A case-control study confirms that microsatellite assay can identify patients at risk of developing oral squamous cell carcinoma within a field of cancerization.

Distinguishing true precursor lesions on the basis of clinical or histological features alone is unreliable but is important so that appropriate intervention can be instigated. Preliminary studies have shown that a microsatellite assay may provide important new prognostic information. To build on these observations, we have performed a case-control study to establish whether we can be confident about incorporating this new information into clinical practice. We have determined the frequency of allelic imbalance (AI) within key chromosomal regions, by matching 39 cases with dysplastic oral lesions that developed a tumor on the same side of the mouth, for as many variables as possible, with controls presenting with similar lesions that did not progress to malignancy when followed for the same period. Our findings confirm that the group that developed tumor had precursor lesions that harbor AI at more loci (P = 0.002). However, no consistent patterns of AI were associated with the three grades of dysplasia: mild, moderate, and severe. One-third of the tumors developed at the same site as the dysplastic lesion and two-thirds at a different site, which revealed that the presence of these aberrations in a dysplastic lesion provided information about the risk of malignant change within a larger field. This suggests that the process of field cancerization is more widespread than previously recognized. On the basis of these findings, we advocate complete excision of all suspicious areas that show AI at two or more key loci, regardless of the degree of dysplasia. However, because the remaining mucosa is also "at risk," these cases should also be targeted to receive dietary advice and chemoprevention, to minimize their risk of tumor formation at a distant site.

Detection of minimal residual cancer to investigate why oral tumors recur despite seemingly adequate treatment.

Improvements in surgery and radiotherapy techniques have led to only a modest increase in the 5-year survival rate for patients with head and neck cancer. This is because the pattern of clinical disease is changing, such that locoregional recurrence now accounts for fewer treatment failures, but more patients develop a second primary cancer or distant metastatic disease. In this study, we have used the p53 phage plaque assay, immunocytochemistry, and mutational analysis to assess the contribution of minimal residual cancer and genetic aberrations in clinically normal upper aerodigestive tract mucosa to treatment failure. Eighteen consecutive patients with oral tumors, with conventional clear margins, have been followed for a minimum of 36 months. Molecular assessment identified tumor-positive surgical margins for 6 of 11 assessable patients and additional tumor-positive lymph nodes for three cases. Disseminated malignant cells were detected in the hematopoietic cell compartment for six cases, and one patient had molecular evidence of field cancerization. Locoregional recurrence developed in five patients with tumors harboring a p53 gene mutation; four of these were associated with tumor-positive surgical margins, and one was associated with molecular evidence of field cancerization. Radiotherapy to the primary site did not prevent development of local recurrence when the residual tumor harbored a p53 gene mutation. Three of six cases with a tumor-positive bone marrow aspirate developed distant metastases. These findings reveal that molecular and immunocytochemical detection of minimal residual cancer and field cancerization can help identify patients who may develop locoregional or distant recurrence and justify further studies to evaluate the contribution of these remaining malignant cells to treatment failure.

Protective effects of viscous solutions in phacoemulsification and traumatic lens implantation.

We compared the endothelial protection offered by 1% hyaluronate sodium (Healon), 3% hyaluronate sodium and 4% chondroitin sulfate (Viscoat), and a nonviscous irrigating solution (BSS Plus) during phacoemulsification with and without traumatic intraocular lens implantation. Vital-dye staining and scanning electron microscopy were used to determine acute damage to rabbit corneal endothelium. Cell damage during phacoemulsification alone was not significantly different from that in unoperated controls (12.5%). Cell damage after traumatic lens insertion was significantly greater in the groups treated with BSS Plus (76.2%) and Healon (41.4%) than in either paired Viscoat-treated group (21.1% and 17.4%, respectively). Viscoat (but not Healon) was noted to be adherent to the cornea at the end of the procedure in one third of the cases, indicating that Viscoat remains in the anterior chamber during surgery. We attribute this to chondroitin sulfate's newtonian characteristics, allowing it to maintain viscosity in the face of high flow rates.

The FHIT gene in oral squamous cell carcinoma: allelic imbalance is frequent but cDNA aberrations are uncommon.

