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ABSTRACT During the illustrious career of Martin C. Mihm Jr., MD, the diagnosis of melanoma underwent significant changes, to which he made many contributions. In early descriptions, melanomas were fungating tumor masses that were obviously malignant, and highly lethal. In seminal work by Dr. Mihm and his mentor, Wallace H. Clark, Jr., MD, the early phases of development of these neoplasms were recognized and distinguished from the more advanced disease. It was generally believed that the early stage of melanoma, termed radial growth phase (RGP) and characterized by absence of vertical growth phase (VGP) and by favorable microstaging attributes could be recognized, excised, and cured, thus preventing the development of advanced disease. However, strenuous efforts in this direction over several decades have resulted in little or no change in mortality, leading to the recognition that many of these neoplasms, at least, may not be true biological malignancies, and to the conclusion that overdiagnosis commonly occurs in this disease, which is defined as representing diagnosis as melanoma of a neoplasm that would not have had the capacity to cause death or symptoms in the lifetime of the host. Although there may be other subsets of neoplasms in this category, an important category of overdiagnosis in melanomas is concentrated in T1a melanomas that lack VGP. If these neoplasms can be recognized with sensitive and specific criteria, which may already be available, changes in terminology may be appropriate, recognizing that some of them may have low malignant potential, whereas others may have no capacity at all for metastasis and may not warrant the use of the term “melanoma.” [ABSTRACT FROM AUTHOR]

Cutaneous-skeletal hypophosphatemia syndrome (CSHS) is a rare disorder characterized by the presence of melanocytic nevi, dysplastic cortical bony lesions, and fibroblast growth factor 23 (FGF23)-mediated hypophosphatemic rickets. Herein, we describe the diagnosis of an 8-year-old girl presenting with short stature, reduced lower limb mobility, and abnormal gait due to muscle weakness and constant pain in the legs. Biochemical parameters demonstrated hypophosphatemia, hyperphosphaturia, slight increase in parathyroid hormone (PTH), high levels of alkaline phosphatase, and elevated FGF23. Burosumab improved phosphate-wasting, serum phosphorus, alkaline phosphatase, and PTH, followed by a significant mineralization in vertebral bodies evidenced by radiographic assessment. Our report shows a long-term follow-up of CSHS with a notable improvement promoted by an anti-FGF23 therapy. [ABSTRACT FROM AUTHOR]

Cutaneous malignant melanoma accounts for 5% of cancer diagnoses and is the fifth most common cancer diagnosed in the United States. Risk factors for cutaneous malignant melanoma include ultraviolet radiation from sun exposure, Fitzpatrick skin type I or II, a history of dysplastic nevi, indoor tanning, older age, and a personal or family history of melanoma. The U.S. Preventive Services Task Force recommends counseling with patient education on minimizing early ultraviolet radiation exposure, including the use of protective clothing and sunscreen, especially for patients 6 months to 24 years of age. Tools to aid in the diagnosis of cutaneous malignant melanoma and the decision to biopsy include the ABCDE mnemonic, ugly duckling sign, and dermoscopy. Any suspicious pigmented lesion should be biopsied. Biopsy with a deep scoop shave, saucerization, punch biopsy, or full-thickness excision is preferred to ensure the entire lesion is removed to obtain an accurate measurement of Breslow depth. Breslow depth is important in staging, treatment consideration, and prognosis. Wide local excision by a dermatologist or surgeon with appropriate margins is the primary treatment of choice. Thin lesions with a Breslow depth of less than 0.8 mm usually do not need further treatment after wide local excision and have an excellent prognosis. Lesions with a Breslow depth greater than 0.8 mm may need further diagnostic tests or procedures, including sentinel lymph node biopsy, complete lymph node dissection, gene mutation analysis, and possible treatment with systemic immunotherapy. Use of systemic immunotherapies has improved the prognosis for advanced melanoma (stages III and IV), with 5-year survival rates of 74.8% and 35%, respectively, compared with 62.6% and 16% from 1975 to 2011 before immunotherapy was available. [ABSTRACT FROM AUTHOR]

PRAME (PReferentially expressed Antigen in Melanoma) immunohistochemistry has proven helpful in distinguishing malignant from benign melanocytic tumors. We studied PRAME IHC expression in 46 thin melanomas and 39 melanocytic nevi, mostly dysplastic nevi. Twenty-six percent (26.09%) of the melanomas showed diffuse PRAME staining in over 76% of the tumor cells (4+), and 34.78% of the melanomas showed PRAME expression in over 51% of the tumor cells (3+ or 4+), while 8% were entirely negative for PRAME. No melanocytic nevi were PRAME 4+ or 3+. More than half of the nevi (64%) were entirely negative for PRAME staining, and 36% of the nevi showed staining expression in 1–25% (1+) or 26–50% of the cells (2+). No nevi were stained with a color intensity of 3, while 16.67% of the melanomas were stained with this color intensity. Most nevi (78.57%) were stained with an intensity of 1. With a lower positivity threshold, sensitivity increases with still reasonable specificity. The best accuracy was obtained for the 2+ positivity threshold. In conclusion, PRAME staining helps distinguish thin melanomas from dysplastic nevi. However, the threshold of positivity should be lowered in order not to miss thin melanomas. [ABSTRACT FROM AUTHOR]

