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Acrolentiginous melanomas

Schoenewolf, Nicolaa; Tonolla, Sabinaa; Dummer, Reinharda; Elwan, Nagwab

Journal of the Egyptian Women's Dermatologic Society: July 2011 - Volume 8 - Issue 2 - p 55–62
doi: 10.1097/01.EWX.0000398176.41107.86
Review article

Acrolentiginous melanoma (ALM) accounts for 5% of all melanoma types. Even though it occurs in all ethnic groups, a preference in dark skin has been observed over the time. A lack of typical alarming signs still results in late diagnosis. Recently, distinct molecular characteristics have been defined for melanoma by Bastian et al. ALM and mucosal melanoma are suggested to show aberrations in the cKIT gene. It is involved in tumorigenic growth signaling. cKIT tyrosine kinase receptor has been yet proven as a successful target in chronic myeloid leukemia and in gastrointestinal stromal tumors. Histologically, mucosal melanomas show ALM characteristics. Specific staining with proliferating cell nuclear antigen for cutaneous melanoma in general and cKIT protein expression for ALM and mucosal melanomas in particular, can help to identify this tumor in comparison with benign melanocytic lesions. Genetic aberrations do not necessarily correlate with the KIT protein expression. Several studies applying small molecule inhibitors such as Imatinib have been performed in patients with melanoma. Single-patient cases with known cKIT mutations revealed impressive clinical response.

aDepartment of Dermatology, Zurich University, Switzerland and

bDepartment of Dermatology, Tanta University, Tanta, Egypt

Correspondence to Nagwa Elwan, MD, Department of Dermatology, Faculty of Medicine, Tanta, Egypt Tel: +2012 2818631; fax: +2 040 3280 141; e-mail:

Received August 15, 2010

Accepted September 30, 2010

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Epidemiology of acrolentiginous melanoma

Acrolentiginous melanoma (ALM) is a subtype of melanoma, first described as a ‘distinct clinicopathological entity’ by Reed in 1976 [1]. In general, ALM accounts for approximately 5% of all diagnosed melanomas [2].

The most interesting aspect of the epidemiology of ALM is its occurrence in all ethnic groups. Multiple studies investigating different ethnic groups have reported a wide variation in the proportion of ALM to all types of melanoma. It varies from a low of 2–13% in Caucasians [3,4] to significantly higher proportions in other ethnic groups: 50–70% in African–Americans [3,5], 35–49% in Asians [3,5,6], and 34% in Hispanics [3]. Stevens et al. [7] found that the annual area-adjusted and age-adjusted incidence rates were 1–7/million per year for blacks and 2.0/million per year for whites with no statistically significant difference in incidence between the two races. They concluded that the high proportion of plantar melanoma in more darkly pigmented races is most likely due to the low occurrence of melanoma on other parts of the skin, but it should be noted that they evaluated incidence rates of plantar melanoma, not ALM specifically.

Almost 20 years later, Bradford et al. [8] reported the incidence of ALM in the USA, from 1986 to 2005. They found that the proportion of ALM among all melanoma subtypes was greatest in people of color, corroborating with the observations of Jimbow et al. [9] and Seiji and Takahashi [10] in the 1980s. ALM was shown to account for 36% of all cutaneous malignant melanoma (CMM) in blacks, 18% in Asian/Pacific Islanders, 9% in Hispanic whites, and only 1% in non-Hispanic whites. In Brazil, ALM represented 22.3% of CMM [11].

Given the higher proportion of ALM in more darkly pigmented races, it was suggested that persons in these groups are at a higher risk than Caucasians of developing ALM. However, a higher proportion does not necessarily translate into higher risk [12].

ALM occurs in an older age group than other subtypes of melanoma, although the age at diagnosis of ALM may be decreasing [12]. In 1983, Paladugu et al. [13] reported that 72% of ALM occurred between the sixth and eighth decades. However, studies after this demonstrated a younger age at diagnosis, ranging between 50 and 60 years [8,14,15].

ALM appears to occur with a slight female preponderance [13–15], in contrast to malignant melanoma, which occurs more frequently in men than in women [16]. In contrast, Bradford et al. [8] reported similar rates of incidence of ALM in men and women.

