INTRODUCTION

Malignant melanoma (MM) is the deadliest form of skin cancer worldwide¹.

According to GLOBOCAN 2018, MM ranks thirteenth in global prevalence, with the highest number of cases reported in the United States, Germany, the United Kingdom, and Australia^2,3. The main histological subtypes of cutaneous melanoma are superficial spreading melanoma, nodular melanoma, lentigo maligna, and acral melanoma. Acral melanoma is defined by its location and was first described by Reed in 1976, with the most common histological subtype being acral lentiginous melanoma (ALM)⁴.

While the genesis of non-acral melanoma is related to intermittent sun exposure, the pathogenesis of ALM is not fully defined¹. Some studies have associated it with traumatic injuries, ultraviolet light exposure, and chemical exposure as risk factors, while others do not find these associations^5-8. Clinically relevant prognostic factors for malignant cutaneous melanoma include tumor depth, clear margins, sentinel lymph node biopsy, and ulceration. Mitosis count is no longer considered relevant for prognosis. For the ALM subtype, clinically relevant prognostic factors include tumor depth and clinical stage⁹.

From a pathophysiological perspective, the use of NLR (neutrophil-to-lymphocyte ratio) is supported by the roles of both cell populations. Neutrophils, with their pro-tumoral phenotype, promote tumor growth, angiogenesis, and invasion, while lymphocytes, particularly T lymphocytes, play a crucial role in immune surveillance and response against cancer. An elevated NLR suggests a pro-inflammatory environment that may favor tumor progression and exhibit an ineffective immune response against cancer. Recently, new prognostic parameters such as the NLR have emerged, widely used in other types of neoplasms. We previously reported that NLR is related to survival in patients with aggressive B-cell and T-cell lymphomas^10,11.

The clinical relevance of using NLR in Peruvian patients with ALM lies in its non-invasive and easily accessible nature, allowing for early prognosis estimation and risk stratification. Therefore, this study aims to demonstrate the prognostic value of NLR in patients with ALM, the most common cutaneous melanoma in Peru.

METHODS

RESULTS

A total of 69 patients were analyzed, with a significant predominance of females (51.1%). The mean age was 68 years, and 68% of patients were over 60 years old. The plantar location was the most frequently affected site in ALM, with 88.4%, followed by palmar location at 8.6%, and subungual location at only 2.9% of cases (Table 1).

In relation to the pathological characteristics, it was found that a Breslow thickness between 0.01 and 1 mm was present in 18.8% of the patients, 1.01-2 mm in 21.7%, 2.01-4 mm in 13% and more than 4 mm in 37.7% of patients. Ulceration was absent in more than half of the patients (58.0%) and most patients did not have perineural infiltration, lymphocyte infiltration and vascular invasion (89.9%, 82.6%, and 89.9%, respectively). Anaplasia and microsatellitosis were present in 5.8% and 1.4%, respectively. No tumor regression was found. Nodal involvement was present in 17.4%. Pathological stage I was present in 28.9% of the patients, stage II in 34.8%, stage III in 24.6%, and stage IV in 5.8% (Table 2).

82.6% of patients with clinical stage I to III underwent surgical intervention, and 76.9% of the patients had a complete lymph node dissection (CLND). Adjuvant treatment was performed in 32.3% of patients with stage IIB to IIIC. All patients with stage IV received the best supportive care and no systemic treatment due to poor functional status. The overall 5-year survival rate was 54.3% with a median of 6.3 months.

Univariate analysis using a Cox proportional hazards regression model showed that the variables Clark levels IV-V (HR: 1.8, 95% CI, 1.1-3.2, p = 0.016), anaplasia (HR: 3.0, 95% CI, 1.5-5.7, p = 0.022), lymphocyte infiltration (HR: 2.8, 95% CI, 1.6-5.0, p = 0.035), advanced clinical stage (HR: 2.5, 95% CI, 1.5-4.1, p = 0.030), and NLR > 3.5 (HR 2.1; 95% CI, 1.1-4.19, p = 0.002) were associated with poor prognosis. (Table 3).

The multivariate analysis using a Cox proportional hazards regression model showed that the variables Clark levels IV-V (HR 3.5; 95% CI, 1.6-7.8, p = 0.002) and NLR >3.5 were associated with lower overall survival (HR: 3.9, 95% CI, 1.5-10.3, p = 0.005) (Table 4).

The Kaplan-Meier survival curves for NLR levels according to the cutoff point of 3.5 to evaluate overall survival in patients diagnosed with acral lentiginous melanoma showed statistically significant differences between the high NLR and low NLR groups, according to the log-rank test (p<0.001). (Figure 1)

Figure 1: Kaplan-Meier curve for NLR with a cutoff point of 3.5 to evaluate prognosis in patients diagnosed with Acral Lentiginous Melanoma 

DISCUSSION

This is the first report in Latin America to study the role of NLR in ALM. In our cohort of 135 patients with cutaneous melanoma, 51.1% had ALM (69 cases). A previous Peruvian study found that ALM is the most frequent subtype of melanoma, accounting for 61.2% compared to non-acral melanomas¹⁴.