This article discusses a rare case of amelanotic melanoma arising from a giant congenital melanocytic nevus (GCMN) in an infant. GCMN is a type of birthmark that can increase the risk of developing melanoma. The article highlights the challenges in diagnosing amelanotic melanoma and emphasizes the importance of fine needle aspiration (FNA) in providing an accurate diagnosis. The authors recommend close monitoring of GCMN and early treatment for better outcomes. They also discuss the differential diagnoses and the use of immunocytochemistry to confirm the diagnosis. [Extracted from the article]

Melanoma is the most severe type of skin cancer and among the most malignant neoplasms in humans. With the growing incidence of melanoma, increased numbers of therapeutic options, and the potential to target specific proteins, understanding the basic mechanisms underlying the disease's progression and resistance to treatment has never been more important. LOXL3, SNAI1, and NES are key factors in melanoma genesis, regulating tumor growth, metastasis, and cellular differentiation. In our study, we explored the potential role of LOXL3, SNAI1, and NES in melanoma progression and metastasis among patients with dysplastic nevi, melanoma in situ, and BRAF+ and BRAF− metastatic melanoma, using immunofluorescence and qPCR analysis. Our results reveal a significant increase in LOXL3 expression and the highest NES expression in BRAF+ melanoma compared to BRAF−, dysplastic nevi, and melanoma in situ. As for SNAI1, the highest expression was observed in the metastatic melanoma group, without significant differences among groups. We found co-expression of LOXL3 and SNAI1 in the perinuclear area of all investigated subgroups and NES and SNAI1 co-expression in melanoma cells. These findings suggest a codependence or collaboration between these markers in melanoma EMT, suggesting new potential therapeutic interventions to block the EMT cascade that could significantly affect survival in many melanoma patients. [ABSTRACT FROM AUTHOR]

Background Increasing melanoma incidence with less increasing mortality is observed in several countries. This discrepancy is not well understood. Objectives In this study, our aim was to discuss factors [ultraviolet radiation (UVR) exposure, melanoma treatment, diagnostic activity, overdiagnosis, pathologists' diagnostic threshold and clinicians' propensity to remove suspect skin lesions] that might influence melanoma incidence and mortality in Denmark. Methods This was a register study with the number of melanocyte-related lesions and melanoma mortality based on comprehensive national pathology and mortality databases for the period 1999–2019. We investigated melanocyte-related diagnoses and mortality in a population of 5.5 million with a national healthcare system. Age-adjusted melanoma mortality and age-adjusted incidence of benign naevi, atypical lesion, or melanoma in situ and of invasive melanoma were computed for data analysis. Results In total, 1 434 798 biopsies were taken from 704 682 individuals (65% female). The mean age at biopsy was 39.8 years in males and 37.6 in females. In males and females, the incidence of invasive melanoma increased by 87% during the period 1999–2011. During the subsequent period it increased by 9% in males but remained unchanged in females. The incidence of melanoma in situ increased by 476% in males and 357% in females during the study period, while the increases for atypical melanocytic lesions were 1928% and 1686%, respectively. Biopsy rates increased by 153% in males and 118% in females from 1999 through 2011 but fell by 20% in males and 22% in females during the subsequent period. Mortality varied slightly from year to year without any significant time trend for males or females. We identified no evidence of increased UVR exposure over the latest 30 years in Denmark. Immunotherapy of advanced melanoma was introduced in Denmark in 2010 and came into general use in 2014. Conclusions Comprehensive national data demonstrate increasing melanoma incidence correlated with increasing biopsy rates, but with no change in mortality. Previously suggested explanations for such a trend are a lowered threshold of melanoma diagnosis among pathologists, increased diagnostic activity in the presence of overdiagnosis and improved melanoma treatment. Because the study is observational and we have more explanatory factors than outcomes, the findings do not warrant conclusions about causal relationships. [ABSTRACT FROM AUTHOR]

This article discusses a feasibility study on the use of mobile teledermoscopy for monitoring high-risk melanoma patients. The study involved 75 patients from two Australian tertiary centers who used a portable teledermoscope compatible with their mobile phones. The study found that mobile teledermoscopy was effective in detecting skin cancers, with the potential to fast-track 37% of visits for concerning lesions. Participants aged ≤40 years and those with tertiary education provided more reliable transmissions. The study also noted a small additional cost to the healthcare system. The authors of a letter to the editor discuss the study and suggest that mobile teledermoscopy can be used to support conventional practice for high-risk patients under certain criteria. The study was supported by the NHMRC Centre of Research Excellence in Melanoma and the Melanoma Institute of Australia. [Extracted from the article]

Background: In melanomas, mutations in the BRAF gene are common and their occurrence represents an early oncogenic event. Our goal was to determine and compare the frequency of BRAF gene mutations in dysplastic nevi (ND) and melanomas in situ (MIS), as well as whether there is a correlation between the presence of BRAF gene mutations and various anamnestic, clinical, and histopathologic variables. Methods: A total of 175 patients—106 with ND, 41 with MIS, and 28 with lentigo maligna (LM) were included in the study. DNA was extracted from tissue samples and analyzed using the competitive allele-specific TaqMan chain reaction by polymerase in real time to detect the presence of BRAF V600E and V600K mutations. The data were compared with anamnestic, clinical, and histopathological data. Results: There is a statistically significant correlation between the presence of BRAF mutation and the diagnosis of melanoma in situ (χ2 test, χ2 = 29.17, p < 0.0001). Patients with LM had a significantly lower incidence of BRAF mutations compared to patients with ND and MIS. There was a significant correlation between the presence of a BRAF mutation and tumor localization, as well as the age of the patient, but no statistically significant correlation between the presence of a BRAF mutation and sex, tumor size, or previous melanoma diagnosis. Conclusions: BRAF mutations in ND are essentially required; however, they are an insufficient oncogenic trigger for the development of melanoma. This research contributes to a better understanding of the etiopathogenesis of melanoma and the role of ND as possible precursor lesions. [ABSTRACT FROM AUTHOR]

