The majority of ALM are pigmented lesions, namely macules, papules, or nodes, that develop on the distal parts of the extremities. Subungual ALM manifest as pigmented streaks in the nail plate that extend towards the proximal or lateral nail fold [1]. In general, the feet are affected much more frequently than the hands, while ALM developing in the non-acral skin are increasingly rare [2].

ALM tend to be of dark blue, even black color, but pink and red, amelanotic ALM have also been identified [1] [3] [4]. Most of these tumors are poorly circumscribed. Patients may describe the respective lesions to change in size, color, or form. An initially flat lesion may become raised or nodular [5]. In this context, asymmetry, irregular pigmentation, and diameters >7 mm rather suggest melanoma than benign conditions [6]. ALM may also be bleeding, especially during advanced stages of the disease, when the tumor becomes friable. Ulceration and hemorrhages may be interpreted as a sign of vertical growth. On rare occasions, pain and itching are claimed [5].

Clinical findings may allow for a tentative diagnosis of ALM, but a histopathological confirmation is always required. Even though ALM may fulfill one or more of the so-called ABCDE criteria, the absence of asymmetry, irregular borders, variability in color, a large diameter, and visible enlargement do not rule out this type of cancer. On the contrary, the non-fulfillment of ABCDE criteria frequently lead to diagnostic delays with detrimental consequences.

Radial growth is typical of early-stage ALM, whereas vertical growth is usually observed when excisional or biopsy specimens from advanced-stage cancers are examined. Months or years may pass until this change occurs, and tumors change their microscopic features over time [7]. According to the histopathological findings, the tumor's Clark level should be defined.

• Initially, degenerated melanocytes coalesce into non-cohesive, poorly circumscribed nests that are irregularly distributed throughout the lower epidermis. Still, tumor cells tend to ascend along the crests up to the upper epidermis. Their nuclei may be more than twice as large as keratinocytic ones; they may be of irregular shape, be hyperchromatic, and contain prominent nucleoli [6].
• During the subsequent radial growth phase, atypical melanocytes proliferate along the dermo-epidermal junction in a diffuse, lentiginous manner. The overlying epidermis may be hyperplastic. Acanthosis and elongated rete ridges are often observed [8].
• In the vertical growth phase, degenerated melanocytes spread to the dermis, subcutis, and adjacent tissues. Vertical growth has been proposed to be the basis of metastatic spread, because tumor cells in the dermis may invade blood vessels or reach the lymphatic system. Save for the rare exceptions where the formation of metastasis had apparently occured during the radial growth phase, vascular invasion is still considered characteristic of advanced-stage ALM [9]. Tumor cells in the dermis are mostly spindle-shaped within a desmoplastic stroma [1]. Furthermore, high mitotic rates as well as dedifferentiation and lack of pigment production are commonly noted during this stage of tumor development. Microscopic satellites may be detected. At this point in time, the tumor's surface is often ulcerated, and lymphocytic infiltrates can be readily observed in the underlying dermis [1] [3].

Beyond native histopathology, immunohistochemical stains may be realized to check for the expression of markers S100 protein, melanoma antigen/MART-1, and HMB-45. For these markers, positive results are obtained in 95, 80, and 70% of ALM [10].

The patient should undergo a complete staging procedure including a detailed inspection and palpation of the skin, subcutaneous tissues, and lymph nodes, and diagnostic imaging of the chest and abdomen. Evidence regarding the usefulness of sentinel lymph node biopsies as staging procedures is scarce. According to the authors of a retrospective study conducted in Japan, sentinel lymph node biopsies should be carried out in those presenting with ulcerating tumors or melanomas with a thickness of >1 mm [8]. If anamnestic data suggest the presence of metastases in determined organ systems, additional measures have to be carried out to confirm or refute this suspicion [11].

Complete tumor resection is the most common approach to ALM. Yet, local recurrence is likely, even in case of an early diagnosis. This fact highlights the importance of wide surgical margins, regardless of the tumor stage [7]. It may pose a major challenge to maintain sufficiently wide margins, to preserve the functionality of the affected hand or foot, and to obtain an acceptable esthetic result, but every possible effort should be made to adhere to the respective guidelines [11]:

• Surgical margins of 0.5-1.0 cm for ALM in situ
• Surgical margins of 1.0-2.0 cm for ALM with a thickness of 1-2 mm
• Surgical margins of 2.0 cm for ALM with a thickness of >2 mm

According to these guidelines, ALM of a finger or toe requires the amputation of the digit.

Similarly, positive lymph nodes are surgically removed. Surgeons may refrain from regional lymph node dissection if unresectable distant metastases are detected. These commonly form in lungs, liver, bones, and the central nervous system. Chemotherapy, radiation, and/or vaccine therapy may be offered to those suffering from metastatic ALM, or a palliative approach may be chosen. Neither of these strategies has been shown to improve disease-specific or overall survival [12].

Of note, vaccination against melanoma aims at inducing an anti-tumor immune response in patients who failed in immunosurveillance during early stages of the disease. Thus, research focuses on the development of immunotherapeutics that aid the patient in destroying both microsatellites and macroscopic metastases, but so far, the clinical activity of all compounds tested fell short of expectations [13].

