Melanoma is an aggressive tumor with high mortality when diagnosed in advanced stages. Its incidence is increasing drastically all over the world, as well as its cases of death.1,2 Despite promising therapeutic advances, treatments capable of significantly prolonging the survival of patients with metastasis have not yet been developed. For this reason, the main strategy to reduce mortality is based on the early identification of the primary tumor and of the patients at risk for metastatic disease.3

Different risk factors for the development of cutaneous melanoma metastases were studied extensively. Clinical and epidemiological aspects such as age, gender and site of the tumor are associated to disease progression.4 Certain histopathologic, immunologic, genetic and molecular characteristics were also implicated in the development of melanoma metastasis.1,5

Due to the alarming increase in the incidence of melanoma and to the high mortality rates from metastatic disease, the data of patients seen with primary melanoma in the department of dermatology of a university hospital and a private surgical oncology practice between 1995 and 2012 were analyzed with the aim of identifying prognostic factors for the development of metastasis in melanoma.

Melanoma is an aggressive skin cancer, characterized by the high risk of metastasis and death.1 Although it represents only 4% of skin cancers in Brazil, it is responsible for the death of almost 50% of these patients.2

Data from 780 patients with the diagnosis of melanoma confirmed by anatomopathological examination seen at 2 reference centers participating in the study between 1995 and 2021 were collected. It is a large sample of cases included in a single Brazilian study.

In the sample studied, male gender, nodular clinicopathological type, Breslow thickness >1mm and the presence of ulceration were considered prognostic factors for the occurrence of metastasis.

Other authors also found a poorer course of melanoma in men.6,7 According to Pollack et al.,4 men had a lower survival at 1 and 5 years, regardless of the age at melanoma diagnosis. Vries et al.8 showed that men have a 1.87-fold higher risk of death by melanoma than women, even after adjusting for other risk features such as age, site of the primary tumor, clinicopathological type and Breslow thickness. Recently, Liljana Mervic,9 who followed 7,338 patients in a German university, showed that women had lower risks of melanoma spread and a longer interval between the primary tumor and the first metastasis. Besides, that study showed that females develop metastasis with a more favorable prognosis, such as satellite or in-transit metastasis, when compared to those of males.

The reason for the lower risk of melanoma spread in women is still unknown. A possible explanation for this could be the fact that women pay more attention to their own bodies and seek medical care earlier.10 Hormonal influence was also postulated as responsible for a longer survival in women, but recent studies suggest that melanoma is not hormone-dependent.11,12 In a recent study, Joosse et al.reported that oxygen free radicals, such as the superoxide anion and hydrogen peroxide, are involved in the mealanogenesis of the tumor.13 The authors postulated that the oxidative stress, more pronounced in men, could be responsible for the increased ability of melanoma to spread.

Patients with nodular melanoma had a 2.89-fold higher risk for disease spread when compared to the superficial spreading and lentigo maligna melanoma types, parameters used as reference and analyzed as group, independently from the other variables analyzed. The second highest risk type was acral melanoma. However, in the multivariate analysis, it did not reach statistical significance (HR: 1.50).

In 2010, Kunte et al.14 studied the risk factors for lymph node metastasis in patients with melanoma. The nodular clinicopathological type was the second most important prognostic factor for lymph node involvement, overcome only by tumor thickness. The same study showed that the nodular component in any other clinicopathological type increased the likelihood of lymph node involvement. Superficial spreading melanomas without nodular component had an OR of 0.56, and those with a nodular component had an OR of 0.78. In this study, acral melanoma was also the second clinicopathological type of worse prognosis. Lindholm et al.7 prospective cohort also pointed towards a lower survival for patients with nodular melanoma. It is thought that the nodular type presents a worse prognosis due to its vertical growth, leading to a premature arrival of tumor cells in the lymphatic and blood vessels of the dermis.15-17 Distinct genetic characteristics can also explain the more aggressive course of this tumor. In 2008, Viros et al.demonstrated a high frequency of BRAF mutations (68.8%) and a low frequency of NRAS mutations (12.5%) in 16 patients with nodular melanoma.18 However, the influence of genetic abnormalities in the prognosis of melanoma is not yet established.

The acral type is also considered an independent risk factor for the occurrence of metastases. According to Garbe et al.,nodular and acral melanomas show a reduction in survival of 10 years, although its influence was smaller than other parameters as thickness, gender and site.19 The study that included the population of the program SEER (Surveillance, Epidemiology and End Results), with 51,704 patients of 13 different American institutions, indicated that acral melanoma was the one with lower 5-year and 10-year survival, from 1986 to 2005.9 The study by Chang et al.,16 which included 181 Chinese patients, phototype III and IV (according to Fitzpatrick’s classification), showed that acral and nodular melanoma were risk variables for the reduction of 5-year survival. Nonetheless, the authors affirmed that the importance of the clinicopathological type was inferior to the other variables such as gender, stage of the disease and tumor thickness, due to the reduction in the values of the HR from the univariate to the multivariate analysis.

