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 KIT gene in AM and mucosal melanoma has led to the molecular targeted therapy by approved drugs targeting KIT, such as imatinib, for advanced cases (Curtin et al., 2006). This would represent a first decisive step toward the individualized treatment of melanoma (Garrido &Bastian, 2010)
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 BRAF or NRAS gene. In contrast, BRAF or NRAS mutations are rather infrequent in melanomas arising from sun-protected areas, such as acral skin, nail apparatus and mucosa (Table 2). Instead, these types of melanomas show a higher degree of chromosomal aberrations; specifically, genomic amplifications involving small portions of chromosome arms (Curtin et al., 2005). In AM, the most frequently amplified region is chromosome 11q13 which contains the cyclin D1 gene. Narrow amplifications of other chromosome regions, including 4q12, 5p15, 11q14 and 22q11-13, are also found (Bastian et al., 2000). Target genes of 4q12 and 11q14 amplifications appear to be KIT and GAB2, respectively (Curtin et al., 2006; Chernoff et al., 2009).
|Acral melanomas||Melanomas from intermittently sun-exposed skin||Reference|
|BRAF||23% mutated||59% mutated||(Curtin et al., 2005)|
|NRAS||10% mutated||22% mutated||(Curtin et al., 2005)|
|(Curtin et al., 2006)|
|Cyclin D1||44% amplified||5% amplified||(Sauter et al., 2002)|
|GAB2||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, cyclin D1 gene amplifications in AM are detected early in the radial growth phase (Bastian et al., 2000). Furthermore, copy number increase of cyclin D1 gene was observed even in normal-looking melanocytes in the epidermis beyond the histopathologically recognizable margin of melanoma (Bastian et al., 2000; North et al., 2008), as well as in very early acral melanoma in situ lesions, which shows slight increase of non-atypical melanocytes in the basal cell layer of the epidermis (Yamaura et al., 2005). These genetically aberrant cells with normal morphology are “ field cells” (Bastian, 2003), which represent a latent progression phase that precedes the stage of atypical melanocyte proliferation in the epidermis. These observations suggest that amplification of the cyclin D1 gene might be one of the earliest events in AM development. The presence of amplifications, however, indicates that other aberrations likely cause genomic instability (North et al., 2008). Investigations in a radial growth phase AM cell line SMYM-PRGP harboring cyclin D1 amplification (Fig. 5) suggest that overly expressed cyclin D1 protein may act as a survival factor (Murata et al., 2007). While the progressive increase of the cyclin D1 copy number from normal-looking melanocytes to the in situ portion to the invasive melanoma was observed, suggesting that the increased cyclin D1 gene dosage confers a growth advantage during later stages of tumor progression (North et al., 2008), this may simply reflect the increase of genomic instability associated with melanoma progression (Takata et al., 2010).
While mutations of the BRAF and NRAS genes are infrequent in AM, a substantial number of AM harbor mutations or amplifications of the KIT gene encoding a receptor tyrosine kinase (Curtin et al., 2006). Recent studies have revealed KIT mutations and amplification in 14% and 24% of AMs, respectively (Table 2) (Woodman &Davies, 2010). About 30% of the tumors with KIT mutations also show increased copy number/amplification of KIT. The KIT mutations identified in AM differ from those found in gastrointestinal stromal tumors (GIST). The majority of KIT mutations in GIST are deletions or insertions, whereas those found in melanoma are substitution mutations. In addition, KIT mutations are not present in exon 9, which is the location of 15% of KIT mutations in GIST. More than half of KIT mutations in melanoma are found in exon 11, which encodes juxtamembrane domain of KIT receptor, whereas mutations are also found in exons 13, 17 and 18 encoding kinase domains (Woodman &Davies, 2010).
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 GAB2 amplification in 5 of 23 (19%) AMs, while amplifications were rare in other types of cutaneous melanomas (Table 2). The majority of GAB2 amplification occurred independent from genetic alterations in BRAF, NRAS, KIT and cyclin D1, suggesting a critical role of GAB2 in a subset of AM (Chernoff et al., 2009).
