Radical (chemo)radiotherapy in oropharyngeal squamous cell carcinoma: Comparison of TNM 7th and 8th staging systems.

PURPOSE: To evaluate whether the 8th staging system is a better discriminator of overall survival (OS) than the 7th edition for oropharyngeal cancer patients after definitive (chemo)radiotherapy (CRT). MATERIAL AND METHODS: Data from oropharyngeal cancer patients treated with CRT with curative intent between 2010 and 2016 at Guy's and St Thomas' Hospitals were reviewed. Human papillomavirus (HPV) status was ascertained in all cases. Patients were staged using the 7th edition and the 8th edition TNM staging system. Demographics, tumor characteristics and treatment response data were included in univariate and multivariate analysis for OS. OS and disease-free survival (DFS) were estimated using the Kaplan-Meier method. In addition, a multivariate survival Cox regression analysis of several clinical variables was performed. RESULTS: A total of 273 patients were included. The median follow-up was 4.7 years. Overall 63 patients died. In multivariate analysis, HPV status, complete response at 3 months and ≤21 units/week alcohol were prognostic for OS. For the entire cohort, the 5-year OS and DFS rates were 78.1% (95% confidence interval CI 0.719-0.831) and 73.9% (95% CI 0.677-0.792), respectively. Better stratification of OS and DFS was recorded by 8th edition for the entire cohort. In HPV-positive cases, risk stratification based on tobacco smoking and nodal stage resulted in statistically higher discrimination in OS rates (5-year OS 90.7% in low risk patients and 84.6% in intermediate risk, p = 0.05) and DFS rates (5-year DFS 91.5% in low risk and 76.1% in intermediate risk, p = 0.001). CONCLUSION: The 8th edition TNM staging system provides better OS stratification in oropharyngeal cancer after definitive CRT compared with the 7th edition. Other clinical variables, such as complete response at 3 months, alcohol and tobacco smoking, should also be considered in future classifications as they provide additional risk stratification information in both HPV-positive and HPV-negative disease.

Utility of neck dissection for management of carcinoma of the parotid gland.

To validate the use of neck dissection as part of the management of patients with parotid carcinomas, we retrospectively reviewed pathological and clinical data from the head and neck pathology archive at Guy's and St Thomas' Hospital on all patients who had primary parotid carcinomas resected between 1992 and 2014. The main outcome measure was the incidence of metastatic disease. A total of 54 of the 82 patients identified had neck dissections. Nodal metastases were detected in 10 with high-grade, invasive carcinoma ex-pleomorphic adenomas, two with salivary duct carcinomas, one with a high-grade adenocarcinoma not otherwise specified (NOS), one with an adenoid cystic carcinoma, and one with a high-grade acinic cell carcinoma. No metastases were found in those with a low-grade acinic cell carcinoma, low-grade mucoepidermoid carcinoma, epithelial-myoepithelial carcinoma, or non-invasive carcinoma ex-pleomorphic adenoma. The findings of this study support the use of routine neck dissection for the treatment of high-grade, invasive carcinoma ex-pleomorphic adenoma, salivary duct carcinoma, high-grade adenocarcinoma NOS, adenoid cystic carcinoma, and high-grade acinic cell carcinoma.

Biopsy of the sentinel lymph node in oral squamous cell carcinoma: analysis of error in 100 consecutive cases.

UK national guidelines in 2016 recommended that sentinel lymph node biopsy should be offered to patients with early oral cancer (T1-T2 N0) in which the primary site can be reconstructed directly. This study describes the pitfalls that can be avoided in the technique of biopsy to improve outcomes. We retrospectively analysed the data from 100 consecutive patients and recorded any adverse events. Lymphatic drainage of tracer failed in two patients as a result of procedural errors. Two patients with invaded nodes developed recurrence after total neck dissection, one after micrometastases had been diagnosed, and the other as a result of extranodal spread that had led to understaging and therefore undertreatment. Two results would not have been mistakenly classified as clear if all the harvested nodes had been analysed histologically according to the protocol. The disease-specific (96%) and disease-free (92%) survival were better than expected for a group of whom a third had stage 3 disease. If all harvested nodes had been analysed by the correct protocol then two of the three nodes wrongly designated clear would have been detected, two deaths potentially avoided, and the false-negative rate would have fallen from 8.3% to 2.7%. We conclude that minor deviations from protocol can result in a detrimental outcome for the patient.

