Abstract
Acral melanoma is defined as melanoma affecting the palms, soles, and nail apparatus. This is not a synonym of acral lentiginous melanoma in Clark’s classification, which is defined histopathologically. Acral melanoma is characterized by peculiar chromosomal and genetic alterations distinct from other subtypes of melanoma. These characteristics certainly reflect its unique pathogenesis, in which sun exposure is not a major causative factor. In this chapter, genetic characteristics of acral melanoma were first summarized and its molecular pathogenesis was discussed. Amplification of CCND1 and TERT may be early events in the development of acral melanoma. Mutations of BRAF/NRAS may be also involved in the early developmental phase of acral melanoma along with KIT mutations/amplification, which can be utilized as targets by small molecular inhibitors for the treatment of advanced acral melanoma. Next, essential points in the clinical,dermoscopic, and histopathologic diagnoses of acral melanoma were described. Particularly, dermoscopy is very helpful in diagnosing primary lesions of acral melanoma by the parallel ridge pattern, which contrasts with the parallel furrow pattern found in the vast majority of acral nevi. These different pigmentation patterns suggest de novo genesis of acral melanoma, namely, melanoma and nevus arise independently in this anatomical site. Finally, management of acral melanoma is discussed, including some suggestions in the surgical treatment and recently introduced molecular targeting therapies.
Definition and Epidemiology of Acral Melanoma
Clark’s histopathologic classification of melanoma was first described in 1969, in which the following three subtypes were proposed: the superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM). Thereafter, Reed (1976) introduced the concept of acral lentiginous melanoma (ALM). Already in 1974, however, Seiji, a Japanese dermatologist renowned for his melanosome studies, reported that plantar and subungual melanomas often showed a distinctive adjacent intraepidermal proliferation of atypical melanocytes (Seiji and Takahashi 1974). ALM was soon later incorporated into Clark’s classification.
ALM is defined by characteristic histopathologic features, namely, proliferation of atypical melanocytes in a lentiginous pattern along the basal layer of the peripheral epidermis, which usually shows moderate acanthosis and rete ridge elongation (Fig. 1). ALM is seen on acral volar skin (glabrous/non-hair-bearing skin) but can be seen on other anatomical sites such as on the dorsum of the foot. Furthermore, other subtypes, such as SSM and NM, can occur on the acral skin. In 2005, Bastian’s group proposed a new classification system of melanomas based on their data of chromosomal and genetic investigation (Curtin et al. 2005). They identified the following four types: (1) melanoma on non-chronic sun-damaged skin (non-CSD melanoma), (2) melanoma on chronic sun-damaged skin (CSD melanoma), (3) acral melanoma (Fig. 1), and (4) mucosal melanoma. The non-CSD melanoma mostly corresponds to SSM, the CSD melanoma to LMM, and acral melanoma to ALM. But in a strict sense, acral melanoma is not identical to ALM. Acral melanoma was defined as melanoma affecting the palms, soles, or nail apparatus, irrespective of histopathologic features. Of note, according to the supplemental data in the paper by Bastian’s group, 5 of 36 acral melanomas were SSM in Clark’s subtypes. The study by Bastian’s group has revealed that acral melanoma is genetically characterized by rare mutations of BRAF and NRAS and by chromosomal gains on 6p, 7, 8q, 17q, and 20q and loss on 6q, 9p, 10, and 21q. Acral melanoma is particularly unique in that gene amplifications are frequently detected throughout the genome, including CCND1 (11q13), TERT (5p15), RICTOR (5p13), KIT (4q12), and CDK4 (12q14) (Curtin et al. 2005). In this chapter, the author adopts the terms and concept defined by Bastian’s group but uses the terms of Clark’s classification when they were used in the past literatures. In the genetic classification put forth in The Cancer Genome Atlas Network, acral melanoma mainly falls into the category of “triple wild-type” melanomas (2015).
Incidence and subtypes of malignant melanoma are substantially different among races. While non-CSD melanoma is the most prevalent type in White populations, acral melanoma is a predominant subtype in other world populations. The proportion of acral melanoma/ALM in all cutaneous melanomas is highly variable among races, accounting for approximately 5% in White people, over 80% in Black people, and around 50% in Asian people. Given that acral volar skin (palms and soles) occupies only about 5% of the total body surface area, the abovementioned site predilection of melanoma in dark-skinned peoples is surprising and indicates that the transformation risk of melanocytes in acral volar skin is elevated compared to melanocytes of non-glabrous skin. Moreover, the absolute incidence of acral melanoma was reported to be similar among all races (Stevens et al. 1990), and the very low relative proportion of acral melanoma in White populations is mainly due to increased incidence of the non-CSD melanoma in Whites. The major causative factor of the non-CSD melanoma is suspected to be sun exposure, particularly intermittent intense sun exposure. The fair skin of White people contains little melanin with a decreased eumelanin to pheomelanin ratio, resulting in reduced UV shielding. Thereby, melanocytes situated in the epidermal basal layer of fair skin are vulnerable to sun damage, and thus DNA of melanocytes is easily damaged by ultraviolet radiation. These may be the major reasons for the higher incidence of non-CSD melanomas in White people. In contrast, sun exposure is not a major causative factor of acral melanoma. This is reflected in a significantly lower somatic mutation burden in acral melanomas compared to non-CSD melanoma or CDS-melanoma (Turajlic et al. 2012; Hayward et al. 2017). Acral melanoma has distinctive chromosomal and genetic aberrations, the details of which are discussed in the following section.