The FHIT (fragile histidine triad) gene at chromosome 3p14.2 spans the FRA3B fragile site and encodes for a diadenosine triphosphate hydrolase-type protein. FHIT is frequently abnormal in solid tumours including those of the upper aerodigestive tract (UAT) and has therefore been proposed as a tumour-suppressor gene. This proposition was evaluated here for oral squamous cell carcinoma (SCC) using microsatellite analysis, reverse transcription-polymerase chain reaction (RT-PCR), FHIT exon 5 PCR and direct sequencing. Fifty-eight primary oral SCCs were examined with two FHIT gene microsatellite markers (D3S4103 and D3S1300) and two markers flanking FHIT. Allelic imbalance (AI) occurred in 28 of 52 informative cases (54%) at one or both FHIT markers (D3S4103: 53%; D3S1300: 42%). A significant association was noted between frequency of AI and advanced stage tumours for D3S4103 but not between AI frequency and smoking. AI frequency at D3S1300 and at a flanking marker correlated with low survival. Of eight oral/UAT SCC cell lines examined, six produced abundant wild-type transcript and one yielded mostly truncated transcripts, the most abundant of which lacked exons 5-7. A double deletion was also detected in one of 11 primary oral SCCs. Our microsatellite assay results show that the FHIT gene is frequently disrupted in oral SCC. However, as FHIT was shown to be expressed normally in the great majority of oral/UAT SCCs studied, its likely involvement in the molecular pathogenesis of the disease as a tumour suppressor remains doubtful.

New insights into p53 protein stabilisation in oral squamous cell carcinoma.

p53 is a transcription factor which regulates cell proliferation and apoptosis to prevent division of potentially malignant cells. In many tumours mutation of the p53 gene leads to stabilisation of this protein which can be detected by immunohistochemistry (IHC). However, there are many reports describing detection of p53 by IHC in the absence of gene mutation, and in these cases other factors stabilise p53. To shed light on the mechanisms which permit detection of this protein in these mutation-negative cases we have examined 45 primary oral squamous cell carcinomas (SCCs) by IHC and gene sequencing for p53 (exons 4-8) and related the results to a FAL score (determined using microsatellite assay and expressing the number of loci showing allelic imbalance as a fraction of the total number of informative markers for each case). We also investigated the pattern of MDM2 expression in these tumours. High levels of p53 protein were detected in 24/45 cases and point mutations involving exons 4-9 were seen in 11 cases. A further four cases harboured deletions or a stop codon. For 6/48 cases there was concordance of AI within the p53 gene and mutation. However nine cases showed p53 mutation only and 5 AI without mutation, suggesting that oral tumours frequently retain one normal p53 allele. Detection of p53 by IHC correlated strongly with the FAL score. Thus whilst it is possible that some tumours harbour p53 mutations outside the open reading frames examined, or are missed due to sequencing a mixture of normal and tumour tissue, a subgroup of tumours may express high levels of wild-type p53 as a reflection of the high FAL score and ongoing genomic stress. Levels of MDM2 transcripts and protein were similar in all SCCs examined. However, MDM2 may be non-functional, or there may be defects affecting other important regulatory proteins in tumours which which express wild type p53 protein.

The role of nitric oxide in oral diseases.

Although previously regarded as a toxic pollutant gas, nitric oxide (NO) is a short-lived molecule that plays a key role in many physiological and pathological processes. It is produced in vivo from the amino acid L-arginine by a complex family of enzymes termed nitric oxide synthase (NOS). Since its discovery as a biological messenger in 1987, NO has been implicated in many disease processes, ranging from septic shock to cancer. It is a highly reactive free radical and causes concentration-dependent conformational changes in proteins, enzymes and DNA, predominantly by its reaction with transition metals and thiol residues. Although high concentrations of NO are cytotoxic, the levels produced in many human cancers possibly facilitate tumour growth and dissemination. The interest in this molecule by scientists and clinicians involved with the oral cavity and head and neck regions is fairly recent, and only a tiny minority of 50,000 papers currently cited on NO relate to diseases in this anatomical area. This review gives an overview of NO, outlining its basic chemistry, formation by NOS and its possible roles in the oral diseases studied to date. The implications for possible therapeutic manipulation of NO are also discussed.

The surgical management of lip cancer.

The history of surgical reconstruction of the lips is outlined and a series of procedures described, which together enable lip reconstruction to be successfully undertaken in a variety of different circumstances.

