Faculty Bibliography

Metastatic melanoma is a disease with a poor prognosis that currently lacks effective treatments. Critical biological features of metastasis include acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma pathogenesis, a genome-wide search using bacterial artificial chromosome array comparative genomic hybridization and single nucleotide polymorphism arrays in a series of 64 metastatic melanoma samples and 20 melanoma cell lines identified increased copy numbers of Gab2 located on 11q14.1. Gab2 is an adaptor protein that potentiates the activation of the Ras-Erk and PI3K-Akt pathways and has recently been implicated in human cancer; however, its role in melanoma has not been explored. In this study, we found that Gab2 was either amplified (approximately 11%) and/or overexpressed (approximately 50%) in melanoma. Gab2 protein expression correlated with clinical melanoma progression, and higher levels of expression were seen in metastatic melanomas compared with primary melanoma and melanocytic nevi. We found that overexpression of Gab2 potentiates, whereas silencing of Gab2 reduces, migration and invasion of melanoma cells. Gab2 mediated the hyperactivation of Akt signaling in the absence of growth factors, whereas inhibition of the PI3K-Akt pathway decreased Gab2-mediated tumor cell migration and invasive potential. Gab2 overexpression resulted in enhanced tumor growth and metastatic potential in vivo. These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis.

BACKGROUND:Germ-line mutations in CYLD are found in patients with familial skin appendage tumours. The protein product functions as a deubiquitinase enzyme, which negatively regulates NF-kappaB and c-Jun N-terminal kinase signalling. Brooke-Spiegler syndrome (BSS) is characterised by cylindromas, trichoepitheliomas and spiradenomas, whereas in familial cylindromatosis (FC) patients present with cylindromas and in multiple familial trichoepitheliomas (MFT) with trichoepitheliomas as the only skin tumour type. Although described as distinct entities, recent studies suggest that they are within the spectrum of a single entity. OBJECTIVE:To investigate the mutation spectrum of CYLD and possible genotype-phenotype correlations. METHODS:25 families including 13 BSS, 3 FC, and 9 MFT families were examined and evaluated for mutations in the CYLD gene. RESULTS:In total, 18 mutations in CYLD, including 6 novel mutations, were identified in 25 probands (72%). The mutation frequencies among distinct phenotypes were 85% for BSS, 100% for FC, and 44% for MFT. The majority of the mutations were insertions, deletions or nonsense mutations leading to formation of truncated proteins. All mutations were located between exons 9 to 20, encoding the NEMO binding site and the catalytic domain. Genotype-phenotype analysis failed to reveal a correlation between the types of mutations and their location within the gene and the patients' phenotypes and disease severity. CONCLUSIONS:This study provides further evidence on the role of CYLD in the pathogenesis of skin appendage tumours characterised by cylindromas, trichoepitheliomas and/or spiradenomas, but the molecular mechanisms of CYLD in skin tumorigenesis and the reasons for phenotypic variability remain to be explored.

BACKGROUND: The gold standard for diagnosing melanocytic neoplasms is by histopathologic examination. However, lack of agreement among expert dermatopathologists in evaluating these tumors has been well established in experimental settings. OBJECTIVE: This study examines the discordance among dermatopathologists in evaluating difficult melanocytic neoplasms in a clinical setting where the diagnosis impacts patient management. METHODS: Retrospective review of consultation reports over a 6-year period. Results: There was complete agreement among the consultants in 54.5% of the cases. However, a high level of disagreement was found in 25% of the cases. LIMITATIONS: The analysis was limited to two consultant dermatopathologists. CONCLUSIONS: There are limitations to the practical applications of histologic criteria for diagnosing difficult melanocytic tumors. It is not malpractice for a pathologist to have rendered a diagnosis that did not predict clinical outcome as long as 'standard of care' has been followed in his/her evaluation of the specimen.