Pathogenesis and Genetic Alterations of Acral Melanoma
Pathogenesis of Acral Melanoma
The age distribution of patients with acral melanoma peaks in the seventh decade, irrespective of races. The most prevalent site is the sole. In Japanese, plantar melanomas account for approximately 30% of all cutaneous melanomas. Plantar melanoma is about ten times more prevalent than palmar melanoma. In a study of a total of 177 acral melanomas in Koreans, the most prevalent subsites of acral melanoma were physically stressed sites, such as the center of the heels and inner forefoot (Jung et al. 2013). Among melanomas of the nail apparatus, the finger nails are more frequently affected than toe nails, with the thumbnail being the most frequently affected site. These data suggest that chronic mechanical pressure and/or repeated minor trauma could be a causative factor of acral melanoma (Saida 2007). In addition, the low melanin content in the epidermis of these anatomical sites could contribute to transformation of melanocytes because of decreased antioxidant effects.
Genetic Alterations of Acral Melanoma
While initial studies have analyzed the genetic evolution of non-acral cutaneous melanomas from pre-neoplastic lesions (Shain et al. 2015), the genetic evolution of acral melanoma remains to be explored. Here, the author summarizes characteristic genetic and molecular alterations of acral melanoma described in the literatures to date.
Summing up the genetic findings described below, the author proposes a molecular/genetic model of development and progression of acral melanoma as illustrated in Fig. 2, though it is very preliminary.
CDKN2A
It is well known that CDKN2A located at 9p21 is an important gene responsible for melanomagenesis. Germline mutation of this gene was reported in families prone to develop non-CSD melanoma. CDKN2A deletion seems related to the invasive stage of melanoma. In the recent study by Bastian’s group, CDKN2A aberrations were detected in invasive melanoma in most cases (Shain et al. 2015). In SMYM-PRGP, an acral melanoma cell line we established from the radial growth phase of plantar melanoma, neither mutation nor copy number loss of CDKN2A was detected (Murata et al. 2007), which suggests, also in acral melanoma, CDKN2A deletion may be a later occurring event.
CCND1
Acral melanoma is characterized by focal amplifications of various chromosomal loci. Particularly, amplification of 11q13, where cyclin D1 gene/CCND1 is located, is frequently detected (Curtin et al. 2005). CCND1 positively regulates the activity of CDKs, leading to phosphorylation of Rb and promoting entry into mitosis. Amplification of CCND1 is detected in about 45% of acral melanoma (Sauter et al. 2002). More recent study showed that CCND1 amplifications were found in 10 of 14 (71%) invasive and 4 out of 5 (80%) in situ lesions of acral melanoma (North et al. 2008). An immunohistochemical study revealed CCND1 was expressed in 68% of acral melanoma.
Although, in cancers of other organs, gene amplifications are generally found in later progression stages, CCND1 amplifications in acral melanoma are detected in earlier developmental stages including acral melanoma in situ (Bastian et al. 2000). Furthermore, copy number increase of CCND1 was detected in non-atypical melanocytes located in the peripheral epidermis beyond the histopathologically recognizable margin of acral melanoma (North et al. 2008). Bastian (2003) called these genetically aberrant cells with normal morphology “field cells” and proposed that they represent an early progression phase preceding the histopathologically apparent stages of melanoma in situ. Such field cells in acral melanoma occasionally extend far beyond the histopathological margin, and the extent does not correlate with tumor depth or diameter of the lesion (North et al. 2008). The concept of field cells is important in the diagnosis and treatment of acral melanoma. Amplification of CCND1 was detected in an early acral melanoma cell line, SMYM-PRGP (Murata et al. 2007). These data strongly suggest the CCND1 amplification is one of the earliest events in the development of acral melanoma and identify CCND1 as a possibly driver gene relevant to the early evolving phase of acral melanoma.
TERT and AURKA
Activation of telomerase by the upregulation of human telomerase reverse transcriptase gene (TERT) , located at chromosome 5p15.33, can immortalize somatic cells through extension of telomeres. TERT may play an important role in oncogenesis of acral melanoma. It was reported that TERT amplifications were detected in 7 of 14 (50%) invasive and 4 out of 5 (80%) in situ lesions of acral melanoma (North et al. 2008). Another study showed that gains of TERT were detected in 31.2% of 17 primary ALM lesions (Puig-Butillé et al. 2013). TERT promoter mutation was reported to be uncommon in ALM (6%, 2/32), while the mutation was detected in 33% (3/9) in non-acral melanomas (Liau et al. 2014). In a larger cohort of non-acral melanomas, TERT promoter mutations were detected in a total of 77% of areas of in situ or intermediate lesions (Shain et al. 2015). These data suggest that the TERT promoter mutations are caused mostly by UV exposure. An early acral melanoma cell line, SMYM-PRGP, shows distinctive amplification of TERT and CCND1 (Murata et al. 2007), while it is wild in BRAF and NRAS. These data suggests importance of TERT amplification in the early developmental phase of acral melanoma.
TERT aberrations may have clinical significance. It was found that fluorescence in situ hybridization (FISH) analysis using CCND1, TERT, and AURKA (a gene encoding Aurora A kinase which is a member of a family of mitotic serine/threonine kinases) probes could improve sensitivity of histopathologic diagnosis for acral melanomas (sensitivity 97%; specificity 100%) (Diaz et al. 2014a). In this study, amplification of AURKA was detected in 2 of 34 (6%) primary lesions of ALM. Note that AURKA amplification was reported to contribute increased chromosomal instability in cancer cells. Another study revealed that amplification of TERT was associated with poor outcome of patients with ALM (Diaz et al. 2014b).
