Comparison of melanoma types between the United States and Japan. 1)SSM, superficial spreading melanoma; NM, nodular melanoma; LMM, lentigo maligna melanoma; ALM, acral lentiginous melanoma
Acral melanomas (AM) is a distinct subtype of melanoma affecting the palms, soles and nail apparatuses. It is mostly identical to acral lentiginous melanoma according to Clark’s classification (Clark et al., 1986), but it may also include nodular melanoma and superficial spreading melanoma that developed on glabrous skin and nail apparatus (Curtin et al., 2005). While AM is the least frequent subtype of cutaneous melanoma overall in Caucasians, it is the most prevalent type of melanoma in people of color. Prognosis of AM is generally poor, which may be in part due to delay in diagnosis (Bradford et al., 2009).
The distinct histological and phenotypic characteristics suggest that AM might differ biologically from other types of cutaneous melanomas. Recent molecular genetic studies characterized AM as a unique type of melanoma showing higher frequency of chromosomal aberrations, especially focused amplifications of particular chromosome regions (Bastian et al., 2000; Curtin et al., 2005). Furthermore, recent discovery of frequent mutation or amplification of
Although AM accounts for 5% of all melanomas in the United States (Markovic et al., 2007)(Table 1), it is a predominant form of melanoma in individuals with darker skin (ie, Blacks, Asians and Hispanics) (Cormier et al., 2006). The proportion of AM among all melanoma subtypes is greatest in blacks followed by Asians/Pacific islanders and Hispanic whites (Bradford et al., 2009). The nation-wide survey in Japan shows that AM accounts for 41% of all melanomas (Ishihara et al., 2008)(Table 1), the rate being almost the same in Chinese (Chi et al., 2011). However, the absolute incidence of AM in darker-skinned individuals is similar to that in whites (Stevens et al., 1990; Bradford et al., 2009), who have a much higher incidence of melanoma overall due to the strong susceptibility to sunlight (Cormier et al., 2006). Thus, carcinogens other than ultraviolet light (UVL) equally affecting all ethnic groups or endogenous mutagenesis may play a role in the development of AM. Trauma may have a role in AM development, since 13% to 25% of patients with AM reported prelesional trauma, such as puncture wounds, friction blisters and stone bruises (Coleman et al., 1980; Phan et al., 2006). The mean age at diagnosis of AM is 62.8 years, compared with 58.5 years for cutaneous melanoma overall. Incidence of AM significantly increases with each year of advancing age, which is seen across the different racial groups (Bradford et al., 2009).
|Type of Melanoma1)||United States|
(Markovic et al., 2007)
(Ishihara et al., 2008)
Although acral volar skin and nail beds constitutes only a few % of skin surface, the fact that nearly half of cutaneous melanomas arise on these anatomical sites in darker-skinned individuals indicates that these are predilection sites of melanomas not causally related to UVL exposure. The melanocyte density in palmoplantar skin is five times lower than that found in nonpalmoplantar sites. Furthermore, the growth and differentiation of palmoplantar melanocytes are suppressed by dickkopf 1 (DKK1) secreted from dermal fibroblasts through the down-regulation of microphthalmia-associated transcription factor (MITF) and beta-catenin (Yamaguchi et al., 2004). The reason why such growth-suppressed melanocytes in palmoplantar skin are more susceptible to melanoma development is currently unknown.
3. Clinical features
Clinically, AMs on palms and soles begin with irregularly pigmented macular lesions. The soles of the feet are most commonly involved. Morphological characteristics of early AM lesions include variable shades of brown from tan to black color, irregular and asymmetric shape often accompanied by notching at the periphery, and over 7mm in diameter (Saida, 1989) (Fig. 1a).
Dermoscopic observations of these early lesions show band-like pigmentation on ridges of the skin markings, designated as a “parallel ridge pattern”(Fig. 2a). This is in sharp contrast to the dermoscopic patterns in acral melanocytic nevi, which show parallel linear pigmentation along the sulci of the skin markings, designated as a “parallel furrow pattern”(Fig. 2b) and its variants “lattice-like pattern“ (Fig. 2c) and “fibrillar pattern”(Fig. 2d) (Oguchi et al., 1998; Miyazaki et al., 2005). The sensitivity and specificity of the parallel ridge pattern in diagnosing early AM is 86% and 99%, respectively (Saida et al., 2004). A simple three-step algorism effectively discriminating early AM from acral melanocytic nevi has been proposed (Fig. 3) (Saida et al., 2011). This algorism classifies acquired pigmented lesions on acral volar skin by the dermoscopic findings and the maximal diameter, and recommends three management options including “no need to follow-up”, “periodic follow-up”, and “excision of the lesion for histopathological evaluation”.
