Establishment of a CD8+ T cells-related prognostic risk model for acral melanoma based on single-cell and bulk RNA sequencing.

BACKGROUND: CD8+ T cells have been recognized as crucial factors in the prognosis of melanoma. However, there is currently a lack of gene markers that accurately describe their characteristics and functions in acral melanoma (AM), which hinders the development of personalized medicine. METHODS: Firstly, we explored the composition differences of immune cells in AM using single-cell RNA sequencing (scRNA-seq) data and comprehensively characterized the immune microenvironment of AM in terms of composition, developmental differentiation, function, and cell communication. Subsequently, we constructed and validated a prognostic risk scoring model based on differentially expressed genes (DEGs) of CD8+ T cells using the TCGA-SKCM cohort through Lasso-Cox method. Lastly, immunofluorescence staining was performed to validate the expression of four genes (ISG20, CCL4, LPAR6, DDIT3) in AM and healthy skin tissues as included in the prognostic model. RESULTS: The scRNA-seq data revealed that memory CD8+ T cells accounted for the highest proportion in the immune microenvironment of AM, reaching 70.5%. Cell-cell communication analysis showed extensive communication relationships among effector CD8+ T cells. Subsequently, we constructed a prognostic scoring model based on DEGs derived from CD8+ T cell sources. Four CD8+ T cell-related genes were included in the construction and validation of the prognostic model. Additionally, immunofluorescence results demonstrated that ISG20 and CCL4 were downregulated, while LPAR6 and DDIT3 were upregulated in AM tissues compared to normal skin tissues. CONCLUSION: Identifying biomarkers based on the expression levels of CD8+ T cell-related genes may be an effective approach for establishing prognostic models in AM patients. The independently prognostic risk evaluation model we constructed provides new insights and theoretical support for immunotherapy in AM.

Clinical Characteristics and Special Considerations in the Management of Rare Melanoma Subtypes.

Rare histologic subtypes of melanoma, including acral, mucosal, uveal, and desmoplastic melanomas, only make up 5% of all diagnosed melanomas and are often underrepresented in large, randomized trials. Recent advancements in systemic therapy have shown marked improvement in pathologic response rates, improving progression-free and overall survival among cutaneous melanoma patients, but there are limited data to demonstrate improved survival among rarer subtypes of melanoma. Acral melanoma has a poor response to immunotherapy and is associated with worse survival. Mucosal melanoma has a large variability in its presentation, a poor prognosis, and a low mutational burden. Uveal melanoma is associated with a high rate of liver metastasis; recent adoption of infusion and perfusion therapies has demonstrated improved survival among these patients. Desmoplastic melanoma, a high-risk cutaneous melanoma, is associated with high locoregional recurrence rates and mutational burden, suggesting this melanoma may have enhanced response to immunotherapy. While these variants of melanoma represent distinct disease entities, this review highlights the clinicopathologic characteristics and treatment recommendations for each of these rare melanomas and highlights the utility of modern therapies for each of them.

Pattern Analysis of Benign and Malignant Atypical Melanocytic Skin Lesions of Palms and Soles: Variations of Dermoscopic Features According to Anatomic Site and Personal Experience.

Background: The differential diagnosis of atypical melanocytic skin lesions localized on palms and soles represents a diagnostic challenge: indeed, this spectrum encompasses atypical nevi (AN) and early-stage melanomas (EN) displaying overlapping clinical and dermoscopic features. This often generates unnecessary excisions or delayed diagnosis. Investigations to date were mostly carried out in specific populations, focusing either on acrolentiginous melanomas or morphologically typical acquired nevi. Aims: To investigate the dermoscopic features of atypical melanocytic palmoplantar skin lesions (aMPPLs) as evaluated by variously skilled dermatologists and assess their concordance; to investigate the variations in dermoscopic appearance according to precise location on palms and soles; to detect the features with the strongest association with malignancy/benignity in each specific site. Methods: A dataset of 471 aMPPLs-excised in the suspect of malignancy-was collected from 10 European Centers, including a standardized dermoscopic picture (17×) and lesion/patient metadata. An anatomical classification into 17 subareas was considered, along with an anatomo-functional classification considering pressure/friction, (4 macroareas). A total of 156 participants (95 with less than 5 years of experience in dermoscopy and 61 with ≥than 5 years) from 17 countries performed a blinded tele-dermoscopic pattern analysis over 20 cases through a specifically realized web platform. Results: A total of 37,440 dermoscopic evaluations were obtained over 94 (20%) EM and 377 (80%) AN. The areas with the highest density of EM compared to AN were the heel (40.3% EM/aMPPLs) of the sole and the "fingers area" (33%EM/aMPPLs) of the palm, both characterized by intense/chronic traumatism/friction. Globally, the recognition rates of 12 dermoscopic patterns were non statistically different between 95 dermatology residents and 61 specialists: aMPPLs in the plantar arch appeared to be the most "difficult" to diagnose, the parallel ridge pattern was poorly recognized and irregular/regular fibrillar patterns often misinterpreted. Regarding the aMPPL of the "heel area", the parallel furrow pattern (p = 0.014) and lattice-like pattern (p = 0.001) significantly discriminated benign cases, while asymmetry of colors (p = 0.002) and regression structures (p = 0.025) malignant ones. In aMPPLs of the "plantar arch", the lattice-like pattern (p = 0.012) was significant for benignity and asymmetry of structures, asymmetry of colors, regression structures, or blue-white veil for malignancy. In palmar lesions, no data were significant in the discrimination between malignant and benign aMPPLs. Conclusions: This study highlights that (i) the pattern analysis of aMPPLs is challenging for both experienced and novice dermoscopists; (ii) the histological distribution varies according to the anatomo-functional classification; and (iii) different dermoscopic patterns are able to discriminate malignant from benign aMPPLs within specific plantar and palmar areas.