Background: Lentigo maligna (LM) exhibits a particular epidemiological profile compared to other histopathologic subtypes of melanoma, with a propensity for the head and neck area and a higher mean age at diagnosis. Few small‐scale studies have exclusively evaluated the risk factors for the development of LM. Objective: This study aims to compare LM to other histological subtypes of melanoma for the prevalence of known melanoma risk factors, including pigmentary characteristics, history of occupational sun exposure, nevus count, and familial melanoma history. Patients and methods: We conducted a case–control study of 152 patients with LM and 784 patients with other melanoma subtypes (OM). The Mann–Whitney t‐test and Pearson chi‐squared test were used to detect differences between the two groups in continuous and categorical variables, respectively. Univariate and multivariate logistic regression models were then constructed to identify risk factors for developing LM compared to other melanoma subtypes. Results: In multivariate logistic regression analysis, LM was positively associated with a lentigines count >50 and occupational sun exposure compared to OM (OR 2.10, 95% CI 1.35–3.29 and OR 2.18, 95% CI 1.33–3.57, respectively). In contrast, patients with an increased nevus count and fair or medium skin color were less likely to develop LM than OM (OR 0.93, P < 0.001, 95% CI 0.91–0.94, and OR 0.28, P < 0.001, 95% CI 0.17–0.46, respectively). In univariate analysis, LM exhibited a weaker association with all pigmentary traits than OM. No significant associations were found for atypical nevi count and family history. Conclusion: We found significant differences in the prevalence of known melanoma risk factors between LM and other melanoma subtypes, which supports the hypothesis of a distinct pathogenetic pathway of LM. [ABSTRACT FROM AUTHOR]

PurposeMethodsResultsConclusionTo report a case of Cogan-Like Syndrome following treatment with nivolumab for metastatic cutaneous melanoma.A case report.A 54-year-old female sought a second opinion from us regarding the recently diagnosed uveitis in both eyes. She had a diagnosis of metastatic cutaneous melanoma in the right arm and was undergoing treatment with nivolumab. Four weeks following the initiation of nivolumab therapy, she experienced tinnitus and bilateral sensorineural hearing loss, which was treated with oral and intratympanic steroids. While tapering the oral steroids, she developed iridocyclitis with papillitis in both eyes. This combination of vestibuloauditory symptoms and ocular inflammation was strikingly reminiscent of Cogan’s syndrome. Because of the timing in relation to the nivolumab therapy and the steroid responsiveness of her presentation, this was speculated to be due to immune overactivation from the nivolumab. Given her complex condition, which involved toxicity and multiple metastases, the patient was advised to consider either topical and/or local corticosteroids or intravenous immunoglobulin. The patient chose to persist with corticosteroid therapy.Nivolumab could potentially be linked to an immune-related condition resembling Cogan syndrome. In cases involving patients with a complex condition necessitating nivolumab treatment, the use of topical and/or local corticosteroids or intravenous immunoglobulin, might constitute the sole viable treatment options. [ABSTRACT FROM AUTHOR]

Background/Objectives: Although excision of melanocytic nevi with high‐grade dysplasia is recommended by the World Health Organization (WHO), clinical studies investigating the approach based on the grading dysplasia of melanocytic lesions with peripheral globules (PGs) are lacking. We investigated the grades of dysplasia and their distinguishable dermoscopic and clinical features to provide accurate data for managing these lesions. Methods: We retrospectively classified histologically confirmed melanocytic lesions with PGs according to the 2018 WHO Classification of Skin Tumours criteria in a university hospital in Turkey. Dermoscopic features, lesions, and patient characteristics were recorded. Results: Sixty‐six lesions of 56 patients were included. After classification, 9.1% (n: 6) of lesions were melanomas, 39.4% (n: 26) were high‐grade dysplastic nevi, and 50% (n: 33) were low‐grade dysplastic nevi (n: 33, 50%). There was one nevus with no dysplasia (n: 1, 1.5%). Univariate analysis revealed that ≥31 years of age, irregular shape of peripheral globules, black colour, total colour count, and maximum diameter of the lesion were associated with high‐grade dysplasia and melanoma. In the multivariate analyses, ≥31 years of age (OR = 3.80, 95% CI, 1.17–12.37), irregular shape of peripheral globules (OR = 3.90, 95% CI, 1.15–13.2), and total colour count (OR = 3.21, 95% CI, 1.2–8.5) were significant predictive factors for the lesions with high‐grade dysplasia and melanomas. Conclusions: To avoid the underdiagnosis of both melanomas and high‐grade dysplastic nevi with PGs, the irregular shape of peripheral globules and multiple colours after the third decade may be useful in making an excision decision. The risk increases every 1‐year increase in age. Excision is suggested for all melanocytic lesions with PGs for patients 60 years or older because of the high risk of melanoma and melanocytic nevus with high‐grade dysplasia. [ABSTRACT FROM AUTHOR]