BACKGROUND: Melanoma occurring during childhood and adolescence is rare. Although a few limited studies suggest that the prognosis of childhood melanomas is similar to those in adults, and is dependent on the initial stage of the tumor, there is controversy with respect to the biologic behavior of childhood melanomas. Spitzoid melanoma is a subtype of melanoma with distinct clinical and histopathologic features. The prognosis of spitzoid melanoma in children, despite metastasis, has been suggested to be better than that observed in adults; however, this assertion remains controversial. Whereas a number of spitzoid melanomas with regional lymph node metastasis with no further progression have been reported, cases leading to widespread metastasis and fatal outcomes are also well documented. METHODS: A retrospective review of the literature was conducted between 1949 and 2006. A total of 82 cases of spitzoid melanoma with regional and/or widespread metastasis that occurred in children, 17 years of age and under, were selected for the analysis. RESULTS: The 5-year survival rate in children diagnosed with metastatic spitzoid melanomas between 0 and 10 years of age was 88% compared with 49% in those between 11 and 17 years of age. CONCLUSIONS: The findings support the notion that younger age (< or =10) may be associated with longer survival in children with metastatic spitzoid melanomas.

Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT), originally described as distinct inherited disorders, are characterized by a variety of skin appendage neoplasms. Mutations in the CYLD gene are found in individuals with these syndromes. We describe a single family with affected members exhibiting either the FC or the MFT phenotypes associated with a mutation in the CYLD gene. These findings support the notion that BSS, FC, and MFT represent phenotypic variation of a single defect. Of interest, one of the affected individuals described in this report exhibits a severe phenotype illustrating the morbidity of the disorder.

BACKGROUND: Although the majority of melanomas demonstrate high rates of mutations in B-RAF or N-RAS that result in constitutive activation of the mitogen-activated protein kinase-signaling pathway, emerging data suggest molecular differences among melanoma subtypes. In this study, the authors evaluated the contribution of B-RAF and N-RAS mutations to the pathogenesis of Spitzoid melanomas. METHODS: In total, 33 Spitzoid melanomas were analyzed for clinical and pathologic characteristics as well as for hot-spot mutations in the B-RAF and N-RAS genes. In the majority of patients (28 of 33 melanomas), the tumors were confined to the skin with no evidence of metastasis (average follow-up, 32.5 mos). There were five metastasizing melanomas (5 of 33 tumors) with regional or systemic spread. RESULTS: Of 33 Spitzoid melanomas, only 1 showed the V600E mutation in the B-RAF gene (1 of 33 tumors; 3%). It was noteworthy that none of the metastatic Spitzoid melanomas (0 of 5 tumors; 0%), of which 2 resulted in fatal outcomes, demonstrated mutations in B-RAF or N-RAS. CONCLUSIONS: In contrast to the majority of cutaneous melanomas, activating hot-spot mutations in B-RAF or N-RAS were not involved in the pathogenesis of Spitzoid melanoma. These data suggested that Spitzoid melanoma is a distinct form of melanoma with unknown genes and/or signaling pathways involved in its development.

BACKGROUND: The success of Mohs surgery relies on the ability to histologically differentiate tumor from the normal background tissue of the patient. In most cases of basal cell carcinoma and nonmelanoma skin cancer, this is a relatively straightforward process. However, in distinction, when only subtle histopathologic features differentiate the background tissue from the tumor of interest, the determination of a tumor-free margin becomes more challenging. OBJECTIVE: Our objective is to highlight the histopathologic features that we used to differentiate our patient's near-confluent background of trichoepitheliomas from the basal cell carcinoma that we were extirpating. METHODS: Case report. RESULTS: A 41-year-old white female with a history of familial multiple facial trichoepitheliomas presented for removal of a basal cell carcinoma on her right lower cutaneous lip. Mohs surgery was used to remove the tumor. The characteristic features of basal cell carcinoma and trichoepithelioma were used to differentiate the basal cell carcinoma that we were removing from the surrounding trichoepitheliomatous neoplasia. CONCLUSION: Mohs surgical extirpation of a basal cell carcinoma in a patient with multiple familial trichoepitheliomas requires a clear understanding of the histopathologic features that differentiate a trichoepithelioma from a basal cell carcinoma

In the past decade the molecular basis of many inherited syndromes has been unravelled. This article reviews the clinical and genetic aspects of inherited syndromes that are characterised by skin appendage neoplasms, including Cowden syndrome, Birt-Hogg-Dube syndrome, naevoid basal cell carcinoma syndrome, generalised basaloid follicular hamartoma syndrome, Bazex syndrome, Brooke-Spiegler syndrome, familial cylindromatosis, multiple familial trichoepitheliomas, and Muir-Torre syndrome.