Volar location and degree of pigmentation are associated with poor survival and first metastasis pattern in acral melanoma.

The risk factors affecting acral melanoma metastasis and prognosis remain unclear. The study included 168 patients with invasive acral melanoma who were followed for ≥3 years. We evaluated patient demographics, stages, clinicopathological features, anatomic site of melanoma including nail versus volar surface, and degree of melanoma pigmentations, sentinel lymph node biopsy results, and the first metastasis sites. Of the 168 patients (mean age 64.5 years; 52.4% male), 43 (25.6%) had invasive melanoma without metastasis, 113 (67.3%) had invasive melanoma with a first lymph node metastasis, and 12 (7.1%) had invasive melanoma with invasive melanoma with a first distant metastasis. Advanced T stage, high mitotic rate, ulceration, and the degree of pigmentation were significant risk factors for metastasis. Amelanotic and mild pigmentation of acral melanoma was associated with first distant metastasis, whereas heavy pigmentation was associated with first lymph node metastasis. Advanced TNM stages, high mitotic rate, volar location (hazard ratio = 2.24, 95% confidence interval 1.18-4.26), and low-pigmentation (hazard ratio = 2.02, 95% confidence interval 1.17-3.49) were associated with melanoma-specific mortality.

Stromal inflammatory cells are associated with poorer prognosis in primary cutaneous melanoma.

We observed that non-tumor-infiltrating inflammatory cells are often present in the stroma of melanoma. The role of these stromal inflammatory cells (SIC) in cancer has not been studied. We evaluated the prognostic significance of SIC in 299 patients with vertical growth phase primary melanomas with at least 10 years of clinical follow-up. Lymphatic density and lymphatic invasion in the areas with SIC was quantified. The prognostic significance of these factors was evaluated using univariable and multivariable Cox models for melanoma-specific death and the time to first recurrence. Of the 299 melanomas, 161 exhibited areas with SIC. Percentages of vertical growth phase tumor-infiltrating lymphocytes and radial growth phase regression were significantly higher in cases with SIC compared to those without SIC (P = .005); lymphatic invasion was also detected more frequently in cases with SIC (P = .001). Lymphatic density in SIC areas was higher than that in other areas of the melanomas. Patients with SIC had poorer clinical outcome. Vascular endothelial growth factor-C (VEGFC) staining in a subset of these melanoma patients showed that VEGFC expression in the stromal macrophages was associated with lymphatic invasion in SIC areas. In conclusion, SIC in melanoma is associated with poorer prognosis, and the prognostic effect is partially mediated through induction of lymphangiogenesis with increased lymphatic invasion.

A cellular blue nevus with pigmented epithelioid melanocytoma-like pattern on the ipsilateral upper arm associated with a congenital plaque-type blue nevus on the hand.

A 36-year-old man presented with a subcutaneous nodule on the right upper arm. A small nodule had developed 8 years earlier, and grew in size, accompanied by a tingling sensation and numbness. In addition, he had a bluish irregular patch on the right hand since birth, which crossed from the palm to the dorsal hand. Skin biopsies from the hand showed a heavily pigmented melanocyte proliferation in the dermis with perieccrine, perivascular, and perineural involvement, and a diagnosis of congenital plaque-type blue nevus was made. The tumor on the arm was located closely along the median nerve, and was observed as a large black pedunculated round tumor. Histopathologically, the tumor on the arm consisted of densely packed tissue with nevoid cells without atypia in the larger nodular part, and heavily pigmented spindle and epithelioid melanocytes in the slender stalk area, which was diagnosed as cellular blue nevus with pigmented epithelioid melanocytoma-like pattern. Next-generation sequencing revealed GNAQ mutations in the hand lesion, and in the lesions on the arm. This case suggests that the areas of skin following the same neural distribution of a congenital plaque-type blue nevus on the extremities should be followed up for secondary changes.

Genetic Alterations in Primary Acral Melanoma and Acral Melanocytic Nevus in Korea: Common Mutated Genes Show Distinct Cytomorphological Features.

Acral melanoma occurring on the palms, soles, and nails is the most common subtype of cutaneous melanoma in Asians. Genetic alterations in acral melanoma and acral melanocytic nevus are not well known. We performed next-generation sequencing and evaluated the correlations between genetic information and the clinicopathologic characteristics from 85 Korean patients with acral melanocytic neoplasms. Of the 64 patients with acral melanoma, most had lesions at the T2 stage or higher, and the heel was the most common anatomical site of melanoma (n = 34 [53.1%]). The five most common mutations were BRAF (22 [34.4%]), NRAS (14, [21.9%]), NF1 (11, [17.2%]), GNAQ (12, [17.2%]), and KIT (7, [10.9%]). In the 21 acral melanocytic nevi, those five gene mutations were also common. Copy number variations were also frequently detected in 75% of acral melanomas and 47.6% of acral melanocytic nevi, and amplification was more common than deletion in both lesions. BRAF mutation was associated with round epithelioid cells and NRAS and NF1 mutations with bizarre cells. NF1 and GNAQ mutations showed elongated and spindle cells with prominent dendrites in acral melanomas. KIT mutations were common in amelanotic acral melanoma. This study suggests that common mutated genes are associated with distinct cytomorphological features in acral melanocytic lesions.

Modulation of Melanogenesis by Heme Oxygenase-1 via p53 in Normal Human Melanocytes.

As a key regulator of melanogenesis, p53 controls microphthalmia-associated transcription factor (MITF) and tyrosinase expression. The anti-oxidant enzyme heme oxygenase-1 (HO-1) is induced by various forms of cellular stress and diverse oxidative stimuli. However, few studies have examined the role of HO-1 in melanogenesis. Therefore, the aim of this study was to determine the role of HO-1 in melanogenesis and the mechanism underlying this relationship. Cultures of normal human melanocytes were treated with the HO-1 inducer cobalt protoporphyrin (CoPP) or the HO-1 inhibitor zinc protoporphyrin (ZnPP). We then measured the melanin content of the cells. Additional analyses consisted of Western blotting and RT-PCR. The results showed that the cellular melanin content was increased by CoPP and decreased by ZnPP. The Western blot and RT-PCR analyses showed that CoPP increased p53, MITF and tyrosinase levels, and ZnPP reduced all of them. The knockdown of p53 by siRNA transfection was followed by large decreases in the expression levels of p53, MITF and tyrosinase at 3 h of transfection. The presence of CoPP or ZnPP had no significant increased or decreased effects on MITF and tyrosinase levels from 15 h in the siRNA transfectants. Our results suggest that HO-1 modulates melanogenesis in human melanocytes via a p53-dependent pathway.