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The epidermal growth factor receptor (EGFR) is activated in skin cells following UV irradiation, the primary cause of nonmelanoma skin cancer. The EGFR inhibitor AG1478 prevented the UV-induced activation of EGFR and of downstream signaling pathways through c-Jun NH 2 -terminal kinases, extracellular signal-regulated kinases, p38 kinase, and phosphatidylinositol 3-kinase in the skin. The extent to which the UV-induced activation of EGFR influences skin tumorigenesis was determined in genetically initiated v-ras Ha transgenic Tg.AC mice, which have enhanced susceptibility to skin carcinogenesis. Topical treatment or i.p. injection of AG1478 before UV exposure blocked the UV-induced activation of EGFR in the skin and decreased skin tumorigenesis in Tg.AC mice. AG1478 treatment before each of several UV exposures decreased the number of papillomas arising and the growth of these tumors by f50% and 80%, respectively. Inhibition of EGFR suppressed proliferation, increased apoptotic cell death, and delayed the onset of epidermal hyperplasia following UV irradiation. Genetic ablation of Egfr similarly delayed epidermal hyperplasia in response to UV exposure. Thus, the UVinduced activation of EGFR promotes skin tumorigenesis by suppressing cell death, augmenting cell proliferation, and accelerating epidermal hyperplasia in response to UV. These results suggest that EGFR may be an appropriate target for the chemoprevention of UV-induced skin cancer. (Cancer Res 2005; 65(9): 3958-65)

Context-PTEN, a tumour suppressor gene located on chromosome 10q23, develops somatic mutations in various tumours and tumour cell lines including brain, endometrium, prostate, breast, kidney, thyroid, liver, and melanoma. Objectives-To investigate the mutational profile of this gene further, as well as its role in tumour progression in melanoma. Design, Settings-We examined 21 metastatic melanoma samples for 10q23 allelic losses and PTEN sequence alterations. Additionally, we screened these samples for mutations in CDKN2A, a gene in which alterations are well documented in primary melanoma as well as in the germline of familial melanoma. Results-Loss of heterozygosity (LOH) at 10q23 was observed in 33% (7/21) of the samples tested. We identified four sequence alterations in PTEN (19%) and two in CDKN2A (9.5%). Of interest, only one case showed mutations in both genes. Conclusions-These data support the notion that PTEN alterations occur in some metastatic melanomas, and that mutation of this gene plays a role in the progression of some forms of melanoma. (J Med Genet 2000;37:653-657) Keywords: PTEN; CDKN2A; melanoma A tumour suppressor gene, PTEN (also known as MMAC1 or TEP1), was isolated by mapping homozygous deletions on human chromosome 10q23 from glioblastoma, prostate, and breast cancer cell lines.1-3 Subsequently, a series of mutations in PTEN were identified in sporadic tumours and cancer cell lines from various tissues including brain, endometrium, prostate, breast, kidney, thyroid, liver, and melanoma. 4-11Among all these tumours, PTEN is mutated with a high frequency in advanced stages of gliomas and prostate cancers, and in all stages of endometrial cancers.4 5 12 13 Furthermore, this tumour suppressor gene has been found to be the susceptibility gene for an inherited hamartoma syndrome with an increased risk of malignancy, Cowden syndrome (CS).14-18 Of interest, while breast and thyroid cancers are the most commonly observed tumours in CS, an increased risk of melanoma has not been documented in these patients.PTEN is a phosphatase containing 403 amino acids. It is encoded by nine exons. The phosphatase catalytic domain is between the residues 122-132. Additionally, two potential phosphate acceptor sites are present at residues 233-240 and 308-315.2 The sporadic and germline mutations in PTEN cluster within the presumptive catalytic domain, with many mutations altering residues required for enzymatic activity. 19 Recent studies show that PTEN modulates cell cycle progression and cell survival by regulating phosphoinositide-3-kinase (PI3K) and the protein-Ser/Thr kinase (AKT) signalling pathway. 20-22Loss of heterozygosity (LOH) studies in melanoma have shown a high frequency of loss of 10q. [23][24][25][26] Several studies suggested involvement of chromosome 10q22-10qter in melanoma, 27 as well as 10q24-26 in benign melanocytic proliferations, such as compound and dysplastic naevi.26 28 After the isolation of PTEN from cancer cell lines harbouring homozygous deletions in 10q23, melanoma c...

We apply the term atypical lymphocytic lobular panniculitis to this distinctive form of lymphocytic panniculitis manifesting this light microscopic, phenotypic, and genotypic profile.

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Recognition of this under-reported form of SCC is essential if an inappropriate diagnosis of metastatic SCC, with potentially harmful and inappropriate therapy and investigation, is to be avoided.

: The authors report an unusual case of malignant peripheral nerve sheath tumor with malignant differentiation arising as a subcutaneous nodule in the thigh of a 53-year-old woman with a history significant for neurofibromatosis type 1. Peripheral nerve sheath tumors containing a glandular component, commonly referred to as glandular peripheral nerve sheath tumors, are rare neoplasms found largely in patients with neurofibromatosis type 1. These tumors are frequently malignant; recognition of metastatic potential is made based on the atypical spindle-cell component. Rarely, as in our case, the glandular component is also histologically malignant. Only 5 such tumors have been described in the literature to date. Glandular differentiation, particularly with malignant features, can be a potentially misleading feature when found as a component of malignant peripheral nerve sheath tumors and raise a wide spectrum of differential diagnoses, including metastatic Sertoli-Leydig tumors. The patient is free of disease for 22 months after wide tumor reexcision, which contrasts with previously reported devastatingly poor prognosis of these tumors.

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