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.     

Expression of soluble adenylyl cyclase in acral melanomas

Soluble adenylyl cyclase (sAC) regulates melanocytic cells, and is a diagnostic marker for pigmented skin lesions. Because only a few studies on sAC expression in acral melanomas have been performed, we investigated the histopathological significance of sAC expression in 33 cases of acral melanoma, and assessed its diagnostic value in distinguishing melanoma in situ (MIS, n = 17) from acral invasive melanomas (n = 16) and melanocytic naevi (n = 11). Acral melanomas exhibited more marked nuclear immunopositivity compared with acral melanocytic naevi. sAC expression significantly correlated with the nuclear morphology of melanocytes and melanoma cells, namely, hyperchromatic nuclei and prominent nucleoli within vesicular nuclei. sAC expression was predominantly observed in the hyperchromatic nuclei of MIS and the prominent nucleoli invasive melanomas, respectively. In vitro culture models of melanocytes and melanoma cell lines exhibited sAC staining patterns similar to those of acral melanomas. Differentiation induction showed that nuclear and nucleolar expression varied depending on cell morphology. sAC immunostaining may be useful for the differential diagnosis of acral melanocytic lesions, and sAC expressed in the nucleus and nucleolus might be related to cytological and nuclear changes associated with invasion and progression of acral melanomas.     

Is the survival rate for acral melanoma actually worse than other cutaneous melanomas?

It is still not clear whether the survival rate for acral melanoma (AM) is better or worse than that of cutaneous melanoma developed at other sites. We sought to evaluate the difference in survival depending on the primary tumor site of cutaneous melanoma. We retrospectively reviewed primary cutaneous melanoma cases diagnosed at Samsung Medical Center, a tertiary institution in Korea, from January 1995 to July 2017. The cohort consisted of 642 patients, with 389 non-acral cutaneous melanoma (NACM) patients and 253 AM patients. The AM patients had a higher percentage of stage 0 diagnoses than the NACM patients (31.6% vs 6.9%, respectively). The factors associated with overall survival were primary tumor site, sex, age, American Joint Committee on Cancer stage, surgery and medical treatment (P < 0.05). Non-acral sites showed worse survival in multivariable analysis (hazard ratio [HR], 1.457; 95% confidence interval [CI], 1.051–2.020; P = 0.0240). Among the NACM, melanomas on the trunk were associated with a higher risk of mortality compared with AM (HR, 1.883; 95% CI, 1.142–3.107; P = 0.0131). Acral melanoma was associated with a better prognosis than non-acral melanoma, specifically when located on the trunk, in Korean patients.     

Detecting copy number alterations of oncogenes in cell-free DNA to monitor treatment response in acral and mucosal melanoma

BackgroundReliable biomarkers are necessary for assessment of treatment responses. Acral and mucosal melanomas are commonly associated with copy number (CN) alterations rather than specific point mutations, with CN alterations inKIT, CDK4, and CCND1 occurring frequently. Cell-free DNA is released to peripheral blood by both normal and tumor cells, and therefore contains the same genetic alterations present in the source tumor.ObjectiveTo investigate the usefulness of detecting CN alterations in oncogenes in cell-free DNA for monitoring treatment response in acral and mucosal melanomas.MethodsWe isolated cell-free DNA from peripheral blood and assessed the CN alterations in the cell-free DNA. Using droplet digital PCR, we examined CN alterations ofKIT, CDK4, and CCND1 in tumors from 37 melanoma patients (acral, n = 27; mucosal, n = 10) and peripheral blood from 24 melanoma patients (acral, n = 17; mucosal, n = 7).ResultsCN gain was detected in at least one of the genes examined in 62.9 % (17/27) of acral melanomas and 70 % (7/10) of mucosal melanomas. CN gains were also detected in the plasma of some patients. Furthermore, plasma CN ratio was correlated with clinical condition. This correlation was especially clear in patients with high CN ratios in tumors and high tumor burdens.ConclusionPlasma CN ratios may be useful for evaluating treatment responses in patients with acral and mucosal melanoma.     