Baumert et al. [17] analyzed 6475 patients with melanoma in Munich between 1977 and 2000 to assess time trends of tumor thickness by age group, tumor site, and melanoma subtypes. A positive time trend with decreasing tumor thickness was observed during the observation period in most subgroups. However, no significant time trend was observed in patients with a melanoma on the feet or with a nodular or acrolentiginous melanoma. Tumor thickness of patients with melanoma on the feet remained widely constant and on a high prognostically unfavorable level throughout the whole observation period. A possible explanation might be that these melanomas do not share the universal alarming signs of ‘classical’ melanomas. Furthermore, correct diagnosis of ALMs or subungual melanoma may be difficult.

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Molecular findings in acrolentiginous melanomas in comparison with melanomas of other sites

Recently, some researchers [18,19] detected distinct patterns of chromosomal aberrations and mutations in melanoma. It was hypothesized that the genetic alteration correlated more with the location of the primary tumor and the grade of the sun-induced damage of the skin than with the clinical melanoma-type classification [18–22]. According to this new classification system, ALM and mucosal melanoma (MM) show genetic similarities [21], which are different from nodular MM, superficially spreading melanoma, and lentigo maligna melanoma. Superficially spreading melanoma and nodular MM show a high percentage of B-rapidly growing fibrosarcoma mutations [22].

These molecular differences in the genetic background of melanoma support the existence of distinct melanoma subtypes. The limitations of the clinical melanoma classification system are among others approved by the fact that successful treatment options are still lacking [23].

ALMs are localized in areas naturally protected from sun exposure, such as palms and soles. Frequent mutations have been detected in the receptor tyrosine kinase KIT, which is encoded by the cKIT gene [18]. KIT belongs to the class III tyrosine kinase receptor family [24–27].

C-KIT mutations are so far well known and studied in gastrointestinal stroma tumors (GISTs), chronic myeloid leukemia, mastocytosis, and germline tumors such as testicular cancer and small lung cell cancer [26].

KIT overexpression leads to constant survival, proliferation, differentiation, and migration in melanocytes [28]. Thus far, KIT has been proven as a potential target for therapeutic approaches by small molecules in GIST and several ALM and MM cases [29–36].

The recent genetic information has offered a new target for therapy and provides an improvement of the existing classification of melanoma. Therefore, an advancement of the therapy of patients with melanoma with distant metastases could be aimed for a goal.

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Acral anatomical features and clinical presentation of acrolentiginous melanoma

ALM occurs in the following areas: the hand and palms. It can be localized subungually on both, hands and feet, and on the foot sole (plantar). Noteworthy is the anatomical speciality in these areas, as the stratum corneum is quite thick. The palms and feet soles are characterized by quite a number of sweat glands, but in turn no hair follicles are present here.

ALM is sometimes referred to as a ‘hidden melanoma’ because these lesions occur on sites that may be overlooked during examination. ALM develops on acral surfaces, specifically the palms, soles, and nails. Mucous membrane affection involving those lining the mouth, nose, and female genitalia can also occur.

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Acrolentiginous melanoma on palms and soles

On palm or sole, ALM occurs most frequently on the plantar surface. When the digits are involved, the thumb and hallux are most commonly affected. Clinically, it is similar to superficial spreading melanoma, with the ABC criteria for detecting melanoma, meaning ‘A’ refers to asymmetry, ‘B’ to border irregularity, and ‘C’ to color variegation [37,38]. In later lesions, nodular components may be present, which are typically associated microscopically with the dermal component. Areas of ulceration may or may not be present [4].

The epidermal component of the lesion is typically of striking black color, whereas the dermal component is often elevated and associated with a dusky blue, or amelanotic region [39]. Differential diagnosis of palmar and plantar ALM include melanoctyic lesions such as lentigines and nevi and nonmelanocytic lesions such as traumatic hemorrhage, tattoos with silver nitrates, pyogenic granuloma, and pigmented basal cell carcinoma [4,38]. Occasionally, verrucous and nonpigmented ALM masquerades as a wart [40].

Dermoscopically, melanocytic lesions on palms and soles exhibit distinctive dermoscopic patterns different from those observed on nonglabrous skin. The two most prevalent dermoscopic patterns of ALM in a Japanese study, were parallel-ridge pattern (PRP), which is accentuated pigmentation on the ridges of the skin markings arranged in parallel patterns on glabrous skin and irregular diffuse pigmentation (Fig. 1a and b, Fig. 2a and b). It has been demonstrated that PRP is characteristic of the macular portion of ALM and is present in as many as 86% of cases [41–43]. The PRP highlights the small, round eccrine openings and is quite distinct from the other patterns associated with benignity, such as the furrow, fibrillar, or lattice patterns [42].