This survey represents the first endeavor to assess the clarity of the dermoscopic language by a chatbot, unveiling insights into the interplay between dermatologists and AI systems within the complexity of the dermoscopic language. Given the complex, descriptive, and metaphorical aspects of the dermoscopic language, subjective interpretations often emerge. The survey evaluated the completeness and diagnostic efficacy of chatbot-generated reports, focusing on their role in facilitating accurate diagnoses and educational opportunities for novice dermatologists. A total of 30 participants were presented with hypothetical dermoscopic descriptions of skin lesions, including dermoscopic descriptions of skin cancers such as BCC, SCC, and melanoma, skin cancer mimickers such as actinic and seborrheic keratosis, dermatofibroma, and atypical nevus, and inflammatory dermatosis such as psoriasis and alopecia areata. Each description was accompanied by specific clinical information, and the participants were tasked with assessing the differential diagnosis list generated by the AI chatbot in its initial response. In each scenario, the chatbot generated an extensive list of potential differential diagnoses, exhibiting lower performance in cases of SCC and inflammatory dermatoses, albeit without statistical significance, suggesting that the participants were equally satisfied with the responses provided. Scores decreased notably when practical descriptions of dermoscopic signs were provided. Answers to BCC scenario scores in the diagnosis category (2.9 ± 0.4) were higher than those with SCC (2.6 ± 0.66, p = 0.005) and inflammatory dermatoses (2.6 ± 0.67, p = 0). Similarly, in the teaching tool usefulness category, BCC-based chatbot differential diagnosis received higher scores (2.9 ± 0.4) compared to SCC (2.6 ± 0.67, p = 0.001) and inflammatory dermatoses (2.4 ± 0.81, p = 0). The abovementioned results underscore dermatologists' familiarity with BCC dermoscopic images while highlighting the challenges associated with interpreting rigorous dermoscopic images. Moreover, by incorporating patient characteristics such as age, phototype, or immune state, the differential diagnosis list in each case was customized to include lesion types appropriate for each category, illustrating the AI's flexibility in evaluating diagnoses and highlighting its value as a resource for dermatologists. [ABSTRACT FROM AUTHOR]

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a newly recognised adult-onset multisystem autoinflammatory disease caused by a somatic mutation in the UBA1 gene in myeloid or erythroid precursor cells. This report describes an atypical presentation of recurrent dacryoadenitis associated with VEXAS syndrome and provides a review of the literature. A 68-year-old male presented with three episodes of unilateral alternating dacryoadenitis followed by bilateral involvement over a 4-year period. Each episode of orbital inflammation was characterised by upper lid swelling, oedema and enlarged lacrimal glands. In addition, he experienced intermittent flares of angioedema-like lesions involving the face and extremities, recurrent jaw aches, rash, progressive pulmonary fibrosis, and myelodysplastic syndrome. His inflammatory symptoms lessened with prednisolone but were refractory to methotrexate. Mycophenolate was subsequently trialled with a reasonable clinical response. Genetic testing established the diagnosis of VEXAS syndrome and tofacitinib, a JAK inhibitor, was commenced with resolution of inflammatory symptoms. [ABSTRACT FROM AUTHOR]

The article explores the diagnostic accuracy of GPT-4's novel image analytics feature in dermatology, highlighting its potential in integrating textual and visual information for diagnosis. The study collected 100 clinical images from DermNet™ and found that GPT-4 correctly diagnosed 23% of images and included the correct diagnosis in 53% of cases. However, the tool displayed limited sensitivity for malignant and precancerous images, indicating its current clinical limitations. The study emphasizes the importance of caution in relying solely on AI platforms like GPT-4 for medical advice due to potential misdiagnoses and patient distress. [Extracted from the article]

The article discusses primary dermal melanoma (PDM), a rare subtype of melanoma, focusing on a case series of nine patients diagnosed with clinical primary dermal melanoma (cPDM). The study highlights the challenges in diagnosing and distinguishing PDM from other skin conditions, emphasizing the importance of early recognition and intervention to prevent disease progression and metastasis. The research underscores the need for further studies to establish diagnostic criteria, staining techniques, and histopathological markers for PDM to aid in prompt identification and treatment planning. [Extracted from the article]

The article discusses the factors that increase the likelihood of a diagnostic upgrade for ambiguous melanocytic tumors after clinicopathological correlation (CPC). The study found that advanced age and the presence of dermoscopic streaks were associated with a higher chance of a diagnosis changing from nevus to melanoma after CPC. The presence of streaks in particular requires increased vigilance by clinicians, as they are strongly associated with melanoma. The study suggests that a holistic approach, integrating clinical appearance, dermoscopic morphology, histopathology, epidemiology, and natural history, is necessary for accurate diagnosis and management of melanocytic tumors. [Extracted from the article]

Liver cancer is one of the most prevalent forms of cancer worldwide. A significant proportion of patients with hepatocellular carcinoma (HCC) are diagnosed at advanced stages, leading to unfavorable treatment outcomes. Generally, the development of HCC occurs in distinct stages. However, the diagnostic and intervention markers for each stage remain unclear. Therefore, there is an urgent need to explore precise grading methods for HCC. Machine learning has emerged as an effective technique for studying precise tumor diagnosis. In this research, we employed random forest and LightGBM machine learning algorithms for the first time to construct diagnostic models for HCC at various stages of progression. We categorized 118 samples from GSE114564 into three groups: normal liver, precancerous lesion (including chronic hepatitis, liver cirrhosis, dysplastic nodule), and HCC (including early stage HCC and advanced HCC). The LightGBM model exhibited outstanding performance (accuracy = 0.96, precision = 0.96, recall = 0.96, F1-score = 0.95). Similarly, the random forest model also demonstrated good performance (accuracy = 0.83, precision = 0.83, recall = 0.83, F1-score = 0.83). When the progression of HCC was categorized into the most refined six stages: normal liver, chronic hepatitis, liver cirrhosis, dysplastic nodule, early stage HCC, and advanced HCC, the diagnostic model still exhibited high efficacy. Among them, the LightGBM model exhibited good performance (accuracy = 0.71, precision = 0.71, recall = 0.71, F1-score = 0.72). Also, performance of the LightGBM model was superior to that of the random forest model. Overall, we have constructed a diagnostic model for the progression of HCC and identified potential diagnostic characteristic gene for the progression of HCC. [ABSTRACT FROM AUTHOR]

