Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

OBJECTIVE: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC. METHODS: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases. RESULTS: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort. CONCLUSIONS: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

Transoral laser resection versus lip-split mandibulotomy in the management of oropharyngeal squamous cell carcinoma (OPSCC): a case match study.

The objective of this study was to compare transoral laser microsurgery (TLM) with lip-split mandibulotomy (LSM) and radial forearm free-flap reconstruction, for the resection of squamous cell carcinoma of the oropharynx (SCCOP). This study is designed as a case-control study matching 24 patients treated with TLM for SCCOP with those treated with LSM. Patients were matched by age (in 5-year epochs), sex, TNM stage, tumour sub site and type of neck dissection. Each group comprised 20 males and 4 females (mean age 56 years). Seven patients treated with TLM had an elective tracheostomy compared with all patients undergoing LSM. Moreover, the time for decanulation was reduced in patients undergoing tracheostomy for TLM. Although similar rates of patients were able to swallow to some degree on discharge, 29% of patients having LSM were discharged requiring enterostomy feeding compared with 4% of patients treated using TLM. Of those able to swallow on discharge, patients who had TLM resumed swallowing in half the time taken for those having LSM. Moreover, those treated with TLM remained in hospital for half the length of time than those treated with LSM. Due to these factors, overall cost for TLM is reduced in comparison with LSM. In comparison with LSM, TLM for the treatment of SCCOP results in fewer tracheostomies and shorter time to decanulation; a quicker recovery of swallowing function and a reduced length of hospital stay. As a result of this, treatment with TLM is on average cheaper. These factors should be considered when deciding on the surgical treatment of a patient with SCCOP.

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy.

BACKGROUND: Epigenetic silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre. METHODS: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas. RESULTS: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation >non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS. CONCLUSIONS: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification.

Expression of cell cycle associated proteins influences radiocurability of T2N0 squamous cell carcinoma of the larynx.

Cell cycle modulators are important in carcinogenesis and may be of prognostic and therapeutic relevance. This study has examined the influence of the proliferation index (Ki-67) and immunocytochemical expression of epidermal growth factor receptor (EGFR), cyclin D1, and retinoblastoma protein on recurrence rates at the primary site in 50 patients with T2N0 laryngeal carcinomas treated with radical irradiation. Pre-treatment biopsies were retrieved and sections scored for the four immunocytochemical markers. Statistical analysis for association, interaction and survival was performed. Five cases showed loss of expression of Rb protein. The median Ki-67 index was 50%, the median cyclin D1 index 21% and the median EGFR index 47% of cells. EGFR and cyclin D1 expression were positively correlated and, whilst local recurrence tended to occur with a Ki-67 labelling index of <50%, this was not statistically significant. When interactions were examined using Multiple Logistic Regression it was found that there was a direct relationship between EGFR and cyclin D1 expression. If the EGFR index was >20% and the cyclin D1 index >10%, then the odds ratio in favour of a primary site recurrence was very high (5.32 +/-0.41). This study demonstrates that the relationship between EGFR index and cyclin D1 index has a very strong association with primary site recurrence for T2 N0 laryngeal carcinomas treated by irradiation.

Genetic and metabolic predictors of chemosensitivity in oligodendroglial neoplasms.

