systemic therapy.

To demonstrate the prognostic information derived from the AJCC 7th Edition compared with the AJCC 8th Edition, and the impact of a SNB having been performed, Table 1 gives the example of a hypothetical patient who has had a melanoma 1.8 mm in thickness removed by excision biopsy.

Table 1. Differences in prognosis for a patient with a primary cutaneous melanoma 1.8 mm in Breslow thickness, using the AJCC 7th and AJCC 8th editions for staging

* Sentinel node status unknown.
^ Sentinel node negative.

The table is instructive because it demonstrates how, from a counselling perspective, greater precision about their prognosis is possible when speaking to a patient. At times we can be more upbeat than we might have been in the past, or alternatively we may recommend that the patient see a medical oncologist with the aim of potentially improving survival outcome with adjuvant systemic therapy. The table outlines the impact of the AJCC 8th Edition when the patient has an ulcerated melanoma and is sentinel node-positive, who is then classified as having Stage IIIB melanoma and thus eligible to be considered for such adjuvant therapy.

Thus, in the past 15–20 years, we have advanced from simply performing a wide re-excision of a melanoma, and providing broad and imprecise prognostic information. By performing SNB, more detailed and accurate prognostic information is obtained, forecasting an individual’s likely outcome based on information provided by sentinel node pathology in combination with the primary tumour pathology, without having to subject the patient to the morbidity of having an ELND, at the same time reducing substantially the risk of regional node field recurrence. These matters can be explained to the patient. As well, SNB will allow an informed decision to be made about adjuvant systemic therapy based on its likely benefits and risks.

In the future, basic science technology such as gene expression profiling may provide prognostic information from the primary melanoma alone and obviate the need for SNB and the prognostic information it provides. However, for the present, standard histopathological assessment of the primary tumour in combination with SNB results will indicate prognosis with considerable precision and reliably identify patients who are most likely to benefit from adjuvant systemic therapies, while the performance of the SNB will also minimise the risk of node field recurrence.

Professor B Mark Smithers is the Head of Academy and Mayne Chair of Surgery at the University of Queensland, is part of the Queensland Melanoma Project, and is Director of the Upper Gastro-intestinal and Soft tissue Unit at Princess Alexandra Hospital in Brisbane.

Professor Richard A Scolyer is Co-Medical Director at Melanoma Institute Australia, a Conjoint Professor at The University of Sydney and is a Senior Staff Specialist Pathologist (Melanoma) at Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology.

Professor John F Thompson is Emeritus Professor of Surgery (Melanoma and Surgical Oncology) at the University of Sydney, Senior Surgeon at Melanoma Institute Australia and former Head of the Department of Melanoma and Surgical Oncology at Royal Prince Alfred Hospital in Sydney.

DISCLOSURES
B Mark Smithers has no disclosures. Richard Scolyer is the recipient of a National Health and Medical Research Council Practitioner Fellowship (APP1141295), and has received fees for professional services from MetaOptima Technology, F Hoffmann-La Roche, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Merck Sharp and Dohme, GlaxoSmithKline, Bristol-Myers Squibb, Dermpedia, Novartis, Myriad, NeraCare and Amgen. John Thompson has received honoraria for advisory board participation from GSK, Merck Sharpe and Dohme Australia, Provectus and Bristol-Myers Squibb Australia, and travel and conference expenses from GSK, Provectus. and Novartis.

The statements or opinions expressed in this article reflect the views of the authors and do not necessarily represent the official policy of the AMA, the MJA or InSight+ unless so stated.

Subscribe to the free InSight+ weekly newsletter here. It is available to all readers, not just registered medical practitioners.

If you would like to submit an article for consideration, send a Word version to mjainsight-editor@ampco.com.au.