Genome-wide association studies identified a melanoma- and nevus count-associated locus on chromosome band 9q34.13. Fine-mapping and melanocyte expression data collectively suggest two potential causal genes with opposite association with risk: higher levels of Rap guanine nucleotide exchange factor 1 (RAPGEF1) and lower levels of uridine-cytidine kinase 1 (UCK1). Colocalization analyses and conditional TWAS suggest multiple causal cis -regulatory sequence variants in partial linkage disequilibrium (LD) to each other. Melanocyte capture-HiC and CRISPR-inhibition demonstrated regulatory interactions between fine-mapped variants and the RAPGEF1 and UCK1 promoters. Focusing on RAPGEF1 , we demonstrate RAPGEF1 expression promotes melanocyte growth and drives malignant transformation of human immortalized melanocytes. Following treatment with human EGF, RAPGEF1 overexpression activated both RAP1 and RAS. Further, we show RAPGEF1 expression is significantly enriched in melanomas lacking strongly activating RAS-MAPK mutations, suggesting that RAPGEF1 may promote oncogenic RAS-MAPK signaling in melanomas. Furthermore, in these tumors, we provide preliminary evidence to support the prognostic relevance of RAPGEF1 expression in patients lacking RAS or BRAF mutations. Together with other recent studies, these data suggest that germline variation influencing RAS activation may play a key role in nevus development and melanoma risk.

Spitz tumors represent a heterogeneous group of melanocytic neoplasms ranging from benign Spitz nevi to malignant spitzoid melanoma. Atypical Spitz tumors (ASTs) occupy an intermediate category with uncertain biological potential and pose significant diagnostic challenges, particularly in pediatric patients. We report the case of a 14-year-old girl presenting with a recently changing pigmented lesion on the upper back. Histopathologic examination revealed an asymmetric melanocytic proliferation composed predominantly of epithelioid cells with limited mitotic activity and evidence of dermal maturation. Immunohistochemistry showed diffuse Melan-A and SOX10 positivity, retained p16 expression, a gradient HMB45 staining pattern, and negative PRAME expression. For diagnostic purpose, as a part of diagnosis, next-generation sequencing was performed and identified a RET::MXT1 gene fusion in the absence of additional pathogenic mutations or copy number alterations. To our knowledge, this is the first reported case showing this type of RET fusion. This case highlights the importance of an integrated morphologic, immunophenotypic, and molecular diagnostic approach in atypical spitzoid lesions. Identification of an isolated RET fusion supports classification within the Spitz tumor spectrum and provides valuable information for risk stratification and clinical management in pediatric patients.

Nevus lipomatosus superficialis (NLS) is an uncommon benign hamartoma characterized by ectopic adipocytes within the dermis and may present with features that overlap clinically with other soft, pedunculated, or cerebriform lesions. We report a rare presentation with mixed morphologic traits that created diagnostic uncertainty on gross examination. The lesion demonstrated atypical surface contour and texture, prompting multimodal evaluation to clarify the differential diagnosis and support safe outpatient management. Point-of-care ultrasound (POCUS) was used to evaluate lesion architecture and vascularity. Findings provided real-time, noninvasive support for benign morphology and informed procedural planning. Subsequent histopathologic analysis established the diagnosis by demonstrating dermal adipose deposition consistent with NLS. This case underscores the value of integrating gross examination with sonographic assessment and histopathology when cutaneous lesions have overlapping clinical features. In addition, it contributes to the limited literature describing ultrasound findings in NLS. Incorporating POCUS into the assessment of atypical cutaneous growths may improve diagnostic confidence, reduce unnecessary escalation of care, and support efficient, safe treatment in outpatient settings.

Nevus lipomatosus cutaneous superficialis (NLCS) is a rare benign cutaneous hamartoma characterised by the presence of mature adipose tissue within the dermis. We report the case of a woman in her mid-20s who presented with an uncomfortable progressively enlarging lesion over the gluteal region. Histopathological examination of a skin biopsy demonstrated mature adipocytes interspersed among dermal collagen bundles, confirming the diagnosis. The patient underwent surgical excision for symptomatic relief, with no recurrence at one-year follow-up. This case underscores the importance of clinicopathological correlation in differentiating NLCS from other dermal and subcutaneous nodular lesions.

Blue rubber bleb nevus syndrome is a rare congenital vascular malformation disease characterized by venous malformations affecting multiple organs throughout the body. Cases complicated with esophageal cancer are exceedingly uncommon. In April 2025, Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine, admitted a patient with blue rubber bleb nevus syndrome complicated with esophageal cancer. The patient was treated using da Vinci robotic-assisted surgery. This system may provide a new solution for such complex cases due to its precision and minimally invasive capabilities.