Robin E. Howell

Etiology of fibrous dysplasia and McCune-Albright syndrome

In this paper, the etiology of monostotic fibrous dysplasia and McCune-Albright syndrome is explained. Both monostotic fibrous dysplasia and McCune-Albright syndrome are sporadically occurring disorders in which a mutation in the GNAS1 gene occurs postzygotically in a somatic cell. All cells descended from the mutated cell can manifest features of McCune-Albright syndrome or fibrous dysplasia. Cells descended from non-mutated cells develop into normal tissues. Thus, the clinical pattern is variable in distribution and appearance. More generalized vs more localized expression depend on (a) how small or how large the cell mass is during embryogenesis when the mutation occurs and (b) where in the cell mass the mutation occurs. Topics discussed include G proteins and their receptors, cycling of stimulatory G protein between active and inactive forms, and specific mutations in GNAS1. We also discuss four possibilities: (a) Are there masked mutations? (b) Are there effects of imprinting? (c) Are there non-classical mutations? and (d) Is fibrous dysplasia a neoplasm?

Extranodal oral lymphoma. Part II. Relationships between clinical features and the Lukes-Collins classification of 34 cases

Thirty-four cases of extranodal oral lymphoma were classified according to the Lukes-Collins system on the basis of morphology and immunoperoxidase staining, and these findings were correlated with the clinical features of each case. Vestibule and gingiva, mandible, palatal soft tissue, and maxilla were, respectively, the most common locations for all the tumors, and the most frequently stated signs and symptoms were swelling, pain, paresthesia, anesthesia, ulceration, and discoloration. Eighty percent of the lymphomas were composed of transformed follicular center cells or postfollicular cells. Patients with lymphomas composed of nontransformed follicular center cells had a greater mean age than those with tumors of transformed follicular center cells or postfollicular cells, and a trend of decreasing age with increasing B cell transformation of the tumor type was seen. Within each Lukes-Collins category, the percentage of tumors that presented with bone involvement increased as the tumor category advanced in B cell transformation. Follow-up information indicated that the prognosis was poorest with postfollicular lymphomas, intermediate with transformed follicular center cell lymphomas, and best with nontransformed follicular center cell lymphomas.

Extranodal oral lymphoma. Part I. A morphologic and immunoperoxidase study of 34 cases

Thirty-four cases of oral lymphoma were classified by the Lukes-Collins system on the basis of morphology and immunoperoxidase staining. Ninety-seven percent of these were morphologically identified as B-cell neoplasms: 6% SCFCC, 9% LCFCC, 26% SNCFCC, 24% LNCFCC, 12% IBS, and 18% malignant plasma cell proliferations. Monoclonal immunoperoxidase staining for cytoplasmic immunoglobulin was positive in 41% of the cases overall, but 100% of the cases of immunoblastic sarcoma and malignant plasma cell lesions stained positively.

Human papillomavirus type 16 in an oral squamous carcinoma and its metastasis

DNA was extracted from fresh frozen tissues of eight patients with primary oral squamous carcinoma. Samples of normal oral mucosa were available in seven cases and metastatic tumor in two cases. The samples were probed for human papillomavirus types 16 and 18 by Southern hybridization. In one case of squamous carcinoma of the floor of the mouth, human papillomavirus type 16 was identified in the primary tumor and a lymph node metastasis, but it was not detectable in normal oral mucosa from this patient. Human papillomavirus DNA was not detected in any other sample of primary tumor, metastasis, or normal oral mucosa. Restriction enzyme digests of the human papillomavirus positive primary tumor and its metastasis revealed that the viral DNA was identical to the prototype human papillomavirus type 16 and present at 50 to 100 copies per cell in an episomal state with no evidence of integration into the host DNA. Compared to the human papillomavirus DNA in the primary tumor, the viral DNA in the metastasis was of the same type, in the same physical state, and at the approximately the same copy number. The consistent maintenance of human papillomavirus DNA in metastases from human papillomavirus positive primary tumors supports the hypothesis that human papillomaviruses are cofactors in the pathogenesis of some carcinomas.

CEA immunoreactivity in odontogenic tumors and keratocysts.

Forty-five oral tumors and cysts were stained immunohistochemically for the presence of carcinoembryonic antigen (CEA). CEA, or a CEA-like antigen that is not nonspecific cross-reacting antigen (NCA), was demonstrated in the majority of aggressive or malignant tumors showing squamous differentiation, including cases of ameloblastoma, odontogenic carcinoma, and squamous carcinoma. CEA immunoreactivity was also found in cases of odontogenic keratocyst and focally in squamous odontogenic tumors but was not found in any of the ameloblastic fibromas, myxofibromas, odontogenic adenomatoid tumors, malignant melanomas, or apical cysts.

Human X-chromosome inactivation pattern distributions fit a model of genetically influenced choice better than models of completely random choice.