Epithelioid Haemangioendothelioma of the mandibular gingiva: case report and literature review.

INTRODUCTION: Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm that exhibits the potential for recurrence and metastasis but rarely involves the oral cavity. PRESENTATION OF CASE: We report the management and long term follow up of recurrent EHE in a 23- year-old woman. The lesion initially presented as a small area of erythematous gingival swelling with localised bone loss around the lower anterior teeth. It was treated by buccal and lingual stripping of the gingival tissues. The patient suffered local recurrence after 7 years and was treated with a wider surgical excision of the buccal and lingual gingivae, conserving the adjacent teeth and bone with an excellent cosmetic outcome. Over 21 years later, there have been no further recurrences. DISCUSSION: This case highlights the management challenges of EHE and is the only case in the literature to have reported a case of mandibular gingivae with a long review period of 21 years. CONCLUSION: Oral EHE is an unpredictable lesion with a relatively benign course, unlike non-oral EHE where up to one third of cases may metastasise. Because of the propensity to recur locally after excision and curettage, a wide local excision with close clinical follow has been suggested in the literature as the treatment of choice for oral lesions. However, the lack of metastases from oral lesions, the small size, mandibular site and bland histology in this case suggests that a limited soft tissue excision and bone curettage, with long term follow-up would be appropriate for similar gingival lesions in future.

Mucoepidermoid carcinoma in a thyroglossal duct remnant.

INTRODUCTION: Thyroglossal duct cysts (TDC) are common midline neck swellings resulting from embryological remnants of the thyroglossal duct. They often contain ectopic thyroid tissue and malignant transformation has been reported, most commonly to papillary thyroid carcinoma. Mucoepidermoid carcinoma (MEC) usually occurs in the salivary glands and only rarely in the thyroid. This is the first case of a MEC occurring within a thyroglossal duct remnant. PRESENTATION OF A CASE: A 73 year old lady presented with a thyroglossal duct cyst. She declined surgical excision, as she was adamant she wanted to avoid surgery. The neck mass rapidly enlarged at two years following initial diagnosis. Fine needle aspiration cytology was suspicious for carcinoma. She underwent total thyroidectomy and selective central compartment neck dissection with adjuvant radiotherapy. She remains alive and well two years post treatment. DISCUSSION: Mucoepidermoid carcinoma is the most common malignant neoplasm of salivary glands, although it has rarely been reported in diverse locations including the thyroid, lung and pancreas. To the best of our knowledge, this is the first reported case of mucoepidermoid carcinoma arising from a thyroglossal duct remnant. CONCLUSION: This case adds weight to the literature favouring surgical excision of thyroglossal duct remnants due to the risk of malignant transformation.

Bortezomib sensitises TRAIL-resistant HPV-positive head and neck cancer cells to TRAIL through a caspase-dependent, E6-independent mechanism.

Human papillomavirus (HPV) is causative for a new and increasing form of head and neck squamous cell carcinomas (HNSCCs). Although localised HPV-positive cancers have a favourable response to radio-chemotherapy (RT/CT), the impact of HPV in advanced or metastatic HNSCC remains to be defined and targeted therapeutics need to be tested for cancers resistant to RT/CT. To this end, we investigated the sensitivity of HPV-positive and -negative HNSCC cell lines to TRAIL (tumour necrosis factor-related apoptosis-inducing ligand), which induces tumour cell-specific apoptosis in various cancer types. A clear correlation was observed between HPV positivity and resistance to TRAIL compared with HPV-negative head and neck cancer cell lines. All TRAIL-resistant HPV-positive cell lines tested were sensitised to TRAIL-induced cell death by treatment with bortezomib, a clinically approved proteasome inhibitor. Bortezomib-mediated sensitisation to TRAIL was associated with enhanced activation of caspase-8, -9 and -3, elevated membrane expression levels of TRAIL-R2, cytochrome c release and G2/M arrest. Knockdown of caspase-8 significantly blocked cell death induced by the combination therapy, whereas the BH3-only protein Bid was not required for induction of apoptosis. XIAP depletion increased the sensitivity of both HPV-positive and -negative cells to TRAIL alone or in combination with bortezomib. In contrast, restoration of p53 following E6 knockdown in HPV-positive cells had no effect on their sensitivity to either single or combination therapy, suggesting a p53-independent pathway for the observed response. In summary, bortezomib-mediated proteasome inhibition sensitises previously resistant HPV-positive HNSCC cells to TRAIL-induced cell death through a mechanism involving both the extrinsic and intrinsic pathways of apoptosis. The cooperative effect of these two targeted anticancer agents therefore represents a promising treatment strategy for RT/CT-resistant HPV-associated head and neck cancers.