KIT
KIT encodes a receptor tyrosine kinase, whose ligand is stem cell factor (SCF). KIT–SCF signaling is essential for melanocyte to differentiate, proliferate, migrate, and survive in the fetal and postnatal tissue. In 2006, Curtin, Busam, Pinkel, and Bastian reported an important role of KIT in subsets of melanomas. They found mutations of KIT in 3 of 24 (12%) of acral melanomas, 8 of 38 (21%) of mucosal melanomas, and 4 of 18 (22%) of CSD melanomas. By contrast, none of the non-CSD melanomas had KIT aberrations. Later immunohistochemical studies detected expression of KIT in 40–80% of acral/mucosal melanomas. The rate of KIT mutations in acral melanoma seems to be less frequent in White persons: 15% of acral/mucosal melanomas in patients seen at MD Anderson Cancer Center (Torres-Cabala et al. 2009) and 6.8% of acral/mucosal melanomas (4.2% of acral melanoma) in a Canadian population (Abu-Abed et al. 2012). The mutation rates of KIT seem higher in Asians: 25% of nail apparatus melanomas and 15.6% of melanomas on palms and soles in Japanese (Sakaizawa et al. 2015), 33% of amelanotic acral melanomas in Koreans (Choi et al. 2013), and 23% of acral melanomas in Chinese (Dai et al. 2013). These data suggest that KIT is an important oncogene in the development of acral/mucosal melanoma and could be used as a therapeutic target of this type of melanoma.
In vitro studies have shown that growth of melanoma cells harboring KIT mutations is suppressed with small molecular inhibitors targeting KIT, such as imatinib and sunitinib (Ashida et al. 2009). More importantly, oral administration of imatinib exerted dramatic clinical effects on acral/mucosal melanomas with KIT mutations (to be discussed later in detail).
BRAF and NRAS
BRAF is the most commonly aberrated gene in non-CSD melanomas. Mutations of BRAF are detected in around 70% of this type of melanoma (Curtin et al. 2005), and 90% of the mutations are V600E. On the other hand, NRAS mutations have been found in about 15% of non-CSD melanoma. BRAF and NRAS mutations in melanomas are mutually exclusive in most cases. In contrast, in acral melanoma, mutation rates of BRAF and NRAS are reported to be much lower, around 10% and 5%, respectively. In a Spanish population, with the multiple-ligation-dependent probe amplification method on frozen samples, no BRAF mutations were detected in 17 primary lesions of ALM, but NRAS mutations were detected in 17% of them (Puig-Butillé et al. 2013). According to a study of 88 Swedish patients with ALM, BRAF mutations were detected in 17% and NRAS mutations were in 15% (Zebary et al. 2013). In a Japanese series, BRAF mutation was detected in 8.9% (4/45) of melanomas on palms and soles and in 12.5% (3/24) of nail apparatus melanomas (Sakaizawa et al. 2015). In the series, NRAS mutations were detected in 20% of melanomas on palms and soles. In another study in Japan, BRAF mutations were detected in 18.8% of ALM (9.5% in stage I/II, 36.4% in stage III/IV) (Yamazaki et al. 2015). In the latter Japanese series, BRAF mutations were detected in 64.7% of SSM, 50% in LMM, and 20% in NM. In a Korean subject, BRAF V600E mutation was detected in 19.4% (7/36) of patients with ALM.
Collectively, the mutation rate of BRAF in acral melanoma is lower than in non-CSD melanoma, but the rates are substantially variable among studies, the highest rate being 36.4% in Japanese patients with stage III/IV ALM. The mutation rate of NRAS in acral melanoma is around 15–20%. These data suggest MAPK inhibitors can be effective in selected patients with acral melanoma.
NUAK2
Chromosome 1q32 has been known to be frequently altered in melanoma cells. It was also reported that genomic gains of this locus were associated with tumor thickness of melanoma. NUAK2 , located at this locus, was recently implicated as a relevant gene of melanoma (Namiki et al. 2011). NUAC2 is a member of the AMP-activated protein kinase (AMPK) family of serine/threonine protein kinase. It was shown that knockdown of NUAK2 induced senescence of melanoma cells and suppressed tumor growth in mice. Expression degrees of NUAC2 were significantly related to survivals of patients with acral melanoma. Risk of relapse was greater in acral melanoma with high levels of NUAK2 expression than in that with low expression level. These findings indicate NUAC2 plays an important role in acral melanoma, particularly in later progressed stages.
The Mutational Landscape of Acral Melanoma
Using next-generation sequencing, whole genomic data were obtained in a case of acral melanoma (Turajlic et al. 2012). Compared to the high-frequency genomic changes in melanoma on sun-exposed sites, the rates of somatic mutation in the acral melanoma were lower, mostly comparable to the rates reported in cancer genomes not associated with mutagenic exposure. Another study was performed in six cell lines of acral melanoma using the techniques of whole-exome sequencing and array comparative genomic hybridization (Furney et al. 2012). The cell lines display a mutation rate comparable to that revealed in the above case. Mutations were identified in oncogenes and tumor suppressors previously linked to melanoma including BRAF, NRAS, KIT, PTEN, and TP53. Mutations were detected in some cancer genes not previously linked to melanoma and in genes linked to DNA repair such as BRCA1 and BRCA2.
According to the recent extensive study conducted by Australian research group, acral and mucosal melanomas showed a markedly different whole-genome landscape from melanomas on sun-exposed sites (Hayward et al. 2017). Acral melanomas were characterized by frequent structural variants (deletions, duplications, foldback inversions) and complex rearrangements. Many acral melanomas had high-level amplifications on the long arm of chromosome 11, often targeting CCND1. Significantly mutated genes in acral melanoma were BRAF, KIT, MAP2K2, NF1, and NRAS, though mutations attributable to ultraviolet radiation were rare. The completely different whole-genome landscape of acral melanoma from melanomas on sun-exposed skin indicates that genomic aberrations in acral melanoma are not caused by UV radiation but by carcinogenic factors shared with cancers of internal organs without exposure to highly mutagenic agents.
Clinical, Dermoscopic, and Histopathologic Diagnoses of Acral Melanoma
Acral melanoma is typically detected at a later stage, explaining its overall poor prognosis. Early detection therefore is important to improve the prognosis. Almost all patients with acral melanoma in situ can be cured by excision, usually without functional or cosmetic impairment. Here, we describe clinical characteristics of melanomas on the palms and soles and those affecting nail apparatus separately because they are substantially different in anatomic and histologic structures.
