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Subungual melanoma (SUM) is a rare tumor with historically poor outcomes. Thus, the benefit of proximal versus distal amputation in SUM remains unclear. We performed a retrospective review of our prospectively-maintained institutional melanoma database, including SUM and non-subungual acral melanoma (AM) patients who underwent sentinel lymph node biopsy (SLNB) between 1999 and 2022. All SUMs had distal joint or proximal amputations. Primary endpoints were overall survival (OS) and recurrence free survival (RFS). Kaplan-Meier estimates, and Cox univariate and multivariate analyses were performed. Tests were repeated on propensity score matched (PSM) populations in a 2:1 ratio. 123 patients underwent resection with SLNB for SUM (n ​= ​27) and AM (n ​= ​96). Median follow-up was 9.2 years. Unadjusted median OS was 149.1 months for AM and 198.1 months for SUM. In the PSM comparison, median OS and RFS remained comparable between SUM and AM (149.5 months versus 198.1 months; p ​= ​0.612). Sentinel node positivity was associated with significantly worse overall survival outcome (Hazard Ratio 5.49; CI (1.59–18.97), p ​= ​0.007). In the PSM population, male sex was also associated with a significant hazard of death (HR 3.00, CI (1.03–8.71), p ​= ​0.043). Proximal amputations were associated with significantly worse OS (p ​< ​0.002) and RFS (p ​< ​0.01) compared to distal amputations in SUM. SUM was well-treated with distal amputations, and had better OS and RFS compared to SUM treated with proximal amputations. Sentinel lymph node status is an important prognostic factor for SUMs and AMs. SUMs can be treated similarly to AMs with comparably good long-term outcomes. •Subungual melanoma has similar prognosis to non-subungual acral melanoma.•Distal amputation consistent with centimeter-based margins is acceptable.•Sentinel node status is a useful prognostic factor in subungual melanoma.

Pachyonychia congenita (PC) is a group of rare hereditary disorders, characterised by hypertrophic nails and palmoplantar keratoderma (PPK), particularly localised to the pressure areas of the feet. At a molecular level, it is caused by mutations in genes encoding KRT6A, KRT6B, KRT6C, KRT16, or KRT17. To identify the underlying gene mutation in a Chinese family with PC presenting with disabling palmoplantar keratoderma and subsequent associated acral melanoma. Genomic DNA was extracted from peripheral blood samples of three available individuals in the Chinese family, which included the patient and his two unaffected sisters. The index patient presented with severe palmoplantar keratoderma as well as a newly diagnosed acral malignant melanoma (MM). Whole-exome sequencing (WES) was carried out with amplification of exon 1 of KRT16 by polymerase chain reaction (PCR). PCR products were then sequenced to identify potential mutations. We identified the proline substitution mutation p.Arg127Pro (c.380G>C) in our patient's 1A domain of KRT16. The same mutation was not found in his sisters or unrelated healthy controls. The mutation (p.Arg127Pro (c.380G>C)) in KRT16 has been reported in Dutch patients with PC. However, it is the first such report of a patient with a PC of Chinese origin. In addition, the acral MM occurred under the background of genetic PPK caused by KRT16 mutation in this patient.

Acral melanoma (AM) is the most common histologic subtype of melanoma in dark-skinned patients and is associated with a worse prognosis and a high mortality rate, largely due to the inconspicuous nature of early-stage lesions, which can lead to late diagnosis. Because of the overlapping clinical and histopathological features of AM with other forms of cutaneous melanomas, early detection of AM requires a multidisciplinary approach that integrates various diagnostic modalities, including clinical examination, dermoscopy, histopathology, molecular testing, radiological imaging, and blood tests. While surgery is the preferred method of treatment for AM, other therapeutic options may be employed based on the stage and underlying etiology of the disease. Immune checkpoint inhibitors, molecular targeted therapy, radiotherapy, chemotherapy, and oncolytic virotherapy represent promising advanced treatment options for AM. In this review, we provide an overview of the latest advancements in diagnostic and therapeutic methods for AM, highlighting the importance of early detection and the prompt, individualized management of this challenging disease.

