Acquired agminated melanocytic nevus in the acral area is a potential mimicker of acral lentiginous melanoma: A three-case series report and published work review

Agminated nevus refers to a clustered group of melanocytic nevi confined to a localized area of the body. It rarely involves acral skin, but recognition of acquired agminated nevus (AAN) in the acral area is clinically important because it may mimic acral lentiginous melanoma (ALM). However, acral AAN has only been described in a few case reports and its clinical characteristics remain unclear. We report three additional cases of acral AAN to further analyze the differential points between ALM. Clinical images, including those of dermoscopy, of three cases of acral AAN were reviewed. The lesions were located on the sole or lateral border of the foot. All acral AAN were flat and large in size (>20 mm in greatest dimension), and associated with asymmetry and irregular border. However, no parallel ridge pattern suggesting ALM was observed on dermoscopy. In two patients, the lesions on the sole were totally resected; microscopic evaluation of these two lesions confirmed junctional nests of banal melanocytes. AAN lesions on the sole with chronic mechanical pressure are slightly larger and more diffuse; thus, they may be more likely to be overdiagnosed as malignancy upon inspection than those in the non-acral area. Understanding the concept of the disease and careful dermoscopic evaluation leads to an accurate diagnosis.     

Consumption of the epidermis in acral lentiginous melanoma

Background: Consumption of the epidermis (hereafter, consumption), namely thinning of the epidermis with attenuation of basal and suprabasal layers and loss of rete ridges adjacent to collections of melanocytes, has been used to differentiate invasive melanoma from Spitz nevi. Evaluation of 213 invasive melanomas, including only two cases of acral lentiginous melanoma (ALM), showed that the frequency of consumption increases with increasing tumor thickness. Methods: We evaluated consumption in 52 acral melanomas relative to age, gender, Breslow depth, tumor thickness (based on the 2010 American Joint Commission on Cancer guidelines), Clark level, mitoses, ulceration, vertical‐growth phase, regression, tumor‐infiltrating lymphocytes and anatomical site. Results: Consumption was more frequent in ALM with increasing Breslow depth (p = 0.01), and in the presence of ulceration (p = 0.0078); in all cases with ulcer, consumption was found adjacent to the ulceration. There was no statistically significant difference in consumption in nail melanomas in comparison to melanomas of acral skin other than the nail. Conclusions: These results support the hypothesis that epidermal thinning in consumption represents an early phase of ulceration. No statistically significant difference in consumption was found between nail melanomas and melanomas of acral skin other than the nail, probably because of similar tumor thickness in both groups. Ohata C, Nakai C, Kasugai T, Katayama I. Consumption of the epidermis in acral lentiginous melanoma.     

Acral lentiginous melanoma: histopathological prognostic features of 121 cases

BACKGROUND: Acral lentiginous melanoma (ALM) is the fourth histopathological subtype of malignant melanoma, accounting for < 10% of all melanomas in white-skinned populations. It is characterized by a lentiginous pattern of proliferation of the intraepidermal component of the tumour. Its individualization is still controversial, especially in regard of its prognostic value. OBJECTIVES: To characterize better ALM from a pathological point of view and to assess the prognostic value of all histopathological features of ALM. METHODS: We performed a review of all cases of ALM followed from 1996 to 2004 at the University Hospital Department of Dermatology, Lyon, France. We examined all haematoxylin, eosin and saffron-stained tissue sections of the primary lesions. Several pathological parameters of interest in melanoma were evaluated for disease-free and specific survival with the Kaplan-Meier method and the Cox proportional hazards regression model. RESULTS: Representative histological material was available for 121 patients. The mean Breslow thickness was 2.5 mm (in situ-20 mm). Fifteen lesions (12%) were in situ, nine (7%) were at Clark level II, 35 (29%) at III, 40 (33%) IV and 22 (18%) V. Extension along adnexal structures was found in almost half of the ALMs (46%), without prognostic significance. Seventeen (14%) lesions showed no microscopic pigmentation. Remnants of pre-existing naevus were found in four (3%) melanomas. The width of the 36 (30%) ulcerated lesions ranged from 1 to 20 mm (mean 7.6). Ulceration and its width were both associated with a large tumour thickness (P < 0.01), a high level of invasion (P < 0.01), the presence of vascular invasion (P < 0.01) and the lack of pigment production (P < 0.01). Among the 99 ALMs which were in the vertical growth phase (VGP), 21 showed a high mitotic rate (> 6 mitoses mm(-2)). A high mitotic rate was found to be significantly associated with the presence of ulceration (P < 0.01). The presence of microscopic satellites was noted in 10 (10%) lesions. The uncommon presence of small cells (8%) in the VGP was statistically significantly (P < 0.01) associated with a worse prognosis compared with other cell types. Multivariate analysis identified mitotic rate (P < 0.01), microsatellites (P = 0.05), Clark level (P = 0.01) and gender (P = 0.03) as independent prognostic factors for disease-free survival. Only the presence of microsatellites (P = 0.02) and a high mitotic rate (P < 0.01) were independently correlated with specific survival in ALM. CONCLUSIONS: This is a detailed pathological study of a large cohort with ALM, an uncommon subtype of melanoma. Mitotic activity appears to be of particular importance in predicting the outcome of ALM.     