Acral Melanoma on the Palms and Soles
Clinical Diagnosis of Melanoma on the Palms and Soles
Clinical diagnosis of advanced melanoma on the palms and soles is not difficult in most cases. As same to advanced melanoma on other anatomical sites, they are seen as a brownish black nodule or plaque, often partly eroded or ulcerated, and surrounded by a pigmented macule with variable shades of brown (Fig. 3). The lesions are typically large in size, often exceeding 2 cm in maximum diameter, and irregular and asymmetric in shape. Note that on the palms and soles, other common pigmented lesions such as seborrheic keratoses and basal cell carcinomas, which are important differential diagnoses of melanoma on other anatomical sites, are rare. However, melanocytic nevi are commonly seen on the palms and soles not only in dark-skinned people but also in Whites. About 10% of Japanese have melanocytic nevi on acral volar skin (Saida et al. 2011a). Acral nevi are typically small, mostly 7 mm or less in diameter, symmetric in color distribution and shape and thereby easily differentiated from invasive acral melanoma in most cases. However, clinical differentiation between early acral melanoma and acral nevus is sometimes very difficult because both can present as brownish macules. Acral melanoma in situ on the palms and soles exhibits the following characteristics: (a) a pigmented macule with asymmetric and irregular shape, often accompanied by notching at the periphery, (b) brown color with variable shades from tan to black, and (c) a diameter that exceeds 7 mm (Fig. 4). The last size criterion was proposed based on a study by the author’s group, which had revealed that the vast majority of acquired acral nevi were 7 mm or less in diameter. Of course, these criteria are not absolute. Occasionally, melanocytic nevi are somewhat irregular in shape and color. Regarding the size, congenital acral nevus is often larger than 7 mm and even acquired acral nevus can become more than 7 mm.
Acral melanomas can occasionally be unpigmented (amelanotic/hypomelanotic) (Fig. 5); the rates of amelanotic/hypomelanotic acral melanomas seem different among races, varying from 30% in a French population and around 10% in Japanese. Differential diagnoses of amelanotic/hypomelanotic acral melanoma on the palms and soles include squamous cell carcinoma (SCC), eccrine poroma, pyogenic granuloma, and various kinds of ulcerated lesions. In rare cases, acral melanomas are hyperkeratotic or verrucous, but most of them are suspected to be melanoma because of brownish black color detected at least focally. However, clinical diagnosis of hyperkeratotic and completely amelanotic acral melanomas can be very difficult to distinguish from other hyperkeratotic lesions such as SCC, verruca vulgaris, and tylosis/clavus.
Dermoscopic Diagnosis of Melanoma on the Palms and Soles
Dermoscopic Features of Melanocytic Lesions on the Palms and Soles
Dermoscopic features of advanced primary acral melanomas on the palms and soles are same as those of melanomas affecting other anatomical sites. These non-site-specific melanoma criteria include irregular blotches with variegated shades of brown, abrupt edge, blue-white veil, and regression structures with whitish or grayish color (Fig. 6). Irregular streaks and irregular dots/globules are also important clues to the diagnosis of advanced acral melanoma. More importantly, the parallel ridge pattern (PRP), that is, striped pigmentation along the ridges of the skin markings, is detected in macular portions within the advanced melanomas (Fig. 7) (described in detail in the next paragraph). In contrast, an atypical pigment network is rare, except for lesions located on the transitional zone between the glabrous and non-glabrous skin. In amelanotic or hypomelanotic acral melanomas, vascular patterns are helpful in determining diagnosis dermoscopically. They are polymorphous vessels, particularly combination of irregular linear or dotted vessels, and milky red areas that can be readily discerned due to the decreased or absent pigmentation.
Dermoscopy is very helpful in the differentiation between early forms of acral melanoma and acral nevi, which can be difficult clinically. Surface skin markings or dermatoglyphs on the palms and soles run in a parallel linear or curvilinear fashion. Acral melanoma in situ in this area shows a unique dermoscopic pattern called the parallel ridge pattern (PRP) (Fig. 8) (Saida et al. 2004; Phan et al. 2010). In this pattern, stripes of pigmentation are detected along the dermatoglyphic ridges and are absent along the sulci. In our study of a total of 712 acral melanocytic lesions including 67 invasive and 36 in situ acral melanomas, diagnostic sensitivity and specificity of the PRP for acral melanoma were 86% and 99%, respectively. Diagnostic performance of the PRP is similarly very high for acral melanoma in situ. Irregular diffuse pigmentation is another important dermoscopic finding of acral melanoma on the palms and soles (Fig. 9); however, this feature is more frequently detected in advanced acral melanomas (Saida et al. 2011a).
By contrast, the major dermoscopic patterns seen in acral nevi are the parallel furrow, lattice-like, and fibrillar patterns (Fig. 10) (Saida et al. 2011a). The parallel furrow pattern (PFP) shows brownish linear pigmentation along the sulci of the surface skin markings (Fig. 10a). There are several variants in the parallel furrow pattern such as dotted line and double-line variants (Fig. 10a and b).The lattice-like and the fibrillar patterns are modifications of the PFP (Saida and Koga 2007). The lattice-like pattern is composed of parallel pigmented lines along the sulci as well as lines crossing the parallel lines (Fig. 10d). The fibrillar pattern shows densely packed, fine pigmented lines, usually arranged in the direction crossing the skin markings (Fig. 10e). Among these, the PFP is the major dermoscopic pattern most frequently seen in acral nevi, accounting for 40–60% of all acral nevi. The prevalence of the lattice-like pattern is 10–15% and that of the fibrillar pattern is 10–20%. The prevalence of these patterns in acral nevi are similar across races. Finally, there are several minor dermoscopic patterns in acral nevi, such as homogeneous/structureless (Fig. 10f), globular, and reticular patterns (Saida et al. 2011a).