Differential response of head and neck cancer cell lines to TRAIL or Smac mimetics is associated with the cellular levels and activity of caspase-8 and caspase-10.

BACKGROUND: Current treatment strategies for head and neck cancer are associated with significant morbidity and up to 50% of patients relapse, highlighting the need for more specific and effective therapeutics. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Smac mimetics (SMs) are promising anticancer agents, but their effect on head and neck squamous cell carcinoma (HNSCC) remains unknown. METHODS: We examined the response of a panel of nine HNSCC cell lines to TRAIL and SMs and investigated the mechanism of cell type-specific response by functional analysis. RESULTS: Head and neck cancer cell lines revealed a converse response pattern with three cell lines being highly sensitive to Smac-164 (SM) but resistant to TRAIL, whereas the other six were sensitive to TRAIL but resistant to SM. Distinct protein expression and activation patterns were found to be associated with susceptibility of HNSCC cell lines to TRAIL and SM. Tumour necrosis factor-related apoptosis-inducing ligand sensitivity was associated with high caspase-8 and Bid protein levels, and TRAIL-sensitive cell lines were killed via the type II extrinsic apoptotic pathway. Smac mimetic-sensitive cells expressed low levels of caspase-8 and Bid but had high TNF-α expression. Smac mimetic-induced cell death was associated with caspase-10 activation, suggesting that in the absence of caspase-8, caspase-10 mediates response to SM. Cotreatment with TNF-α sensitised the resistant cells to SM, demonstrating a decisive role for TNF-α-driven feedback loop in SM sensitivity. CONCLUSIONS: Tumour necrosis factor-related apoptosis-inducing ligand and SMs effectively kill HNSCC cell lines and therefore represent potential targeted therapeutics for head and neck cancer. Distinct molecular mechanisms determine the sensitivity to each agent, with levels of TNF-α, caspase-8, Bid and caspase-10 providing important predictive biomarkers of response to these agents.

The utility of molecular diagnostics to predict recurrence of head and neck carcinoma.

BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for oral squamous cell carcinoma. Molecular diagnostics have the potential to improve on clinicopathological parameters to predict this recurrence and plan adjuvant treatment. The test most frequently applied is based on detecting TP53 mutations, but alternative methodology is required for cases that harbour the wild-type gene. METHODS: One hundred and two cases with tumour-adjacent margins, considered to be clear margins by microscopy, were examined using carefully optimised molecular diagnostics based on detection of the TP53 and Ly-6D markers. The markers were also combined to provide a dual approach. RESULTS: The dual molecular diagnostic identified cases with a significant increase in the probablility of developing locoregional recurrence when tumour-adjacent positive and clear margins were compared (P=0.0001). These tests were most useful when the clearance at the resection margins was 5 mm or less. The TP53-based diagnostic was a better predictor of locoregional recurrence than established clinicopathological parameters. CONCLUSION: The optimised TP53-based diagnostic rapidly identifies an important subgroup of cases with close margins that will benefit from new treatment modalities to reduce the risk of recurrence.

Correlation between Ki-67 immunohistochemistry and 18F-fluorothymidine uptake in patients with cancer: A systematic review and meta-analysis.

