Outcomes of oral squamous cell carcinoma arising from oral epithelial dysplasia: rationale for monitoring premalignant oral lesions in a multidisciplinary clinic.

Surveillance of oral epithelial dysplasia results in a number of newly diagnosed cases of oral squamous cell carcinoma (SCC). The clinical stage of oral SCC at diagnosis influences the magnitude of treatment required and the prognosis. We aimed to document the stage, treatment, and outcome of oral SCC that arose in patients who were being monitored for oral epithelial dysplasia in a dedicated multidisciplinary clinic. Those with histologically diagnosed lesions were enrolled on an ethically approved protocol and molecular biomarker study. Details of clinical and pathological TNM, operation, radiotherapy, recurrence, second primary tumour, and prognosis, were recorded in patients whose lesions underwent malignant transformation. Of the 91 patients reviewed (median follow-up 48 months, IQR 18-96), 23 (25%) had malignant transformation. All were presented to the multidisciplinary team with stage 1 disease (cT1N0M0). Of these, 21 were initially treated by wide local excision, 2 required resection of tumour and reconstruction, and 2 required adjuvant radiotherapy. At follow-up 3 had local recurrence, one had regional recurrence, one had metachronous lung cancer, and 5 had second primary oral SCC. There were further diagnoses of oral dysplasia in 5 during follow-up, and it is estimated that 76% of patients will have one or other event in 5 years. Disease-specific survival was 100% and overall survival was 96% (22/23). Median follow-up after diagnosis of oral SCC was 24 months (IQR 11-58). Specialist monitoring of oral epithelial dysplasia by a multidisciplinary team allows oral SCC to be detected at an early stage, and enables largely curative treatment with simple and usually minor surgical intervention. The high incidence of second primary oral SCC in high-risk patients with oral epithelial dysplasia further supports intensive targeted surveillance in this group.

The clinical determinants of malignant transformation in oral epithelial dysplasia.

BACKGROUND: While the size and clinical appearance are known risk factors for malignant transformation of potentially malignant oral the importance of site, grade of dysplasia and exposure to environmental carcinogens remains controversial. We aim to report the clinical determinants of malignant progression in a series of patients with histopathologically graded oral epithelial dysplasia (OED). METHODS: We recruited patients with a histopathological diagnosis of OED to a longitudinal observational study in a tertiary oral dysplasia clinic. Clinical, histopathological and risk factor data were recorded at baseline. One of three clinical endpoints were determined: malignant transformation, progression of dysplasia grade, remission/stable dysplasia grade. RESULTS: Ninety-one patients meeting the criteria gave consent for inclusion to the cohort, with outcomes reported after a median follow up of 48 months. An estimated 22% (SE 6%) of patients underwent malignant transformation within 5 years, with significant predictors being: non-smoking status (χ(2)=15.1, p=0.001), site (χ(2)=15.3, p=0.002), non-homogeneous appearance (χ(2)=8.2, p=0.004), size of lesion >200 mm(2) (χ(2)=4.7, p=0.03) and, of borderline significance, high grade (χ(2)=5.8, p=0.06). Gender, age, number of lesions and alcohol history did not predict for malignant transformation. CONCLUSIONS: Although a number of these clinical determinants have previously been associated with higher malignant transformation in OED, the high-risk nature of lesions in non-smokers is of particular note and requires a greater emphasis and recognition amongst clinicians dealing with OED. It suggests that those non-smokers with OED, have an inherited or acquired predisposition and should be treated more aggressively; these should form the focus for further investigation.

Quantitative promoter methylation differentiates carcinoma ex pleomorphic adenoma from pleomorphic salivary adenoma.