Figure 1

Figure 1

Figure 2

Figure 2

Occasionally, globules are seen in acral nevi arranged symmetrically on either side of the furrows. Application of liquid ink can help to distinguish the dermatoglyphic furrows in which doubt exists, as these will stain preferentially over the ridges [44].

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Subungual melanoma (acrolentiginous melanoma of nails)

The detection of early ungual melanoma is one of the most challenging diagnoses in clinical dermatology. Melanoma of the nail matrix (subungual) typically presents on the great toe or thumb. Subungual lesions may present with variable clinical findings. One of these findings is that of a pigmented nail streak, enlarging in size and showing color variations (longitudinal melanonychia). The lesion may extend onto the proximal or lateral nail fold, a finding referred to as Hutchinson's sign. Other nail changes indicating ALM include nail dystrophy such as thickening and splitting in early lesions, whereas ulceration and hemorrhage may appear in late stages [38,45].

The differential diagnosis of subungual ALM includes traumatic hemorrhage and onychomycosis [4]. However, a history of trauma does not exclude the diagnosis of melanoma, as it was reported that 46–60% of patients with subungual melanoma reported a history of antecedent trauma [46].

Dermoscopically, the pigmented band can be visualized with greater detail and can be seen as multiple lines of varying pigment, width, and spacing. The parallel nature of the lines that one sees is benign subungual nevi, or lentigines may be lost (disruption of parallelism). Blood spots are not uncommonly seen in melanoma. The major differential diagnosis for subungual melanoma is subungual hematoma, which is readily identified dermoscopically by its color (red through blue–black), splash-like profile, and presence of blood spots. Even when deep purple or blackened in color, a hematoma will not conform to the band-like pattern of a melanoma. The ideal immersion medium for visualizing nail plate or subungual pigmentation is ultrasound gel as it conforms to the undulating and irregular surface without dripping [47].

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Mucous membrane melanoma

Primary melanomas arising from the mucosal epithelia of the respiratory, digestive, and genitourinary tracts are relatively rare [48]. Women are more commonly affected than men, mainly because there is no male counterpart for vulvovaginal lesions [49]. Mucous membrane melanoma is most likely to develop inside the nose or mouth. Early symptoms include nosebleeds, nasal stuffiness, and a pigmented mass inside the mouth [2]. Hislologically, 42% of mucous membrane lesions are defined as ALM. These lesions usually are advanced at initial presentation; consequently, the prognosis is poor [49].

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Amelanotic melanoma (nonpigmented subtype)

Although uncommon, melanoma occasionally does not have brown or black pigmentation. An uncommon subtype called ‘amelanotic melanoma’ usually appears as a pink or red nodule [2] or a skin-colored verrucous plaque [50] (Fig. 3). It is often overlooked by patients and physicians. Subungual amelanotic melanoma can also be seen as a subungual nodule, often destructive to the nail plate and can cause pain [2,51].

Figure 3

Figure 3

Phan et al. [52] have reported a rate of 27% of hypomelanosis or amelanosis among ALM. These unpigmented variants are statistically correlated with a greater Breslow thickness and with a worse prognosis.

Unpigmented ALM on both nail and volar skin is difficult to diagnose. Dermoscopy helps by showing remnants of pigmentation, polymorphic vascular structures, and atypical vessels. The most prominent vascular patterns are milky red areas (95%), dotted vessels (43%), hairpin vessels [53], and linear irregular vessels (49%) [45].

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Histological features of acrolentiginous melanoma

The epidermis shows marked hyperkeratosis, acanthosis, and elongation of rete ridges. Junctional nests of hyperpigmented atypical melanocytes are found in the lower epidermis, whereas the upper epidermis shows atypical pagetoid melanocytes with hyperchromatic nuclei. Dermal invasion, nevus-like cells, spindle cells, or highly pleomorphic cells can be present in the dermis [39,50] (Figs. 4a and b). Additional features include dendritic melanocytes in the epidermis, marked inflammatory cell infiltrate, scattered melanocytes throughout layers of the epidermis, and lack of solar elastosis in dermis [37].

Figure 4

Figure 4

Benign acral nevi may exhibit histologic features typically associated with ALM. Boyd and Rapini [54] described mild pagetoid spread as a common occurrence in benign acral nevi. They found that certain features were more likely to indicate melanoma. These included severe pagetoid spread, asymmetry, loss of circumscription, degree of lymphocytic inflammation, number of atypical cells, and number of mitotic figures [54].