A novel approach to melanoma diagnosis—in vivo molecular skin fluorescence imaging (mSFI)—was developed to identify premalignant changes in the form of tissue remodeling related to melanoma development in humans by imaging the proximal microenvironment of lesions. The method was tested using a fluorescent peptide (ORL‐1) which binds to αvβ3 integrin, a molecule associated with invasive melanoma development. A cut off score of 7 was established, differentiating melanomas from nonmelanoma nevi with 100% sensitivity, and 95.7% specificity, while identifying dysplastic nevi with the potential for melanoma development. Summary In vivo molecular skin fluorescent imaging (mSFI) differentiates between concerning and non‐concerning nevi identifying microenvironmental tissue remodeling changes associated with melanoma development. This method has the potential to improve pigmented lesion assessment during clinical evaluation, consequently improving the selection of lesions for biopsy. [ABSTRACT FROM AUTHOR]

This article provides an overview of tumoural melanosis (TM), a rare condition characterized by the regression of cutaneous melanoma. The authors present four cases of TM from Greece and discuss the clinical, dermatoscopic, and histopathologic characteristics of the condition. They highlight the importance of clinicopathologic correlation in diagnosing TM and recommend aggressive management due to the poor outcomes associated with the condition. Dermatoscopic findings, such as "peppering," whitish or pinkish structureless areas, and blue/grey areas, can assist in the diagnosis of TM. The article includes images to illustrate the cases and provide visual examples of the diagnostic findings. [Extracted from the article]

Introduction: Early relapse and development of metastatic disease are some of the primary reasons for the poor prognosis of patients with head and neck squamous cell carcinoma (HNSCC). HNSCC is a heterogeneous disease which may develop in large premalignant fields of genetically altered cells. Yet knowing which individuals will progress and develop clinically significant cancers during their lifetimes remains one of the most important challenges of reducing HNSCC morbidity and mortality. To further elucidate the molecular mechanisms, we performed a focused analysis of the genome and immune microenvironment from multiple, matched normal squamous tissue, premalignant lesions, as well as primary and recurrent tumors from seven patients with p16-negative HNSCC. Methods: We performed targeted panel Next Generation Sequencing (161 genes) to analyze somatic variants from sequentially collected, matched formalin-fixed paraffin-embedded tissue (normal, premalignant, HNSCC) from two patients. These samples plus samples from five additional patients were analyzed with the Nanostring PanCancer Immune Panel. In addition, we performed shallow whole genome sequencing (0.5x coverage on average) on samples from three of these patients. Patients were, apart from one case, primarily treated with curativeintent surgery, and received subsequent adjuvant treatment, if indicated. Results: The most frequently mutated genes were TP53 and NOTCH1. Other mutated genes included NOTCH3 and CDKN2A, among others. A significant number of mutations were private to dysplasia and invasive carcinoma, respectively, however, almost 20% were shared between them. Increasing genomic instability was observed when comparing histologically normal squamous mucosa with higher levels of dysplasia. High-grade dysplasia showed similarly rearranged genomes as invasive carcinoma. Pathways related to interferon alpha and gamma response were upregulated even in moderate dysplastic lesions with increasing expression in higher grades of dysplasia and carcinoma. SPINK5, a known tumor suppressor gene in HNSCC, was already downregulated in low-grade dysplastic lesions, indicating an early deactivation in the evolution of the disease. Conclusion: Genomic alterations as well as aberrant immune gene expression can be observed early in the evolution of tumors of the upper aerodigestive tract, highlighting the potential for targeting early mechanisms of disease progression. [ABSTRACT FROM AUTHOR]

The oral microbiome has emerged as a critical determinant in the pathogenesis of various oral diseases, including oral mucosal dysplasia and oral cancer. Dysbiosis, characterized by imbalances in the composition and function of the bacteriome and mycobiome, has been implicated in the initiation and progression of these conditions. This review aims to elucidate the intricate relationship between dysbiosis and oral mucosal dysplasia and cancer. We explore the alterations in bacterial and fungal communities associated with dysplastic lesions and malignant transformations within the oral cavity. Additionally, we discuss the potential mechanisms by which dysbiotic changes contribute to the development of oral neoplasms, including microbial-mediated inflammation, immune modulation, and carcinogenic metabolite production. Understanding the dynamics of bacteriome and mycobiome dysbiosis in oral diseases is essential for developing novel diagnostic and therapeutic strategies to combat these conditions. By deciphering dysbiosis, we may pave the way for personalized approaches to oral cancer prevention and management, ultimately improving patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Background: Autofluorescence spectroscopy is effective for noninvasive detection but underutilized in tissue with various pathology analyses. This study evaluates whether AFS can be used to discriminate between different types of laryngeal lesions in view of assisting in vocal fold surgery and preoperative investigations. Methods: A total of 1308 spectra were recorded from 29 vocal fold samples obtained from 23 patients. Multiclass analysis was performed on the spectral data, categorizing lesions into normal, benign, dysplastic, or carcinoma. Results: Through an appropriate selection of spectral components and a cascading classification approach based on artificial neural networks, a classification rate of 97% was achieved for each lesion class, compared to 52% using autofluorescence intensity. Conclusions: The ex vivo study demonstrates the effectiveness of AFS combined with multivariate analysis for accurate classification of vocal fold lesions. Comprehensive analysis of spectral data significantly improves classification accuracy, such as distinguishing malignant from precancerous or benign lesions. [ABSTRACT FROM AUTHOR]