The -1p/-19q genotype predicts chemosensitivity in oligodendroglial neoplasms, but some with intact 1p/19q also respond and not all with 1p/19q loss derive durable benefit from chemotherapy. We have evaluated the predictive and prognostic significance of pretherapy (201)Tl and (18)F-FDG SPECT and genotype in 38 primary and 10 recurrent oligodendroglial neoplasms following PCV chemotherapy. 1p/19q loss was seen in 8/15 OII, 6/15 OAII, 7/7 OIII, 3/11 OAIII and was associated with response (Fisher-Exact: P=0.000) and prolonged progression-free (log-rank: P=0.002) and overall survival (OS) (log-rank: P=0.0048). Response was unrelated to metabolism, with tumours with high or low metabolism showing response. Increased (18)F-FDG or (201)Tl uptake predicted shorter progression-free survival (PFS) in the series (log-rank: (201)Tl P=0.0097, (18)F-FDG P=0.0170) and in cases with or without the -1p/-19q genotype. Elevated metabolism was associated with shorter OS in cases with intact 1p/19q (log-rank: (18)F-FDG P=0.0077; (201)Tl P=0.0004) and shorter PFS in responders (log-rank: (18)F-FDG P=0.005; (201)Tl P=0.0132). (201)Tl uptake and 1p/19q loss were independent predictors of survival in multivariate analysis. In this initial study, (201)Tl and (18)F-FDG uptake did not predict response to PCV, but may be associated with poor survival following therapy irrespective of genotype. This may be clinically useful warranting further study.

Clinical use of genotype to predict chemosensitivity in oligodendroglial tumors.

BACKGROUND: The -1p/-19q genotype has been associated with prolonged survival and chemosensitivity in oligodendroglial neoplasms, but the predictive and prognostic significance of genotype in the routine clinic is not established. METHODS: The authors investigated allelic imbalance in 1p36, 19q13, 17p13, 10p12-15, and 10q22-26 and p53 mutation in a cohort representative of clinical practice at their center (50 primary, 26 recurrent cases) given PCV chemotherapy between 2000 and 2003 and compared with response and outcome following PCV. RESULTS: 1p/19q loss was found in 12/19 OII, 10/23 OAII, 11/13 OIII, and 6/21 OAIII. Response, seen in 92% with 1p/19q loss, was associated with the -1p/-19q genotype (Fisher exact: p < 0.001) regardless of WHO grade or whether primary or recurrent. 1p/19q loss was an independent prognostic factor associated with longer progression-free (PFS) and overall survival (OS) (Cox regression: PFS and OS p < 0.001), with greater impact on PFS than OS in primary tumors, and OS at recurrence. 17p13 loss and p53 mutation were associated with poor prognosis in recurrent tumors and chromosome 10 loss was associated with short PFS and OS in primary tumors. Histologic subtype did not influence outcome in tumors of equivalent genotype. Genotype had greater association with response and outcome than conventional clinical factors. A total of 29% with intact 1p/19q and a variety of genetic or clinicopathologic characteristics responded in association with increased PFS and OS. CONCLUSIONS: The -1p/-19q genotype predicted response and favorable outcome following PCV chemotherapy corroborating genetic analysis to guide routine clinical management. However, some cases with intact 1p/19q also had clinical benefit.

MRI in the diagnosis and treatment of suspected malignant spinal cord compression.

It remains unclear whether MRI is essential in all patients with suspected malignant spinal cord compression (MSCC), or whether some patients can be treated on the basis of plain radiographic findings and neurological examination. A prospective study was carried out of 280 consecutive patients with suspected MSCC, and the results of neurological examination plus plain radiographs were compared with MRI. 201 patients had MSCC (186 extradural, 5 intradural extramedullary and 10 intramedullary) and 11 patients had thecal sac compression without evidence of spinal cord compression. 25% of patients with MSCC had two or more levels of compression, 69% of these involving more than one region of the spine. A paraspinal mass was noted at the site of extradural spinal cord compression in 28%, and only one-third of these were detected on plain radiography. Focal radiographic changes and consistent neurology were present in 91 (33%) patients who had not had previous radiotherapy. MRI confirmed the presence of MSCC in 89/91 patients (specificity and positive predictive value of radiographic/clinical findings 98%) and the level of disease in all. MRI led to a change in the radiotherapy plan in 53% of patients (21% major change). The sensory level when present was four or more segments below the MRI level in 25/121 (21%) patients, and two or more levels above in 8/121 (7%) patients. Although focal radiographic abnormalities with consistent neurological findings, when present, accurately predicted the presence and level of MSCC, whole spine MRI is indicated in most patients with suspected MSCC because the additional information may alter the management plan. Treatment may be appropriately initiated on the basis of focal radiographic changes and consistent neurology if MRI is contraindicated or delayed, and in patients with a poor prognosis. In patients in whom there are no focal radiographic abnormalities and consistent neurological findings, urgent MRI is mandatory before radiotherapy is commenced.

