cyclin-d1 and Hair-Diseases

Pilomatrix carcinoma, a malignant counterpart of pilomatrixoma, is a rare skin neoplasm composed of basaloid and shadow cells that characterize differentiation toward the hair matrix. The authors present a case of pilomatrix carcinoma of the clitoris, a very unusual location not previously reported. Diagnostic criteria and differential diagnoses are discussed. Pilomatrix carcinoma should be differentiated from benign pilomatrixoma and other carcinomas with shadow cells, including basal cell carcinoma with matrical differentiation and metastases of visceral carcinomas with shadow cells.

Topics: beta Catenin; Biomarkers, Tumor; Carcinoma, Basal Cell; Cell Nucleus; Clitoris; Cyclin D1; Diagnosis, Differential; Fatal Outcome; Female; Hair Diseases; Humans; Pilomatrixoma; Skin Neoplasms; Vulvar Neoplasms

Mutations in beta-catenin are present in benign pilomatrixomas. beta-catenin is a downstream effector in the WNT-signalling pathway, acting as a signal for differentiation and proliferation. Mutations in CTNNB1, the gene encoding beta-catenin, are present in a wide variety of benign and malignant neoplasms. We examined beta-catenin in a series of pilomatrix carcinomas (15 cases) by using immunohistochemistry and DNA sequencing of exon 3 from CTNNB1, and compared these to a series of benign pilomatrixomas (13 cases). All 11 pilomatrix carcinomas available for examination showed nuclear localization of beta-catenin and mutations in exon 3 similar to those demonstrated in benign pilomatrixomas. Two of 11 pilomatrix carcinomas showed significant nuclear accumulation of p53, whereas this was absent in all 13 benign pilomatrixomas. Expression of nuclear cyclin D1 was similar in both benign pilomatrixomas and pilomatrix carcinomas. Clinical follow-up from the 15 malignant cases reported in this study and by others indicates that wide excision offers superior control of local recurrence, compared to simple excision. Immunohistochemical and molecular analysis of beta-catenin reveals that both pilomatrix carcinomas and benign pilomatrixomas harbour mutations in beta-catenin. This implies a common initial pathogenesis and is compatible with the proposition that pilomatrix carcinomas may at least on occasion arise from their benign counterparts.

Topics: Adolescent; Adult; Aged; Amino Acid Sequence; beta Catenin; Cell Nucleus; Child; Cyclin D1; Cytoskeletal Proteins; DNA Mutational Analysis; Female; Hair Diseases; Humans; Immunohistochemistry; Male; Mutation; Pilomatrixoma; Polymerase Chain Reaction; Skin Neoplasms; Trans-Activators; Tumor Suppressor Protein p53

The proliferation of keratinocytes in the hair follicle varies from slowly cycling, intermittently proliferating stem cells in the bulge to rapidly proliferating, transient cells in the bulb. To better understand the biological differences between these two compartments, we sought to identify differentially expressed genes using cDNA macroarray analysis. Cyclin D1 was one of 13 genes increased in the bulge compared to the bulb, and its differential expression was corroborated by quantitative real-time polymerase chain reaction (PCR) on the original samples. Using immunohistochemical staining, laser-capture microdissection (LCM) and quantitative real-time PCR, we localized cyclin D1 to the suprabasal cells of the telogen bulge and anagen outer root sheath (ORS). Surprisingly, cyclin D1, D2, and D3 were not detectable by immunohistochemistry in the rapidly proliferating hair-producing cells of the anagen bulb (matrix cells), while these cells were strongly positive for Ki-67 and retinoblastoma protein. In contrast, pilomatricoma, a tumor thought to be derived from matrix cells, was positive for cyclin D1, D2, and D3. Our results suggest that cyclin D1 may mediate the proliferation of stem cells in the bulge to more differentiated transient amplifying cells in the suprabasal ORS. In contrast, non-cyclin D1-proteins appear to control cell division of the highly proliferative bulb matrix cells. This non-cyclin D1-mediated proliferation may provide a protective mechanism against tumorigenesis, which is overridden in pilomatricomas. Our data also demonstrate that the combination of DNA macroarray, LCM and quantitative real-time PCR is a powerful approach for the study of gene expression in defined cell populations with limited starting material.

Topics: Computer Systems; Cyclin D1; Cyclin D2; Cyclin D3; Cyclins; Dissection; Gene Expression; Hair Diseases; Hair Follicle; Humans; Oligonucleotide Array Sequence Analysis; Pilomatrixoma; Polymerase Chain Reaction; Skin Neoplasms; Tissue Distribution