Melanoma, a malignant neuroectodermic tumor originating from the neural crest, presents a growing global public health challenge and is anticipated to become the second most prevalent malignancy in the USA by 2040. The CDKN2A gene, particularly p16INK4a, plays a pivotal role in inhibiting the cell cycle via the cyclin D/CDK2-pRb pathway in certain tumors. In familial melanomas (FM), 40% exhibit CDKN2A mutations affecting p16INK4a, impacting checkpoint G1, and stabilizing p53 expression. This study aims to establish a scoring system using immunohistochemical antibodies, providing a cost-saving approach to classify multiple primary melanomas (MPM) and FM patients based on their mutational status, thus mitigating genetic testing expenses. This retrospective study included 23 patients with MPM and FM, assessing the p16, CD8, and Ki67 immunohistochemical status. Analyses of each parameter and associations between their value intervals and genetic CDKN2A status were conducted. A total score of at least 9 out of 10 points per tumor defined melanomas with homozygous CDKN2A deletions, exhibiting a sensitivity of 100% and specificity of 94.11%. In conclusion, p16, CD8, and Ki67 individually serve as valuable indicators for predicting melanoma evolution. The algorithm, comprising these three immunohistochemical parameters based on their prognostic and evolutionary significance, proves to be a valuable auxiliary diagnostic tool for cost-effective prediction of mutational status in detecting multiple and familial primary melanomas with CDKN2A homozygous deletion. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Hematopoietic neoplasms can cause adrenal infarction. In cases of thrombosis occurring at uncommon sites, it is necessary to consider evaluating for the JAK2V617F mutation, even in the absence of notable abnormalities in blood counts. Adrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46‐year‐old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm‐unclassifiable, featuring a JAK2V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms. We should consider evaluating for JAK2V617F mutation even in cases of thrombosis at unusual sites, including adrenal infarction, even if there are no considerable abnormalities in blood counts. [ABSTRACT FROM AUTHOR]

Improved understanding of TP53 biology and the clinicopathological features of TP53-mutated myeloid neoplasms has led to the recognition of TP53-mutated acute myeloid leukemia/myelodysplastic syndrome (TP53m AML/MDS) as a unique entity, characterized by dismal outcomes following conventional therapies. Several clinical trials have investigated combinations of emerging therapies for these patients with the poorest molecular prognosis among myeloid neoplasms. Although some emerging therapies have shown improvement in overall response rates, this has not translated into better overall survival, hence the notion that p53 remains an elusive target. New therapeutic strategies, including novel targeted therapies, immune checkpoint inhibitors, and monoclonal antibodies, represent a shift away from cytotoxic and hypomethylating-based therapies, towards approaches combining non-immune and novel immune therapeutic strategies. The triple combination of azacitidine and venetoclax with either magrolimab or eprenetapopt have demonstrated safety in early trials, with phase III trials currently underway, and promising interim clinical results. This review compiles background on TP53 biology, available and emerging therapies along with their mechanisms of action for the TP53m disease entity, current treatment challenges, and recently published data and status of ongoing clinical trials for TP53m AML/MDS. [ABSTRACT FROM AUTHOR]

Introduction: Oral leukoplakia (OLP) is one the most common potentially malignant disorders account 0.2 to 4.9% of malignant transformation and dysplastic lesions vary from 3-6% this rate of malignant conversion depends on the different grades of epithelial dysplasia. Recent literature suggests that increased levels of COX-2 in potentially malignant disorders and malignant tumors show prominent genetic evidence in tumorigenesis. Assessment of Cyclooxygenase-2 - 2 (COX-2) immunohistochemical expression in different grades of oral epithelial dysplasia. Material and Methods: A total of forty formalin-fixed, paraffin-embedded tissue blocks were obtained from departmental archives which are histopathological diagnoses of different grades of oral epithelial dysplasia each grade ten samples was included. Stained with COX-2 and positive cells were counted and tabulated for statistical analysis. Results: Comparison between genders in oral leukoplakia males was more when compared with females. The mean age in mild epithelial dysplasia was more when compared with moderate and severe epithelial dysplasia. Expression of COX-2 was increased from mild to severe epithelial dysplasia increases. The mean number of positive cells was increased. A comparison of all groups was not statistically significant (p=0.05). Conclusion: Oral leukoplakia (OLP) is one the most common potentially malignant disorders which accounts for 0.2 to 4.9% of malignant transformation. COX-2 can be used for early detection and prognostic makers in different grades of oral epithelial dysplasia. [ABSTRACT FROM AUTHOR]

This article explores the occurrence of treatment-emergent mutations in patients with myelodysplastic syndrome (MDS) with del(5q) who are being treated with lenalidomide. The study analyzes the genetic changes in 10 patients with MDS-del(5q) before and after lenalidomide therapy. The results reveal the emergence of TP53 mutations, as well as other mutations, during treatment. These findings contribute to our understanding of the genetic changes that occur during lenalidomide treatment in MDS-del(5q) patients and highlight the importance of monitoring mutations in these patients. The study also suggests the need for alternative therapies in cases where TP53 mutations are present. [Extracted from the article]

