John W. Eveson

Molecular changes in oral cancer may reflect aetiology and ethnic origin

Oral cancer, although uncommon in the Western world, accounts for up to 40% of all malignancies in parts of India and South East Asia. Recognised aetiological agents of oral cancer include tobacco and alcohol. This paper reviews the spectrum of molecular changes found in oral squamous cell carcinomas from Western (U.K., U.S.A., Australia) and Eastern (India, S.E. Asia) countries. p53 mutations are common in tumours from the West (47%) but are infrequent in the East (7%). Tumours from India and South East Asia are characterised by the involvement of ras oncogenes, including mutation, loss of heterozygosity (H-ras) and amplification (K- and N-ras), events which are uncommon in the West. The possibility that these genetic differences reflect aetiology and/or ethnic origin is discussed.

Superficial mucoceles: Pitfall in clinical and microscopic diagnosis

Extravasation mucoceles can be so superficial that they are seen as subepithelial blisters. These may rupture and cause superficial painful ulcers, which usually heal quickly. Occasionally such lesions may be seen in association with other mucosal disorders, particularly lichen planus, and a biopsy is undertaken to establish the diagnosis. In addition, the reporting pathologist may make an erroneous diagnosis of a subepithelial vesiculating disorder such as mucous membrane pemphigoid, especially when the clinical history is vague. Eight cases are described that illustrate some of the pitfalls in clinical and microscopical diagnosis of superficial mucoceles.

Epidermoid cyst of the buccal mucosa.

An uncommon case of a large epidermoid cyst arising within the buccal mucosa is described.

Adenosquamous carcinoma of the mouth: a rare variant of squamous cell carcinoma

Adenosquamous carcinoma is a rare tumour in the oral cavity and is characterised histologically by carcinomatous change in surface epithelium, in association with adenocarcinoma affecting the ducts of minor salivary glands. Only a dozen cases have previously been reported in the oral cavity, but all have shown an aggressive course with 60% of patients dying of disease. We report three further cases and review the literature, which suggests that this lesion should be regarded as a high-grade variant of squamous cell carcinoma.

Pyostomatitis vegetans: Oral manifestation of ulcerative colitis

Abstract Two cases of pyostomatitis vegetans, an uncommon oral manifestation of ulcerative colitis, are reported, and the literature is reviewed.

TGF-β1 acts as a tumor suppressor of human malignant keratinocytes independently of Smad 4 expression and ligand-induced G1 arrest

This study examined the role of TGF-β1 in human keratinocyte malignancy. Two carcinoma-derived human oral keratinocyte cell lines, BICR 31 and H314, were selected on the basis of their known resistance to TGF-β1-induced G1 arrest, the presence of wild type TGF-β cell surface receptors and normal Ras. Smad 4 protein was undetectable in both cell lines, but Smad 2 and Smad 3 were expressed at levels comparable with a fully TGF-β responsive cell line, and treatment of the cells with TGF-β1 resulted in the phosphorylation of Smad 2. Treatment with exogenous TGF-β1 resulted in a failure to induce transcription from an artificial Smad-dependent promoter and a failure to down-regulate c-myc, but resulted in an up-regulation of AP-1 associated genes (Fra-1, JunB and fibronectin). Transient transfection of Smad 4 into BICR 31 restored TGF-β1-induced growth inhibition and Smad-dependent transcriptional activation. Protracted treatment of cells with exogenous TGF-β1 resulted in the attenuation of cell growth in vitro. To over-express TGF-β1, both cell lines were transfected with latent TGF-β1 cDNA; neutralization studies of conditioned media demonstrated that whilst the majority of the peptide was in the latent form, a small proportion was present as the active peptide. Cells that over-expressed endogenous TGF-β1 grew more slowly in vitro compared to both the vector-only controls and cells that did not over-express the peptide. Orthotopic transplantation of cells that over-expressed endogenous TGF-β1 to the floor of the mouth in athymic mice resulted in marked inhibition of primary tumor formation compared to controls. Expression of a dominant-negative TGF-β type II receptor in cells that over-expressed endogenous TGF-β1 resulted in enhanced cell growth in vitro and diminished the tumor suppressor effect of the ligand in vivo, indicating that the endogenous TGF-β1 was acting in an autocrine capacity. The results demonstrate that over-expression of endogenous TGF-β1 in human malignant oral keratinocytes leads to growth inhibition in vivo and tumor suppression in vitro by mechanisms that are independent of Smad 4 expression and TGF-β1-induced G1 arrest.