A report of 50 patients with carcinoma of the hypopharynx treated by total pharyngolaryngo-oesophagectomy repaired by gastric transposition.

Extensive carcinoma of the hypopharynx requires aggressive surgery, which can lead to loss of function and a high morbidity and mortality. This paper reports 50 patients with carcinoma of the hypopharynx treated with total pharyngolaryngo-oesophagectomy and gastric transposition. Thirty-two patients had primary surgery and 18 had salvage surgery for recurrence following radiotherapy. Two technical modifications to the standard procedure that have evolved during this period are the use of a diverticuloscope for dissection of the middle third of the oesophagus and the routine insertion of chest drains peroperatively. Complications were relatively unusual in the primary surgery group, but were a problem in those patients undergoing salvage surgery. Stenosis did not tend to occur with gastric transposition repair, but three patients had delayed gastric emptying with prolonged hospital stays. The tumour-specific actuarial survival at 4 years was 39% and the observed survival was 25%. Pharyngolaryngo-oesophagectomy and gastric transposition is becoming safer owing to increased multidisciplinary experience in this form of surgery. Survival is improved with the use of postoperative radiotherapy in patients undergoing primary surgery.

Development of simultaneous purification methodology for multiple synthetic peptides by reversed-phase sample displacement chromatography.

We have developed a low-pressure protocol, designed as a rapid, simple and cost-effective procedure for the efficient and parallel purification of multiple peptide mixtures. This was achieved through adaptation of our novel reversed-phase sample displacement chromatography (SDC) method, where the major separation process takes place in the absence of organic modifier, to modular solid-phase extraction (SPE) technology. Thus, crude peptide sample is applied at overload conditions to extraction columns consisting of SPE tubes containing silica-based reversed-phase packing. By applying a vacuum to draw the solution through the packing, product separation from hydrophobic and hydrophilic impurities is accomplished in a two-stage purification unit: a short pre-column functions as a trap for hydrophobic impurities, while a second, longer SPE column is used as a product isolation column. Thus, under ideal SDC conditions, washing with a 100% aqueous solvent will achieve retention of hydrophobic impurities on the trap, with displacement of product and hydrophilic impurities from the trap to the product isolation column; hydrophilic impurities are thus displaced off the product isolation to waste, leaving only product retained on the main column. In this initial evaluation, this purification system has demonstrated excellent separation of product, in good yield, from both hydrophilic and hydrophobic impurities over a wide range of peptide hydrophobicity and crude composition for model synthetic peptide systems representing crude peptide mixtures.

Performance data and survival in head and neck cancer.

A retrospective longitudinal investigation of 2701 patients extending from 1963 was conducted to study the effect of performance status on survival, locoregional recurrence and associations with host and tumour factors. It was found that those patients who are physically fit tended to have smaller tumours, less risk of neck node metastases and more chance of laryngeal cancer. In patients with advanced disease, locoregional recurrence did not appear to be more common in those with poor general condition but the death rate from the tumour appeared to increase as the general physical condition decreased. It is assumed this is due to the development of distant metastases. There is evidence that immunity is less well developed in those with poor general condition and this in turn, may be due to alcohol abuse and poor general nutrition.

Laboratory-based calculation of coronary heart disease risk in a hospital diabetic clinic.