Efficacy of combined radiotherapy and anti‐programmed death 1 therapy in acral and mucosal melanoma

Some studies showed that clinical response to immune check point inhibitors is lower in acral and mucosal melanoma than in cutaneous melanoma. Although the synergistic effect of radiotherapy (RT) and ipilimumab has been reported in patients with brain metastasis, the efficacy of combined RT and anti‐programmed death 1 (PD‐1) therapy for acral and mucosal melanoma is unclear. The present study aimed to evaluate the efficacy of combined RT and anti‐PD‐1 therapy for acral and mucosal melanoma. We retrospectively analyzed patients with acral or mucosal melanoma who were treated with anti‐PD‐1 and RT at Sapporo Medical University Hospital. In 10 patients (acral, 3; mucosal, 7), the response rate (RR) and the disease control rate (DCR) were 40% and 60%, respectively. As regards mucosal melanoma, four of the seven patients had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Meanwhile, two of the three patients with acral melanoma had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). Vitiligo developed after RT in five (50%) patients at a median duration of 2 months after RT. The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti‐PD‐1 therapy could be effective in some patients with mucosal melanoma.     

Sentinel lymph node biopsy for 102 patients with primary cutaneous melanoma at a single Japanese institute

Sentinel lymph node biopsy (SLNB) is a widely accepted standard procedure for patients with clinically localized melanoma. Melanoma prevalence and Clark's subtype differ between Asians and Caucasians. Here, we evaluated our experience on SLNB for cutaneous melanoma in a Japanese population. SLNB was performed for patients with melanoma between July 2000 and June 2014. We retrospectively analyzed 102 patients regarding association of clinicopathological features with sentinel lymph node (SLN) status, melanoma‐specific survival (MSS) and disease‐free survival (DFS). A positive SLN was significantly associated with primary Breslow thickness. Compared with 43 patients with negative SLN, 59 patients with positive SLN had significantly shorter MSS (5‐year survival rate, 94.3% vs 63.2%; P = 0.0002) and DFS (5‐year survival rate, 92.7% vs 63.4%; P = 0.0004). According to our subgroup analyses, nine patients with positive non‐SLN had significantly shorter MSS compared with 32 patients with negative non‐SLN (5‐year survival rate, 32.4% vs 68.5%; P = 0.0273). The survival of 51 Japanese patients with acral lentiginous melanoma (ALM) was not inferior to the survival of patients with other Clark's subtype. Breslow thickness is an important factor for both MSS and DFS, and the status of SLN is the most predictive prognostic factor in Japanese patients with clinically localized melanomas, as in case of Caucasians. Features of ALM may be different between Asians and Caucasians.     

Key points in dermoscopic differentiation between early acral melanoma and acral nevus

Acral skin is the most prevalent site of malignant melanoma in non-Caucasian populations. On acral skin, other various kinds of pigmented lesions are also detected. Particularly, melanocytic nevus is commonly seen on acral volar skin; approximately 10% of Japanese have a nevus on their soles. Prognosis of acral melanoma is still generally poor because of delayed detection in the advanced stages. To improve the prognosis, early detection is essential. Early acral melanoma is seen as a brownish macule, which is clinically quite similar to acral nevus. Therefore, clinicians often face a dilemma when they see a pigmented macule on acral volar skin. Introduction of dermoscopy was a great epoch in this field. Pigmentation pattern on dermoscopy is completely opposite between early acral melanoma and acral nevus; pigmentation on the ridges of the surface skin markings is detected in early acral melanoma, whereas pigmentation along the furrows of the skin markings is seen in acral nevus. We termed these dermoscopic patterns the parallel ridge pattern and the parallel furrow pattern, respectively. These features are highly helpful in the differentiation between the two biologically distinct entities. The sensitivity and specificity of the parallel ridge pattern in diagnosing early acral melanoma is 86% and 99%, respectively. However, we must be aware that dermoscopic features in acral nevus sometimes mimic the parallel ridge pattern and that other conditions also could show dermoscopic features similar to the parallel ridge pattern. In this review article, we summarize key points of the dermoscopic diagnosis of early acral melanoma and then describe the three-step algorithm for the management of acral melanocytic lesions, which surely aids us in effectively detecting early acral melanoma and in reducing unnecessary resection of benign nevus.     

