Acral Lentiginous Melanoma of Foot and Ankle: A Clinicopathological Study of 7 Cases

Discussion

We report seven cases of ALM on the foot and ankle with their clinical manifestation, histopathology and treatment. In our small series, the patients' age ranged from 38 to 84 years, with a mean of 65. This is comparable with reported means of 62.7 (7) and 62.8 (6), and 63 (10). These data suggest that ALM occurs predominantly in populations older than 60. The 38-year old white female patient had a strong family history of cancers where her mother had breast cancer and both her maternal and paternal uncles as well as one cousin had melanomas, suggesting that patients with a strong family history of multiple cancers may develop ALM younger than the general population.

Clinically, ALM can be located anywhere on the foot, including plantar surface, tips and dorsal surface of the toes, and heel. Most of the ALM present as an asymmetric, irregularly bordered, black-brown, unevenly discolored, thick hyperkeratotic verrucoid or flat papule or nodule, with or without pain, larger than 0.5 cm. Ulceration can be noticed on the surface of the lesions.

Three of seven patients had a previous history of cancers before diagnosis of ALM: one had breast cancer, one Non-Hodgkin's lymphoma and one appendiceal tumor. Wolff et al. have shown that 61 out of 554 patients with melanomas (11%) had second malignancies, with basal cell carcinomas being the most frequent tumor, followed by skin, gastrointestinal tract, genital, brain and lung cancer (11). Bae et al. have analyzed 432 melanomas and noticed 51 with secondary cancers (11.3%); the most frequent secondary cancer was gastrointestinal cancer, followed by thyroid, lung, and breast (12). Patients with acral melanomas had a higher chance to have a secondary cancer compared with those with non-acral melanomas (12.8% vs. 9.6%) (12).

The standard treatment of patients with ALM involving foot is wide local excision (WLE) with safe margins free of tumor or toe amputation and sentinel lymph node (SLN) biopsy, depending on tumor location, size, depth of invasion and SLN status. Complete lymphadenectomy should be carried out when SLN biopsies are positive for lymphatic metastasis (13). Treatments for late stage ALM with spread to other organs include radiotherapy, cryotherapy and immunotherapy when surgical interventions fail (14). All of our patients were treated by either WLE for ALM on the plantar surface and heel, or toe amputation for ALM on the toes. The 38-year female with ALM on the surface of the 3rd toe was treated with WLE and skin graft upon patient's request.

Prognosis of ALM is determined by multiple factors, including patient's age, tumor location, size, Breslow thickness, and SLN involvement (15). SLN status is the most important factor to predict recurrence and survival of ALM patients (13, 15). It has been reported that the overall five- and ten-year melanoma-specific survival rates of acral melanoma were lower than that of cutaneous malignant melanoma (80.3% vs. 91.3% and 67.5% vs. 87.5%, respectively) (6). The 84-year old African-American female with nodular growth on the right hallux died from metastasis at follow-up of 16 months after toe amputation. This patient had a long history of DM and was at a late stage when diagnosed. All other patients had no recurrence at follow-up, from 12 to 48 months.

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Figure 1.

Clinical presentations of acral lentiginous melanoma. A. A thick, black, rough and verrucoid lesion on the plantar surface (patient 1); B. An irregular shaped, dark, unevenly discolored papule with central breakdown and dystrophy on the plantar heel (patient 2); C. A brown to black, raised nodule with irregular border and middle ulceration at the tip and distal one third nail bed of right big toe (patient 4); D. A black, uneven, asymmetric papule with irregular border on lateral distal dorsal tip extending towards the nail matrix proximally underneath the left first toenail (patient 6); E. A raised, ulcerated tissue with yellow thick moist tissue and mild erythema on the medial dorsal side of the 3rd toe (patient 7).

Histologically flate or papular ALMs are characterized by multiple dysplastic single and nested melanocytes growing lentiginously along the dermal-epidermal junction. The pagetoid single cell and nested cells can infiltrate up into any level of the epidermis and down into dermis. Nodular ALM is featured with atypical melanocytes growing in the papillary dermis and vertically invading down to a deeper level in the dermis. ALM in situ shows multiple single or small clustered dysplastic melanocytes growing in the epidermal layer along the dermal-epidermal junction. Immunostaining for biomarkers of malignant melanocytes displayed positive staining for MART-1, HMB-45, S-100, and focal PHH3 but negative staining for cytokeratin AE1/AE3, which are helpful for the diagnosis and differential diagnosis.