BACKGROUND: potential epigenetic biomarkers for malignant transformation to carcinoma ex pleomorphic adenoma (Ca ex PSA) have been sought previously with and without specific comparison with the benign variant, pleomorphic salivary adenoma (PSA). Previous analysis has been limited by a non-quantitative approach. We sought to demonstrate quantitative promoter methylation across a panel of tumour suppressor genes (TSGs) in both Ca ex PSA and PSA. METHODS: quantitative methylation-specific real-time polymerase chain reaction (qMSP) analysis of p16(INK4A), CYGB, RASSF1, RARß, human telomerase reverse transcriptase (hTERT), Wilms' tumour 1 (WT1) and TMEFF2 gene promoters was undertaken on bisulphite-converted DNA, previously extracted from archival fixed tissue specimens of 31 Ca ex PSA and an unrelated cohort of 28 PSA. All target regions examined had formerly been shown to be hypermethylated in salivary and/or mucosal head and neck malignancies. RESULTS: the qMSP demonstrated abnormal methylation of at least one target in 20 out of 31 (64.5%) Ca ex PSA and 2 out of 28 (7.1%) PSA samples (P<0.001). RASSF1 was the single gene promoter for which methylation is shown to be a statistically significant predictor of malignant disease (P<0.001) with a sensitivity of 51.6% and a specificity of 92.9%. RARß, TMEFF2 and CYGB displayed no apparent methylation, while a combinatory epigenotype based on p16, hTERT, RASSF1 and WT1 was associated with a significantly higher chance of detecting malignancy in any positive sample (odds ratio: 24, 95% CI: 4.7-125, P<0.001). CONCLUSIONS: we demonstrate the successful application of qMSP to a large series of historical Ca ex PSA samples and report on a panel of TSGs with significant differences in their methylation profiles between benign and malignant variants of pleomorphic salivary adenoma. qMSP analysis could be developed as a useful clinical tool to differentiate between Ca ex PSA and its benign precursor.

Cytoglobin is upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer.

BACKGROUND: Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancer syndrome of the upper aerodigestive tract. METHODS: Cytoglobin expression and promoter methylation were investigated in sporadic head and neck squamous cell carcinoma (HNSCC) using a cross-section of clinical samples. Additionally, the putative mechanisms of Cygb expression in cancer were explored by subjecting HNSCC cell lines to hypoxic culture conditions and 5-aza-2-deoxycitidine treatment. RESULTS: In clinically derived HNSCC samples, CYGB mRNA expression showed a striking correlation with tumour hypoxia (measured by HIF1A mRNA expression P=0.013) and consistent associations with histopathological measures of tumour aggression. CYGB expression also showed a marked negative correlation with promoter methylation (P=0.018). In the HNSCC cell lines cultured under hypoxic conditions, a trend of increasing expression of both CYGB and HIF1A with progressive hypoxia was observed. Treatment with 5-aza-2-deoxycitidine dramatically increased CYGB expression in those cell lines with greater baseline promoter methylation. CONCLUSION: We conclude that the CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour's biological aggression.

Prognostic importance of site in squamous cell carcinoma of the buccal mucosa.

While stage and grade of oral cancer have a profound and well-recognised influence on outcome, the effect of site is less clear and there have been relatively few published series that specifically address how site affects prognosis. Recent series have found that buccal cancers have a relatively poor prognosis compared with other sites, and suggest that this may be because the tumours are more aggressive. We examined 482 consecutive patients with oral cancers that had been operated on in a single unit, and report the presentation, treatment, and outcome of buccal tumours compared with those of other oral sites with reference to other prognostic variables. There were no significant differences between buccal and other cancers in patients' characteristics, clinical presentation, or pathological staging, except in buccal tumours that rarely had pT1 stage (n=13,16%) compared with other sites (n=112, 28%, pT1-4, p=0.02). Despite a higher rate of frankly involved margins (p=0.02), the 5-year disease-specific survival was 70% for buccal tumours compared with 75% for other sites (p=0.34). We conclude that site had little influence on prognosis, and that the poor outcome of buccal cancers reported from other centres has not been replicated in our series.

The topography of cervical lymph node metastases revisited: the histological findings in 526 sides of neck dissection from 439 previously untreated patients.