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.     

Tratamiento quirúrgico del melanoma primario: consideraciones prácticas

The treatment of choice for localized primary melanoma is excisional biopsy followed by margin expansion based on the Breslow depth. Partial biopsies may be appropriate in the initial study of extensive melanomas or in complex locations. The recommended margins for melanoma in situ are 0.5-1 cm, although it seems that, especially in the lentiginous type, they are more convenient the closer to the centimeter. For invasive melanomas, margins of 1 cm in Breslow depth < 1 mm, 1-2 cm in Breslow depth 1-2 mm, and 2 cm in Breslow depth > 2 mm are recommended. Single-stage excision can be considered when selective sentinel node biopsy is rejected, but it is not currently supported by the guidelines. In those cases in which the precision of the complete excision of the lesion must be maximized, mainly in facial lentigo maligna, margin control techniques are recommended. On the other hand, acral melanomas, both subungual, palmar or plantar, require special management given their anatomical complexity.     

Dermoscopic features of acral lentiginous melanoma in a large series of 110 cases in a white population

Summary Background Acral lentiginous melanoma (ALM) is a rare but distinctive subtype of melanoma. The diagnosis is often delayed and misdiagnosis is common, due to frequently unusual clinical presentation and a higher rate of amelanosis than in other melanoma subtypes. Objectives We aimed to investigate the dermoscopic features of a large series of ALM in a white‐skinned population, in order to emphasize their diagnostic value. Methods All recorded dermoscopic photographs of ALM, including nail unit variants, were collected from the files of the University Hospital Department of Dermatology (Lyons, France) and reviewed. Results In total 110 lesions, including 66 (60%) palmoplantar ALM and 44 (40%) ALM of the nail apparatus, were analysed for dermoscopic characteristics. The mean Breslow thickness was 2·6 mm. In volar skin melanomas, the two most prevalent patterns were irregular diffuse pigmentation (60%) and the parallel‐ridge pattern (53%). Minor dermoscopic patterns, commonly noted in benign lesions, were also detected but only focally within the lesions. Among the 44 nail unit lesions, 31 (70%) presented irregular lines with variegations in colours, spacing, width and disruption of parallelism. Two cases of melanonychia striata had a triangular shape. Both corresponded to early ungual ALM. Association with subungual haemorrhage was not uncommon. The study included 37 (34%) amelanotic melanomas. However, dermoscopy enabled detection of microscopic remnants of pigmentation in most cases. The vascular pattern found in almost half of these lesions was polymorphous, with combinations of milky‐red areas (95%), linear irregular vessels (49%), dotted vessels (43%) and hairpin vessels (41%). Conclusions The presence of a parallel‐ridge pattern and/or irregular diffuse pigmentation within the lesion is highly indicative of melanoma on volar skin. An irregular lines pattern is the most prominent dermoscopic feature of pigmented ALM of the nail apparatus. Amelanotic ALM either in volar skin or in nail apparatus is characterized by remnants of pigmentation and a polymorphic vascular pattern.     

趋化因子受体4、7在皮肤黑素瘤、色素痣组织中的表达及意义

目的 探讨皮肤黑素瘤和色素痣组织中趋化因子受体4(CXCR4)和趋化因子受体7(CXCR7)的表达及其与病理特征的相关性.方法 免疫组化法检测CXCR4、CXCR7在两个组(黑素瘤组及色素痣组)中的表达情况.结果 黑素瘤组与色素痣组免疫组化比较:CXCR4分别是20％(8/40)和50％(20/40)为(-);12.5％(5/40)和42.5％(17/40)为(+);32.5％(13/40)和7.5％(3/40)为(++);35％(14/40)和0％(0/40)为(+++);差异有统计学意义(均P＜ 0.05).CXCR7分别是15％(6/40)和35％ (14/40)为(-);10％(4/40)和62.5％ (25/40)为(+);22.5％(9/40)和2.5％(1/40)为(++);52.5％(21/40)和0为(+++);差异有统计学意义(均P＜0.05).CXCR4的表达水平在年龄、性别、Breslow厚度、溃疡情况、淋巴细胞浸润情况分组中差异无统计学意义(P＞0.05);在发病部位、Clark分级、淋巴结转移分组中差异有统计学意义(P＜ 0.05);CXCR7的表达水平在年龄、性别、溃疡情况、淋巴细胞浸润情况、淋巴结转移分组中差异无统计学意义(P＞0.05);在发病部位、Breslow厚度、Clark分级分组中差异有统计学意义(P＜0.05).结论 皮肤黑素瘤和色素痣组织标本中,CXCR4和CXCR7有不同程度的表达,CXCR4和CXCR7可能参与黑素瘤的发生发展.     