Background: Acral amelanotic melanomas (AAMs), a rare subset of melanomas located on acral sites such as the palms, soles, and subungual areas, are diagnostically challenging due to their lack of typical pigmentation and often benign clinical appearance. Misdiagnosis is common, leading to delays in treatment and potentially worse outcomes. This systematic review aims to synthesise evidence on cases of AAM initially misdiagnosed as other conditions, to better understand their clinical and epidemiological characteristics, diagnostic pitfalls, and management strategies. Methods: A comprehensive search of the MEDLINE/PubMed, EMBASE, and SCOPUS databases was conducted up to March 2024. Case reports and small case series of AAMs initially misdiagnosed as other conditions were included. Data on patient demographics, clinical presentation, and diagnostic methods were collected and analyzed. Results: Of the 152 records identified, 26 cases from 23 articles met the inclusion criteria. A demographic analysis revealed that the gender distribution appears to be perfectly balanced, with an age range of 38 to 91 years. Misdiagnoses included non-healing ulcers or traumatic lesions (37.5%), benign proliferative lesions (29.2%) and infectious lesions (20.8%). The foot was the most affected site (53.8%). Notably, a histological evaluation was performed in 50% of cases involving the upper extremities, in contrast to only 7.1% of cases involving the foot and 0% of cases of the heel. This discrepancy suggests a reluctance to perform biopsies in the lower extremities, which may contribute to a higher misdiagnosis rate in these areas. Conclusions: The underutilization of biopsy in the diagnosis of lower extremity lesions contributes significantly to the misdiagnosis and delay in treatment of AAMs. Especially when the clinical assessment and dermoscopy are inconclusive, biopsies of suspicious lesions are essential. Immunohistochemistry and markers such as PRAME are critical in differentiating melanoma from other malignancies such as clear cell sarcoma. This review highlights the need for increased vigilance and a proactive diagnostic approach to increase early detection rates and improve prognostic outcomes.

Nail apparatus melanoma (NAM) is a rare type of cutaneous melanoma that belongs to the acral melanoma subtype. NAM is managed principally in accordance with the general treatment for cutaneous melanoma, but there is scarce evidence in support of this in the literature. Acral melanoma is genetically different from non-acral cutaneous melanoma, while recently accumulated data suggest that NAM also has a different genetic background from acral melanoma. In this review, we focus on recent advances in the management of NAM. Localized NAM should be surgically removed; amputation of the digit and digit-preserving surgery have been reported. Sentinel lymph node biopsy can be considered for invasive NAM for the purpose of accurate staging. However, it is yet to be clarified whether patients with metastatic sentinel lymph nodes can be safely spared completion lymph node dissection. Similar to cutaneous melanoma, immune checkpoint inhibitors and BRAF/MEK inhibitors are used as the first-line treatment for metastatic NAM, but data on the efficacy of these therapies remain scarce. The therapeutic effects of immune checkpoint inhibitors could be lower for NAM than for cutaneous melanoma. This review highlights the urgent need to accumulate data to better define the optimal management of this rare melanoma.

Background/Objectives: Acral melanoma (AM) is a rare and aggressive melanoma subtype that arises on sun-shielded, non-hair-bearing skin of the palms, soles, and nail beds. Although more common among individuals of non-European descent, AM remains underrecognized and understudied in the Middle East and North Africa (MENA). This study presents the first dedicated AM registry from Lebanon, aiming to characterize clinical, histopathological, and molecular features and evaluate diagnostic, referral, treatment approaches, and clinical outcomes over a 12-year period. Methods: This retrospective cohort study was conducted at the American University of Beirut Medical Center (AUBMC), a major tertiary referral center in the MENA region. All melanoma cases diagnosed between January 2012 and January 2024 were identified through electronic health records. From this cohort, all adult patients (≥18 years) with biopsy-confirmed AM or tumors located on the palms, soles, or under the nails were selected. Results: Our cohort consisted of 26 adult AM patients, identified from a total of 331 melanoma cases during the study period (8%). Median age at diagnosis was 58.5 years; 54% were female; and 96% of Middle Eastern origin. Most tumors were plantar (81%), and over half (53%) were diagnosed at early stages (Stage I–II). Surgery was performed in 92% of patients, yet 55% had positive margins. Sentinel lymph node biopsy was performed in 46%, and 35% received immunotherapy. Only 35% underwent molecular testing, identifying BRAF mutations in 11% of those tested; no patients received circulating tumor DNA analysis. At a median follow-up of 24.5 months, recurrence occurred in 27%, and metastasis developed in 23%. At the last follow-up, 92% were alive. Conclusions: Despite early-stage detection, high rates of positive margins and limited molecular testing reveal care gaps. This first national registry highlights the need to improve surgical management and expand access to precision oncology in the region.