Of all variables analyzed in this study, Breslow thickness was considered the most important for the occurrence of melanoma metastasis. As the thickness of the tumor increased, so did the risk of metastasis (p=0.0628 for tumors between 1-4mm and p=0.0011 for tumors >4 mm). Such result confirms the findings of various authors since the description of this variable by Breslow in 1970.20 It is believed that thicker lesions can represent more advanced tumors with more intrinsic biological aggressiveness than those with radial growth only.21,22

According to Brauer et al.,thick melanomas increase the risk of early metastasis (between six months to three years of the initial tumor), compared to late metastases, that occur after eight years of the primary tumor.23 An increased risk of local or in-transit metastasis was seen with increased melanoma thickness in the study by Stucky et al.24 According to Faries et al.,there was an increased risk of occult lymph node recurrence with thicker Breslow in patients with thin melanomas (<1mm).25 The case-control study conducted by Sartore et al.detected an increased risk of sentinel lymph node micrometastasis with the increased thickness of the primary tumor. 26

The presence of ulceration was also considered an independent risk factor for the development of melanoma metastasis in this study. Many authors confirmed the importance of ulceration in the prognosis of melanoma and the reduction in disease-free survival and survival of patients.27-29 According to Balch et al.,the presence of ulceration in patients with localized melanoma reduces survival in 5 years from 80% to 55%.30 The authors also observed that lesions with histological ulceration are associated to nodular and thicker tumors. Eigentler et al. showed the reduction in the 10-year survival in patients with T2 and T3 tumors (stage I) when ulceration was present. However, this variable did not influence T1 (≤1mm) and T4 (>4mm) tumors.31 Staging based on Breslow thickness and ulceration was the variable that most influenced 10-year survival in patients with localized melanoma in the study by Francken et al.32

According to the univariate analysis, the presence of mitoses in the histopathology was a statistically significant variable for the occurrence of metastasis in patients (p<0.0001). However, it was not possible to analyze it with the Cox method, because there was no metastasis in patients without detectable mitosis within the tumor. This invalidated the statistical method and the variable was excluded from the multivariate analysis. We can assume that, due to the low p value in the univariate analysis, the presence of mitosis is important for the prediction of metastasis in the study population.

According to Murali et al.,the presence of mitosis correlated with the reduction in the time for disease recurrence.33 The mitotic index was also significantly correlated to tumor thickness (Breslow thickness) and to the presence of ulceration, but was not independently significant in the overall survival of patients. Nagore et al.34 also detected a higher risk of metastasis in those tumors with mitosis, as well as Karjalainen et al.35 According to Gimotty et al., who studied 396 patients with thin melanoma, the patients diagnosed with metastasis within their tumors had a higher risk of recurrence in 10 years than those with a mitotic index of zero (HR=6.7).36 Svobodová et al. demonstrated that the presence of mitosis in the histopathology was associated to the reduction in disease-free survival (RR=1.911).27 It is postulated that the mitotic index is related to a worse melanoma prognosis because it reflects a superior proliferative index, what would facilitate the occurrence of more aggressive cellular clones with a higher potential to create metastases.34,37

The results of this study show that age was not an independent variable to predict the risk for metastasis (p>0.05). Even though the authors have not shown the influence of age in the recurrence of melanoma, what can actually have happened with the population in this study, another factor could explain the lack of association with age in the study sample: the lack of distinction between locoregional and distant metastases, grouped in a single outcome.38,39 Some authors postulate that the occurrence of lymph node metastasis is more common in younger individuals, and in contrast distant dissemination of the disease is lower and survival is higher in this group of patients.28,40,41 Kretschmer et al. showed that patients younger than 40 years had a higher risk of sentinel lymph node metastasis.42 However, this age group had a lower risk of local and distant disease, besides a longer specific survival. Thus, the highest rates of lymph node metastasis that occur in younger patients could have been similar to the higher rates of distant metastasis in older patients in this study, affecting the final result.

In this study, family history of melanoma did not alter the disease-free survival (p=0.985). Similarly, Hornbuckle et al. did not show differences in recurrences, in the pattern of metastasis distribution and survival among patients with and without family history of melanoma either.43 Of note, the sample of patients with metastasis and family history of melanoma of this cohort was restricted: only 11 of the 135 patients with metastasis had family members with the disease. This limits the interpretation of the results regarding this variable. Considering the studies published to date, we cannot affirm that a positive family history of melanoma is a risk factor for disease progression.

This study did not show differences in the spreading of the disease among patients with axial tumors (head, neck and trunk) compared to those with tumors on the extremities (upper and lower limbs). Other authors did not find association between the site of the primary melanoma and disease progression either.44 According to Faries et al., the occurrence of lymph node metastasis was not associated to the site of the primary tumor.25 Patients with localized melanoma on the head and neck did not show a reduced survival when compared to those with tumors on other sites, as reported by Hoersh et al. The appearance of metastases was not influenced by the site of the primary tumor in the study by Kelly et al. M-raz Gernhard et al. did not find an association between the site of melanoma and the occurrence of lymph node micrometastasis. In patients with thick melanoma, there was no difference in the reduction of disease-free survival between those with axial tumors and those with tumors on the extremities, according to Kim et al.45-48

Male gender, nodular clinicopathological type, Breslow thickness >4mm and the presence of ulceration were considered risk factors for the occurrence of metastasis in patients with primary cutaneous melanoma in this study.

Financial support: None.

Conflict of interest: None