Showing papers by "George L. Mutter published in 1997"

Disseminated peritoneal leiomyomatosis. Clonality analysis by X chromosome inactivation and cytogenetics of a clinically benign smooth muscle proliferation.

Abstract: Disseminated peritoneal leiomyomatosis (DPL, leiomyomatosis peritonealis disseminata) is a rare condition in which multiple histologically benign smooth muscle tumorlets diffusely stud peritoneal and omental surfaces in females, predominantly of reproductive age. Although the distribution of these lesions suggests a metastatic process, DPL generally has a benign clinical course and has been regarded as a metaplastic process. We assessed clonality of 42 tumorlets and 15 normal tissues from four females with DPL by analyzing X chromosome inactivation as indicated by the methylation status of the androgen receptor gene (HUMARA). In each of the four patients, the same parental X chromosome was nonrandomly inactivated in all tumorlets, consistent with a metastatic unicentric neoplasm, or alternatively, selection for an X-linked allele in clonal multicentric lesions. Anomalous demethylation of the marker for X inactivation (HUMARA) was associated with loss of heterozygosity for markers spanning the X chromosome, or monosomy X, in part of one leiomyomatous lesion. Biallelic demethylation of the HUMARA microsatellite polymorphism was also found in one intramural leiomyoma. Two of six DPL lesions karyotyped had cytogenetic abnormalities involving chromosomes 7, 12, and 18, suggesting a pathogenesis in common with uterine leiomyomas.

Pathobiology of vulvar squamous neoplasia.

Abstract: Vulvar squamous carcinoma is an uncommon neoplasm that afflicts a spectrum of women and has been associated with granulomatous vulvar diseases, papillomaviruses, and chronic inflammatory disorders of the vulva. Histopathological, molecular, and epidemiological studies have revealed two subsets of vulvar squamous neoplasia, which are distinguished by their association with human papillomaviruses and patient demographics. This review summarizes the evidence both supporting the diverse pathogenesis of these tumors and the existence of factors that may be common to both groups. Ultimately, the pathway to both human papillomavirus positive and negative vulvar cancers may involve not only obvious precancerous changes but also biological events in the vulvar mucosa that precede the onset of morphological atypia.

Monoclonal origin of vulvar intraepithelial neoplasia and some vulvar hyperplasias.

Abstract: Squamous neoplasms of the female genital tract, including vulvar intraepithelial neoplasia, presumably are derived from a single cell. This study addressed this hypothesis and determined the clonal status of other squamous epithelial alterations associated with vulvar carcinoma, including hyperplasia and lichen sclerosis. X chromosome inactivation patterns of 22 epithelial lesions and matched normal epithelium were determined using a polymerase chain reaction (PCR)-based assay targeting the X-linked human androgen receptor gene (HUMARA). Clonality was inferred by comparing matched lesional and control tissues as follows: 1) monoclonal, if intensity of either PCR product was skewed relative to normal reference epithelium (control), 2) polyclonal, if both lesional and control were unskewed, and 3) unknown, if both lesion and control tissues were skewed toward the same allele. Two cases were excluded because of noninformative homozygous HUMARA alleles. Of 8 vulvar intraepithelial neoplasias analyzed, 7 were scored monoclonal and 1 polyclonal. Of 12 hyperplasias, 6 were monoclonal, including one with lichen sclerosis, 2 were polyclonal, and in 4, the clonal status could not be determined. The PCR-based clonal assay supports a monoclonal derivation for vulvar intraepithelial neoplasia and, in some cases, vulvar hyperplasia, and lichen sclerosis. The finding of monoclonal hyperplasia and lichen sclerosis suggests that clonal expansion may evolve before the development of morphological atypia in these epithelia.

Role of imprinting in abnormal human development

Abstract: Parental-specific differences in the expression of certain genes (imprinting), may be implicated in the pathogenesis of anomalous gestations, but only a minority manifest themselves as malformation syndromes. Delayed or lost gestations are much more frequent sequelae, as are those disorganized to such an extent that they are usually classified as neoplastic rather than developmental processes. Expression levels from imprinted loci are dependent not only on the number of genomic alleles present and their structural integrity, but also on their specific parental origin. Anomalous expression of imprinted genes during development is sometimes caused by imbalanced representation of maternal and paternal contributions, 'uniparental disomy'. Uniparental parthenogenetic or androgenetic gestations form ovarian teratomas or complete hydatidiform moles, respectively--examples of an arrested developmental program. Uniparental disomy of individual chromosomes or portions thereof has been associated with developmental delay or gestational loss. The phenotype of hemizygous mutation or deletion of imprinted genes is modified by the parental origin of the mutant copy, with dichotomous syndromes defined by parental inheritance, as in the Prader-Willi and Angelman syndromes. Lastly, failure of the imprinting process itself, 'loss of imprinting', may quantitatively alter expression levels of normally imprinted transforming or tumor-suppressing genes, thereby increasing risk for developmental tumors such as Wilms' tumor or choriocarcinoma.