Secondary alveolar bone grafting in clefts of the lip and palate.

A short review of the literature is presented outlining the role of alveolar bone grafting in cleft patients. An analysis of a series of 47 secondary alveolar bone grafts in 34 patients is presented. The age range was 7-24 years. At the time of evaluation, 30 canines were in final occlusion and good alveolar bone levels were present in 83% of patients. Of the 13 bilateral cases (26 clefts), 14 canines were in final occlusion and all cases had good alveolar bone levels. No major complications were encountered. The graft was completely resorbed in 3 cases (6.4%) only.

Tumours of the head and neck in children. A clinico-pathological analysis of 1,007 cases.

Tumours of the head and neck in children are uncommon, representing only 2-3% of all head and neck tumours. During the twenty year period 1964-1983, 12,876 childhood tumours were submitted for pathological diagnosis. Of these 1,007 (7.8%) were in the head and neck region, and it is this group that has been analysed. 30.6% (308 cases) were malignant neoplasms, 27.8% (280 cases) were benign neoplasms, 24.2% (244 cases) presented as tumour-like conditions and 17.4 (175 cases) were dysplasias arising from embryonal remnants. The overall sex ratio was 1.5:1 in favour of males. Lymphomas accounted for 15.9% overall (52.3% of the malignant neoplasms). Of benign tumours, haemangiomas were the most frequent (38.5%) and of the tumour-like conditions, dermoid and epidermoid cysts accounted for 36.1%. Of the embryonal remnant dysplasias, thyroglossal duct cysts accounted for 71.4%.

Unusual presentation of tuberculosis of the head and neck region. Report of three cases.

Three cases are reported in which the diagnosis of tuberculosis has only been made following surgery for suspected salivary gland tumor, sebaceous cyst and carotid body tumour. Surgery could have been avoided if tuberculosis had been considered in the initial differential diagnosis.

Temporomandibular joint eminence augmentation by down-fracture and inter-positional cartilage graft. A new surgical technique.

A new surgical technique for the treatment of recurrent temporomandibular joint subluxation or dislocation is described. Following a horizontal osteotomy and down-fracture of the articular eminence an inter-positional bovine cartilage xenograft is inserted in order to augment the vertical height of the eminence. The procedure combines simplicity with minimal post-operative morbidity. The increase in eminence height is both predictable and stable.

Craniofacial growth in bilateral cleft lip and palate patients following secondary premaxillary setback.

Data of an experimental group of bilateral cleft lip and palate patients (BCLP) who had undergone premaxillary setback at a mean age of 10.2 years were compared with a control group of standard cephalometric values for the white population, and with cephalometric data of BCLP patients from the Oslo Cleft Lip and Palate Archive who did not have premaxillary setback. Cephalometric lateral skull radiographs were taken at a mean age of 16.6 years when most facial growth is completed. Overall, the most marked difference between the two cleft samples was a slightly more concave profile in the experimental BCLP group, mainly due to clockwise rotation of the maxillary plane. Other differences were a longer face and a larger mandible in the experimental group.

A comparison of one hundred and fifty consecutive parotidectomies for tumours and inflammatory disease.

The demographic profile and complications are compared and contrasted for 150 consecutive parotidectomies. All patients were under the care of one surgeon (JDL) over a twenty-year period (1977-1997). The case records and contemporaneous database were analysed retrospectively. 111 (74%) procedures were performed for tumours and 39 (26%) for inflammatory disease. The incidence of unexpected permanent facial nerve palsy was 1.8% in the tumour group and zero in the inflammatory group. The overall unexpected palsy rate was 1.3%. Transient paralysis was more common in the inflammatory group than the tumour group (61.5% compared with 33.3%, P<0.02) and was more likely to be panfacial (48.7% compared with 17.1%, P<0.0002). The overall incidence of Frey's syndrome was less than 20% and both salivary fistulae and sialocoeles were infrequent.

The inferiorly based masseter muscle flap: anatomical basis for its use in head and neck reconstructive surgery.