AIMS: To develop an estimation of risk of coronary heart disease (CHD) based on the Framingham equation for use in a diabetes clinic, given concerns about the accuracy of the Sheffield risk tables in this setting. METHODS: A computer program using the Framingham equation based on patients' age, sex, systolic blood pressure, smoking history, presence of diabetes and left ventricular hypertrophy was applied to requests for lipid screening of patients attending the diabetes clinics of Birmingham Heartlands Hospital. The calculated risks for the population were compared with those estimated from the Sheffield tables. RESULTS: Of 1060 patients with diabetes mellitus, 215 (20%) had an annual CHD risk > or =3%, which is considered to be the threshold at which lipid-lowering drugs are cost-effective. Only 24 of these 215 patients (11%) were correctly identified by the Sheffield tables, which we conclude have an unacceptably low sensitivity in diabetes mellitus. CONCLUSIONS: A laboratory-based CHD risk calculation system is a practical alternative to the Sheffield system and may have a greater sensitivity in the diabetic clinic.

Improved survival in patients with head and neck cancer in the 1990s.

It is generally felt amongst the medical profession and the lay public that cancer is being treated more successfully than in the past. This is certainly true for childhood malignancies and leukaemia but evidence that significantly improved survival is occurring in the common solid tumours is lacking. Since 1963 the University of Liverpool Department of Otolaryngology/Head and Neck Surgery has collected data on all patients with head and neck tumours presenting to the department. The present study investigates patients with histologically proven squamous cell carcinoma of the four main sites: larynx, hypopharynx, oral cavity and oropharynx. From 1963 until the end of 1989, 2738 patients were seen by the department and from 1990 a further 717 patients have been seen. Since 1990 patients have tended to be in better general physical condition but, on the other hand, have tended to have more advanced disease at the primary site. The department has latterly tended to see fewer laryngeal cancers and more cancers of the oropharynx. Significantly fewer patients have presented with neck node metastases. Multiple logistic regression suggests that the most significant difference between the two groups is the great reduction in neck node recurrence rates in the group of patients seen since 1990 (P = 0.0001). The recurrence of tumours at the primary site since 1990 has been 35% compared with 41% before 1990, and recurrence in the neck nodes since 1990 has been 12%, compared with 15% before 1990. These differences are significant (P = 0.0141 and P = 0.0494, respectively). When studying survival in the 1960s, 1970s and 1980s, the 5-year cure rate was 50%, whereas since 1990 the figure has risen to 60% tumour-specific 5-year survival--a significant difference. A similar effect was noted in observed survival. This improvement in cure rate occurred for all four main sites. The results were confirmed by Cox's proportional hazards model where year of treatment was highly significantly associated with improved survival (P = 0.0001). It has been demonstrated that locoregional recurrence has improved since 1990 and this is reflected in improved survival figures. Although there are differences in the parameters of tumours referred before 1990 and since 1990, multivariate analysis suggests that the improvement in neck node recurrence rates may be responsible for this improved survival rate. Multivariate analysis for survival also suggests that the improvement in cure rates is independent of compounding variables and dependent on the year of presentation of the tumour. This improved survival may be related to factors, such as the administration of radical postoperative radiotherapy.

Malignant spinal cord compression: prospective study of delays in referral and treatment.

OBJECTIVES: To examine the delay in presentation, diagnosis, and treatment of malignant spinal cord compression and to define the effect of this delay on motor and bladder function at the time of treatment. DESIGN: Prospective study of all new patients presenting to a regional cancer centre with this condition. SETTING: Regional cancer centre. SUBJECTS: 301 consecutive patients. MAIN OUTCOME MEASURES: Interval from onset of symptoms to presentation and treatment, delay at each stage of referral, and functional deterioration. RESULTS: The median (range) delay from onset of symptoms of spinal cord compression to treatment was 14 (0-840) days. Of the total delay, 3 (0-300) days were accounted for by patients, 3 (0-330) days by general practitioners, 4 (0-794) days by the district general hospital, and 0 (0-114) days by the treatment unit. Initial presentation to the regional cancer centre with symptoms of malignant spinal cord compression led to a significant reduction in delay to treatment and improved functional status at the time of treatment. Deterioration of motor or bladder function >=1 grade occurred at the general practice stage in 28% (57) and 18% (36) of patients, the general hospital stage in 36% (83) and 29% (66), and the treatment unit stage in 6% (19) and 5% (15), respectively. CONCLUSIONS: Unacceptable delay in diagnosis, investigation, and referral occurs in most patients with malignant spinal cord compression and results in preventable loss of function before treatment. Improvement in the outcome of such patients requires earlier diagnosis and treatment.