Adjuvant treatment with anti-PD-1 in acral melanoma: A nationwide study.

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HRadj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM.

Misdiagnosis and Clinical Insights into Acral Amelanotic Melanoma-A Systematic Review.

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.

Mutation p.Arg127Pro in the 1A Domain of KRT16 Causes Pachyonychia Congenita in Chinese Patient: A Case Report of PC Associated with Acral 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.

Integrative molecular and spatial analysis reveals evolutionary dynamics and tumor-immune interplay of in situ and invasive acral melanoma.

In acral melanoma (AM), progression from in situ (AMis) to invasive AM (iAM) leads to significantly reduced survival. However, evolutionary dynamics during this process remain elusive. Here, we report integrative molecular and spatial characterization of 147 AMs using genomics, bulk and single-cell transcriptomics, and spatial transcriptomics and proteomics. Vertical invasion from AMis to iAM displays an early and monoclonal seeding pattern. The subsequent regional expansion of iAM exhibits two distinct patterns, clonal expansion and subclonal diversification. Notably, molecular subtyping reveals an aggressive iAM subset featured with subclonal diversification, increased epithelial-mesenchymal transition (EMT), and spatial enrichment of APOE+/CD163+ macrophages. In vitro and ex vivo experiments further demonstrate that APOE+CD163+ macrophages promote tumor EMT via IGF1-IGF1R interaction. Adnexal involvement can predict AMis with higher invasive potential whereas APOE and CD163 serve as prognostic biomarkers for iAM. Altogether, our results provide implications for the early detection and treatment of AM.

Corrigendum: The utility of high-frequency 18 MHz ultrasonography for preoperative evaluation of acral melanoma thickness in Chinese patients.

[This corrects the article DOI: 10.3389/fonc.2023.1185389.].

Prognostic and Predictive Significance of Ki67 in Primary Non-metastatic or Recurrent Acral Melanoma: Evidence from a Multicenter Retrospective Study.

BACKGROUND: The purpose of this work was to investigate the prognostic significance of Ki67 in acral melanoma (AM). PATIENTS AND METHODS: Ki67 values in primary lesions (pKi67) of 481 patients with primary non-metastatic AM (primary cohort) from three tertiary hospitals and in recurrent lesions (rKi67) of 97 patients (recurrent cohort) were recorded. The associations of p/rKi67 with clinicopathological features and prognosis were analyzed. RESULTS: In the primary cohort, high pKi67 group tended to have more ulceration, pT4, lymph node metastasis (LNM), nodal macrometastases, and recurrence (all P < 0.05). Logistic regression analysis revealed that pKi67 was significantly associated with pT4 and LNM (P = 0.004 and 0.027, respectively). Furthermore, both 5-year overall survival (OS) and recurrence-free survival (RFS) rates in high pKi67 group were significantly worse than those in moderate and low pKi67 groups (OS 47.8% versus 55.7 versus 76.8%, P = 0.002; RFS: 27.1 versus 42.8 versus 61.8%, P < 0.001). Similarly, in the recurrent cohort, the 5-year survival after recurrence (SAR) rates in high rKi67 group was significantly worse than those in moderate and low rKi67 groups (31.7 versus 47.4 versus 75%; P = 0.026). Stratified analysis also indicated a significant survival difference among pKi67 groups within various subgroups. Most importantly, multivariate Cox analysis demonstrated that pKi67 could be independently associated with OS and RFS, as well as rKi67 for SAR (all P < 0.05). CONCLUSIONS: A high Ki67 value was significantly associated with adverse pathological and prognostic features in both primary and recurrent AM cohorts. Ki67 should be routinely evaluated to guide risk stratification and prognostic prediction.