The aim of this study was to investigate and elucidate the anatomical basis for the use of the inferiorly based masseter muscle flap in the reconstruction of oropharyngeal defects after ablative surgery. The anatomy of the masseter muscle, with particular emphasis on its blood supply, was studied using plain and coloured resin injected dissections and a series of digital subtraction angiograms and external carotid arteriograms. Both techniques were demonstrated to be reliable and effective means of anatomical investigation of blood vessels. The vascular anatomy of the masseter muscle and the anatomical and angiological results as well as a case report are described. The masseter muscle, when used as an inferiorly based flap, provides the necessary bulk for reconstruction of moderate size defects in the lateral border of the tongue, posterior floor of the mouth, retromolar trigone, anterior tonsillar pillars and lateral pharyngeal wall. Although the masseter muscle has small dimensions, it offers a reliable method of reconstruction in selected defects without the disadvantages of cosmetic and functional loss.

Repair of the radial forearm flap donor site with a full-thickness graft.

A method of closing the radial forearm free flap donor site defect with a defatted, full-thickness skin graft is described. Its advantages of improved patient mobilization, protection of tendons, and cosmesis are discussed with reference to 16 consecutive patients treated over a period of 1 year.

Expression of type 2 nitric oxide synthase and p21 in oral squamous cell carcinoma.

Nitric oxide (NO) has a complex role in tumour biology. Most cancer research has focused on the enzyme nitric oxide synthase-2 (NOS2), an inducible isoform responsible for prolonged NO production. In normal cells exposed to high NO concentrations, the tumour-suppressor gene, p53, promotes apoptosis via the p21 pathway, in an attempt to safeguard against potential NO-mediated DNA damage. In cancer cells with mutant p53, this pathway is unlikely to occur directly, although, p53-independent p21 expression and subsequent apoptosis can occur at higher NO concentrations. In this study, the possible direct association between NOS2 and p21 was assessed in oral squamous cell carcinoma. Immunohistochemistry was performed for NOS2 and p21 on 56 cases, and NOS2 activity was determined with citrulline assays in selected cases. A significant relationship was demonstrated between the immunohistochemical expression of NOS2 and its activity (P<0.001), but not between NOS2 and p21 expression (P=0.76). It is unlikely that the NO concentrations found in oral cancer (up to 10.3 pmol NO min(-1) mg protein(-1)) are sufficient to cause direct (p53-independent) p21 accumulation and subsequent apoptosis. As with many other tumours, since NO production has a detrimental role, its pharmacological inhibition in oral cancer represents an exciting area for possible future therapeutic manipulation.

Combined treatment of adenoid cystic carcinoma of the salivary glands.

A retrospective review of the experience of a single surgeon over a 20-year period is presented. Fifteen patients with primary adenoid cystic carcinoma of the major (6) or minor (9) salivary glands underwent combined treatment with wide local excision and radical postoperative radiotherapy. The actuarial survival is 100% at 5 years and 62% at 10 and 15 years. The disease-specific survival is 100% at 5 years and 86% at 10 and 15 years. There were no loco-regional recurrences. Wide local excision and radical postoperative radiotherapy seems to be an effective treatment for adenoid cystic carcinoma of the salivary glands.

Management of oral cancer.

Oral cancer is a serious disease that is on the increase. The most pressing need is early recognition and referral for specialist treatment. Too many cases present with advanced tumours. Radiotherapy and surgery remain the primary modalities of curative treatment, but understanding of tumour pathology and developments in surgical and radiotherapeutic technique have combined to produce a rational approach to management. In many instances 'radical' methods of surgical access can be combined with a more 'conservative' resection of the mandible or cervical lymph nodes. One-stage reconstructive procedures, often incorporating osteotomy techniques, miniature bone plating and free tissue transfer, have minimised the morbidity and functional deficit so often seen after earlier operations. All surgeons involved in the modern management of oral cancer should have expertise in these techniques or be part of a team which can provide them.

The team approach in the management of oral cancer.

The management of cancer of the head and neck is so complex that it demands the participation of two teams, one major or curative and the other minor or supportive, and also of the patient. The make-up of these teams and the functions of their members are discussed. The principles of treatment planning along these lines are outlined and the importance of close interdisciplinary collaboration is emphasised.

The masseter muscle cross-over flap--a versatile flap for reconstruction in the oral cavity.

The use of the masseter muscle cross-over flap is described for reconstruction in the floor of mouth, retromolar trigone, lateral pharyngeal wall and posterior palate areas. Various modifications are described which increase the versatility of this readily available flap. Case reports are used to illustrate the applications of this flap.