Towards diagnostic criteria for malignant deep penetrating melanocytic tumors using single nucleotide polymorphism array and next-generation sequencing.

Cutaneous deep penetrating melanocytic neoplasms frequently simulate melanoma and might occasionally progress to metastatic melanoma. Distinguishing deep penetrating nevi (DPN) and deep penetrating melanocytomas (DPM) from malignant deep penetrating tumors (MDPT) is difficult based on histopathology alone, and diagnostic criteria for MDPT are currently lacking. Using a molecular workup, we aimed to provide readily available diagnostic tools for classification of deep penetrating tumors. We used clinical follow-up and Single Nucleotide Polymorphism (SNP) array for tumor classification of 20 deep penetrating neoplasms to identify associations with histopathological, immunohistochemistry, and NGS findings. Ten neoplasms were classified as MDPT, four as DPM, and six as DPN. Two MDPT showed metastases. The following parameters were statistically significantly associated with MDPT: severe nuclear atypia (risk ratio [RR] 2.9, p < 0.05), absence of a nevus component (RR 10.0, p = 0.04), positive PRAME expression (RR 9.0, p = 0.02), complete loss of p16 expression (RR 3.5, p = 0.003), TERT-p and APC mutations (RR 11.0, p = 0.01 and RR 2.7, p = 0.002, respectively), and ≥1 additional pathogenic mutation (RR 9.0, p = 0.02). Ki-67 expression ≥ 5% was not significantly associated with MDPTs, although it was <5% in all DPNs. Three MDPT did not show nuclear ß-catenin expression despite having a CTNNB1 (n = 2) or an APC mutation (n = 1). Our findings suggest that complete loss of p16 and positive PRAME expression, a driver mutation in APC, ≥ 1 additional pathogenic mutation, especially in TERT-p, support an MDPT diagnosis in deep penetrating neoplasms. Besides severe nuclear atypia and possibly severe inflammation, we did not identify specific histopathological criteria for malignancy. Non-aberrant nuclear ß-catenin expression might not exclude a deep penetrating signature in MDPT.

Diving with psychotropic medication: review of the literature and clinical considerations.

This review discusses the safety concerns associated with diving while using psychotropic medication and the limited literature available on the topic. Despite the risks, some divers continue to dive while taking these medications, and their reasons for doing so are unclear. The exact mechanisms of action of these drugs in hyperbaric environments are poorly understood. While current standards and advice for fitness-to-dive assessments are based on limited evidence and expert opinion, developing evidence-based strategies could improve patient care and optimise diving safety. This review appraises relevant literature in diving medicine and provides clinical perspectives for diving physicians conducting fitness-to-dive assessments on patients using psychotropic medication.

[Melanocytoma, an intermediate entity between nevus and melanoma: implications of the WHO classification of melanocytic skin tumours]. / Melanocytoom, intermediair tussen naevus en melanoom.

The WHO classification of melanocytic skin tumours published in 2018 describes a new classification with nine different pathways based on molecular driver mutations, localization, clinical context and solar damage. The dichotomous concept of benign (nevus) versus malignant (melanoma) is replaced by a gradual concept starting with a benign nevus with progression into low to high grade intermediate melanocytic lesions, called melanocytoma, and ending at melanoma. The current European recommendation is (re-)excision with 2-5mm margin of low grade melanocytoma and with 5-10mm margin of high grade melanocytoma. Low grade melanocytoma needs no follow-up. For high grade melanocytoma a follow-up for at least 5 years every 6 months is recommended. Routine sentinel node procedure is not indicated. If diagnosis melanoma cannot be ruled out the lesions have to be treated as melanoma. Correct classification of a melanocytoma is a diagnostic challenge, but of high importance for therapeutic choices and prognosis.

Genome-wide copy number variations as molecular diagnostic tool for cutaneous intermediate melanocytic lesions: a systematic review and individual patient data meta-analysis.

Cutaneous intermediate melanocytic neoplasms with ambiguous histopathological features are diagnostically challenging. Ancillary cytogenetic techniques to detect genome-wide copy number variations (CNVs) might provide a valuable tool to allow accurate classification as benign (nevus) or malignant (melanoma). However, the CNV cut-off value to distinguish intermediate lesions from melanoma is not well defined. We performed a systematic review and individual patient data meta-analysis to evaluate the use of CNVs to classify intermediate melanocytic lesions. A total of 31 studies and 431 individual lesions were included. The CNV number in intermediate lesions (median 1, interquartile range [IQR] 0-2) was significantly higher (p<0.001) compared to that in benign lesions (median 0, IQR 0-1) and lower (p<0.001) compared to that in malignant lesions (median 6, IQR 4-11). The CNV number displayed excellent ability to differentiate between intermediate and malignant lesions (0.90, 95% CI 0.86-0.94, p<0.001). Two CNV cut-off points demonstrated a sensitivity and specificity higher than 80%. A cut-off of ≥3 CNVs corresponded to 85% sensitivity and 84% specificity, and a cut-off of ≥4 CNVs corresponded to 81% sensitivity and 91% specificity, respectively. This individual patient data meta-analysis provides a comprehensive overview of CNVs in cutaneous intermediate melanocytic lesions, based on the largest pooled cohort of ambiguous melanocytic neoplasms to date. Our meta-analysis suggests that a cut-off of ≥3 CNVs might represent the optimal trade-off between sensitivity and specificity in clinical practice to differentiate intermediate lesions from melanoma.