Although ALM is believed to be one of the four subtypes of melanoma, some believed it belongs to a continuous spectrum of CMM [55]. Ackerman [56] believed in a ‘unifying concept’ among the four melanoma subtypes. He concluded that the same repetitive sequence of malignant histologic changes and clinical features can be observed in malignant melanoma at all anatomic sites, and that some clinicohistologic features are just more common in certain sites than others [56]. Weyers et al. [55] examined 915 melanomas with regard to 72 histopathologic parameters and concluded that the histopathologic criteria did not distinguish between the melanoma subtypes. Sondergaard and Olsen [53] reported that ALM shares overlapping histopathologic features with other melanoma subtypes. The only clear conclusion is that although multiple histologic features have been described in the literature, no consensus exists as to which criteria are absolutely necessary for the diagnosis of ALM. This lack of a ‘gold standard’ for defining ALM accounts for some of the difficulties in determining not only histopathologic features of ALM but also such features of epidemiology, etiology, and prognosis [12]. However, as described in chapter 2, recent findings of molecular genetic distinction in ALM and other melanoma subtypes hint at a new way of subtype classification.

Proliferating cell nuclear antigen (PCNA), a cofactor for DNA polymerase delta, is a cell cycle-dependent antigen that increases at the time of cell proliferation and serves as a marker of proliferating cells [57]. PCNA positivity rate was found to be much higher in malignant melanoma including ALM (Fig. 4c) than dysplastic nevi or benign melanocytic nevi. It was reported that PCNA positivity was found to be more in thick malignant melanoma and melanoma metastases than in thin malignant melanomas. PCNA index has a high efficacy in predicting locoregional and distant recurrences in patients with primary cutaneous melanoma [50,58].

P53 is a 53 kDa tumor suppressor protein, which plays a central role in normal cellular growth control. Mutation of the p53 gene occurs at many sites and represents a common genetic alteration in human malignancy. It was reported that p53 immunoreactivity was observed in malignant melanoma including ALM (Fig. 4d), in contrast to benign melanocytic lesions, which showed negative expression. A significant correlation was observed between melanomas with poor prognostic histological indices and p53 immunoreactivity [50,59].

Besides the immunohistochemical Melan-A staining, cKIT expression analysis can serve as a helpful tool too. The latter can correlate positively stained cells or areas to a cKIT-related molecular mechanism of this particular melanoma subtype. Nevertheless, cKIT staining does not serve as a screening method, but rather can prove and complete the diagnosis already made. Went et al. [60] found that positive cKIT expression is not necessarily correlated to cKIT mutations and/or amplification of the gene.

For PCNA, p53, and cKIT, it could be concluded that these markers may be additional tools in histopathological differentiation of malignant melanomas including ALM from other melanocytic lesions.

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Surgical therapy

For all melanoma types, diagnosis should be based on a full-thickness excisional biopsy with a small side margin. The diagnosis of melanoma is made histologically. The final operative removal should be carried out 4–6 weeks after the primary resection. A safety margin of 1–2 cm, depending on the tumor thickness, should be respected.

In the past decade, sentinel lymph node biopsy (SLNB) has become standard for staging patients diagnosed with cutaneous melanoma. The method's accuracy and reliability and the status of the SLN as the single most important prognostic factor for recurrence and survival for patients with melanoma have been proven beyond any reasonable doubt (level of evidence IV) [61]. Nevertheless, the impact of SLNB on survival remains unclear. There is general agreement that SLNB will help to identify patients who might benefit from further therapy, such as completion lymph node dissection and adjuvant interferon therapy [62,63], even if clinical trials aiming to determine the impact of these adjuvant measures are still ongoing. The recently published proceedings of an expert panel clarify the indication of SLNB as a staging tool [61]. SLNB should be discussed with and offered to all patients with primary melanoma with the Breslow thickness equal to or greater than 1.0 mm and clinically normal regional lymph nodes (determined by physical examination and ultrasound).

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New molecular therapeutic approaches

One of the first small molecules targeting KIT was the 2-phenyl-aminopyrimidine, Imatinib [64–67]. It shows activity against several receptors such as bcr-abl, KIT, platelet-derived growth factor receptors α and β, Abelson murine leukemia, and Abelson-related gene [64]. It functions as a competitive inhibitor, competing with ATP for the binding site of the tyrosine kinase domain of the KIT receptor. Imatinib can only bind to the nucleotide-binding site within the juxtamembrane domain, when the DFG (ASP810, Phe811, Gly812) (D: ASP, F: Phe, G: Gly) motif is present [68,69].