Long-term outcomes after amputation and sentinel node biopsy for subungual melanoma: A single-institution series.

BACKGROUND: Subungual melanoma (SUM) is a rare tumor with historically poor outcomes. Thus, the benefit of proximal versus distal amputation in SUM remains unclear. METHODS: 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. RESULTS: 123 patients underwent resection with SLNB for SUM (n â€‹= â€‹27) and AM (n â€‹= â€‹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 â€‹= â€‹0.612). Sentinel node positivity was associated with significantly worse overall survival outcome (Hazard Ratio 5.49; CI (1.59-18.97), p â€‹= â€‹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 â€‹= â€‹0.043). Proximal amputations were associated with significantly worse OS (p â€‹< â€‹0.002) and RFS (p â€‹< â€‹0.01) compared to distal amputations in SUM. CONCLUSION: 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.

Trauma plays an important role in acral melanoma: A retrospective study of 303 patients.

INTRODUCTION: Acral melanoma (AM) is the most common subtype of malignant melanoma in China, with a very poor prognosis. Despite the frequent reporting of trauma events in AM cases, the precise etiology of AM remains elusive. METHODS: A retrospective analysis was conducted on a cohort of 303 AM patients at Nanjing Drum Tower Hospital. The patients were categorized into four distinct groups based on different patterns of disease onset: trauma type (Type 1), pigmented nevus type (Type 2), pigmented nevi with trauma (Type 3), and pigmented nevi with natural ulceration (Type 4). Differences in clinicopathological features, genetic alterations, and tumor immune microenvironment (TIME) were analyzed. RESULTS: Traumatic events accounted for a large proportion of AM cases. Among these categories, Type 1 patients displayed the least favorable pathological traits and an immunosuppressive TIME. Common copy number variations (CNVs) were observed in CCND1, RB1, FGF19, and IL7R, while CNVs in CDK4 and TERT occurred less frequently in patients with a history of trauma (Type 1 and Type 3). Type 2 patients exhibited the most favorable pathological characteristics and genetic profiles, and demonstrated the lowest incidence of CCDN1 and RB1 CNVs but had the highest CDK4 CNVs. In contrast, the pathological behavior of Type 3 and Type 4 patients was in between Type 1 and Type 2. And patients in Type 3 and Type 4 displayed a more favorable overall microenvironment. CONCLUSION: This study provides a clinical classification of Chinese AM based on diverse clinical onset characteristics and highlights the important role of trauma in AM. These findings may help to guide the diagnosis, treatment, and prognosis of AM patients. Further investigations are imperative to elucidate the underlying mechanisms governing the association between trauma and AM.

Multidisciplinary approach and treatment of acral and mucosal melanoma.

Acral and mucosal melanoma are uncommon variants of melanoma. Acral melanoma has an age-adjusted incidence of approximately 1.8 cases per million individuals per year, accounting for about 2% to 3% of all melanoma cases. On the other hand, mucosal melanoma, with an incidence of 2.2 cases per million per year, makes up around 1.3% of all melanoma cases. These melanomas, in addition to being biologically and clinically distinct from cutaneous melanoma, share certain clinical and pathologic characteristics. These include a more aggressive nature and a less favorable prognosis. Furthermore, they exhibit a different mutational pattern, with KIT mutations being more prevalent in acral and mucosal melanomas. This divergence in mutational patterns may partially account for the relatively poorer prognosis, particularly to immune checkpoint inhibitors. This review explores various aspects of acral and mucosal melanoma, including their clinical presentation, pathologic features, mutational profiles, current therapeutic approaches, outcomes associated with systemic therapy, and potential strategies to address resistance to existing treatments.

A European Multicentric Investigation of Atypical Melanocytic Skin Lesions of Palms and Soles: The iDScore-PalmoPlantar Database.

