Paul M. Speight

Photodynamic therapy using 5-aminolevulinic acid for premalignant and malignant lesions of the oral cavity.

Premalignant changes in the mouth, which are often widespread, are frequently excised or vaporized, whereas cancers are treated by excision or radiotherapy, both of which have cumulative morbidity. Photodynamic therapy (PDT) is another option that produces local tissue necrosis with light after prior administration of a photosensitizing agent. This heals with remarkably little scarring and no cumulative toxicity. This article describes the use of PDT with the photosensitizing agent 5‐aminolevulinic acid (ALA) for premalignant and malignant lesions of the mouth.

Photodynamic effects of toluidine blue on human oral keratinocytes and fibroblasts and Streptococcus sanguis evaluated in vitro

Some oral bacteria are susceptible to killing by red light after their sensitization with toluidine blue O (TBO). The photochemotherapy of periodontal disease in vivo would require a therapeutic window where bacteria could be killed without adjacent normal tissue damage.

αvβ6integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9

The integrin αvβ6 is a fibronectin receptor, which is not detectable on normal epithelium but is neo‐expressed in oral epithelial dysplasia and oral squamous‐cell carcinoma (SCC), suggesting a role in promoting malignant behaviour and tumour progression. We used transfection and retroviral infection to create a panel of SCC cell lines expressing various levels of αvβ6 to examine this possibility. We found that increased expression of αvβ6 in malignant keratinocytes up‐regulates MMP‐9 and MMP‐2 expression and promotes invasion in an MMP‐9‐dependent manner. Our results suggest a possible mechanism for the involvement of αvβ6 in squamous carcinoma in vivo.

Predictors of lymphoma development in primary Sjögren's syndrome

OBJECTIVE To determine the clinical and laboratory predictors of lymphoma development in primary Sjögrens syndrome (pSS). METHODS Seventy-two patients with pSS were studied. Demographic data, clinical features, serum gamma-globulin levels, autoantibodies, and HLA status were reviewed. For statistical analysis, Mann-Whitney U-test, Fishers exact test, logistic regression analysis, Kaplan-Meier method, and log-rank tests were applied. RESULTS Five patients developed a distinct non-Hodgkins lymphoma of mucosa-associated lymphoid tissue (MALT). A history of swollen salivary glands, lymphadenopathy, and leg ulcers predicted lymphoma development. CONCLUSION Patients with pSS are at increased risk of lymphoma development, and those who have the above risk factors must be carefully observed.

Differential expression of bcl-2 and bax in squamous cell carcinomas of the oral cavity

The bcl-2 oncogene is a member of a family of genes encoding for proteins which regulate apoptosis (programmed cell death). Recent evidence suggests that the bcl-2 protein is regulated by a homologous protein bax which counteracts its effects and promotes apoptosis. Overexpression of bcl-2 has been reported in a number of human cancers, although correlations with tumour differentiation and clinical outcome are conflicting and depend on tumour type and site. We studied bcl-2 and bax protein expression in adjacent serial sections of 30 squamous cell carcinomas of the oral cavity and correlated this with tumour differentiation. Examination of normal epithelium showed bcl-2 expression confined to basal keratinocytes and dendritic cells. The bax immunostaining was seen throughout the thickness of the epithelium but was most intense in the suprabasal cells. Overall, moderate or marked immunostaining for bcl-2 was identified in 18/30 (60%) carcinomas and for bax in 19/30 (63%) tumours. The bcl-2 immunoreactivity was strongest in the poorly differentiated carcinomas where 6/7 (86%) showed strong staining. By contrast, bax immunoreactivity was strongest in the well-differentiated carcinomas with 8/11 (72%) staining strongly. In the well-differentiated tumour islands, there was inverse topographic distribution of bcl-2 and bax, with both proteins showing a pattern that recapitulated normal epithelium. Upregulation of bcl-2 protein was identified in dysplastic epithelium adjacent to invasive tumour and in many cases there was reduced bax immunostaining. These results suggest that alterations of bcl-2 and bax may play a role in the development of squamous cell carcinoma. Furthermore, disturbances of protein expression in dysplastic epithelium suggest a role in the early stages of epithelial carcinogenesis.

Comparison of integrin, cadherin, and catenin expression in squamous cell carcinomas of the oral cavity

In addition to their role in maintenance of tissue integrity, cell adhesion molecules regulate the growth and differentiation of stratified squamous epithelia. Reduced expression of E‐cadherin and the α2β1, α3β1 and α6β4 integrins is already reported to correlate with poor histological differentiation in oral squamous cell carcinomas. However, it is not clear how closely cadherin and integrin loss are related in any given tumour, nor whether cadherin loss is correlated with changes in expression of the cytoplasmic regulatory proteins known as catenins. Double‐label immunofluorescence has been used to stain a panel of 22 oral squamous cell carcinomas with antibodies to ten proteins, including E‐ and P‐cadherin, the major keratinocyte integrin subunits, and α‐, β‐ and γ‐catenin. Overall, E‐cadherin expression and integrin expression correlated well with tumour grade, while P‐cadherin staining was more variable. All tumours, regardless of differentiation status, showed reduced staining for at least two of the catenins, implying that the adhesive function of E‐ and P‐cadherin could be impaired even when cadherin expression is normal. It is concluded that in all squamous cell carcinomas, regardless of degree of histological differentiation, there is some perturbed expression of cell adhesion molecules and that integrin and E‐cadherin loss are closely related.