In eutherian mammals, one X-chromosome in every XX somatic cell is transcriptionally silenced through the process of X-chromosome inactivation (XCI). Females are thus functional mosaics, where some cells express genes from the paternal X, and the others from the maternal X. The relative abundance of the two cell populations (X-inactivation pattern, XIP) can have significant medical implications for some females. In mice, the ‘choice’ of which X to inactivate, maternal or paternal, in each cell of the early embryo is genetically influenced. In humans, the timing of XCI choice and whether choice occurs completely randomly or under a genetic influence is debated. Here, we explore these questions by analysing the distribution of XIPs in large populations of normal females. Models were generated to predict XIP distributions resulting from completely random or genetically influenced choice. Each model describes the discrete primary distribution at the onset of XCI, and the continuous secondary distribution accounting for changes to the XIP as a result of development and ageing. Statistical methods are used to compare models with empirical data from Danish and Utah populations. A rigorous data treatment strategy maximises information content and allows for unbiased use of unphased XIP data. The Anderson–Darling goodness-of-fit statistics and likelihood ratio tests indicate that a model of genetically influenced XCI choice better fits the empirical data than models of completely random choice.

Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2

The gene dosage inequality between females with two X-chromosomes and males with one is compensated for by X-chromosome inactivation (XCI), which ensures the silencing of one X in every somatic cell of female mammals. XCI in humans results in a mosaic of two cell populations: those expressing the maternal X-chromosome and those expressing the paternal X-chromosome. We have previously shown that the degree of mosaicism (the X-inactivation pattern) in a Canadian family is directly related to disease severity in female carriers of the X-linked recessive bleeding disorder, haemophilia A. The distribution of X-inactivation patterns in this family was consistent with a genetic trait having a co-dominant mode of inheritance, suggesting that XCI choice may not be completely random. To identify genetic elements that could be responsible for biased XCI choice, a linkage analysis was undertaken using an approach tailored to accommodate the continuous nature of the X-inactivation pattern phenotype in the Canadian family. Several X-linked regions were identified, one of which overlaps with a region previously found to be linked to familial skewed XCI. SA2, a component of the cohesin complex is identified as a candidate gene that could participate in XCI through its association with CTCF.

Qualitative assessment of the emotional and behavioural responses of haemophilia A carriers to negative experiences in their medical care

Summary.  Previous discussions with haemophilia A (HA) carriers suggested that carriers may experience inappropriate care, resulting in poor relationships with healthcare providers (HCPs; principally physicians and nurses), and unfortunate and extreme emotional and behavioural responses. This was a qualitative study to explore medical experiences of HA carriers and their emotional and behavioural responses. Eleven HA carriers and five Haemophilia Treatment Centre nurses were interviewed. Themes were identified using QSR NVivo 8.0. Carriers and nurses reported HA‐related bleeding symptoms in carriers, including life‐threatening haemorrhage following injury or medical intervention. Menorrhagia was common and distressing. Negative carrier experiences were related in the determination of genotypic and phenotypic status, management, precautions and HCP attitude, including dismissing carriers’ symptoms, concerns or requests for care. Carriers responded with mistrust, lost confidence, disappointment, fear, anxiety, doubt of self or child, discussing experiences, avoidance of healthcare and self‐treatment. Dismissive HCP attitudes, ignorance about bleeding disorders in women and unique aspects of the carrier population appear to make errors more likely. This study indicates that carriers experience inappropriate care and encounter dismissive attitudes, and respond emotionally and behaviourally. Our model suggests that systematic medical errors aggravate a negative feedback loop leading to negative emotional and behavioural responses and worsening carrier care. Improved carrier care policies and increased awareness of women’s bleeding disorders may improve this situation. Further research is needed to determine whether the themes identified in this study accurately reflect the experiences of carriers in general.

Human cervical and hamster oral epithelial neoplasia—Colposcopic similarities

Epithelial dysplasias and squamous carcinomas were experimentally produced in the cheek pouches of Syrian hamsters. These lesions were observed and photographed in the living animals with the aid of a stereoscopic microscope at magnifications of 20 and 40 times. Very apparent similarities were noted in the vascular patterns and epithelial configurations between the hamster oral dysplasias and carcinomas and the corresponding lesions seen in published cases of cervical intraepithlial neoplasia and invasive squamous carcinoma. It is speculated that these similarities reflect common factors in the interaction between neoplastic squamous epithelium and its blood supply. These findings are important in understanding the biology of cervical neoplasia and may be useful in the diagnosis and management of human oral neoplasia.

Starch artifacts in oral cytologic specimens

Starch powder from surgical gloves is a common artifact that may superficially resemble atypical epithelial cells or spores in oral cytologic specimens. This article describes the distinguishing features of starch granules visible under a light microscope and discusses their clinical relevance.