Clinical relevance of Imatinib inhibition was shown for the stable phase of chronic myelogenous leukemia, GIST, and in 16 cases of melanoma [29–36]. The existence of activating mutations in cKIT-exon 11 (codons 550–586) and exon 13 (position K642E, in particular) showed enhanced Imatinib efficacy when compared with wild-type cKIT [70,71]. Jiang et al. [72] emphasized this by demonstrating excellent in-vitro sensitivity to Imatinib in MM.

Imatinib resistance occurred in the patients in which mutations at residues T670I (the so-called ‘gatekeeper’/kinase domain), Y823D, D816 V (kinase domain/activation loop, both exon 17), and V654A (exon 13) evolved [68,73–75], for position D816V: [31,76]. Interestingly, if the oncogenic mutation is located in the same allele, next to the V654A mutation, it remains constitutively active. What is special about this locus is that it is located in the drug-binding site. Thus, it is suggested that the mutation disrupts drug binding by removing hydrophobic contacts between the central diaminophenyl ring of Imatinib and D310 and T610 [68].

SU5416 and SU6597, two indolinone tyrosine kinase inhibitors, were mainly attributed to targeting cell growth [77]. Nilotinib (AMN197), another novel KIT receptor inhibitor, has been approved for cases of Imatinib-resistant patients with chronic myeloid leukemia. Furthermore, AMN107 is able to inhibit wild type and mutant KIT selectively for (V560del and V560G/exon 11, K642E/exon 13). Activity against ‘double-mutants’, meaning a combination of mutated spots of exons 11, 13, and 17 is proven for Nilotinib and Dasatinib [78–81]. The efficacy is doubted against exon 14 mutants such as T670I. KIT mutations in the juxtamembrane domain (V559D and V560G) are supposed to be better inhibited by Dasatinib than Imatinib [79]. Tumors harboring D820Y are reported to be resistant to Imatinib, but Sunitinib may prove effective [82,83]. Sorafenib (BAY 43-9006), originally meant to target the serine–threonine–kinase rat fibrosarcoma, was shown effective against KIT in vitro [84]. Quintás Cardama et al. [85] could prove its efficacy in vivo. In this study, one patient expressing the V560D mutation showed complete response under Sorafenib treatment.

As for B-rapidly growing fibrosarcoma, Garrido et al. [86] found a possible explanation for KIT being mutated rather during disease progression, whereas in the beginning, histologically undetectable so-called ‘field cells’ could give the first hint to possible melanoma disease [86,87].

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Imatinib in melanoma clinical trials – successes and problems

Imatinib has been tried in patients with melanoma in several clinical studies. The first clinical trial was performed by Ugurel et al. [88] in 2005. Unfortunately, neither subgrouping of melanoma occurred nor was the mutational status of KIT considered in a large group. Of the four cell cultures studied, no mutations were found. Toxicity was outstandingly high in that study. These problems were also present in this study performed by Wyman et al. [89] in 2006: no distinction between melanoma subtypes and neither immunohistochemical nor mutation analysis before running the study. Coincidentally, one patient suffered from MM, but no activating mutations were detected. Imatinib treatment was thus insufficient.

Of the 31 patients studied by Kim et al. [90], one patient suffered from ALM, showing high KIT expression. Imatinib treatment led to a complete response lasting up to 1 year. RNA sequencing revealed a deletion at codon 715 (kinase domain), a splice variant, which was however not specific. Biopsies were taken twice, before and during treatment. The one responding patient showed no alterations in KIT expression during treatment, whereas the nonresponding patients showed either reduction, increase, or no change in expression intensity. Staining was not predictive.

In a clinical phase II study, Heinrich et al. [91] explored the efficiency of Imatinib in the treatment of several life-threatening malignancies. Among these, seven patients with melanoma were treated, but no effect of Imatinib was observed. In 2009, Sunitinib showed promising effects in acral and MM in vitro [92]. At the annual American Society of Clinical Oncology meeting in May 2009, an abstract by Carvajal et al. [36] emphasized the relevance of KIT mutations being a positive predictor for successful Imatinib treatment. In a phase II study, a cohort of 81 patients was screened for either KIT mutations or amplifications. Those showing positivity for mutations or amplifications in KIT were subsequently treated with Imatinib. The response rate was correlated significantly to the existence of mutations or amplifications [36].

There is no conflict of interest to declare.

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acrolentiginous; clinical features; epidemiology; melanoma; pathology

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