Photodynamic therapy using mTHPC for malignant disease in the oral cavity

Photodynamic therapy (PDT) produces local tumor necrosis, on activation of a previously administered sensitizer with non‐thermal light of an appropriate wavelength. It is attractive for treating tumors of the mouth as tissue healing is particularly good. We describe the use of the photosensitizing agent meta tetrahydroxyphenyl chlorin (mTHPC, Foscan®) for PDT of oral cancer, including patients with field cancerization. Nineteen patients with histologically confirmed oral cancer (8 with field change disease) and one with severe dysplasia, were sensitised with mTHPC intravenously. Activation was carried out 72–96 hr later with laser light at 652 nm using a range of light doses. The results were assessed clinically and histologically. Multiple biopsies were taken during the ulcerative stages to look at the effects of PDT and after healing to assess the overall treatment result. All single lesions up to stage T3 cleared after one PDT treatment (total of 6 patients). Three out of 6 T4 tumours were also cleared. Lesions in patients with field change disease did less well, only 9 of 14 T1 and T2s clearing, including 4 that required extra treatments with a higher light dose. Most healed very well, but tongue tethering was seen in 1 patient and another had necrosis in normal areas due to light scattering within the mouth. PDT using mTHPC is a promising new treatment for patients with oral cancer. Int. J. Cancer 73:25–32, 1997.

Update on Oral Epithelial Dysplasia and Progression to Cancer

Precursor lesions of the upper aerodigestive tract are similar regardless of site and can be defined as altered epithelial lesions, which have an increased likelihood of progressing to squamous cell carcinoma. In the oral cavity the most common lesions recognised as potentially malignant are leukoplakia and erythroplakia, but it is also apparent that as many as 50% of oral squamous cell carcinomas arise from apparently clinically normal mucosa. The prognostic significance of an individual lesion is difficult to determine, and none of the currently available molecular markers have proved to be prognostically significant and none have yet been evaluated in large prospective studies. At present therefore, the gold standard for the assessment of oral potentially malignant lesions is microscopic evaluation of haematoxylin and eosin stained sections for the presence of architectural and cytological changes, which are generally referred to as epithelial dysplasia. Some texts use the terms squamous intraepithelial neoplasia (SIN) or squamous intraepithelial lesions (SIL; Table 1) [1]. The categories under each scheme are similar, but the terminology is not exactly synonymous. In the oral cavity, use of the SIL terminology of ‘atypical hyperplasia’ may lead to confusion because of the large number of common benign hyperplastic lesions, which may be encountered. In oral and maxillofacial pathology therefore, oral epithelial dysplasia is regarded as the standard terminology [2, 3]. Criteria for the Diagnosis of Oral Epithelial Dysplasia

B-cell monoclonality, Epstein Barr virus, and t(14;18) in myoepithelial sialadenitis and low-grade B-cell MALT lymphoma of the parotid gland

Low-grade mucosa-associated lymphoid tissue (MALT) type B-cell lymphomas of the salivary gland arise in a background of myoepithelial sialadenitis (MESA). usually in association with Sjögrens syndrome. The distinction between benign MESA and early lymphoma has proved difficult using histological criteria alone and the significance of B-cell monoclonality in this respect is controversial. We have used immunohistochemistry and polymerase chain reaction (PCR) amplification of immunoglobulin heavy-chain VDJ regions to assess clonality in biopsies from 45 patients with lymphoid infiltration of the parotid. Sequential biopsies spanning 3–18 years were available from seven patients, three of whom had developed disseminated nodal B-cell lymphoma. In light of previous studies, each biopsy was additionally analyzed for the presence of t(14:18) and Epstein Barr Virus (EBV) DNA using PCR. Monoclonality was detected in 34/45 cases. Comparison of histology with clonality confirmed earlier suggestions that the emergence of an identifiable population of centrocyte-like B cells around ducts or epithelial islands correlated with monoclonality. In six of seven patients with sequential biopsies PCR fragments of identical size were amplified from each biopsy, suggesting that demonstrable monoclonality in “lymphoepithelial” lymphoproliferative lesions of the salivary gland is indicative of lymphoma. No t(14:18) chromosome translocations were identified: EBV sequences were detected in three of 45 cases.

Proliferative verrucous leukoplakia: a report of ten cases.

A particularly aggressive form of oral leukoplakia that commences with a hyperkeratosis, spreads to become multifocal and verruciform in appearance, and later becomes malignant has been termed proliferative verrucous leukoplakia. Ten patients with persistent multifocal verruciform white patches were investigated. Lesions were often bilateral and affected predominantly mandibular alveolar and buccal mucosa. At first biopsy no lesion was graded higher than a verrucous hyperplasia, but subsequently all patients had squamous cell carcinoma, and two patients have died of their disease. Lesions were managed with surgery, carbon dioxide laser, and photodynamic therapy. The patients presented here confirm the existence of proliferative verrucous leukoplakia as a clinicopathologic entity. Careful examination of the whole mouth is essential when a hyperplastic white patch is seen to check for possible proliferative verrucous leukoplakia. Early aggressive treatment must then be started, and regular long-term review is crucial.