Background: Maximizing survival for patients with primary cutaneous melanomas (melanomas) depends on an early diagnosis and appropriate management. Several new drugs have been shown to improve survival in high-risk melanoma patients. Despite well-documented guidelines, many patients do not receive optimal management, particularly when considering patient age. Objective: to provide an update on melanoma management from the time of the decision to biopsy a suspicious skin lesion. Methods: We reviewed melanoma-management research published between 2018 and 2023 and identified where such findings impact and update the management of confirmed melanomas. Pubmed, Google Scholar, Ovid and Cochrane Library were used as search tools. Results: We identified 81 publications since 2017 that have changed melanoma management; 11 in 2018, 12 in 2019, 10 in 2020, 12 in 2021, 17 in 2022 and 18 in 2023. Discussion: Delayed or inaccurate diagnosis is more likely to occur when a partial shave or punch biopsy is used to obtain the histopathology. Wherever feasible, a local excision with a narrow margin should be the biopsy method of choice for a suspected melanoma. The Breslow thickness of the melanoma remains the single most important predictor of outcome, followed by patient age and then ulceration. The BAUSSS biomarker, (Breslow thickness, Age, Ulceration, Subtype, Sex and Site) provides a more accurate method of determining mortality risk than older currently employed approaches, including sentinel lymph node biopsy. Patients with metastatic melanomas and/or nodal disease should be considered for adjuvant drug therapy (ADT). Further, high-risk melanoma patients are increasingly considered for ADT, even without disease spread. Invasive melanomas less than 1 mm thick are usually managed with a radial excision margin of 10 mms of normal skin. If the thickness is 1 to 2 mm, select a radial margin of 10 to 20 mm. When the Breslow thickness is over 2 mm, a 20 mm clinical margin is usually undertaken. In situ melanomas are usually managed with a 5 to 10 mm margin or Mohs margin control surgery. Such wide excisions around a given melanoma is the only surgery that can be regarded as therapeutic and required. Patients who have had one melanoma are at increased risk of another melanoma. Ideal ongoing management includes regular lifelong skin checks. Total body photography should be considered if the patient has many naevi, especially when atypical/dysplastic naevi are identified. Targeted approaches to improve occupational or lifestyle exposure to ultraviolet light are important. Management also needs to include the consideration of vitamin D supplementary therapy. [ABSTRACT FROM AUTHOR]

Background: Mucosal gastric atrophy and intestinal metaplasia (IM) increase the risk for the development of gastric cancer (GC) as they represent a field for development of dysplasia and intestinal-type gastric adenocarcinoma. Methods: We have investigated the expression of two dysplasia markers, CEACAM5 and TROP2, in human antral IM and gastric tumors to assess their potential as molecular markers. Results: In the normal antral mucosa, weak CEACAM5 and TROP2 expression was only observed in the foveolar epithelium, while inflamed antrum exhibited increased expression of both markers. Complete IM exhibited weak CEACAM5 expression at the apical surface, but no basolateral TROP2 expression. On the other hand, incomplete IM demonstrated high levels of both CEACAM5 and TROP2 expression. Notably, incomplete IM with dysplastic morphology (dysplastic incomplete IM) exhibited higher levels of CEACAM5 and TROP2 expression compared to incomplete IM without dysplastic features (simple incomplete IM). In addition, dysplastic incomplete IM showed diminished SOX2 and elevated CDX2 expression compared to simple incomplete IM. CEACAM5 and TROP2 positivity in incomplete IM was similar to that of gastric adenomas and GC. Significant association was found between CEACAM5 and TROP2 positivity and histology of GC. Conclusions: These findings support the concept that incomplete IM is more likely associated with GC development. Overall, our study provides evidence of the heterogeneity of gastric IM and the distinct expression profiles of CEACAM5 and TROP2 in dysplastic incomplete IM. Our findings support the potential use of CEACAM5 and TROP2 as molecular markers for identifying individuals with a higher risk of GC development in the context of incomplete IM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies, melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of β-hexachlorocyclohexane (β-HCH), the most studied organochlorine pesticide, causing cancer induction including melanoma. Methods: We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. Results: We demonstrated that β-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/β-catenin signaling, and AMPK activation, resulting in lowering energy reserve, cell proliferation, and pigment production. Conclusions: In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in its function of melanin production with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Although the role of MMPs in the pathogenesis of melanoma is known, few studies have investigated their role in the development of nevi and dysplastic nevi. This study aims to search the expression differences of MMP-9, MMP-13, MMP-21, and TIMP-1 between malignant melanoma (MM), intradermal nevi (IDN), and dysplastic nevi (DN). METHODS: MMP-9, MMP-13, MMP-21, and TIMP-1 antibodies were studied immunohistochemically for 60 cases in our pathology clinic archive between 2013 and 2014. RESULTS: The MM group had the highest expression percentage and intensity for MMP-9 (p<0.001). There was no statistical significance between MMP-13 expression intensities of lesion cells and stromal cells and stromal expression intensities (p>0.05). MMP-21 lesion staining intensities in DN and MM compared to IDN were statistically significant (p=0.001, p=0.011, respectively). For TIMP-1, there was a significant difference between the IDN and the MM group regarding the staining proportion of lesion cells (p<0.01). There was a statistically significant difference in all groups according to lesion cells’ expression intensity. (IDN-DN p<0.001, IDN-MM p=0.044, DN-MM p<0.001). CONCLUSION: The following markers can be helpful when lesions cannot be differentiated; increased staining proportions and intensity of MMP-9 in both lesion and stromal cells favor MM in cases where MM and IDN cannot be differentiated. The increased MMP-13 staining proportion of lesion cells can favor DN in cases where the pathologist cannot differentiate DN and MM. Intense expression of MMP-21 by lesion cells can be a potential marker for evaluating the lesion in favor of DN in cases where DN and IDN cannot be differentiated. The high expression intensity of TIMP-1 in lesion cells can favor DN in cases where there is ambiguity between DN and MM. High expression proportion and intensity of stromal cells of TIMP-1 can be useable in favor of MM in cases where MM and DN cannot be differentiated. [ABSTRACT FROM AUTHOR]