The pathological reports, minimum datasets and topographical plots of the neck dissections from 439 cases of oral and oropharyngeal cancer reported by a single pathologist following a standard protocol were analysed. Metastasis was evident in 47% of patients including bilateral metastases in 6%, extracapsular spread in 29% and matting in 7%. The extent of metastasis (both volume and distribution) was greatest in tumours of the oropharynx followed by lateral tongue, ventral tongue and floor of mouth. The typical 'inverted-cone pattern' was seen in 67% of patients with metastasis. A single micrometastasis was seen in 14%, skip lesions in 10% and involvement of 'other' nodal groups in 4%. Contralateral neck metastases (0.4%), peppering (2%), flushing of lymph node sinuses (1%) and all nodes positive (0.4%) accounted for the remaining 'aberrant' patterns. Skip lesions were seen in tumours at all sites other than retromolar.

A comparison of outcomes for patients with oral squamous cell carcinoma at intermediate risk of recurrence treated by surgery alone or with post-operative radiotherapy.

Controversy remains about which patients at intermediate risk of recurrence of oral squamous cell carcinoma would benefit from radiotherapy. A retrospective review of computerised database and medical records for 462 consecutive patients at the Regional Maxillofacial Unit in Liverpool who were treated with primary surgery with or without post-operative radiotherapy was carried out. We classified 29% (134) of patients as being at 'low' risk of disease recurrence (pT1-2, N0 with clear margins), 29% (135) at 'high' risk (involved margins or lymph node extracapsular spread) and the remaining 42% (193) at 'intermediate' risk. Of those at intermediate risk, 41% (80/193) received adjuvant radiotherapy and their 5 year survival (SE) was 54% (6%) compared to 71% (5%) for those with primary surgery alone (P=0.002). A higher proportion of patients having radiotherapy had loco-regional recurrence (19/80 24%) compared to those treated by surgery alone (17/113 15%). The improved salvage rate for recurrent disease in the surgery alone group (8/17 53%), compared to those receiving radiotherapy (2/19 13%, P=0.05), indicates an advantage in withholding radiotherapy for patients at intermediate risk of recurrence. This study indicates a potential disadvantage associated with the use of postoperative radiotherapy for patients at intermediate risk of recurrence. A randomised trial comparing a watch and wait policy to postoperative radiotherapy in patients with an intermediate risk of recurrence is required to confirm the trend indicated in this retrospective data.

Salvage neck dissections in oral and oropharyngeal squamous cell carcinoma: histological features in relation to disease category.

The histological findings in a series of 37 salvage neck dissections from patients who had an oral or oropharyngeal squamous cell carcinoma managed initially by primary surgery with or without neck dissection, and without postoperative radiotherapy, are described. None of the cases had an intraoral relapse. Pathological stage N2 or N3 disease was seen in 87% of the 15 salvage dissections from 'wait and watch' necks, 100% of the 10 salvage dissections of contralateral necks and 50% of the 12 salvage dissections of operated necks. The typical 'inverted-cone' pattern of metastasis was seen in 87% of 'wait and watch' necks. Skip or non-contiguous metastases to level III/IV accounted for relapse in 30% of the contralateral and 66% of the operated necks. The median time interval between original surgery and the salvage neck dissection was 15 months (range 1-48 months). In at least 15% of cases, the short time interval coupled with the histopathological features suggested that the metastatic disease suddenly became more rapidly progressive following removal of the primary tumour.

The national head and neck histopathology external quality assurance scheme: evolution, design, and analysis of 11 circulations from 1999 to 2005.

The background and design of a specialised head and neck histopathology external quality assurance (assessment) scheme with optional oral and ENT arms is described. Participation (submission of response forms) exceeded 85% in eight of 11 slide circulations. In 60% of the 168 circulated cases, up to 33% (and in occasional cases, up to 56%) of respondents gave incomplete or wrong responses owing to a lack of awareness of specific diagnostic entities or to the misinterpretation of specific histological features. In all, there were 118 wrong responses, of which 58% could be considered "potentially serious". The scheme incorporates several design features which optimise the educational value. The stringent marking of cases, and the flagging of performances showing "a meaningful deviation in standard" based on the decision of peer members rather than a rigid numerical formula, encourages high standards.