Adult linear immunoglobulin A disease manifesting as desquamative gingivitis

Desquamative gingivitis is a manifestation of various dermatoses, particularly lichen planus and mucous membrane pemphigoid. A rare example of adult linear immunoglobulin A disease manifesting as desquamative gingivitis is presented. Although the initial clinical features were typical of desquamative gingivitis, the persistence of ulceration after dental extractions was unusual, and the management of the oral lesions proved difficult. The clinical, immunopathologic, and therapeutic aspects of linear immunoglobulin A dermatoses are reviewed.

Attenuated type II TGF-beta receptor signalling in human malignant oral keratinocytes induces a less differentiated and more aggressive phenotype that is associated with metastatic dissemination.

We examined the effect of stable transfection of dominant negative TβR‐II (dn TβR‐II) cDNA in a human oral carcinoma cell line that contained normal Ras and was growth inhibited by TGF‐β1. Two clonal cell lines containing dn TβR‐II were isolated and compared to the vector‐only control and parent cell line. The treatment of cells with exogenous TGF‐β1 resulted in a decrease in ligand‐induced growth inhibition and loss of c‐myc downregulation in test cells compared to controls; transcriptional activation of certain genes including fra‐1 and collagenase was retained. Cells containing dn TβR‐II grew faster in monolayer culture, expressed less keratin 10 and exhibited increased motility and invasion in vitro compared to control cell lines. Endogenous TGF‐β1 production and the regulation of MMP‐2 and MMP‐9 by TGF‐β1 remained unchanged. After orthotopic transplantation to the floor of the mouth in athymic mice, cells containing dn TβR‐II formed comparable numbers of primary tumours at the site of inoculation as controls but the tumours were less differentiated as demonstrated by the absence of keratin 10 immunostaining. Further, metastatic dissemination to the lungs and lymphatics was more evident in grafts of cells containing dn TβR‐II than controls. Taken together, the results demonstrate that attenuation of TGF‐β signalling through transfection of dn TβR‐II cDNA leads to an enhanced growth rate, a loss of tumour cell differentiation and an increase in migration and invasion, characteristics that corresponded to the development of the metastatic phenotype.

Oral epithelial dysplasia: clinical characteristics of western European residents

To detail the clinical presentation of oral epithelial dysplasia in a large cohort of residents in western Europe. Descriptive statistical analysis of the data were calculated using chi-square and Fishers exact tests. Oral epithelial dysplasia manifested typically as a white or mixed red and white lesion on the tongue, buccal mucosa or floor of mouth. The peak age of presentation of oral epithelial dysplasia was the 6th decade. Most clinically detected lesions had only mild oral epithelial dysplasia. Although uncommon, lesions with severe dysplasia were most likely to arise on the floor of mouth or lateral border of tongue. Oral epithelial dysplasia is likely to manifest as a solitary white patch, but it is not possible to accurately predict the likely degree of dysplasia from the clinical features of such lesions.

Deregulated Bag‐1 protein expression in human oral squamous cell carcinomas and lymph node metastases

Bag‐1 is an anti‐apoptotic protein that promotes metastasis in some tumour cell types. To determine whether Bag‐1 expression is altered in 64 oral squamous cell carcinomas, tumour samples were compared with 17 samples of normal oral epithelium. Normal oral epithelia had pronounced nuclear staining in the basal and maturation layers and weak cytoplasmic staining that was most pronounced in the basal and suprabasal layers. Oral squamous cell carcinomas demonstrated a tendency for reduced nuclear staining intensity (p=0.036). Cytoplasmic staining intensity was not significantly different between tumour and normal tissue. However, many tumours were observed to have less of a difference between nuclear staining intensity and cytoplasmic staining intensity than normal oral epithelium. Furthermore, in lymph node metastases, cytoplasmic Bag‐1 staining was stronger in 8/13 cases than in corresponding primary tumours (p=0.021). Western blotting using nine oral primary carcinoma cell lines and four normal keratinocyte cultures showed that the isoforms Bag‐1S, Bag‐1M, and Bag‐1L were expressed in normal and malignant oral epithelial cells. Bag‐1L unique sequences were shown to adopt an exclusively nuclear, and predominantly nucleolar, localization by use of transiently transfected N‐terminal Bag‐1L‐EGFP. However, levels of Bag‐1L in carcinoma cells did not differ significantly from those of normal keratinocytes. Therefore the reduced nuclear staining observed in oral squamous cell carcinomas compared with normal epithelium may reflect changes in the localization of Bag‐1 isoforms, rather than decreased expression of Bag‐1L. Alterations in the relative proportions of Bag‐1S, Bag‐1M, and Bag‐1L were detected in 6/9 oral carcinoma cell lines; 5/9 oral carcinoma cell lines had a significantly greater proportion of Bag‐1M than normal keratinocytes and in another cell line, Bag‐1L was significantly underrepresented. Overall, the results suggest that Bag‐1 deregulation plays a role in oral carcinogenesis at two different stages: during primary carcinoma development and during lymph node metastasis. Copyright