Dermoscopic Guidelines for Detection of Melanoma on the Palms and Soles
Two kinds of dermoscopic guidelines have been proposed for effective detection of melanoma on the palms and soles: the three-step algorithm and the BRAAFF checklist. These may be helpful for clinicians in their daily practice.
The Three-Step Algorithm
In 2007, our group proposed the original three-step algorithm for effective detection of melanomas on the palms and soles (Saida and Koga 2007) and revised it in 2011 (Koga and Saida 2011). The algorithm proceeds as follows (Fig. 11) (Saida et al. 2011a; Saida and Koga 2013):
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Step 1: The lesion on the palms and soles is examined for the presence of the PRP. If the PRP is found in any part of the lesion, it should be biopsied regardless of the size. If the lesion does not show the PRP, proceed to Step 2.
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Step 2: The lesion is examined for the presence of the typical benign dermoscopic patterns (i.e., typical PFP, typical lattice-like pattern, regular fibrillar pattern). If the lesion shows one or orderly combination of two or three typical benign patterns (Fig. 12), further dermoscopic follow-up is not needed because they are certainly benign acral nevus without risk of developing to melanoma. If the lesion shows equivocal dermoscopic features, proceed to Step 3.
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Step 3: The maximum diameter of lesions that do not show typical benign dermoscopic patterns is measured. Lesions >7 mm should be excised or biopsied for histopathologic evaluation. Lesions ≤7 mm in maximum diameter should be monitored clinically and dermoscopically at 3- to 6-month intervals.
There are several notes in the application of this algorithm (Saida and Koga 2013):
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1.
Congenital acral nevi have to be excluded. Congenital acral nevi are often but not always larger than 7 mm in diameter. Dermoscopic features of the congenital acral nevi are the typical PFP, the crista dotted pattern, and the peas-in-a-pod pattern (Fig. 13). The crista dotted pattern consists of brown dots/globules regularly distributed on the ridges of the skin markings. The peas-in-a-pod pattern is a combination of the parallel furrow and the crista dotted patterns. Nonetheless, it is not rare to see acral nevi whose type (acquired or congenital) cannot be determined; however the three-step algorithm can be used for such indeterminate lesions.
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2.
It is crucial to correctly identify the dermatoglyphic furrows and ridges, which can be facilitated by performing the furrow ink test (Uhara et al. 2009). The peripheral areas of the lesion are marked with a whiteboard marker pen, preferably blue or green in color, and then the skin surface is gently wiped with a dry paper towel in the direction crossing the skin markings. The furrows retain the blue or green ink and become clearly visible on dermoscopic examination as thin inked lines and distinguish PRP and PFP (Fig. 14). The ink can be easily removed with a wet paper towel.
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3.
Note that the PRP or its similar features could be detected in several benign conditions (Saida and Koga 2013). They include volar macules of Peutz–Jeghers or Laugier–Hunziker syndromes, acral pigmentation due to anticancer drugs, pigmented and ridged plantar warts, volar melanotic macules, subcorneal hemorrhage (e.g., so-called black heel due to friction with shoes and PlayStation purpura due to friction with the game controller), and pigmentation due to external pigment such as paraphenylenediamine (Fig. 15). However, most of these conditions can be easily differentiated from early acral melanoma by evaluating the clinical characteristics, number of lesions (single or multiple), personal and/or family history, and other associated clinical signs and symptoms (Saida et al. 2011a; Saida and Koga 2013).
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4.
In the second step, the clinician must assess whether the benign patterns are typical/regular. Typical parallel furrow or lattice-like patterns are symmetrically and evenly distributed across the lesion. The criteria for classifying a fibrillar pattern as regular are (a) symmetrical and regular overall arrangement of the fibrillar pigmentation, (b) even thickness and length of each fibril, and (c) alignment of the starting points of the fibrils on a surface furrow (Fig. 16a). In contrast, the irregular fibrillar pattern seen in acral melanoma exhibits asymmetrical arrangement of the fibrillar pigmentation and the fibrils vary in thickness and color (Fig. 16b).
BRAAFF Checklist
Several recent studies found that the sensitivity of the PRP for acral melanoma is only around 60%. This can be explained by the fact that the PRP is a characteristic feature of early acral melanoma and becomes obliterated as the lesions progress. The BRAAFF checklist was proposed for improved dermoscopic detection of acral melanoma (Table 1) (Lallas et al. 2015). This algorithm was based on the analysis of a total 603 acral melanocytic lesions including 131 acral melanomas (42 of them were in situ melanoma). In this study, the checklist shown in Table 1 diagnosed acral melanoma with 93.1% sensitivity and 86.7% specificity.
Clinical applicability and usefulness of the three-step algorithm and of the BRAAFF checklist in daily practice must be investigated and compared in further studies.
Histopathologic Diagnosis of Melanoma on the Palms and Soles
Clinically equivocal acral lesions are biopsied and evaluated histoapthologically. Histopathologic diagnosis of advanced melanoma on the palms and soles is not difficult. The criteria for the diagnosis are common to those for other subtypes of melanoma, but compared with SSM/non-CSD melanoma, intraepidermal upward migration of melanocytes is not prominent in most cases of acral melanoma. The neoplastic cells are typically small oval or dendritic rather than pagetoid, and their cytoplasmic melanin granules are not as fine and dusty as those seen in melanocytes of SSM/non-CSD melanoma (Fig. 17).
One important histopathologic differential diagnosis of acral melanoma is Spitz nevus, which is not rare on the palms and soles. The histopathologic criteria for the differentiation are similar as for differentiation between both entities on non-glabrous skin. Spitz nevi are symmetric with an evenly hyperplastic epidermis, and melanocytes are arranged mainly in nests, which are situated mostly in the lower epidermis. The nests are sharply demarcated, with artifactual clefts separating them from the surrounding epidermis (Fig. 18). The intradermal component (when present) shows “maturation” with cells becoming smaller in size in the deeper portions, and at the bottom of the lesion, nevus cells tend to be arranged as solitary units among collagen bundles.