Acral lentiginous melanoma: a clinicoprognostic study of 126 cases

BACKGROUND: Although the histopathological subtype of melanoma has not been clearly proven to carry independent prognostic significance, acral lentiginous melanoma (ALM) seems to confer a poorer prognosis mainly because disease is often more advanced at the time of diagnosis. OBJECTIVES: To investigate the distinctive epidemiological and clinical characteristics of ALM, a peculiar histological entity, and to identify prognostic factors. METHODS: We performed a register-based review of cases from a single large referral centre, the University Hospital Department of Dermatology, Lyons, France. We reviewed patient demographics, the initial presentation of the lesion, and clinical outcome. ALM-specific and disease-free survival were estimated using the KaplanMeier method and compared using the log-rank test. A Cox model was used to identify prognostic factors. RESULTS: One hundred and twenty-six patients were identified as having histopathology-proven ALM in our melanoma patient register from 1996 to 2004. There were 46 (37%) subungual ALM and 80 (63%) ALM on soles, palms and nonvolar sites. The mean age at diagnosis was 63 years. There were 44 (35%) men and 82 (65%) women, sex ratio M/F 1 : 1.86. The mean Breslow thickness was 2.51 mm (range: in situ to 20 mm). There was no evidence of overexposure to ultraviolet radiation, nor was there found a predisposing genetic trait. Only 16 (13%) patients recalled a history of trauma. Thirty-four ALM (28%) were unpigmented. The median ALM-specific and disease-free survival were 13.5 and 10.1 years, respectively. The 5-year survival rate was 76%. Multivariate analysis identified tumour thickness, male gender and amelanosis as independent clinical prognostic factors for both ALM-specific and disease-free survival. CONCLUSIONS: Our study provides specific information on the clinical characteristics and outcome of this uncommon histological subtype of melanoma. However, the pathogenesis remains unknown. Breslow thickness, male gender and amelanosis were significantly associated with a poorer prognosis.     

Acral lentiginous melanoma: conventional histology vs. three-dimensional histology

Background  Patients with acral lentiginous melanoma (ALM) seem to have a poor prognosis. ALMs represent 4–10% of cutaneous melanomas in white populations. Surgery is mostly based on conventional histological evaluation. With micrographic surgery, continuously spreading tumours can be excised with smaller excision margins for better cosmesis and function.
Objectives  Clinical parameters and surgical strategies influencing the prognosis of patients with ALM were evaluated.
Methods  Two hundred and forty-one patients (44% male, 56% female) with stage I/II ALM were recorded during 1980–2006. One hundred and thirty-three patients underwent complete histology of three-dimensional excision margins (3D histology) using the paraffin technique. Risk factors for disease-specific and recurrence-free survival were estimated.
Results  Patients were aged 26–87 years (median 63) with median tumour thickness of 2·0 mm. The median follow-up was 41 months. Multivariate analysis identified ulceration, conventional histology and tumour thickness as risk factors for recurrence-free and disease-specific survival. Using 3D histology, excision margins were significantly smaller (median 7 vs. 20 mm) without an increased risk of local recurrences. Patients with 3D histology had a 5-year survival of 81% compared with 63% with conventional histology. Retrospective analysis with immunohistological methods (anti-Melan-A) could improve the diagnostic specificity in detecting further melanocytic cell nests.
Conclusions  Clinical and surgical risk factors seem to have different influences on the outcome of ALM. 3D histology allows reduction of excision margins by two-thirds without an increased risk of local recurrences and with better prognosis. 3D immunohistology could be a valuable diagnostic tool to reduce the rate of local recurrences.     

