COMMENTARY See related article on pg 384
Clinical, Epidemiological, and Molecular Heterogeneity in Acral Melanoma Cristina Carrera1 and Joan Anton Puig-Butille2 Acral melanoma comprises a poorly characterized and distinct type of melanoma, in terms of differing roles of UVR, molecular substrate, distribution among all ethnicities, and poor prognosis. Haugh et al. explore clinical, histological, and molecular aspects of acral melanomas and provide insights into the complexity of these tumors. Journal of Investigative Dermatology (2018) 138, 254e255. doi:10.1016/j.jid.2017.09.027
Knowledge of melanoma has increased in the last decade as a result better characterization at the clinicohistopathological, epidemiological, and molecular levels. It is well recognized that melanoma comprises a heterogeneous group of tumors with distinct pathophysiological features and molecular mechanisms mainly depending on the body site of primary tumors. The number of clinical or molecular studies focusing on acral melanoma is limited. Moreover, acral melanomas have been excluded from recent initiatives such as The Cancer Genome Atlas project. Thus, studies such as that reported by Haugh et al. (2017) are crucial to promote progress in the prevention and targeted treatment of rare melanomas such as those that arise in acral body locations. Cutaneous melanoma is a heterogeneous group of tumors
Cutaneous melanoma has commonly been classified into four major histopathological subtypes: lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, and acral lentiginous melanoma (ALM). However, tumors can be categorized by
Melanomas from acral body sites may exhibit clinical and molecular features of UV-related melanomas other characteristics such as body site of origin. Tumors from different body sites differ in clinical and epidemiological features and degree of UVR exposure. More recently, the identification of molecular bases of the disease has revealed the existence of multiple carcinogenic processes across melanoma subtypes, and this has led to a classification of tumors based on molecular criteria. There are three major clinical presentations of the disease: melanomas arising on chronically sundamaged skin (melanomas on the head and neck, usually lentigo maligna type with slow radial growth over a long period, mainly affecting older patients and unrelated to nevogenesis); melanomas arising on intermittently sun-exposed areas (melanomas on the trunk and limbs, usually superficial spreading subtype, following the
1
Melanoma Unit, Dermatology Department, Hospital Clı´nic and IDIBAPS (Institut d’Investigacions Biome`diques August Pi i Sunyer), Barcelona, Spain; and 2Melanoma Unit, Biochemistry and Molecular Genetics Department, Hospital Clı´nic and IDIBAPS (Institut d’Investigacions Biome`diques August Pi i Sunyer), Barcelona, Spain Correspondence: Joan Anton Puig-Butille, Melanoma Unit, Dermatology Department, Hospital Clı´nic and IDIBAPS (Institut d’Investigacions Biome`diques August Pi i Sunyer), Villarroel 170, Barcelona 08036, Spain. E-mail:
[email protected] ª 2017 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
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nevus-melanoma progressive model of mutation acquisition, affecting mainly white populations, and younger patients with multiple nevi); and those non-UVR-related melanomas (melanomas on mucosae, palms, soles, and nails, categorized as mucosal or acral melanomas, mostly lentiginous subtypes). ALM affects all ethnicities and is the most common melanoma subtype in non-white populations accounting for more than 60% of cases, whereas in Caucasians it accounts for only around 10% of cases. The high percentage of ALM in non-white populations is due to the overall low incidence of sun-related melanoma in these populations. Acral melanoma is usually a term used to refer to any histopathological subtype of melanoma that affects acral sites. Although most of the series comprise mainly the ALM subtype, melanomas classified as nodular and superficial spreading subtypes can be found on acral sites. In this sense, the Haugh et al. study reflects the broad spectrum of histopathological melanomas found at acral sites. Interestingly, they observed different epidemiologic patterns in acral melanomas from the dorsal surface of the hand and foot compared with melanomas from subungual or interdigital spaces or melanomas from volar surfaces. This is similar to what happens on the whole body surface because of differences in UVR, and illustrates how sun exposure impacts on tumors that develop in a reduced area of the body such as the acral sites. Epidemiological data indicate that prominent cutaneous melanoma risk factors (presence of multiple nevi, Caucasian ethnicity, and history of chronic/intermittent sun exposure) are not related to acral melanoma incidence (Nagore et al., 2009). However, multiple acral melanomas in patients at high risk for melanoma such as familial melanoma cases have been reported (Lacruz et al., 2014). A major melanoma risk factor is the presence of multiple common nevi or dysplastic nevi. The specific role of the presence of acral nevi in the development of acral melanomas has been suggested in case-control studies in the Caucasian population; however, the multistep progressive process of acquiring