In contrast to the advanced lesions, histopathologic diagnosis of early acral melanoma on the palms and soles is sometimes very difficult (Saida 1989) because benign acral nevi not infrequently show prominent proliferation of melanocytes as solitary units within the epidermis and the proliferation occasionally reaches the upper epidermis, mimicking the features of melanoma in situ. Such confusing histopathologic features are particularly prominent in the tissue sections cut in the direction parallel to the skin markings (Fig. 19). Thus, when we histopathologically evaluate melanocytic lesions on the palms and soles, the tissue specimen should be cut perpendicularly to the skin markings. In such a section, we can recognize two kinds of epidermal rete ridges, one is under the surface furrows and the other under the surface ridges. In early acral melanoma in situ, solitary melanocytes are concentrated in the epidermal rete ridges underlying the surface ridges (Fig. 20a), corresponding to the dermoscopic PRP. In contrast, in most acral melanocytic nevi, nevus cells arranged in nests are mainly detected in the epidermal rete ridges underlying the surface furrow (Fig. 20b), corresponding to the dermoscopic PFP. However, in some cases, nevus cells are detected also in epidermal rete ridges underlying the surface ridges. Even in such cases, melanin granules in the cornified layer are arranged in a columnar fashion selectively under the surface furrow (Saida et al. 2011b). This finding aids in the histopathologic differentiation of acral nevus from melanoma in situ.
Melanocytic nevi located on the transitional zones between glabrous and non-glabrous skin (i.e., far peripheral areas of the palms and soles, lateral aspects of fingers and toes, and webs) not infrequently show prominent proliferation of melanocytes arranged as solitary units within the epidermis, histopathologically mimicking melanoma in situ. This is probably due to the complex structures of the epidermal rete ridges in these areas. Similar prominent solitary arrangement of melanocytes is occasionally found also in acral nevi located on the arch area. We consider these histopathologically confusing acral nevi to be a pseudomelanoma. The differentiating features of these nevi from melanoma are a symmetrical, orderly intraepidermal distribution of melanocytes without nuclear atypia and typical nevus cells in the dermis, when there is an intradermal component (Fig. 21).
Histopathologic changes of early acral melanoma in situ on the palms and soles are sometimes very subtle, showing only a slightly increased number of melanocytes in the epidermis. In 1994, several cases of problematic plantar pigmented lesions were described (Nogita et al. 1994). The brownish macular lesions were large in size and irregular in color and shape, fulfilling the clinical criteria for melanoma in situ. However, histopathologically, the lesions showed only a slightly increased number of melanocytes at the basal layer of the epidermis, which did not fulfill the histopathologic criteria for acral melanoma in situ. The authors considered these lesions could not be diagnosed as acral melanoma in situ and called these lesions atypical melanosis of the foot, implying their biologic nature was uncertain (Fig. 22). Later, however, it was revealed that most of these lesions showed the PRP on dermoscopy, strongly suggesting these are acral melanoma in situ. Moreover, in recent years, it was shown that plantar lesions originally diagnosed as the atypical melanosis of the foot later developed into apparent acral melanoma (Kilinc Karaarslan et al. 2007; Chiu et al. 2008). We now realize that most lesions of the atypical melanosis of the foot represent a special subtype of slowly evolving acral melanoma in situ.
Biological Meanings of the Dermoscopic Parallel Ridge Pattern
Histopathological findings indicate that the differential dermoscopic pattern in acral nevi and melanoma in situ are due to differential localization of neoplastic melanocytes in the epidermis. This difference strongly suggests that acral melanoma and acral nevus develop independently, supporting the concept of a de novo genesis of acral melanoma as opposed to an evolution from a preexisting nevus.
The preferential localization of melanocytes in the epidermal rete ridges under the surface ridges rather than the surface furrows in evolving acral melanoma could be explained by their emergence from melanocytes from a particular stem cell niche. As opposed to non-glabrous skin, where the stem cell niche is in the bulge of hair follicles, the stem cell niche for melanocytes is located in the secretory portion of eccrine sweat glands (Okamoto et al. 2014). The ducts of these glands ascend and pass through the epidermis and open at the center of the surface ridges. In acral melanoma in situ, neoplastic melanocytes with stem cell-like features can be detected in the secretary portions of eccrine glands as well as in intradermal eccrine ducts. These melanocytes are small and unpigmented but express MART1 and MCM2, markers for melanocytes and the non-G0 of the cell cycle, respectively, and show amplification of CCND1, confirming their neoplastic nature. In contrast, the MART1 and MCM2 positive melanocytes with amplified CCND1 were not detected in the sweat glands of normal acral skin tissues nor in those of benign acral nevus lesions (unpublished data).
What are the biological meanings of these findings? The concept of cancer stem cell could explain pathogenesis of the PRP. Although melanoma stem cells have been not yet biologically delineated definitely, altered melanocytes in early stages of melanoma in situ could possess some common biological and molecular properties to melanocyte stem cells. In a lesion of evolving acral melanoma in situ, the altered/transformed melanocytes can be maintained and proliferate preferentially in the stem cell niche, which is located in eccrine sweat glands connecting to the epidermal rete ridges underlying the surface ridges through intradermal eccrine ducts. This could be a reason why early acral melanoma in situ specifically exhibits the PRP on dermoscopy. It is still unclear whether acral melanoma cells originate from a melanocyte stem cell in the niche within the eccrine gland or they are transformed epidermal melanocytes which acquire genetically and/or biologically common natures to melanocyte stem cells.
Acral Melanoma of the Nail Apparatus
The nail apparatus is anatomically complex. Although melanomas affecting the nail apparatus have been called subungual melanoma, the term “nail apparatus melanoma” may be preferable (Saida 1992). They typically first manifest as longitudinal melanonychia, reflecting increased amount of melanin granules in the nail plate, which are produced by transformed melanocytes in the nail matrix.