Acral lentiginous melanoma versus other melanoma: A single‐center analysis in Japan

We summarize herein our 14‐year experience of conventional treatment outcomes before the era of molecular‐targeted therapy and immunotherapy. Specifically, we conducted a retrospective review of our 252 patients with primary cutaneous melanoma (acral lentiginous melanoma [ALM], n = 121; non‐acral lentiginous melanoma [non‐ALM], n = 131), and compared the prognostic factors between ALM and non‐ALM. Melanoma‐specific survival and disease‐free survival were estimated using the Kaplan–Meier method. Regarding the results, all patients were Japanese (106 male and 146 female), with a mean age of 60.1 years. Among ALM patients, age was elder and primary tumor size was larger than non‐ALM. As for tumor thickness, in situ lesions were more frequently observed in ALM. There was no significant difference in the distribution of tumor thickness between the two groups when excluding the in situ lesions. For treatment of the primary melanoma, 248 patients (98.4%) had undergone curative surgical excision and 120 patients with more than 1 mm or ulcerated melanoma had undergone sentinel lymph node biopsy. Patients with systemic metastasis primarily underwent dacarbazine‐based chemotherapy. The Kaplan–Meier survival curves revealed no significant difference in melanoma‐specific survival and disease‐free survival between those with ALM and non‐ALM. The results also showed that both ALM and non‐ALM, when they initially metastasize, first affect the regional lymph nodes. Incisional biopsy was not an adverse prognostic factor. These results suggest that ALM does not differ in its biological behavior from non‐ALM, so we can consider ALM as being equivalent to non‐ALM. The initial treatment for ALM and non‐ALM can involve the same strategy.     

基于SEER数据库的肢端雀斑样痣黑素瘤预后分析

【摘要】 目的 调查肢端雀斑样痣黑素瘤（ALM）的预后因素,构建列线图验证预测的价值。方法 从美国国立癌症研究所的监测、流行病学、结果（SEER）数据库中收集2004年至2015年共1 537例ALM患者的临床资料,提取年龄、性别、溃疡状态、SEER分期、手术情况、T分期、N分期和M分期与癌症的总生存率和特异生存率数据。应用卡方检验比较患者临床病例特征与总生存率及黑素瘤特异性生存率的相关性,采用单因素及多因素Cox比例风险回归模型探究预后影响因素并且建立预测模型。结果 1 537例ALM中,男714例,女823例,64岁以下818例,白种人1 363例。1 205例皮损出现在下肢和臀部,974例有溃疡;根据SEER分期,1 048例皮损位于局部（未扩散）。不同诊断年龄、性别、溃疡状态、SEER分期、手术情况、T分期、N分期、M分期患者的死亡率差异有统计学意义（均P < 0.001）。单因素、多因素Cox回归分析显示,年龄 ≥ 65岁、男性、有溃疡、SEER分期远处淋巴结转移会增加患者死亡风险（均P < 0.05）,T2、T3、T4期患者死亡率高于T1期（均P < 0.05）,N1、N2、N3期死亡率高于N0期（均P < 0.05）。结论 年龄、性别、溃疡状态、SEER分期、T分期、N分期为ALM总生存率和特异生存率的独立预后影响因素。     

Acral cutaneous melanoma in caucasians: clinical features, histopathology and prognosis in 112 patients

BACKGROUND: Acral lentiginous melanoma (ALM) is the fourth distinct variant of cutaneous melanoma. The histological diagnosis and prognosis of ALM are still controversial. OBJECTIVES: To review the features of a large series of patients with ALM, and confirm the validity of the histological criteria for this type of melanoma. METHODS: A collection of 2642 patients with cutaneous melanoma was recorded during the period 1986-97, among these 187 were located on acral sites. Histological specimens were reviewed in 112 acral melanomas; the following study is based on this subgroup. RESULTS: Histological examination revealed acral lentiginous melanomas predominantly in palmoplantar and subungual locations (60%), while superficial spreading melanomas (SSM) were found mainly on the dorsal aspects of hands and feet (30%). Nodular melanomas (NM) (9%) occurred in all acral sites. The histological re-examination confirmed the characteristics of ALM as described by Reed in 1976. With increasing tumour thickness nesting of tumour cells and upward migration to the cornified layer was similarly observed. The 5-year survival rate for patients with primary acral melanoma without recognizable metastasis was 82%. ALM differed significantly in survival from SSM (P = 0.001) and lentigo maligna melanoma (P < 0. 001), but survival rates were similar to NM (P = 0.9). CONCLUSIONS: ALM, as diagnosed by current histological criteria, occur on the palms, soles and subungual sites, and have a poor prognosis.     

