The neutrophil–lymphocyte ratio and locoregional melanoma: a multicentre cohort study

The incidence of melanoma has risen faster than any other cancer worldwide [1, 2] and the status of the sentinel lymph node (SLN) is the single most important prognostic factor [3]. Whilst there are several algorithms for predicting metastases of melanoma to the SLN [4‐10] their external validity is weak [4, 11‐14]. Consequently, only 1 in 5 patients undergoing SLN biopsy yield a node with microscopic deposits [15]. SLN biopsy for melanoma carries an 11% risk of complication [16] and recent trials [17, 18] suggest no additional survival benefit from completion lymphadenectomy. Therefore, whilst staging the draining nodal basin remains an important goal, there is a pressing need to improve patient selection and avoid unnecessary SLN biopsies which might be achieved using host biomarkers [19].

For surgically resected BRAF V600-positive Stage III melanoma, adjuvant dabrafenib and trametinib improves survival, although discontinuation due to adverse effects is common (25%) [20]. Further, adjuvant treatment for non-BRAF-mutated tumours improves survival but again, 15% experience drug-related adverse effects and rarely, premature-death [21]. Therefore, it may be desirable to refine the selection of patients for adjuvant therapy to those at the highest risk of recurrence.

With recent advances in adjuvant therapy [22] and a rising incidence, the number of patients living with melanoma has dramatically increased. In light of the findings of the Multicentre Selective Lymphadenectomy Trial (MSLT-II) trial [19] yet more patients will be subject to surveillance rather than up-front lymphadenectomy. Therefore, early detection of recurrent disease is desirable as systemic therapies are more efficacious in patients with a lower disease burden [23]. Hence, there is an unmet need for a cheap, simple and reliable biomarker to augment the selection of patients for SLN biopsy and adjuvant therapy, and to aid in the surveillance of patients with melanoma.

In response to malignancy and for reasons that are not yet fully elucidated, the host induces a myeloid immune response (manifesting as neutrophilia and thrombocytosis) whilst suppressing the adaptive immune (lymphoid) lineage; paradoxically, this favours tumour growth, angiogenesis, and regional and distant metastasis [24, 25]. This inflammatory response is manifested in the peripheral blood neutrophil–lymphocyte ratio (NLR) [26‐29], which has become an established biomarker of systemic inflammation and various outcomes in numerous cancers [30‐32]. Further, the NLR has a strong association with survival in melanoma [33‐39]. Currently, there is a gap in the literature concerning the relationship between NLR and outcomes in locoregional melanoma, the most prevalent form of the disease, which formed the rationale for this study.

After per-protocol exclusions, data were available for 1489 of 2438 eligible patients at baseline and a nested cohort of 235 individuals had repeated blood data for testing (Fig. 1).

This study suggests that the neutrophil–lymphocyte ratio (NLR) is proportional to the volume of cutaneous melanoma at presentation. This finding supports the wider literature on other cancers which infers that the NLR represents the host response to malignancy and thus, is a reliable and personalised biomarker.

There are three published works concerning the NLR and lymph node metastases of melanoma [34, 37, 38], all of which agree with our findings that a raised NLR is associated with occult metastatic disease. Gandini et al. [34] compared absolute blood counts between SLN biopsy positive and negative individuals using rank-based methods and found no evidence of a difference; but when modelled against disease progression using Cox regression (from Stage I/II to III, i.e. when melanoma metastasises), a raised NLR was strongly predictive. This agrees with our data whereby the crude blood counts were not different between groups and highlights the power of ratios which magnify smaller differences to appreciable levels.

Lino-Silva and colleagues [38] showed that a NLR > 2 was associated with nodal metastasis; however, their study concerned acral lentiginous melanoma in the Mexican population which is a biologically distinct tumour and population, respectively. This reduces the generalisability to the majority of affected individuals who are Caucasian with nodular or superficial spreading melanoma [51]. The proportional analysis by Davis et al. [37] showed that the baseline NLR was higher in patients with a more advanced nodal substage and thicker tumours. However, they found no significant difference in the NLR between patients with macroscopic and microscopic metastatic melanoma [37]. Overall, our findings agree with the literature and suggest that a raised baseline NLR is associated with occult metastatic melanoma. Previous works investigated NLR incidentally or as a secondary outcome of interest [34, 37, 38] whereas this study adds an important dimension to the literature because the biomarker was of primary interest, analysed in a comprehensive fashion and adjusted for potential confounding variables. None-the-less, we feel that further prospective research is needed to mitigate biases of selection and information before the NLR is utilised in the management of patients with locoregional melanoma.

There is a wealth of data on haematological biomarkers in metastatic melanoma, which show that a raised baseline NLR is associated with almost twice the risk of recurrence following systemic therapy [HR 1.86 (95% CI 1.2, 2.8)] [52]; however, the literature is comparatively sparse in locoregional melanoma [34, 37‐39]. Of these studies, Lino-Silva [38] is the only one to report the association between baseline NLR and the risk of recurrence. They stated that in 376 patients a baseline NLR ≥ 2 was associated with a higher risk of recurrence (28% versus 22%), although the limitations of their sample have already been discussed. Also, this apparent proportional difference was not subject to a hypothesis test (and so no effect size was offered), nor was it adjusted for important baseline confounders. These factors might explain why it differs to our finding. We add data to this important deficit in the literature concerning biomarkers in locoregional melanoma and suggest that future researchers seek to evaluate the utility of the baseline NLR in a prospective cohort of individuals with locoregional melanoma, with regular repeated measurements (including immediately after surgery) to better understand the temporal change of this valuable biomarker in melanoma.

The translational value of the NLR in the care of patients with melanoma is potentially important because the association between NLR and survival from metastatic melanoma is unequivocal [52]. The systematic review and meta-regression by Ding et al. [53] (using data from 12 studies and 3207 individuals with melanoma) showed that the NLR was strongly predictive of overall survival [HR 2.2 (95% CI 1.6, 3.0)] and disease-free survival [HR 2.2 (95% CI 1.8, 2.7)]. Recent data from our group complements this review and showed that the baseline NLR was a potentially powerful adjunct to SLN biopsy for identifying those individuals at the highest risk of death [39] who might benefit most from adjuvant therapy. Therefore, as SLN status is the best predictor of survival in melanoma, and survival is strongly associated with the NLR, our findings and those of prior studies [34, 37, 38] suggest that NLR might help to better inform treatment choices for patients in the future [19].

The baseline NLR is associated with the volume of cutaneous melanoma at presentation. Further prospective research is needed to understand how this personalised biomarker changes following surgery for melanoma and whether it may also be used for surveillance.