This study was performed to identify clinicopathologic factors associated with survival in acral lentiginous melanoma. A post hoc analysis of a prospective clinical trial and local database was performed in all patients with acral lentiginous melanomas. Multivariate analyses of factors associated with a tumor-positive sentinel lymph node (SLN) biopsy, disease-free survival (DFS), overall survival (OS), and local and in-transit recurrence-free survival (LITRFS) were performed. Kaplan–Meier survival analyses were performed. Eighty-five patients were identified. Age younger than 59 years and Breslow thickness (BT) of 2.0 mm or greater were independent risk factors for a positive SLN. SLN status was the only independent risk factor for DFS and LITRFS on multivariate analysis. A BT of 2.0 mm or greater was the only independent risk factor for OS. SLN status distinguished differences in DFS, OS, and LITRFS on Kaplan–Meier analysis. SLN status is the dominant factor for recurrence and survival in acral lentiginous melanoma. BT and ulceration are less important in this histologic subtype.

Acral and mucosal melanomas are extremely rare in Caucasians; however, they are the predominant melanoma subtypes in Asians and other non-Caucasian populations. Acral and mucosal melanomas share many clinicopathological features, including aggressive phenotypes, similar genetic landscapes, and grim prognoses. In spite of advances in melanoma management, patients with acral and mucosal melanomas show limited benefit from current therapies. The rarity of these subtypes of melanoma is a significant factor contributing to the poor understanding of these pathological subtypes and the lack of effective interventions. Furthermore, the mechanisms contributing to disparities between different types of melanoma remain largely unclear. Herein, we comprehensively review current knowledge on the clinicopathological characteristics and mutational landscapes of acral and mucosal melanomas, as well as providing an overview of current therapies for patients with these aggressive melanoma subtypes, focusing on available immunotherapeutic interventions. We also discuss pathological differences between different melanoma subtypes and summarize current knowledge on melanoma disparities between Asians and Caucasians. Finally, we discuss emerging immunotherapeutic strategies for the treatment of acral and mucosal melanomas, focusing on combination therapies with immune checkpoint inhibitors. Unraveling the unique features of acral and mucosal melanomas is key for their early diagnosis and for the development of effective therapies.

Early stage recognition of acral lentiginous melanoma (ALM) is important for a better prognosis, but in-depth understanding and proper management of ALM in situ is complicated, because there are only a few reports, probably due to its rarity and diagnostic difficulty. We have reviewed our experience with seven patients who were diagnosed as having ALM in situ and discuss how to accurately diagnose and properly manage these rare lesions. Clinically the lesions showed black to brown discoloration of the nail with Hutchinson’s sign and hyperpigmented macules on the heel with color variegation. All the lesions showed a diffuse lentiginous pattern of melanocytic proliferation with variable level of atypism along the dermoepidermal junction. Dermoscopic findings were available in three and revealed parallel ridge patterns. Confrontation of clinical and histopathologic findings was observed in three, and the lesions were not recognized or diagnosed as ALM in situ in the first place. Excision of the primary lesion with variable operative margin was done as an initial treatment. Recurrence was observed in three patients and one developed invasive ALM and lymph node metastasis. Integration of all available information concerning the clinical presentation, histopathology, and dermoscopic findings is very important and can lead to the best classification for correct diagnosis. Lack of knowledge upon clinical course and optimal margin to control ALM in situ provokes the need for further studies with longer follow up and larger number of cases.

Melanoma, a malignant neoplasm originating from melanocytes, is a form of skin cancer with rapidly increasing global incidence, often exacerbated by UV radiation[1]. Particularly, acral melanoma, characterized by its swift metastasis and poor prognosis, underscores the significance of further research into its heterogeneity. Single-cell sequencing has been widely utilized in the study of tumor heterogeneity; however, research related to melanoma remains to be further refined. We employed single-cell RNA sequencing (scRNA-seq) transcriptomic analysis to delve into the melanoma cells from six samples of melanoma patients. This approach enabled the identification of critical melanoma cell subpopulations and their roles in melanoma progression. Subsequently, we examined the interactions among these subpopulations and analyzed their interactions with other cell types. Our analysis identified C3 ID2+ melanoma cells as an early-stage subpopulation and C4 PCLAF+ cells as a late-stage subpopulation in melanoma evolution. Through our analysis, we identified C4 PCLAF+ Melanoma cells as a significant subpopulation in acral melanoma (AM), playing a pivotal role in the differentiation and development of AM. Further analysis of transcription factors, enriched pathways, cell stemness, and cell trajectories highlighted the significant role of C4 PCLAF+ melanoma cells in acral melanoma (AM) proliferation. This study identifies new factors influencing melanoma progression, providing a foundation for subsequent research.