BACKGROUND: Positron emission tomography (PET) imaging using the radiotracer 18F-Fluorothymidine (FLT) has been proposed as an imaging biomarker of tumour proliferation. If FLT-PET can be established as such it will provide a non-invasive, quantitative measurement of tumour proliferation across the entire tumour. Results from validation studies have so far been conflicting with some studies confirming a good correlation between FLT uptake and Ki-67 score and others presenting negative results. METHODS: Firstly we performed a systematic review of published studies between 1998 and 2011 that explored the correlation between FLT uptake and Ki-67 score and examined possible variations in the methods used. Studies were eligible if they: (a) included patients with cancer, (b) investigated the correlation between Ki-67 measured by immunohistochemistry and FLT uptake measured with PET scanning, and (c) were published as a full paper in a peer-reviewed scientific journal. Secondly a meta-analysis of the correlation coefficient values reported from each study was performed. Correlation coefficient (r) values were extracted from each study and 95% confidence intervals (CIs) were calculated after applying Fisher's z transformation. For subgroup analysis, studies were classified by the index used to characterise Ki-67 expression (average or maximum expression), the nature of the sample (whole specimen or biopsy) and the cancer type. FINDINGS: Twenty-seven studies were identified as eligible for the meta-analysis. In the studies we examined there were variations in aspects of the methods and reporting. The meta-analysis showed that given an appropriate study design the FLT/Ki-67 correlation is significant and independent of cancer type. Specifically subgroup analysis showed that FLT/Ki-67 correlation was high in studies measuring the Ki-67 average expression regardless of use of surgery or biopsy samples (r=0.70, 95% CI=0.43-0.86, p<0.001). Of the studies that measured Ki-67 maximum expression, only those that used the whole surgical specimen provided a significant r value (r=0.72, 95% CI=0.54-0.84, p<0.001). Studies that used biopsy samples for Ki-67 maximum measurements did not produce a significant r value (r=0.04, 95% CI=-0.18-0.26, p=0.71). In terms of the cancer type subgroup analysis there is sufficient data to support a strong FLT/Ki-67 correlation for brain, lung and breast cancer. No publication bias was detected. INTERPRETATION: This systematic review and meta-analysis highlights the importance of the methods used in validation studies comparing FLT-PET imaging with the biomarker Ki-67. The correlation is significant and independent of cancer type provided a study design that uses Ki-67 average measurements, regardless of nature of sample, or whole surgical samples when measuring Ki-67 maximum expression. Sufficient data to support a strong correlation for brain, lung and breast cancer exist. However, larger, prospective studies with improved study design are warranted to validate these findings for the rest of the cancer types.

Human Gyrovirus Apoptin shows a similar subcellular distribution pattern and apoptosis induction as the chicken anaemia virus derived VP3/Apoptin.

The chicken anaemia virus-derived protein Apoptin/VP3 (CAV-Apoptin) has the important ability to induce tumour-selective apoptosis in a variety of human cancer cells. Recently the first human Gyrovirus (HGyV) was isolated from a human skin swab. It shows significant structural and organisational resemblance to CAV and encodes a homologue of CAV-Apoptin/VP3. Using overlapping primers we constructed a synthetic human Gyrovirus Apoptin (HGyV-Apoptin) fused to green fluorescent protein in order to compare its apoptotic function in various human cancer cell lines to CAV-Apoptin. HGyV-Apoptin displayed a similar subcellular expression pattern as observed for CAV-Apoptin, marked by translocation to the nucleus of cancer cells, although it is predominantly located in the cytosol of normal human cells. Furthermore, expression of either HGyV-Apoptin or CAV-Apoptin in several cancer cell lines triggered apoptosis at comparable levels. These findings indicate a potential anti-cancer role for HGyV-Apoptin.

Apoptin induces apoptosis by changing the equilibrium between the stability of TAp73 and ΔNp73 isoforms through ubiquitin ligase PIR2.