6. Molecular targeted therapy
Since KIT mutations are detected in ~15% of AM, KIT is a promising molecular target of metastatic AM. Several in vitro experiments using melanoma cell lines harboring KIT mutations have actually shown significant growth suppressive effects of small molecular KIT inhibitors, such as imatinib, which are already approved for other cancers. Imatinib dramatically decreased proliferation, and was cytotoxic to a mucosal melanoma cell line demonstrating a highly amplified KIT exon 11 V559D mutation (Jiang et al., 2008). In contrast, cell viability of another melanoma cell line with KIT exon 11 L576P mutation, the most common KIT mutation in melanoma (34%) (Woodman &Davies, 2010), was not reduced by imatinib. However, dasatinib reduced cell viability of this cell line at concentrations as low as 10nM. Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib but not for dasatinib (Woodman et al., 2009). An acral melanoma cell line with non-amplified KIT exon 17 D820Y was also resistant to imatinib treatment. The KIT D820Y mutation usually arises as a secondary mutation in the setting of imatinib treatment in GIST, which was shown to be sensitive to sunitinib. As expected, treatment of the KIT D820Y cell line with 1 µM of sunitinib showed modest reduction in cell proliferation. (Ashida et al., 2009).
Clinically, dramatic response to imatinib therapy has been observed in several sporadic cases with metastatic acral and mucosal melanomas with KIT mutations, such as exon 13 K642E, 7-codon duplication in exon 11, and exon 11 V599A (Hodi et al., 2008; Lutzky et al., 2008; Terheyden et al., 2010). However, gene amplification and overexpression of wild-type KIT, which is frequently present in acral and mucosal melanomas (Woodman &Davies, 2010), did not translate into clinical efficacy of imatinib (Hofmann et al., 2009). Consistent with an in vitro study, metastatic melanoma patients with the KIT L576P mutation showed marked reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose (FDG)-avidity by positron emission tomography(PET) imaging after dasatinib treatment (Woodman &Davies, 2010). Partial response by dasatinib was also observed in a patient with the KIT exon 13 K642E mutation (Kluger et al., 2010).
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 KIT mutations or amplifications (mostly acral and mucosal melanomas)(Table 3). The NCT00470470 trial selected stage III or IV patients with somatic mutations in KIT. Of the 12 evaluable patients, 2 demonstrated a complete response. Of note, these two patients had both amplification and mutation of KIT. A partial response was observed in two patients. All but two, who had mutations known to be resistant to imatinib in GIST, of the remaining patients had stable disease (Carvajal et al., 2009). In another phase-II trial of imatinib in patients with advanced melanoma from acral skin, mucosa or chronically sun-damaged skin (NCT00424515), five of ten patients with KIT mutations demonstrated a partial response. In contrast, none of the ten patients who had wild-type/amplified KIT showed a clinical response (Fisher et al., 2010). In the NCT00881049 trial which recruited Chinese patients with metastatic melanoma harboring KIT aberrations, a rate of 20% partial response and 40% stable disease was achieved, with 60% overall disease control rate (Guo et al., 2010). These results show clinical benefit of imatinib in a proportion of molecularly selected patients.
|Phase||NCT number||KIT aberrations required for eligibility|
|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 KIT, and is significantly more potent than imatinib against wild-type KIT. A phase-II trial of nilotinib in patients with melanoma characterized by a KIT mutation or amplification is ongoing, and a randomized phase-III, open-label study to compare the efficacy of nilotinib versus dacarbazine for treatment of patients with metastatic melanoma harboring a KIT mutation has been initiated. Phase-II trials testing other tyrosine kinase inhibitors targeting KIT, such as sunitinib and dasatinib, for melanoma are also ongoing (Table 3).
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 BRAF gene may be a key initiating somatic genetic event (Michaloglou et al., 2008). By contrast, AM arises de novo, and equally affects all ethnic groups. The first genetic aberration affecting normal melanocytes in acral volar skin would be one that disrupts the maintenance of genomic integrity. This would lead to the amplification of cyclin D1 and the selection for clonal expansion of affected melanocytes. Then, acquiring activating mutations in oncogenes, such as KIT (Curtin et al., 2006), may be a crucial step inducing proliferation of transformed melanocytes (Takata et al., 2010). Understanding molecular pathogenesis in different types of melanomas will lead to the development of effective prevention and treatment strategies for individual patients.
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.