The prognostic implications of the surgical margin in oral squamous cell carcinoma.

The prime objective of tumour ablation in oral squamous cell carcinoma (OSCC) is the removal, with a 'margin' of normal tissue, of the whole tumour. Definition of what constitutes margin involvement varies. This study aims to examine the factors associated with close and involved surgical margins in the management of OSCC. A cohort of 200 consecutive patients with previously untreated OSCC provided the material for the study. Various clinical, operative and pathological parameters were related to the status of the surgical margin, as well as time to recurrence, and survival. Cox regression analysis of the survival was also undertaken. Of the 200 patients 107 (53.5%) had clear margins, 84 (42%) close and 9 (4.5%) involved. Poor correlation was found between the status of the surgical margin and clinical factors, but in contrast high correlation between histological indicators of aggressive disease and close or involved surgical margins. These results imply that close surgical margins in OSCC could be regarded as an indictor of aggressive disease.

Cervical lymph node metastasis in oral cancer: the importance of even microscopic extracapsular spread.

The prognostic significance of extracapsular spread of cervical metastases in oral cancer is still controversial. To investigate the importance of extent of extracapsular spread; the relationship between extracapsular spread and both traditional measures of metastatic disease and clinical/histological features of the primary tumour, and to determine their relative prognostic significance. The survival of 173 patients undergoing radical surgery and simultaneous neck dissection for oral/oropharyngeal squamous cell carcinoma with histologically confirmed nodal metastasis and followed for 2.2-12.3 years is reported and related to pathological features. The most predictive clinical/histopathological features were determined by Cox regression modelling. The 3-year survival probability was similar for patients with macroscopic and only microscopic extracapsular spread (33 and 36%, respectively, compared with 72% for patients with intranodal metastasis). The Cox model showed the most predictive factor was extracapsular spread followed by status of resection margins. Extracapsular spread should be incorporated into pathological staging systems. Even microscopic extracapsular spread is of critical importance and must be sought especially in small-volume metastatic disease.

Factors that influence the method of mandibular resection in the management of oral squamous cell carcinoma.

The method of conservative (rim) resection of the mandible is now well established and provides good control of disease in the primary site. There are few audits of this technique in terms of margins of resection for both rim and segmental resection of the mandible. Consecutive previously untreated patients managed with resection of the mandible as part of their treatment for oral and oropharyngeal squamous cell carcinoma were recruited for the study. The presence and extent of tumour invasion of the mandible was recorded and a retrospective analysis made to establish the incidence of unnecessary segmental resections. The invasion rate was 33% (8/35) for rims and 83% (54/65) in segmental resections of the mandible, which compares favourably with previous studies and indicates a reasonable accuracy of resection. In between 6 and 11 of the 62 cases (10-17%) a rim resection could have achieved a satisfactory resection margin and retained a functioning lower border of the mandible. The accuracy of resection in terms of margins was greater for mandibular resections (94% clear margins) than soft tissues (62% clear margins). The number of compromised margins was significantly greater in the invaded rim resection group (P=0.018). This study indicates that a more conservative mandibular resection was possible in a few cases. This is unlikely to have an adverse effect on the close or involved margin rate, which depends mainly on the accuracy of the soft tissue resection. Angling the horizontal rim resection to take into account tumour entry at the point of contact will help to ensure a clear bone margin if a conservative approach to mandibular resection is an option.

Radionuclide bone imaging for detection of mandibular invasion by squamous cell carcinoma.