Apoptin, a protein derived from the chicken anaemia virus, induces cell death in various cancer cells but shows little or no cytotoxicity in normal cells. The mechanism of apoptin-induced cell death is currently unknown but it appears to induce apoptosis independent of p53 status. Here we show that p73, a p53 family member, is important in apoptin-induced apoptosis. In p53 deficient and/or mutated cells, apoptin induced the expression of TAp73 leading to the induction of apoptosis. Knockdown of p73 using siRNA resulted in a significant reduction in apoptin-induced cytotoxicity. The p53 and p73 pro-apoptotic target PUMA plays an important role in apoptin-induced cell death as knockdown of PUMA significantly reduced cell sensitivity to apoptin. Importantly, apoptin expression resulted in a marked increase in TAp73 protein stability. Investigation into the mechanisms of TAp73 stability showed that apoptin induced the expression of the ring finger domain ubiquitin ligase PIR2 which is involved in the degradation of the anti-apoptotic ∆Np73 isoform. Collectively, our results suggest a novel mechanism of apoptin-induced apoptosis through increased TAp73 stability and induction of PIR2 resulting in the degradation of ∆Np73 and activation of pro-apoptotic targets such as PUMA causing cancer cell death.

Factors predicting malignant transformation in oral potentially malignant disorders among patients accrued over a 10-year period in South East England.

OBJECTIVE: The aims of the study were to determine how frequently oral potentially malignant disorders (OPMDs) transform to cancer and to identify clinical and histological factors determining the rates of transformation. METHODS: The study included 1357 patients with biopsy-confirmed OPMDs seen at Guy's Hospital between 1990 and 1999 and followed up until 2005. The patients' details (name, date of birth, gender and any other relevant information) were matched to the Thames Cancer Registry (TCR) database and Office for National Statistics (ONS) to identify patients who subsequently developed oral cancer (ICD-10 C00-C06). From each patient's record, we identified their highest grade of dysplasia, graded as none, mild, moderate or severe. The outcome of principal interest was transformation to oral squamous cell carcinoma. To avoid co-existing malignancies, follow-up was started 6 months after the date of the index biopsy. Kaplan-Meier estimates and Cox proportional hazard analysis were undertaken to explore the factors associated with the time to transformation to oral cancer. RESULTS: One thousand three hundred and fifty-seven patients were included in the study. The majority of patients were women (60.9%), and ∼30% were under 47 years of age. The most common OPMD was lichen planus/lichenoid reaction. Among all OPMDs, 204 (15.1%) had oral epithelial dysplasia (30 severe, 70 moderate and 104 mild). Thirty-five patients developed oral cancer over the follow-up period (2.6%). There was an association between dysplasia grade and time to transformation. Patients with severe dysplasia had a higher risk of transformation to oral cancer [HR 35.4 95% CI (14.2-88.3)] compared to those with no dysplasia. This association remained significant although attenuated [HR 21.6 95% CI (5.8-80.5)] following adjustment for sex, age, anatomical site of OPMD and diagnosis. A significant trend over dysplasia grades was evident (P < 0.0001). Transformation to oral cancer was also associated with increasing age (P = 0.0390). CONCLUSIONS: In 2.6% of cases, OPMDs transformed to invasive cancer for a total person follow-up time of 12,273 years (mean 9.04 years). The severity of dysplasia is a significant predictor for malignant transformation.

Grading oral epithelial dysplasia: analysis of individual features.

BACKGROUND: Assessing epithelial dysplasia to predict malignant transformation remains problematic in many tissues because grading systems are poorly structured and individual features poorly defined. Dysplasia grading is criticised for lack of reproducibility and poor predictive value. Grading systems for upper aerodigestive tract dysplasia have evolved over several decades and are not supported by good outcome experimental data. METHODS: This study analysed the individual features of dysplasia in 86 oral dysplastic lesions and determined the reproducibility of scoring for each, and correlated them with other features and clinical factors using complex clustering analyses. RESULTS: A uniform pattern of dysplasia was found in 37 lesions, focal dysplasia in 36 and in 13 lesions dysplasia formed complex discontinuous patterns. There was wide variation in reproducibility of scoring of individual features and many, including thickness, some types of rete morphology, basaloid cell anisonucleosis, basal dyscohesion, and dyskeratosis as deep single cells correlated with sub-sites. Rete morphology, type of keratinisation, hyperchromatism of the basaloid compartment, prickle cell anisonucleosis and extension down salivary ducts correlated with smoking. Conventional grading and oral intraepithelial neoplasia (OIN) grading by 'thirds affected' showed strong correlation overall but scores obtained with the OIN system tended to a higher grade at all sites except soft palate/fauces. There was poor correlation between the systems for moderate dysplasia and also severe dysplasia at some sites. Individual features could not be shown to cluster to form distinct patterns of dysplasia. CONCLUSIONS: These variations may account in part for the lack of reproducibility and poor predictive value of the grading systems in current use and could inform the design of future grading systems.

