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.

Clear Cell Sarcoma (CCS) of soft tissue is a rare and highly malignant neoplasm primarily affecting young adults, often presenting in the deep soft tissues of the extremities. Despite morphological and immunophenotypic similarities to melanoma, CCS arises from connective tissues and is characterized by a distinct genetic hallmark: the EWSR1-ATF1 fusion resulting from t(12;22)(q13;q12) translocation. This genetic signature is absent in melanoma, making molecular diagnosis essential for accurate differentiation. Additionally, recent evidence highlights the utility of PRAME as an immunohistochemical marker to distinguish CCS from melanoma and other neoplasms. Clinically, CCS commonly involves tendons and aponeuroses, with metastatic potential leading to poor prognoses despite optimal local disease management. Histologically, CCS features lobular growth, spindle-to-epithelioid cells with clear cytoplasm, and low mitotic activity, often necessitating a multimodal diagnostic approach incorporating histopathology, immunohistochemistry, and molecular testing. Therapeutically, wide surgical excision remains the cornerstone for localized disease, with sentinel lymph node biopsy aiding in staging. Adjuvant radiotherapy is considered in select cases, while chemotherapy has limited efficacy in metastatic settings. Emerging treatments, including targeted therapies focusing on EWSR1-ATF1-driven pathways and immune checkpoint inhibitors, offer hope for improved outcomes. This review synthesizes current knowledge on CCS, emphasizing diagnostic challenges, the role of PRAME, and advancements in therapeutic strategies to enhance patient care.

Background: In recent decades, dermatological diagnostics have undergone a profound transformation, driven by the integration of new technologies alongside traditional methods. Classic techniques such as the Tzanck smear, potassium hydroxide (KOH) preparation, and Wood’s lamp examination remain fundamental in everyday clinical practice due to their simplicity, speed, and accessibility. At the same time, the development of non-invasive imaging technologies and the application of artificial intelligence (AI) have opened new frontiers in the early detection and monitoring of both neoplastic and inflammatory skin diseases. Methods: This review aims to provide a comprehensive overview of how conventional and emerging diagnostic tools can be integrated into dermatologic practice. Results: We examined a broad spectrum of diagnostic methods currently used in dermatology, ranging from traditional techniques to advanced approaches such as digital dermoscopy, reflectance confocal microscopy (RCM), optical coherence tomography (OCT), line-field confocal OCT (LC-OCT), 3D total body imaging systems with AI integration, mobile applications, electrical impedance spectroscopy (EIS), and multispectral imaging. Each method is discussed in terms of diagnostic accuracy, clinical applications, and potential limitations. While traditional methods continue to play a crucial role—especially in resource-limited settings or for immediate bedside decision-making—modern tools significantly enhance diagnostic precision. Dermoscopy and its digital evolution have improved the accuracy of melanoma and basal cell carcinoma detection. RCM and LC-OCT allow near-histological visualization of skin structures, reducing the need for invasive procedures. AI-powered platforms support lesion tracking and risk stratification, though their routine implementation requires further clinical validation and regulatory oversight. Tools like EIS and multispectral imaging may offer additional value in diagnostically challenging cases. An effective diagnostic approach in dermatology should rely on a thoughtful combination of methods, selected based on clinical suspicion and guided by Bayesian reasoning. Conclusions: Rather than replacing traditional tools, advanced technologies should complement them—optimizing diagnostic accuracy, improving patient outcomes, and supporting more individualized, evidence-based care.

The incidence of skin cancer has risen globally in recent years, with 2024 marking a critical point in understanding its epidemiology and burden on public health. As one of the most common malignancies worldwide, skin cancer results from a combination of genetic predisposition, lifestyle behaviors, environmental exposures, and socioeconomic factors. This chapter provides a comprehensive overview of the current epidemiology of skin cancer, focusing on both melanoma and non-melanoma skin cancers (NMSC). It examines variations in incidence and prevalence across different regions and demographic groups, shedding light on key risk factors such as UV exposure, skin type, geographic location, and evolving trends in sun exposure. The chapter highlights the public health importance of early detection and preventative measures, which are essential to reducing morbidity and mortality associated with skin cancer. The chapter also addresses significant trends, including a marked increase in melanoma among younger populations, particularly in high-UV regions, as well as disparities in access to healthcare that impact skin cancer outcomes. In addition to exploring global NMSC epidemiology—with emphasis on basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) patterns across continents—this chapter reviews the high incidence rates of NMSC in countries like Australia and New Zealand and contrasts them with regions where incidence is lower but mortality rates may be disproportionately high due to limited healthcare access. In discussing melanoma, the chapter analyzes the “divergent pathway” model of tumorigenesis, anatomical site-specific trends, and improvements in diagnostic accuracy due to advances in dermoscopy. Emerging therapeutic options, such as immunotherapies for advanced melanoma, are also explored within the context of reducing melanoma mortality. This chapter thus provides healthcare professionals, researchers, and policymakers with an updated framework for understanding the complexities and pressing needs in skin cancer prevention and management in 2024.