This document is a letter to the editor discussing patient and doctor observations regarding the reduction of unnecessary excisions and the early detection of melanomas. The letter presents a case study of a 55-year-old male with a history of melanoma and his experience with 3D total body photography and sequential digital dermoscopic imaging. The authors argue that longitudinal photographic surveillance can help reduce overdiagnosis of melanoma and facilitate the detection of evolving and de novo lesions. The letter emphasizes the importance of patient-doctor discussions and the value of anecdotal insights in refining the detection of melanoma. [Extracted from the article]

This article discusses the changes that melanocytic nevi, or moles, undergo during pregnancy. The modifications in nevi during pregnancy are primarily physiological and involve alterations in skin pigmentation. While the exact relationship between pregnancy, nevi changes, and the occurrence of melanomas is not fully understood, it is important for gynecologists to monitor these changes and determine when a dermatology consultation is necessary. The article presents a case study of a woman whose nevus underwent significant changes during pregnancy, prompting a biopsy to rule out malignancy. The study emphasizes the need for close monitoring and timely intervention when there are shifts in dermatoscopic characteristics of pigmented lesions during pregnancy. [Extracted from the article]

Objective: Patients with myotonic muscular dystrophy (MMD) were observed to have numerous basal cell carcinoma (BCC) and abnormal dysplastic nevi (DN) on non‐sun exposed skin. Simultaneously a large study published in the Journal of American Medical Association (JAMA) illustrated that patients with MMD have "overall" an increased risk for cancer development. Based on these findings, this author in 2010 postulated that dysregulation of RNA binding proteins (RBP), responsible for clinical manifestations of MMD, is also responsible for the development of BCC and melanoma. Methods: To report new research elucidating the etiology of melanoma, BCC, MMD‐induced cancers, and potentially other environmentally induced malignancies. Results: Dysregulation of RBP induces aberrant mRNA splicing; recent data indicates that abnormal mRNA splicing not just plays a key role in the pathogenesis of melanoma but is a hallmark of essentially all human malignancies. Conclusion: The author's hypothesis is that ultraviolet (UV) radiation induces DNA damage in intronic regions of a variety of genes. Furthermore, these UV‐induced abnormal DNA dimers, repeats and mutations interfere with normal mRNA splicing thus producing abnormal proteins. These abnormal proteins in turn activate oncogenic pathways such as hedgehog, MAP kinase, and WNT. [ABSTRACT FROM AUTHOR]

This article discusses a case of recurrent asymptomatic reddish-brown pigmented macules on the palms of a furniture retailer. Despite thorough examination and testing, a definitive diagnosis was not established. The author suggests that the pigmentation may be related to Cydnidae pigmentation, a condition caused by burrowing bugs that produce a malodorous chemical secretion. The lesions disappeared spontaneously within two weeks. Dermoscopy was used to evaluate the pigmentation and revealed certain dermoscopic features consistent with previously reported cases. The article emphasizes the importance of awareness among dermatologists about this self-limiting condition and highlights the need for further research on the nature and characteristics of the species involved. [Extracted from the article]

This article discusses a study conducted in Greece on familial melanoma, a type of skin cancer that runs in families. The researchers aimed to identify genetic variations associated with familial melanoma in a Greek cohort and to understand how these variations relate to family and patient characteristics. The study found that the CDKN2A gene was the most common gene implicated in familial melanoma in Greece, with a higher frequency of pathogenic variations compared to other Mediterranean populations. Carriers of these variations were more likely to develop multiple primary melanomas at a younger age and had an increased number of nevi and atypical nevi. The study highlights the importance of genetic counseling and testing for families with a history of melanoma. [Extracted from the article]

Background: Atypical chronic myeloid leukemia (aCML) is a BCR::ABL1 negative myelodysplastic/myeloproliferative neoplasm with poor overall survival. Some patients can be treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) from suitable donors. The effectiveness of decitabine or azacitidine (AZA) has recently been reported; however, their combined efficacy with selinexor has not yet been reported. Case description: In this study, we report the case of a patient with aCML who was successfully treated with selinexor combined with AZA. A 67-year-old man with a history of gastric mucosa-associated lymphoid tissue (MALT) lymphoma was admitted to the hospital with fatigue and emaciation. He was diagnosed with aCML and no longer responded to decitabine treatment after undergoing seven cycles. The patient was subsequently administered hydroxyurea (HU), selinexor, and AZA. After four courses of combination therapy, his blood cell counts improved; he no longer required transfusions and was able to discontinue HU. The patient continued receiving selinexor and AZA without severe complications. This case is the first to show that combinatorial selinexor and AZA therapy can effectively treat aCML. Conclusion: Our case sheds light on the importance of selinexor and AZA combined therapy in the exploration of new treatment strategies for aCML. Moreover, this treatment approach offers the possibility of bridging with allo-HSCT. [ABSTRACT FROM AUTHOR]