Clinical Diagnosis of Nail Apparatus Melanoma
Clinical diagnosis of advanced lesions of nail apparatus melanoma is not difficult. It is recognized as a brownish black lesion broadly involving and/or destroying the nail plate (Fig. 23). Nodules may be detected within the lesion, often partly eroded or ulcerated. In addition, in most cases, irregular pigmented macules extend on to the nail fold, which is a diagnostically useful clue for melanoma (Hutchinson’s sign). Nail apparatus melanoma is occasionally amelanotic (Fig. 24) and/or hyperkeratotic, which must be differentiated from SCC, viral wart, and dystrophic lesions of tinea unguium. Dermoscopy is useful in the differentiation of these nonpigmented lesions, just as described in amelanotic melanoma of the palms and soles.
Early nail apparatus melanomas are recognized as longitudinal melanonychia, that is, band-like pigmentation running from proximal areas to distal ends of the nail plate (Fig. 25). Various benign conditions such as melanocytic nevus, ethnic-type melanonychia, Addison’s disease, and subungual hematoma also exhibit longitudinal pigmentation of the nail plate. Clinical differentiation of these conditions is very important in daily practice, because biopsy or excision of the nail apparatus often leads to nail deformities. In 1989, the author proposed clinical criteria for early detection of nail apparatus melanoma (Saida and Oshima 1989). Vast majority of early nail apparatus melanoma is seen as monodactylic longitudinal melanonychia that manifests during adulthood and shows one or more following criteria: (a) the width of the lesion is at least 6 mm, (b) the brownish color variegated from tan to black, and (c) occasionally accompanied by pigmentation on the nail fold (Hutchinson’s sign). The main differential diagnosis to melanoma is melanocytic nevus of the nail apparatus, which typically presents as narrower longitudinal melanonychia less than 4 mm in width, and the color is uniform as opposed to variegated (Fig. 26a).
Note that broad variegated melanonychia is not infrequently observed in the digits of infants or young children, even with a Hutchinson’s sign (Fig. 27a). Histopathologic examination of such nail lesions in infancy reveals increased number of solitary-arranged melanocytes in the epithelium of the nail matrix and nail bed, histopathologically also mimicking acral melanoma in situ. Some investigators considered such lesions to be authentic acral melanoma in situ. Importantly, however, the broad irregular nail pigmentation in children regresses spontaneously in most cases by the end of adolescence (Fig. 27b), confirming this is not a melanoma but a peculiar type of melanocytic nevus. Long-term dermoscopic follow-up of these ambiguous nail lesions in children is a reasonable choice of management (see below).
Dermoscopic Diagnosis of Nail Apparatus Melanoma
Thomas’ group proposed the following dermoscopic criteria for nail apparatus melanoma (Fig. 28): (a) light to dark brown coloration of the background; (b) presence of longitudinal brown to black lines that are irregular in color, spacing, orientation, and thickness (irregular lines), and (c) micro-Hutchinson’s sign (subtle pigmentation of the cuticle that is only visible by dermoscopy) (Ronger et al. 2002). In contrast, melanocytic nevi of the nail apparatus dermoscopically show regular lines (Fig. 26b). In addition, when the pigmentation of the nail lesion spreads to the hyponychial skin, dermoscopy of any hyponychial involvement provides helpful clues such as the PRP indicative of melanoma and the PFP or its modified patterns indicative of acral nevus. Thomas’ criteria are useful; however, the irregularity of longitudinal pigmented lines can be equivocal, not infrequently posing troubles in determining the diagnosis (Koga et al. 2011).
We have recently proposed a melanoma discrimination index for the diagnosis of early nail apparatus melanoma. The index represents randomness of colors in dermoscopic images of longitudinal melanonychia. The index is automatically calculated on a computer installed with an application we have developed. In our preliminary study, the index achieved a high level of diagnostic accuracy, seemingly superior to dermoscopic diagnosis by experts. In our study, diagnostic performance of this diagnostic method was 83% in specificity and 92% in sensitivity in the diagnosis of early nail apparatus melanoma (Koga et al. 2014). This objective evaluation system is also useful in monitoring ambiguous nail lesions seen in infants as well as in adults. While the index of benign nail lesions is static or decreases during the course, the index steadily increases in most cases of early nail apparatus melanoma during the follow-up periods.
Histopathologic Diagnosis of Nail Apparatus Melanoma
Histopathologic characteristics of nail apparatus melanoma are very similar to those of melanoma on the palms and soles. Proliferation of atypical melanocytes are detected in the epithelium of the nail matrix and nail bed as solitary units as well as in nests of variable shapes. Atypical melanocytes also extend into the dermis, arranged in nests or sheets. In advanced lesions, the nail apparatus may be focally or totally destroyed by the proliferation of atypical melanocytes, and in further advanced cases, the underlying bone tissue can be invaded and destroyed. Immunostaining using S-100 or MART-1/Melan-A is useful in diagnosing amelanotic cases.
Histopathologic diagnosis of nail apparatus melanoma in situ is sometimes very difficult. Occasionally only a slightly increased number of melanocytes are detected at the basal layer of the nail matrix and/or nail bed (Fig. 29) (Saida and Oshima 1989). Clues for diagnosis of early nail apparatus melanoma are focal upward migration of melanocytes in the epithelium, uneven distribution of melanocytes, and nuclear atypia of the melanocytes. In addition, melanocytes with long dendrites or dendrites of uneven thickness can be detected in the epithelium. Immunostaining using S-100, MART-1/Melan-A, or HMB-45 is useful to visualize the irregular distribution of melanocytes within the nail epithelium.