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.     

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.     

Distinct melanoma types based on reflectance confocal microscopy

Distinct melanoma types exist in relation to patient characteristics, tumor morphology, histopathologic aspects and genetic background. A new diagnostic imaging tool, reflectance confocal microscopy (RCM), allows in vivo analysis of a given lesion with nearly histologic resolution while offering a dynamic view of the tissue in its ‘natural’ environment. The aim of this study was to analyse cell morphology of consecutive melanomas as they appear on RCM and to correlate morphology with tumor and patient characteristics. One hundred melanomas were visualized by RCM before excision. Clinical data, confocal features and histologic criteria were analysed. Four types of melanomas were identified as follows: (i) Melanomas with a predominantly dendritic cell population (‘dendritic‐cell melanomas’) typically were thin by Breslow index; (ii) Melanomas typified by roundish melanocytes were smaller in size than dendritic cell MMs, but thicker by Breslow index, and predominantly occurred in patients with a high nevus count; (iii) Melanomas characterized by dermal nesting proliferation usually were thick by Breslow index at the time of diagnosis, although frequently smaller in size compared with the other types; and (iv) combined type melanomas may represent an evolution of dendritic cell and/or round cell types. Integration of confocal microscopy with clinical and histologic aspects may help in identifying and managing distinct tumors.     

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.     

Characterization of KIT mutation in melanoma

Background/objectivesRecent studies have shown that the KIT mutational type appears to be a predictive marker for the efficacy of imatinib in treating melanoma. However, a wide range of KIT mutation rates was reported in different types of melanoma, suggesting that the mutation frequency of KIT may be associated with clinicopathological subsets of melanoma.MethodsTo characterize their relationship, we sequenced exons 11, 13, 17, and 18 of KIT in 80 of 85 melanomas collected from two hospitals and categorized KIT mutation by tumor type, age and sex of patients, and mutation hot spots of KIT.ResultsOur results showed that KIT mutation rates were 25%, 22%, and 8% in acral, mucosal, and cutaneous melanomas, respectively. Approximately 38% (5/13) of male patients with acral melanoma and 45% (5/11) of female patients with mucosal melanomas of the anorectal and genitourinary regions had a KIT mutation. Approximately 81% of KIT mutations occurred in L576P, K642E, V559A, and D820Y.ConclusionThis result shows that KIT mutation is enriched in a certain subset of melanoma patients and mutation hot spots do exist.     

Specific dermoscopy patterns and amplifications of the cyclin D1 gene to define histopathologically unrecognizable early lesions of acral melanoma in situ

OBJECTIVE: To define early lesions of acral melanoma in situ that cannot be recognized histopathologically. DESIGN: A retrospective review of the clinical, dermoscopic, and histopathological findings. SETTING: University department of dermatology. PATIENTS: Thirty-three patients with melanocytic lesions on acral volar skin that were clinically suspected of being early melanomas. MAIN OUTCOME MEASURES: Fluorescent in situ hybridization studies to detect the cyclin D1 gene amplification in proliferating melanocytes, which is a characteristic genetic aberration recently found in acral melanoma. RESULTS: Seventeen of 33 lesions were histopathologically diagnosed as either melanoma in situ (8 lesions) or benign melanocytic nevi (9 lesions). Amplification of the cyclin D1 gene was observed in 2 (25%) of the 8 melanomas in situ. None of the 9 nevi showed the amplification. The remaining 16 lesions were, however, difficult to classify histopathologically because most of them showed only a slight increase of nonatypical melanocytes in the basal cell layer of the epidermis. On dermoscopic examination, 9 of these 16 lesions exhibited the parallel ridge pattern that has been reported to be highly specific to melanoma in situ, and 4 (44%) of them had amplifications of the cyclin D1 gene. Amplifications were not found in any of the remaining 7 lesions that showed dermoscopic patterns suggestive of melanocytic nevi. CONCLUSIONS: Cyclin D1 gene amplification detected by fluorescent in situ hybridization identified a very early progression phase of acral melanoma that precedes histopathologically defined melanoma in situ. The present study also indicates the specificity of the parallel ridge pattern on dermoscopy to detect melanomas on acral volar skin at such a very early developmental phase.     