ALM is usually identified during late stages of the disease and has a poor prognosis, whereby the latter seems to be a direct consequence of the former [7] [14]. According to a British study, the average time from the initial presentation to diagnosis is more than a year. Misdiagnoses are very common [5]. Beyond that, advanced age, ulceration of the tumor surface, tumor thickness and spread at the time of diagnosis have been identified as unfavorable prognostic factors [7]. Lymph node involvement and metastases have been reported to decrease disease-specific five-year survival rates from 84 to 38% [8].

The etiology and pathogenesis of ALM remain largely unknown. Contrary to other types of melanoma, sunlight exposure could not be confirmed as an etiological factor. The structural changes and mutation signatures observed in ALM clearly refute the hypothesis of ultraviolet radiation inducing tumor growth [15]. Mechanical stress or injury to the site of tumor development have been considered as possible triggers, but it's unlikely they are the only causes of the disease. The same applies to pre-existing nevi on hands or feet [2]. Furthermore, a general propensity to nevi has been related to a predisposition to ALM. This may suggest a contribution of genetic and environmental factors, other than sunlight, to the genesis of this type of cancer.

The incidence of ALM has been calculated to be <2 per 1,000,000 inhabitants and year, and is similar for all ethnicities [2] [14]. In Caucasians, ALM is the least common type of melanoma and accounts for <10% of all cases. By contrast, about half of melanomas diagnosed in black people correspond to ALM [14]. ALM is generally diagnosed in the elderly. At the time of diagnosis, patients have a mean age of about 65 years [7] [8]. Women are affected more frequently than men [5].

A large share of ALM are triple-wild-type melanomas, i.e., they don't harbor mutations of genes BRAF, NRAS, or NF1. Mutations and focal amplifications of the proto-oncogene KIT, of genes CCND1, KRAS, and MDM2 are more characteristic of this type of cancer. These aberrations are related to alterations of cell cycle regulation and MAP kinase signaling, and they implicate the degradation of tumor suppressors like p53 [15].

No recommendations can be given to prevent the development of ALM, since the triggers of the disease remain elusive. Still, patients should be encouraged to take advantage of preventive medical check-ups and to learn how to self-examine their skin. Suspicious lesions should be clarified by a dermatologist. This way, diagnostic delays may be avoided, and the outcome may be improved.

There are four major types of cutaneous melanoma, namely superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and ALM. Although all types of melanoma have been reported to arise on hands and feet, these are the predilection sites of ALM. This type of cancer is further characterized by as-of-yet unknown triggers other than sunlight, mutational signatures distinct from those observed in other melanomas, and frequent non-fulfilment of the well-known ABCDE criteria. If biopsy specimens are not obtained for a thorough histopathological analysis, ALM are frequently mistaken for benign lesions that don't require surgery. Diagnostic delays of more than a year a not uncommon and are assumed to adversely affect the outcome: At the time of diagnosis, ALM may already have formed metastasis in the regional lymph nodes or in distant organs. The complete surgical removal of the primary tumor and its metastases is rarely feasible, but there are few alternatives. Accordingly, only about one-third of patients found to suffer from metastatic ALM remains alive five years after the diagnosis. The detrimental prognosis of patients diagnosed with metastatic ALM highlights the need for an increased awareness and the timely realization of diagnostic measures to identify ALM.

Of note, "acral melanoma", "hand melanoma", or "foot melanoma" are merely descriptive terms that are used regardless of the histological type of the tumor. While most of them are ALM, this is not always the case.

Malignant melanoma is a common type of skin cancer. It originates from melanocytes, which are pigment-carrying cells. There are four types of melanoma, namely superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma (ALM). ALM is the least common variant. It arises from the palms, soles, or nail beds of the hands or feet, and typically manifests in the form of pigmented macules, plaques, or streaks in the nail plate. Affected individuals may not experience any discomfort, but they frequently observe changes in the lesions' size, color, or form. Beyond such progression, poorly defined borders, asymmetry, and irregular pigmentation should raise suspicion. ALM may grow to considerable sizes, but they may also form metastasis while only measuring a few millimeters in diameter.

The diagnosis of ALM is based on clinical suspicion and the examination of excisional or standard biopsy specimens. An excisional biopsy is obtained if the entire lesion is removed, while a standard biopsy aims at the collection of a representative sample only. Either type of tissue sample needs to be assessed under the microscope. If ALM is diagnosed, the patient is thoroughly checked for the presence of lymph node and distant metastasis. According to the findings of the staging procedure, a treatment schedule is drawn up.

In an ideal scenario, the tumor can be removed in its entirety with wide surgical margins being maintained. If this can be achieved, the patient has a good prognosis. Metastases in the regional lymph nodes may be removed by means of lymph node dissection, but the outcome is questionable. The presence of distant metastases is associated with a poor prognosis. Thus, in order to achieve an optimum outcome, the disease should be recognized in its early stages. Preventive medical check-ups and self-examinations play key roles in this process.

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