The assessment of mandibular invasion is an important part of the pre-operative staging of oropharyngeal squamous cell carcinoma. When bone is surgically resected, histology often shows no direct bone invasion, yet such resections are associated with post-operative complication and morbidity. This prospective study of a large group of patients aims to lay down criteria for bone invasion using radionuclide bone imaging and orthopantomography, and to test their effectiveness when compared with histological analysis. 77 patients with proven squamous cell carcinoma of the oral cavity were investigated pre-operatively by radionuclide bone imaging and orthopantomography. All had bone resected as part of complete resection of the tumour. One patient had systemic bone metastases and was, therefore, excluded. In the remaining 76 patients, there were four false positive assessments for bone invasion radiologically and no false negatives. There were 48 true positive results and 24 true negatives, giving a sensitivity of 100% and specificity of 86%. It is concluded that correct application of the outlined criteria for bone invasion demonstrated that radionuclide bone imaging and orthopantomography are a sensitive test for bone invasion, with an acceptable level of specificity.

Histological distribution of cervical lymph node metastases from intraoral/oropharyngeal squamous cell carcinomas.

The histological frequency and distribution of cervical lymph node metastases was studied in 326 neck dissections from 253 patients with an intraoral/oropharyngeal squamous cell carcinoma. Metastasis was evident in 118 patients (47%) and 18 had bilateral metastasis. For primary sites other than the tongue, metastasis developed initially in a node(s) in the first drainage group (level I or II) with progressive involvement of neighbouring nodes ('overflow'). Simultaneous bilateral metastases were seen in some tumours of the floor of mouth, tongue and oropharynx which involved the midline. An erratic distribution of metastases suggestive of 'fast-tracking' (skip lesions and peppering) was only seen in tongue tumours. The pattern of metastatic spread indicates that level IV nodes must be included in staging and therapeutic neck dissections in tongue cancer. Metastasis to 'accessory' lymph nodes (lingual, buccal) occurs infrequently but may explain some 'local' recurrences.

Micrometastasis in oral/oropharyngeal squamous cell carcinoma: incidence, histopathological features and clinical implications.

The prognostic importance of accurate pathological staging of oral cancer patients with established lymph node metastases is well known. The present study sought to determine the incidence and clinical significance of minimal neck disease (only micrometastases) and to evaluate clinical features of the primary tumour in relation to the pathological metastatic status. Surgical resection specimens from 178 patients with oral/oropharyngeal squamous cell carcinoma were assessed by routine techniques. Micrometastases were defined as intranodal deposits measuring in total no more than 3 mm at any level of sectioning. Fourteen patients (8%) had only micrometastases and 72 (40%) had established nodal metastases. Patients with only micrometastases were younger than those with established metastases, but there were no differences in T site, T stage or sex. The outcome (2-6 years postsurgery) of patients with only micrometastases was similar to those without cervical node metastases. Hence, the main short-term significance of micrometastases seems to be in relation to clinical staging and elective management of the NO neck.

T2 carcinoma of the tongue: the histopathologist's perspective.

The histological characteristics and extent of tumour spread at the primary site and in the neck are described in a series of 50 patients with a T2 squamous cell carcinoma of the oral tongue. The likely site of origin was lateral tongue in 29 cases and ventral tongue in 21 cases. Simultaneous tumours were evident in four resections and multifocal dysplasia in a further 13. Lymph node metastasis was diagnosed histologically in 27 cases, including one case with bilateral metastases. Comparison of the groups, with and without metastasis, showed significant differences in tumour thickness, tumour diameter, multifactorial histological malignancy grade, vessel invasion and nerve invasion. The number of positive lymph nodes per patient ranged from 1 to 16 (mean 3), and 17 dissections showed spread beyond the nodal capsule. Postoperative follow-up ranged from 1 to 6 years and, at the time of analysis, 18 patients had died of or with disease. Loco-regional failure was related to 'high-risk' features at the primary site and extracapsular spread in the neck.

Pathology of the N0 neck.