In non-acral cutaneous melanoma, some studies demonstrate the prognostic value of NLR, and three meta-analyses have confirmed its predictive role with checkpoint inhibitors or anti-BRAF treatment^15,16,17. Recently, Cocorocchio et al. found that clinical stage, elevated serum LDH, and NLR > 5 were prognostic of OS in patients with advanced melanoma receiving BRAFi alone or combined with a MEK inhibitor (MEKi) at recommended doses. These data suggest an immunomodulatory effect of the therapy on the tumor microenvironment in addition to the direct treatment effect and could indicate some potential clinical biomarkers¹⁸. Finally, Bartlett et al. conducted a prospective study with metastatic cutaneous melanoma patients receiving anti-PD1 treatment, describing that patients with NLR > 5 had a higher disease burden and poorer functional status, which correlated with worse OS in both univariate and multivariate analyses¹⁹.

The rationale for NLR is that it measures the tumor inflammatory response (neutrophilia) and the host immune response (lymphopenia). One of its strengths is its simplicity of calculation, defined as the number of absolute circulating neutrophils divided by the absolute lymphocyte count^18,19,20,21. Neutrophils exhibit dual behavior in the tumor microenvironment. Two subtypes or phenotypes have been established: high-density neutrophils (HDN) and low-density neutrophils (LDN)¹⁴.

The HDN subtype has antitumor activity and directly affects tumor cells or indirectly stimulates T-cell-mediated immunity. Conversely, the LDN subtype exhibits pro-tumoral activity that promotes progression, mediated by two mechanisms. LDNs promote the activation of suppressor T cells by secreting Arginine, regulating angiogenesis through the stimulation of vascular endothelial growth factors (VEGF). At the onset of inflammation, neutrophils have the HDN phenotype, but upon resolving this acute inflammation, the LDN phenotype accumulates. Chronic inflammation, as seen in cancer, results in the generation and accumulation of the LDN phenotype, leading to an unfavorable neutrophil phenotype. The proportion of LDN neutrophils increases with the tumor burden¹⁴.

On the other hand, lymphopenia is associated with reduced host immunity and indirectly with the stimulation of suppressor T cells²⁰. These cells contribute to the decreased antitumor immune activity, with the most well-known being CD4+ CD25+ FOXP3+ regulatory T cells (Tregs). These cells are involved in preventing the immune response and inhibiting antitumor immune responses, thus maintaining normal balance in the body. However, Treg accumulation in cancer has been linked to poor outcomes in some cancer types^21,22.

The importance of NLR in ALM has not been well-studied. However, there are few studies in Asia investigating its prognostic value^23,24. Yu et al. evaluated baseline peripheral blood biomarkers to predict early-stage ALM outcomes treated with IFNα-2b and found that NLR ≥2.35 was associated with poor recurrence-free survival and OS²⁵. Conversely, Jung et al. conducted a retrospective study in an Asian population to evaluate the efficacy of Ipilimumab in melanoma, finding that 31% had advanced-stage ALM. They found that NLR levels greater than 5 represented an independent poor prognostic factor for survival. Elevated NLR levels were observed in patients experiencing progressive disease, and low NLR predicted longer progression-free survival (PFS) and OS²⁶. Additionally, Lee et al. conducted a retrospective cohort of 152 patients, of which 58 (38%) had ALM. NLR levels > 2.1 were associated with poorer progression-free survival (median 6.9 vs. 2.4 months, p = 0.015) and OS (median not reached vs. 10.4 months, p < 0.001)^27,28. Our study aligns with these findings, confirming the prognostic role of NLR in ALM survival in the South American population.

This study has limitations. Regarding the study design, being a retrospective cohort with a small population compared to other series, the power and external validity are limited. Moreover, it was a single-center study conducted in one institution where patients were referred for surgical, adjuvant, or first-line treatment, thus requiring careful extrapolation of the study results. Additionally, data collection was based on the review of clinical records, posing a potential selection bias.

This study reports that ALM is a frequent and aggressive subtype of cutaneous melanoma in our country. This is the first Latin American report investigating the prognostic value of NLR in ALM, marking an initial step toward better understanding its tumor microenvironment. It also holds potential for targeting new therapeutic approaches in the future. Further research in prospective trials is needed.

CONCLUSION

The present study showed that NLR levels greater than 3.5 are associated with lower overall survival independently of other variables in patients with acral lentiginous melanoma, thus representing a notable prognostic marker in this population.