Impact of WWOX alterations on p73, ΔNp73, p53, cell proliferation and DNA ploidy in salivary gland neoplasms.

OBJECTIVE: WWOX gene is altered in a variety of neoplasms. Wwox is pro-apoptotic through interaction with p73 and may be involved in chromosomal stability by interaction with p73 and p53. The aims of this study were to characterize WWOX transcription, methylation status and immunoexpression in salivary neoplasms and to determine whether these were associated with p73, p53, cell proliferation and DNA ploidy. MATERIALS AND METHODS: Seven malignant and 21 benign fresh salivary neoplasms were included. WWOX expression was determined by RT-PCR and sequencing of transcripts, quantitative PCR and immunohistochemistry. Methylation-specific PCR was used to assess the methylation of its first exon. For p73, ΔNp73, p53 and ki67 immunohistochemistry and ploidy analysis, 29 malignant samples from archives were included. RESULTS: No consistent pattern of WWOX exon 1 methylation was found, but aberrant and novel transcripts were observed in 17/28 neoplasms; 55% of tumours showed reduced WWOX RNA. WWOX RNA levels were associated with p53 immunopositivity. Immunohistochemical Wwox expression did not correlate with methylation status, p53 or p73 expression or proliferation. p73, proliferation and DNA ploidy were associated with malignant phenotype. CONCLUSION: Aberrant WWOX transcription and decreased expression are frequent in salivary neoplasms and WWOX transcription is associated with p53 staining.

Abnormal DNA content in oral epithelial dysplasia is associated with increased risk of progression to carcinoma.

BACKGROUND: Oral epithelial dysplasia (OED) is a histologically detectable lesion that may progress to carcinoma but there are no accurate markers that predict progression. This study examined the development of carcinoma from oral dysplastic lesions, and the association between abnormal DNA content and progression to carcinoma. METHODS: Epithelial dysplasias from the Oral Pathology Diagnostic Service were matched against the Ontario Cancer Registry database to identify cases that progressed to carcinoma. A case-control study was conducted to compare DNA image cytometry of dysplasias that progressed with those that have not progressed. For a subset of the progressed dysplasias, DNA content of the carcinoma was also analysed. RESULTS: A total of 8% of epithelial dysplasias progressed to carcinoma after 6-131 months. In all, 28 of 99 dysplasias showed abnormal DNA content by image cytometry. In multivariate analysis of time to progression, abnormal DNA content was a significant predictor with hazard ratio of 3.3 (95% confidence interval: 1.5-7.4) corrected for site and grade of dysplasia. Analysis of sequential samples of dysplasia and carcinoma suggested that epithelial cell populations with grossly abnormal DNA content were transient intermediates during oral cancer development. CONCLUSIONS: Abnormal DNA content is a significant biomarker of a subset of OED that progress to carcinoma.

PML involvement in the p73-mediated E1A-induced suppression of EGFR and induction of apoptosis in head and neck cancers.

Epidermal growth factor receptor (EGFR) tyrosine kinase is commonly overexpressed in human cancers; however, the cellular mechanisms regulating EGFR expression remain unclear. p53, p63 and p73 are transcription factors regulating many cellular targets involved in controlling the cell cycle and apoptosis. p53 activates EGFR expression, whereas TAp63 represses EGFR transcription. The involvement of p73 in the regulation of EGFR has not been reported. Here, a strong correlation between EGFR overexpression and increased levels of the oncogenic DeltaNp73 isoform in head and neck squamous cell carcinoma (HNSCC) cell lines was observed. Ectopic expression of TAp73, particularly TAp73beta, resulted in suppression of the EGFR promoter, significant downregulation of EGFR protein and efficient induction of cell death in all six EGFR-overexpressing HNSCC cell lines. EGFR overexpression from a heterologous LTR promoter protected lung cancer cells from TAp73beta-induced EGFR suppression and apoptosis. Expression of TAp73beta efficiently induced promyelocytic leukaemia (PML) protein expression and PML knockdown by shRNA attenuated the downregulation of EGFR and induction of apoptosis by p73 in HNSCC cells. Furthermore, PML was found to be important for E1A-induced suppression of EGFR and subsequent killing of HNSCC cells. Our data therefore suggest a novel pathway involving PML and p73 in the regulation of EGFR expression.