COMMENTARY mutations proposed for nonacral melanomas remains unresolved in acral melanomas, because ALM associated with a preexisting nevus is extremely rare. Interestingly, other factors such as the history of trauma and mechanical stress have been associated with the risk of developing melanoma on acral sites (Costello et al., 2017). Molecular features of acral melanomas
Early molecular studies conducted on melanoma identified recurrent mutations in BRAF (45e60% of cases) and in NRAS (15e25%). Such alterations are mostly present in tumors from intermittent or chronic sun-exposed body sites, which in turn tend to be histologically classified as lentigo maligna melanoma or superficial spreading melanoma. Next-generation sequencing is now used to characterize tumors at the molecular level. Such technologies include the analysis of whole genome, whole exome, or a subset of genes (gene panel). Whole exome/genome studies of melanoma, which have mostly been focused on UV-related melanomas, have found differences between UVR-related melanomas and non-UVR-related melanomas in terms of total mutation burden, type of alteration (C>T or CC>TT transitions are the dominant mutations caused by UVR), and mutated genes. Although UVrelated mutation signature can be detected in a small subset of ALM, this subtype also has other mutation signatures (Hayward et al., 2017). Acral melanomas have a low mutation burden, point mutations in genes such as KIT, and recurrent genomic copy number alterations including gains of 11q13 (CCND1 gene), gains of 20q13 (AURKA gene), and gains of 5p15 (TERT gene) (Diaz et al., 2014; Hayward et al., 2017). Altogether, these data support the hypothesis that non-UVR-derived melanomas have different genetic causal pathways not related to UVR exposure. Notably, such molecular differences are observed in the Haugh et al. study because acral melanomas on the most sun-protected areas (where it is more likely to find a nonsuperficial spreading melanoma)
are the most genomically diverse and conversely dorsal surface acral melanomas exhibit characteristics of sunexposed melanomas.
alterations (Hayward et al., 2017). Further analysis of ALM is needed to identify the crucial molecular factors associated with disease aggressiveness.
Prognosis of acral melanoma
CONFLICT OF INTEREST
It is commonly accepted that melanoma prognosis only depends on the Breslow depth, ulceration, and sentinel node status, and not on primary location or histopathological subtype. Published data suggest that ALM has a worse prognosis compared with other histopathological subtypes (Bradford et al., 2009). However, a study conducted on a large series of ALM found that this melanoma subtype has the same prognostic indicators as the other subtypes of melanoma, suggesting that the unfavorable prognosis derives in part from the delay of diagnosis in comparison to other melanoma subtypes (Teramoto et al., 2017). In addition to late detection, other socioeconomic factors may impact on the prognosis of ALM such as limited access to health services by minorities or age-related factors. Because early diagnosis clearly impacts on the prognosis, it is crucial to improve diagnostic strategies in the clinical setting. Dermoscopy has improved the differential diagnosis of acral lesions, and acral malignant lesions can be accurately detected with the recently described BRAAFF dermoscopic checklist that summarizes the most important positive and negative features for acral melanoma (Lallas et al., 2015). A recent study reported a poor outcome in nodular and ALM subtypes compared with superficial spreading melanoma on acral body sites, independent of age and Breslow index (Carrera et al., 2017) suggesting that the molecular biology related to ALM subtype may impact the aggressiveness of the disease. To date, molecular alterations involved in the prognosis of melanoma are limited to mutations in TERT gene (Diaz et al., 2014). Interestingly, although TERT deregulation in chronic or intermittent UV-exposed melanomas is caused by point mutations (Hayward et al., 2017), in acral melanomas such dysregulation is mainly caused by copy number
The authors state no conflict of interest.
ACKNOWLEDGMENTS The research of Melanoma Unit of Hospital Clı´nic is mainly supported by Fondo de Investigaciones Sanitarias, Spain; by the CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; by the AGAUR 2014_SGR_603 of the Catalan Government, Spain; and by the European Commission under the 7th Framework Programme (Diagnoptics).
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