Clinicopathological characteristics and prognosis of amelanotic acral melanoma: A comparative study with pigmented acral melanoma

We compared the clinicopathological features and prognosis between 16 amelanotic acral melanomas versus 56 pigmented acral melanomas. Amelanotic acral melanomas showed a thicker Breslow thickness (all had a Breslow thickness > 1 mm), more frequent ulceration (15/16, 93.7%) and lower HMB-45 positive rate than pigmented acral melanomas. However, a significant difference in survival was not observed.     

A case of acral lentginous melanoma: the correlation between CD95L expression on melanoma cells and apoptosis of tumor infiltrating lymphocytes

There is an increasing amount of evidence that melanoma cells express the ligand for CD95 (CD95L), a potent inducer of apoptosis which contributes to creating the immune privileged circumstances of tumor sites. However, it still remains to be demonstrated whether the capacity of melanoma cells to express CD95L is acquired during the progression. We addressed this question with a case of acral lentiginous melanoma by employing immunostaining using an antibody directed against CD95L as well as by in situ TUNEL staining. H&E-staining of tumor specimens revealed that there were two different growth patterns. The central part of the tumor showed a deeper invasion into the dermis (Breslow thickness >4 -mm). The horizontally growing edge of the tumor proliferated more superficially (Breslow thickness<3-mm). Relatively fewer lymphocytes were observed around the melanoma nests in central areas, which expressed detectable amounts of CD95L. In contrast, more lymphocytes were observed among the melanoma cells in the peripheral lesion, where CD95L was not detected. To evaluate the relevance of the CD95L expression, in situ TUNEL staining was performed. This indicated a significant correlation of lymphocyte apoptosis with CD95L expression on melanoma cells. Together the data suggest that expression of CD95L is turned on depending on the level of melanoma, and that it may tribute to creating immune privileged circumstances by initiating apoptosis of tumor filrating lymphocytes.     

Genetic alterations in RAS‐regulated pathway in acral lentiginous melanoma

Studies integrating clinicopathological and genetic features have revealed distinct patterns of genomic aberrations in Melanoma. Distributions of BRAF or NRAS mutations and gains of several oncogenes differ among melanoma subgroups, while 9p21 deletions are found in all melanoma subtypes. In the study, status of genes involved in cell cycle progression and apoptosis was evaluated in a panel of 17 frozen primary acral melanomas. NRAS mutations were found in 17% of the tumors. In contrast, BRAF mutations were not found. Gains of AURKA gene (20q13.3) were detected in 37.5% of samples, gains of CCND1 gene (11q13) or TERT gene (5p15.33) in 31.2% and gains of NRAS gene (1p13.2) in 25%. Alterations in 9p21 were identified in 69% of tumors. Gains of 11q13 and 20q13 were mutually exclusive, and 1p13.2 gain was associated with 5p15.33. Our findings showed that alterations in RAS‐related pathways are present in 87.5% of acral lentiginous melanomas.     

Dermoscopic findings and histological correlation of the acral volar pigmented maculae in Laugier-Hunziker syndrome

Laugier-Hunziker syndrome (LHS) is an acquired, benign, macular hyperpigmentation of the lips and oral mucosa, often associated with pigmentation of the nails. Volar acral maculae on the palms and fingertips of patients affected by LHS are a typical feature of this rare entity. Dermoscopic examination of these maculae has been described in a previous report, in which authors found a parallel-furrow pattern. We describe two cases in which a parallel-ridge pattern (PRP) was found on the dermoscopic examination of the pigmented acral lesions. Histological examination showed increased melanin in basal keratinocytes, which was most prominent in those located at the crista intermedia profunda, that is, in the epidermal rete ridges underlying the surface ridges. In our study, dermoscopic features of the pigmented maculae found on LHS differed from those previously described. In addition, by means of this case report, the histological features of these lesions are described for the first time, showing an excellent correlation with dermoscopy. The reported cases prove that although the PRP is very specific of melanoma, it is also possible to find it in benign lesions. Therefore, we must be familiar with the differential diagnosis of PRP, and take into consideration the clinical context in which we find it. Further studies are needed to increase our knowledge on the histological and dermoscopic features of acral pigmented maculae of LHS.     

Combined tumour of aberrant cytokeratin expressing acral lentiginous melanoma and poroma: Diagnostic challenge

Combined tumours are uncommon and therefore these tumours may pose a diagnostic challenge. In the current case report, it is aimed to present the clinicopathological features of a combined tumour including melanoma with aberrant cytokeratin expression and poroma.