Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.

The strong nuclear MYB-positivity in EMPSGC could be useful as a new surrogate marker, especially in mucin-poor EMPSGC cases. Additionally, the staining of PCMC revealed absent MYB-expression leading to the conclusion that EMPSGC might not represent a precursor lesion for primary cutaneous mucinous carcinoma.

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We describe an autosomal-dominant syndrome characterized by multiple non-pigmented, exophytic melanocytic nevi and an increased susceptibility for melanoma, caused by germline mutations in the histone deubiquitinase BAP1. To identify the causative alterations, we performed comprehensive genomic analyses in two unrelated families with numerous dermal nevi composed largely of large, epithelioid melanocytes with abundant amphophilic cytoplasm and large, pleomorphic, vesicular nuclei with prominent nucleoli. Both families each had one proband with uveal melanoma, and three probands in one family had cutaneous melanoma. Array-based comparative genomic hybridization (aCGH) revealed losses of parts of or the entire chromosome 3 in 11 of 22 neoplasms studied. Genotypic analyses revealed that the deletions invariably affected the chromosome from the unaffected parent. Genome partitioning of the minimally deleted region on chromosome 3p21 followed by massively parallel sequencing revealed two different inactivating germline mutations of the BAP1 tumor suppressor gene that in both families segregated with the phenotype. In almost all tumors the remaining wild type BAP1 allele was eliminated by deletion, separate inactivating mutations, or loss of heterozygosity. 35 of 40 nevi (88%) showed mutations in BRAF, while the uveal melanomas had mutations in GNAQ. Our data identify BAP1 as a highly penetrant susceptibility gene for melanocytic neoplasia. Somatic BAP1 mutations have recently been reported in uveal melanoma and linked to the metastatic phenotype. Our observation of frequent bi-allelic inactivation of BAP1 in nevi indicates that the role of BAP1 in melanocytic neoplasia is more complex, and may differ depending on other factors such as the type of melanocyte (uveal or cutaneous) and the co-existing oncogenic mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-125. doi:10.1158/1538-7445.AM2011-LB-125

Spiradenocarcinoma (SC) is a very rare malignant skin adnexal tumor with sweat gland differentiation that develops from a pre‐existing spiradenoma, cylindroma, or hybrid tumor called spiradenocylindroma, or arises de novo. We present two exceptionally rare SC cases showing sarcomatous differentiation; we also discuss the clinicopathologic features of SC, as well as its differential diagnoses and available therapeutic modalities. Given the aggressive behavior of SC, rapid diagnosis and complete removal of the tumor with tumor‐free margins is mandatory. Owing to the marked morphological heterogeneity of individual SC cases, dermatopathologists must be familiar with the different possible histopathologic manifestations of this neoplasm.