Management and Prognosis of Acral Melanoma
Diagnostic Workup and Staging of Acral Melanoma
The AJCC (American Joint Committee on Cancer) staging system is used also for acral melanoma. Thorough physical examination is essential at the beginning of diagnostic workup along with precise histopathologic evaluation of the primary lesion, including presence of ulceration, tumor thickness, and number of mitotic figures, which are necessary to determine the T category. Routine laboratory examinations, sentinel lymph node biopsy, MRI, and/or PET/CT scan is performed in selected cases to determine the stage of the disease.
Surgery of Acral Melanoma
Surgical treatment of acral melanoma is based on similar principles than that of melanoma in other anatomical sites, with some adaptation considering the anatomical differences of acral sites. Recommended surgical margins of a primary lesion are 3–5 mm free margin for melanoma in situ, about 1 cm margin for melanomas with 2 mm or less in thickness, and about 2 cm free margin for lesions more than 2 mm in thickness (Haigh et al. 2003). Due to functional or cosmetic considerations, the width can be reduced in certain situations.
When the primary lesions are located on the heel directly receiving body weight pressure, a medial plantar flap is used to reconstruct the tissue defect after excision of the primary lesion. If a digit has to be amputated to advanced nail apparatus melanoma, ray amputation should be considered if possible, which may contribute to better functions and cosmesis. Amputation can typically be avoided for melanoma in situ or early invasive lesions (Sureda et al. 2011). In such cases, the nail apparatus is excised including periosteum but preserving the underlying bone. Thereafter, artificial dermis is temporarily applied onto the defect until granulation tissue has formed and skin grafting can be performed. Functional and cosmetic outcomes are excellent with this approach (Fig. 30).
Conventional Chemotherapy and Radiation Therapy of Metastatic Acral Melanoma
Therapeutic guidelines for metastatic lesions of acral melanoma are basically same to those of other subtypes of melanoma. If metastasis is solitary or only a few in number, limited to one organ and static for a while, feasibility of surgical resection is evaluated. Surgical resection of such lesions could prolong survival time of the patients.
Clinical effect of conventional chemotherapy on the patients with advanced acral melanoma with multiple metastases is limited. For a long time, dacarbazine was a standard chemotherapeutic agent for patients with metastatic melanoma. However, the response rate with this drug is around 15–20% and long-term remissions are very rare. Various kinds of combination chemotherapy and biochemotherapy including interleukin-2 and interferon-a have been tried. Higher response rates were reported in some regimens; however, all of them failed to show significant improvement of survival. Note that these combination therapies increased incidence and severity of adverse effects.
Radiation therapy can be used as a palliative therapy. Stereotactic radiosurgery for cerebral metastatic melanoma is a choice of treatment for palliation. Pain from bone metastases can be transiently relieved with radiation therapy.
Immunotherapy and Molecular Targeting Therapy for Advanced Acral Melanoma
Among recently introduced new therapies for advanced melanoma, immune checkpoint inhibitors, such as ipilimumab and nivolumab, are effective not only for cutaneous melanomas from sun-exposed skin but also for acral melanoma (Johnson et al. 2015). The opportunity for targeted therapy with BRAF and MEK inhibitors is limited by lower frequency of BRAF mutations in acral melanoma (10–20%).
KIT mutations are another therapeutic target. In 43 patients with metastatic melanoma harboring KIT mutation or amplification, imatinib therapy was effective, 23% overall response rate, with significantly longer survival times (Guo et al. 2011). A multicenter phase II trial of imatinib for KIT-mutated or KIT-amplified acral/mucosal melanomas revealed that overall response rates were 54% (7/13) in KIT-mutated melanomas, whereas no response were noted (0/11) in melanomas with KIT amplification only, indicating KIT gene mutations are a marker of good response with imatinib (Hodi et al. 2013). According to another preliminary trial, response rates with sunitinib were 75% (1 complete response and 2 partial responses in 4 patients) in acral/mucosal melanomas with KIT mutations but 17% (1 partial response in 6 patients) in those with KIT amplification only. A recent multicenter phase II uncontrolled trial of sunitinib showed improved survival of patients with acral/mucosal melanoma that was better than expected based on historic controls (overall disease control rate, 44%; 2-month progression-free survival, 52%). KIT mutation status did not influence on the effect (Buchbinder et al. 2015). Further clinical studies are necessary to confirm clinical significance and predictive biomarkers of different KIT inhibitors in the treatment of acral melanoma.
Prognostic Data of Acral Melanoma
Several papers have reported that acral melanoma/ALM is biologically aggressive and the prognosis of patients with acral melanoma is worse compared with other subtypes of melanoma. A recent study from a group of Memorial Sloan Kettering Cancer Center showed that prognosis of patients with acral melanoma was worse compared with that of patients with extremity non-acral melanoma (Bello et al. 2013). However, in our study of a total of 801 acral melanomas in Japan, 5-year survival rates according to the AJCC staging were as follows: stage IA, 98.1%; stage IB, 95.8%; stage IIA, 93.8%; stage IIB, 73.4%; stage IIC, 64.2%; stage IIIA, 48.0%; stage IIIB, 39.4%; stage IIIC, 44.1%; and stage IV, 16.0% (unpublished data). The survival rates in stages IIA, IIB, IIC, and IIIC appear to be slightly better than those reported in the USA, whose patients were mainly White persons suffering from SSM/non-CSD melanoma.
Conclusion
Acral melanoma is clinically and biologically distinct melanoma subtype that affects all world populations irrespective of skin complexion with similar incidence. Most acral melanomas arise de novo, rather than from melanocytic nevi. Its low mutation burden with a relative absence of UV signature mutations along with the presence of structural rearrangements and numerous copy number change including focal amplifications and deletions indicates that a distinct, yet to be discovered, mutational mechanism drives the molecular evolution of these neoplasms.
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Saida, T. (2018). Acral Melanoma. In: Fisher, D., Bastian, B. (eds) Melanoma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7322-0_5-1
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DOI: https://doi.org/10.1007/978-1-4614-7322-0_5-1
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Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-7322-0
Online ISBN: 978-1-4614-7322-0
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