ALM needs to be differentiated from other benign and malignant conditions including chronic foot diabetic ulcer, acral lentiginous nevus, pyogenic granuloma, paronychia, hematoma, onychomycosis, ischemic necrosis, palmoplantar wart, poroma, schwannoma, and squamous cell carcinoma. Biopsies for histological evaluation with the assistance of specific stains and biomarkers contribute to the final diagnosis.

The pathogenesis of ALM is still unclear. It is believed that trauma may play a role during melanomagenesis. Previous penetrative injury has been reported to be associated with the development of ALM (16). However, this association did not gain support from another report (17). Interestingly, two recent studies have suggested that long-term physical or mechanical stresses may be related to the formation of melanoma on the plantar surface of foot in Korean (18) and Japanese populations (19). These data suggested that constant pressure, stress, friction, maceration and irritation to the sole may contribute to the melanomagenesis on the sole. The 84-year African-American female with diabetes mellitus had a history of bruising and loose right big toenail with paronychia, and she was treated with phenol and alcohol based matrixectomy and cephalexin prior to her diagnosis of ALM six months ago. The patient gradually recovered without events from infection until discoloration and drainage at the tip of toe were noticed. Punch biopsy confirmed the diagnosis of ALM. This case suggests that trauma and infection may play a role in the formation of melanoma in view of the consequential development from infection to the melanoma.

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Figure 2.

Histopathology of acral lentiginous melanoma. A. Multiple dysplastic single and nested melanocytes growing lentiginously along the dermal-epidermal junction (patient 1) (HE, 100×1); B: Nodular acral lentiginous melanoma (ALM) featured with multiple atypical single melanocytes infiltrating all layers of epidermis and a cluster of dysplastic melanocytes proliferating at the papillary dermis (patient 4) (HE, 100×1); C. Malignant melanocytes invading down into deep dermis (patient 4) (HE, 100×1); D and E. ALM in situ showing multiple single and small clusters of dysplastic melanocytes growing in the epidermal layer along the dermal-epidermal junction (patient 5) (HE, D: 100xl, E: 400×1); F. ALM in situ showing multiple pagetoid single and nested cells infiltrating up into all levels of the epidermis (patient 6) (HE, 100×1). Immunostaining for biomarkers of malignant melanocytes being positive for MART-1 (Figure 2G, 100×1, the malignant melanocytes were positively stained with Fast red), HMB-45 (Figure 2H, 100×1, the malignant melanocytes were positively stained with Fast red), S-100 (Figure 2I, 100×1, the malignant melanocytes were positively stained with Fast red), but negative for keratin AE1/AE3 (Figure 2J, 100×1, the malignant melanocytes were negatively stained with DAB whereas the keratinocytes were positively stained with DAB, which served as internal positive control) (patient 6).

Genetic factors may also play a significant role in the genesis of ALM. Our 38-year white female patient had a strong family history of different kinds of cancers, including a mother with breast cancer, both paternal and maternal uncles and one cousin with melanomas, which indicates that ALM may be related to genetic changes in this particular family. Moreover, three of seven ALMs had previous medical history of cancers. Mutations of BRAF, NRAS, KIT and PTEN have been reported in ALM with a frequency being 17%, 15%, 15% and 4%, respectively (20). Mutations in BRAF, NRAS and KIT are involved in the activation of mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3 kinase (PI3K)/Akt pathways, leading to the deregulated cellular proliferation, differentiation and apoptosis, which may contribute to the development of ALM (21). Since tumorigenesis results from dysfunctions of multiple oncogenes and tumor suppressor genes, further investigation is needed to reveal the genes involved in the formation of ALM.

The association between primary cutaneous melanoma and melanocytic nevus has been reported with a frequency between 4% and 72% (10, 22-24). A 15-year prospective study involving 832 patients showed that 54.2% of primary melanomas were associated with melanocytic nevi, and the patients with multiple nevi had a higher frequency of nevus associated melanomas (25). Multiple moles on the soles or other parts of the body have been linked to the development of ALM (16). Our 38-year white female patient had multiple dark brown macules with ill-defined borders and asymmetric pigment network under dermoscope on the central chest, left 5th metatarsal-phalangeal joint, right lateral heel, lower back and right posterior thigh, as well as round to oval, regular to slightly asymmetric, uniformly-pigmented brown macules scattered on the face, neck, trunk, and extremities, suggesting that ALM may arise from transformation from preexisting proliferative neval cells in this patient.

In conclusion, ALM on the foot is a rare entity of malignant melanoma in older populations. It most often occurs on the plantar surface and toes, and presents as asymmetric, irregularly bordered, black to brown papule or raised nodule. Wide local excision or amputation is the standard treatment option. Patients with previous history of malignancies or family history of melanoma or multiple asymmetric moles need to be screened regularly for early diagnosis and treatment.