The incidence, extent and distribution of nodal metastasis is described in 152 neck dissections from patients with an NO neck undergoing surgery for an intraoral/oropharyngeal squamous cell carcinoma. The preoperative N stage had been determined by palpation under general anaesthesia and magnetic resonance imaging. Metastasis was detected histologically in 32 (21%) of the 152 NO necks. The number of positive nodes per NO neck ranged from 1 to 6. In total, 52 positive nodes were found and 29 (56%) measured 10 mm or less in maximum dimension. Twenty-one dissections (66%) contained a single positive node and 24 (75%) showed a single positive anatomical level. Three cases showed 'skipping' of levels within the neck and one case showed 'peppering'. Seventeen (53%) of the 32 positive NO necks and 31 (60%) of the 52 positive nodes contained only 'micrometastases' (deposits < 3 mm). Microscopic extracapsular spread was evident in five NO necks including one case with extracapsular spread at multiple levels. The study concludes that preoperative staging by palpation and routine magnetic resonance imaging cannot be relied upon to detect early cervical metastatic disease, and the topographic distribution of positive nodes indicates that modified neck dissections should include level IV when the primary tumour involves the tongue.

A review of quality of life assessment in oral cancer.

Quality of life is important in patients with oral and oropharyngeal cancer. The assessment of quality of life is complex and it is difficult to identify the studies and questionnaires previously reported that have dealt with quality of life assessment in patients with oral cancer. This article gives guidelines for choosing a questionnaire, provides a tabulated summary of 65 studies published in the English language from 1980 to 1997, and gives a brief description of 27 commonly used questionnaires. The review is of particular assistance to the clinician who is considering embarking upon quality of life research in oral cancer.

Magnetic resonance imaging in the assessment of cervical nodal metastasis in oral squamous cell carcinoma.

OBJECTIVE: The accurate pre-operative assessment of cervical lymph nodes is a well recognized problem in the management of patients with oral squamous cell carcinoma. Imaging techniques have improved the accuracy of staging but cannot determine if nodal enlargement is due to reactive changes or malignant involvement. We assessed the diagnostic performance of magnetic resonance imaging (MRI) in detecting metastatic disease within the neck in oral cancer patients. MATERIALS AND METHODS: A retrospective study was performed on 58 patients treated for oral squamous cell carcinoma. All patients had pre-operative MR imaging including axial and coronal short tau inversion recovery (STIR) sequences and pre- and post-gadolinium axial T1 weighted sequences. Nineteen patients had bilateral neck dissections giving 77 sides of neck for study. MR images were reviewed for nodal involvement at each anatomical level within the neck and correlated with findings at histology. RESULTS: Twenty-seven of the 77 sides of neck contained histologically positive nodes (35.1%). MRI sensitivity was 66.7% and specificity 68%. There was a false-negative rate of 20.9% and false-positive rate of 47.1%. Some enlarged, histologically positive nodes were not detected by MRI. Furthermore, in five cases the only histological evidence of nodal malignancy was the presence of a micrometastasis (<3 mm tumour deposit). MRI detected two of these. CONCLUSION: MRI lacks sufficient sensitivity and specificity to replace elective neck dissection for both staging and prognostic purposes.

Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection.

The outcome of 200 patients with squamous cell carcinoma of the oral/oropharyngeal mucosa managed by primary radical surgery and simultaneous neck dissection and followed for 2.2-8.5 years is reported and related to the pathological features. Ninety-nine patients (50%) had cervical lymph node metastases including 16 (8%) with bilateral metastases. Actuarial (life tables) survival analysis showed the overall 2-year survival probability was 72%, falling to 64% at 5 years. The 5-year survival probability was 81% for patients without metastasis, 64% for patients with intranodal metastases and 21% for patients with metastases showing extracapsular spread. A total of 60 patients (30%) died of/with their cancer: 36 (18%) of local recurrence; 4 (2%) of a metachronous primary tumour; 14 (7%) of regional disease, and 6 (3%) with systemic metastases. A further 15 patients (8%) had relapsed but were clinically disease-free after additional surgery. In all, 7% of the series developed metachronous primary tumours. In addition to nodal metastasis, survival was related to the site and stage of the primary tumour, the histological grade and pattern of invasion, status of the resection margins and pathological TNM stage. For patients with lymph node metastasis, extracapsular spread was an important indicator of tumour behaviour and we recommend its use as a criterion for pathological N staging.