Epidermal consumption in benign and malignant melanocytic neoplasms

Consumption of the epidermis associated with effacement of the rete ridge pattern has been cited as a useful criterion in the diagnosis of melanoma, but the significance of consumption in the absence of rete ridge effacement is unknown. We evaluated 701 melanocytic neoplasms for presence and ‘grade’ of consumption by melanocytic nests relative to diagnosis, body location, gender and age. We defined 1+ consumption as collections of melanocytes occupying greater than two thirds of the viable epidermis, with or without loss of the rete ridge pattern. Nests extending to the bottom of, within, and through the granular layer were graded 2+, 3+ and 4+, respectively. Consumption was more frequent and higher grades were found in melanomas followed by Spitz nevi compared with conventional melanocytic nevi (p < 0.001). Melanomas with higher Breslow thickness showed higher grades (p < 0.05). In conventional nevi, consumption occurred most frequently in back (13.7%), acral (11.9%) and scalp (9.8%) locations. Consumption without the requirement for rete ridge effacement occurs more frequently and at higher grades in melanoma. Higher grades correlate with higher Breslow thickness. Consumption is also common in Spitz nevi and occurs at lower grades in conventional (non‐Spitz) nevi, especially on the back, the scalp and at acral sites.     

Novel LRRFIP2-RAF1 fusion identified in an acral melanoma: A review of the literature on melanocytic proliferations with RAF1 fusions and the potential therapeutic implications

A small subset of cutaneous melanomas harbor oncogenic gene fusions, which could potentially serve as therapeutic targets for patients with advanced disease as novel therapies are developed. Fusions involving RAF1 are exceedingly rare in melanocytic neoplasms, occurring in less than 1% of melanomas, and usually arise in tumors that are wild type for BRAF, NRAS, and NF1. We describe herein a case of acral melanoma with two satellite metastases and sentinel lymph node involvement. The melanoma had a concomitant KIT variant and LRRFIP2-RAF1 fusion. This constellation of molecular findings has not been reported previously in melanoma. We review the existing literature on melanocytic neoplasms with RAF1 fusions and discuss the potential clinical implications of this genetic event.     

Expression of p16 protein in acral lentiginous melanoma

Background Acral lentiginous melanoma (ALM) is a clinicopathologic subtype of cutaneous malignant melanoma. ALM is the most common type of melanoma amongst Asians, Africans, and patients with mixed ancestry. In Brazil, ALM comprises 10% of cutaneous melanoma. ALM develops on palmar, plantar, and subungual skin, and its biology is different from that of other cutaneous melanomas, where sunlight is the major known environmental determinant. Alterations and inactivation of the p16INK4 gene that encodes a specific inhibitor of cyclin‐dependent kinase have been related to melanoma genesis and progression. Few studies, however, have addressed p16 expression in ALM. Methods In order to verify and compare p16 protein expression, 32 paraffin‐embedded ALM specimens were subjected to a immunohistochemical technique using a monoclonal anti‐p16 antibody. The tumors were classified according to thickness (up to 1.0 mm and thicker than 1.0 mm) and the presence of ulceration. Results Twenty‐five (78%) ALMs displayed positive p16 protein expression: 21 of the 25 (84%) with a thickness of more than 1.0 mm, and four of the seven (57%) with a thickness of 1.0 mm or less. Thirteen of the 17 (76%) nonulcerated lesions and 12 of the 15 (80%) ulcerated lesions displayed positive p16 protein expression. Conclusion The data obtained suggest that p16 protein expression per se may not represent a marker of retinoblastoma protein (pRb) pathway disturbance in ALM tumorigenesis.