Management of advanced parotid cancer. A systematic review.

BACKGROUND: Primary adenocarcinomas of the parotid gland are rare and account for less than 5% of all head and neck malignant neoplasms. There is considerable variation in biological behaviour within this group; low-grade tumours exhibit slow growth rates with minimal or no local invasion. High-grade tumours, however, show a high incidence of local recurrence and distant metastasis. AIM: The purpose of this paper is to analyse the important prognostic indicators for this cancer. METHODS: A systematic review was performed involving 19 published studies from 1987 to 2005 which included 4631 patients. T stage, grade of tumour, N stage and adjuvant radiotherapy on overall (5 year) survival were analysed as prognostic indicators. RESULTS: T stage (p=0.041, hazard ratio 1.8 (confidence interval 1.2-2.9)), N stage (p=0.05, hazard ratio 1.1 (0.2-1.8)), and high-grade (p=0.001, hazard ratio 2.1 (1.5-2.7)) were associated with a significantly worse survival. The effect of adjuvant radiotherapy was to improve overall survival: p=0.002, hazard ratio 2.9 (1.5-4.7). The mean 5 year survival for advanced high-grade parotid cancer was 35%. CONCLUSION: High-grade advanced parotid cancers are associated with a poor survival. Adjuvant radiotherapy is indicated in these tumours and this improves survival.

Extracranial glomus faciale tumour.

OBJECTIVES: To describe a unique presentation of a predominantly extracranial glomus faciale tumour. To discuss the role of imaging in the differential diagnosis and evaluation of a hypervascular parotid mass. To review the previous literature concerning the glomus faciale tumour. CASE REPORT: A 54-year-old woman presented with a six-month history of facial weakness, pain and a parotid mass. Ultrasound revealed a hypervascular parotid mass and pre-operative core biopsy suggested a paraganglioma. Computed tomography defined its deep extent and demonstrated involvement of the petrous temporal bone along the descending portion of the facial nerve canal with a pattern of permeative lucency. A tumour was surgically removed which arose from the facial nerve from the second genu to the proximal divisions within the parotid gland and histology confirmed a paraganglioma. CONCLUSIONS: A facial nerve glomus faciale tumour should be considered in the differential diagnosis of a hypervascular parotid mass and may present in a predominantly extracranial location. Computed tomography will prove helpful in such a case in order to limit the differential diagnosis and to define the extent of skull base involvement.

ERBB receptors in developing, dysplastic and malignant oral epithelia.

Some oral squamous cell carcinomas (OSCCs) overexpress epidermal growth factor receptor (EGFR) but little is known about the receptor system overall during oral carcinogenesis. We studied all four ERBB receptors (EGFR, ERBB2-4) in developing (n=2), normal (n=7), dysplastic (n=23) and malignant (n=26) oral epithelia by means of immunohistochemistry. The investigations were supplemented by conducting reverse transcription-polymerase chain reactions in relation to 13 OSCC samples. All four ERBB receptors were detected in developing oral epithelium and, to a lesser degree, in mature oral epithelium. An increase in EGFR immunoreactivity was seen in 61% and 54% of dysplasias and OSCCs, respectively. The corresponding percentages for ERBB2 were 48 and 12, for ERBB3 48 and 43. ERBB4 nuclear staining was increased in 30% of dysplasias and 26% of OSCCs. Changes in ERBB receptor mRNA levels were not statistically significant. The results show that ERBB receptor profiles are specific to each tumour. Increased nuclear translocation of ERBB4 in some OSCCs may alter transcription of target genes and be associated with cancer progression. This information may be useful for clinicians as EGFR inhibitors are becoming treatment options in modern oncology.