In contrast to the palmoplantar melanoma, nail apparatus melanoma more often affects fingers than the toes. The digits most commonly affected are the thumb followed by the great toe. If the AM is situated in the nail matrix, a longitudinal pigmented band of the nail plate is the earliest sign (Fig. 4a). As melanocytic nevi of the nail matrix also typically accompany longitudinal melanonychia, identifying early nail matrix melanoma is challenging. Dermoscopy again provides useful information for this differentiation. The suspicious dermoscopic features of early nail matrix melanoma are irregular lines on a brown background, pigmentation of the cuticle (micro-Hutchingson’s sign), a wide pigmented band, and triangular pigmentation on the nail plate (Fig. 4b) (Koga et al., 2011).
The tumorigenic vertical growth phase of palmoplantar melanoma is characterized by the development of a nodule often associated with ulceration (Fig. 1b). The development of a subungal tumor and the destruction of the nail plate are observed in the vertical growth phase of nail apparatus melanoma.
Histopathology of the earliest lesions of palmoplantar melanoma shows proliferation of solitary arranged slightly atypical melanocytes mainly detected in the crista profunda intermedia, the epidermal rete ridge underlying the ridges of the skin markings (Ishihara et al., 2006). In early nail apparatus melanoma, slightly atypical melanocytes proliferate in the epidermis of nail matrix. Eventually, large atypical melanocytes, frequently with prominent pigmented dendrites, proliferate as single cells in the basal layer of the hyperplastic epidermis while some tumor cells can be found in the upper layer of the epidermis. Nesting of melanocytes is not prominent, and tends to occur at the tips of the rete ridges. Brisk lichenoid lymphocytic infiltrate that may obscure the dermal-epidermal junction is common. In the vertical growth phase, atypical tumor cells are often spindle-shaped. Desmoplastic change is not uncommon (Clark et al., 1986).
5. Molecular genetics
There exists clinical heterogeneity in cutaneous melanoma with different susceptibility to UVL, which may be explained by differences in somatic genetic changes. Recent molecular genetic investigations have revealed that melanomas from intermittently sun-exposed skin, most of which are located on trunk and extremities, show frequent mutations in either
|Acral melanomas||Melanomas from intermittently sun-exposed skin||Reference|
|23% mutated||59% mutated||(Curtin et al., 2005)|
|10% mutated||22% mutated||(Curtin et al., 2005)|
|(Curtin et al., 2006)|
|44% amplified||5% amplified||(Sauter et al., 2002)|
|19% amplified||3% amplifieda||(Chernoff et al., 2009)|
Cyclin D1 positively regulates the activity of cyclin dependent kinases, leading to phosphorylation of retinoblastoma protein promoting entry into mitosis, and acts as an oncogene (reviewed in (Tashiro et al., 2007)). Interestingly, while gene amplifications are usually found in association with disease progression in other cancers,
While mutations of the
GAB2 is a scaffolding protein that mediates interactions with various signaling pathways including RAS-RAF-ERK and PI3K-AKT signaling, and is a critical molecule for melanoma progression (Horst et al., 2009). A recent study found
6. Molecular targeted therapy
Clinically, dramatic response to imatinib therapy has been observed in several sporadic cases with metastatic acral and mucosal melanomas with
Three phase-II trials of imatinib in unselected metastatic melanomas were mostly disappointing, and highlighted the importance of proper patient selection (Ugurel et al., 2005; Wyman et al., 2006; Kim et al., 2008). There are currently three ongoing clinical trials prospectively testing imatinib in selected patients with melanoma showing
|Imatinib||2||00470470||Mutation or amplification|
|Imatinib||2||00424515||Mutation or amplification|
|Imatinib||2||00881049||Mutation or amplification|
|Imatinib and temozolomide||1/2||00667953||Mutation|
|Nilotinib||2||00788775||Mutation or amplification|
|Nilotinib and dacarbazine||3||01028222||Mutation|
|Sunitinib||2||00631618||Mutation or amplification|
|Dasatinib and dacarbazine||1/2||00597038||None|
Nilotinib is a second-generation tyrosine kinase inhibitor of KIT, PDGFR and BCR-ABL. Nilotinib is potent as imatinib against mutant
It is now clear that melanoma arises from multiple pathways, with initiating and promoting factors differing for each. Melanomas on intermittently sun-exposed skin preferentially affect Caucasians who have an inherently high propensity for melanocyte proliferation characterized by high nevus counts (Whiteman et al., 2003). Exposure to intense bursts of UVL radiation, especially in childhood, is the major risk factor. This type of melanomas may arise from pre-existing melanocytic nevus, and the mutation of the
The author’s works were supported by the Grants-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan (15–10 and 21S-7), Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17659336 and 20591318), and a Management Expenses Grant from the Japanease Government to the National Cancer Center (21S-7(6)). I thank many colleagues who worked with me at the Department of Dermatology, Shinshu University, Japan, for their contributions to the studies of acral melanoma.