Although trichoepitheliomas (TEs) are commonly regarded as benign tumors of follicular origin, the natural history of multiple familial trichoepitheliomas (MFT) and their risk for malignancy has been unclear. We describe a 57-year-old male with numerous skin-colored firm papules and plaques present on the central face since 6 years of age. Recently, some lesions had enlarged and ulcerated. Other family members were similarly affected. Biopsies from multiple lesions showed TEs both alone and associated with basal cell carcinoma (BCC) in the same section, suggesting the secondary development of BCCs within TEs. Many prior reports of BCCs arising within TEs in patients with presumed MFT were likely misdiagnosed cases of nevoid BCC. This report is a compelling example of MFT in which BCCs evolved secondarily. Awareness of the potential for the evolution of carcinoma in patients with MFT is important in the management of these patients.
"Conclusions may be presumptuous given that BCC is a common cancer (Lee et al., 2005). However, Pincus et al. reported a patient in which multiple BCCs originated exclusively within the field of his multiple trichoepitheliomas with histopathologic sections showing TE and BCC in direct continuity, supporting transformation of trichoepitheliomas to BCC (Pincus et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 germline CYLD mutations have been reported, occurring in exons 9-20, in 73 families with diverse ethnic and racial backgrounds. Of 51 mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin (Ub)-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma (MFT). CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the nuclear factor (NF)-kappaB and c-Jun N-terminal kinase (JNK) pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked Ub chains but has been shown to act on K48-linked Ub chains as well. In 2008, the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD's unique specificity for K63-linked Ub chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, antimicrobial defense, and inflammation.
Human Mutation 07/2009; 30(7):1025-36. DOI:10.1002/humu.21024 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Basal cell carcinoma (BCC) is the most common type of skin cancer treated by the dermatologic surgeon. The discovery that patients with the nevoid BCC syndrome had mutations in the human homologue of the Drosophila patched gene led to a rapid increase in our understanding of the pathogenesis of BCC. It is theorized that altered regulation at multiple steps in the patched signal transduction pathway may contribute to the development of BCC. This pathway also plays an essential role in embryonic hair follicle development and during the hair cycle. Taken together, a considerable body of evidence suggests that at least some BCC may be derived from deregulated patched signaling in hair follicle stem cells.
To review evidence of a follicular derivation of BCC and to highlight emerging therapeutic strategies to block deregulated patched signaling in BCC.
Deregulation of the patched signal transduction pathway is present in the vast majority of human BCCs. Pharmacologic inhibitors of this pathway may offer a therapeutic strategy to block tumor growth. The author has indicated no significant interest with commercial supporters.
Dermatologic Surgery 07/2009; 35(9):1311-23. DOI:10.1111/j.1524-4725.2009.01236.x · 2.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The authors report a case of Brooke-Spiegler syndrome (BSS) with a novel germline CYLD mutation and various somatic mutations identified in the lesional tissues. The patient was a 46-year-old man with multiple lesions on the face. The available histopathological material included 24 trichoepitheliomas, 2 large nodular basal cell carcinomas (BCCs), 2 spiradenomas, 1 spiradenocylindroma and 1 trichoblastoma composed of large and small nodules with prominent clear cell differentiation. Whereas one of the two BCCs manifested a conventional morphology, the second neoplasm additionally showed foci with high grade cytological features characterized by marked pleomorphism and numerous mitotic figures. There were also numerous signet ring cells and cells containing intracytoplasmic eosinophilic inclusions. The germline mutation was a substitution mutation c.1684 + 1G> A. Somatic mutations were investigated in eight tissue blocks from which high quality genomic DNA had been successfully extracted. Somatic mutations included loss of heterozygosity (LOH) in four lesions and a single sequence mutation, namely a single base deletion c. 2322delA causing a frameshift mutation E774DfsX2. LOH occurred in both BCCs, one trichoepithelioma and one spiradenoma. In the remaining three lesions, the somatic event remained undetected.
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