Background: The differential diagnosis of atypical melanocytic palmoplantar skin lesions (aMPLs) represents a diagnostic challenge, including atypical nevi (AN) and early melanomas (MMs) that display overlapping clinical and dermoscopic features. We aimed to set up a multicentric dataset of aMPL dermoscopic cases paired with multiple anamnestic risk factors and demographic and morphologic data. Methods: Each aMPL case was paired with a dermoscopic and clinical picture and a series of lesion-related data (maximum diameter value; location on the palm/sole in 17 areas; histologic diagnosis; and patient-related data (age, sex, family history of melanoma/sunburns, phototype, pheomelanin, eye/hair color, multiple/dysplastic body nevi, and traumatism on palms/soles). Results: A total of 542 aMPL cases-113 MM and 429 AN-were collected from 195 males and 347 females. No sex prevalence was found for melanomas, while women were found to have relatively more nevi. Melanomas were prevalent on the heel, plantar arch, and fingers in patients aged 65.3 on average, with an average diameter of 17 mm. Atypical nevi were prevalent on the plantar arch and palmar area of patients aged 41.33 on average, with an average diameter of 7 mm. Conclusions: Keeping in mind the risk profile of an aMPL patient can help obtain a timely differentiation between malignant/benign cases, thus avoiding delayed and inappropriate excision, respectively, with the latter often causing discomfort/dysfunctional scarring, especially at acral sites.

Management of acral lentiginous melanoma: current updates and future directions.

Acral lentiginous melanoma is a rare subtype of melanoma generally associated with poor outcomes, even when diagnosed at an early stage. The tumor genetic profile remains poorly understood, but it is known to have a suppressed immune environment compared to that of non-acral cutaneous melanomas, which limits therapy options. There is significant attention on the development of novel therapeutic approaches, although studies are limited due to disease rarity. For local disease, wide local excision remains the standard of care. Due to frequent under-staging on preoperative biopsy, wider margins and routine sentinel lymph node biopsy may be considered if morbidity would not be increased. For advanced disease, anti-PD1 monotherapy or combination therapy with anti-PD1 and anti-CTLA4 agents have been used as first-line treatment modalities. Anti-PD1 and anti-CTLA4 combination therapies have been shown to be particularly beneficial for patients with BRAF-mutant acral lentiginous melanoma. Other systemic combination regimens and targeted therapy options may be considered, although large studies with consistent results are lacking. Regional and intralesional therapies have shown promise for cutaneous melanomas, but studies generally have not reported results for specific histologic subtypes, especially for acral melanoma. Overall, the unique histologic and genetic characteristics of acral lentiginous melanoma make therapy options significantly more challenging. Furthermore, studies are limited, and data reporting has been inconsistent. However, more prospective studies are emerging, and alternative therapy pathways specific to acral lentiginous melanoma are being investigated. As further evidence is discovered, reliable treatment guidelines may be developed.

PRAME Updated: Diagnostic, Prognostic, and Therapeutic Role in Skin Cancer.

Preferentially Expressed Antigen in Melanoma (PRAME), a member of the cancer/testis antigen family, is central to the field of skin cancer diagnostics and therapeutics. As a nuclear receptor and transcriptional regulator, PRAME plays a critical role in inhibiting retinoic acid signalling, which is essential for cell differentiation and proliferation. Its aberrant overexpression in various malignancies, particularly cutaneous melanoma, is associated with more aggressive tumour phenotypes, positioning PRAME as both a diagnostic and prognostic marker. In melanoma, PRAME is typically highly expressed, in contrast to its weak or absent expression in benign nevi, thereby improving the accuracy of differential diagnoses. The diagnostic value of PRAME extends to various lesions. It is significantly expressed in uveal melanoma, correlating to an increased risk of metastasis. In acral melanomas, especially those with histopathological ambiguity, PRAME helps to improve diagnostic accuracy. However, its expression in spitzoid and ungual melanocytic lesions is inconsistent and requires a comprehensive approach for an accurate assessment. In soft tissue sarcomas, PRAME may be particularly helpful in differentiating melanoma from clear cell sarcoma, an important distinction due to their similar histological appearance but different treatment approaches and prognosis, or in detecting dedifferentiated and undifferentiated melanomas. In non-melanoma skin cancers such as basal cell carcinoma, squamous cell carcinoma, and Merkel cell carcinoma, the variable expression of PRAME can lead to diagnostic complexity. Despite these challenges, the potential of PRAME as a therapeutic target in melanoma is significant. Emerging immunotherapies, including T-cell-based therapies and vaccines targeting PRAME, are being investigated to exploit its cancer-specific expression. Ongoing research into the molecular role and mechanism of action of PRAME in skin cancer continues to open new avenues in both diagnostics and therapeutics, with the potential to transform the management of melanoma and related skin cancers.

Recent advancements in the diagnosis and treatment of acral melanoma. / è‚¢ç«¯é»‘è‰²ç´ ç˜¤çš„è¯Šæ–­å’Œæ²»ç–—è¿›å±•.

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.