Tumours of the minor salivary glands.

One hundred and forty-five patients were identified with minor salivary gland tumours. General information and tumour-specific information on stage, grade of tumour, resection margins, recurrence and survival were collected. Data was analysed by both univariate and multivariate methods. Indices predicting tumour recurrence and survival were analysed. Forty-two benign lesions, mostly pleomorphic adenomas were identified, one recurred, all survived. One hundred and three malignant lesions were identified, mostly adenoid cystic carcinomas (70%) or mucoepidermoid carcinomas (19%). Late stage disease and the presence of neck node metastases predicted both early recurrence and high eventual mortality. Survival was favoured by the histological type (mucoepidermoid > adenoid cystic), site of primary (oral cavity and oropharynx > nose, sinuses and larynx) and good general condition. Many tumours recurred after 5 years of disease-free survival and late mortality was a feature (80% survival at 5 years, 20% at 20 years). Many patients survive some time with either local recurrence or distant metastases. Long-term follow-up is advocated as local or distant recurrence may be treatable. The value of super radical treatment of the primary is questionable given the likelihood of recurrence at distant sites.

The effects of age on survival and other parameters in squamous cell carcinoma of the oral cavity, pharynx and larynx.

Many papers have been written on the effect of age on survival from cancer and a number of these papers have concentrated on cancer of the head and neck. The literature is fairly evenly split between those studies that claim that the young patient has a better chance of survival and those that suggest the older patient has a better chance of survival. The present study investigates 2647 patients with histologically proven squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. The tumour-specific 5-year survival of patients with head and neck cancer from the third decade through to the seventh decade at presentation was 54%, whereas this figure dropped to 44% for the eighth, ninth and tenth decades. This difference was statistically significant (P = 0.0001). When the patients in the third to seventh decades of presentation were compared with those from the eighth to tenth decades, it was found that older patients tended to have significantly more advanced disease at the primary site and fewer neck node metastases when compared with younger patients at presentation. These differences were confirmed by multiple logistic regression. Multivariate analysis of survival confirmed that advanced age was associated with poor survival (P = 0.0001). Whilst patients with head and neck cancer in their eighth, ninth and tenth decades fared worse than younger patients, their mean tumour specific survival at 5 years was in the region of 44%, which makes treatment worthwhile, certainly in selected cases.

Treatment of oropharyngeal carcinoma by irradiation or by surgery.

Of previously untreated patients with squamous cell carcinoma of the oropharynx, 145 are reviewed in this study. All were treated in the Department of Head and Neck Surgery at the University of Liverpool from 1990 to 1997. Seventy-seven patients were treated with irradiation, 28 patients by surgery and 40 patients were deemed not suitable for any curative treatment. Univariate analysis showed no difference in the two groups treated by curative modalities but multivariate analysis did suggest that the surgical group tended to have larger neck node metastases. The 5-year tumour specific actuarial survival for all patients was 53%, 65% for the radiotherapy group and 51% for the surgery group. The difference was not statistically significant (chi (1)2 = 1.5070). The modality of treatment had no affect on either the development of a primary or neck node recurrence or the survival after such a recurrence. Where neck node disease was present it was treated as appropriate. As is generally standard practice, lymph nodes over 2 cm were treated with radical neck dissection whether the patient was having irradiation therapy or surgery. If the patient was having irradiation therapy, the neck dissection was carried out before and irradiation after operation, both on the primary and on the neck, if appropriate. It is concluded that irradiation therapy in properly selected cases in combined head and neck clinics is a safe and effective treatment for squamous cell carcinoma of the oropharynx. Neck node disease should be treated appropriately, but there is no support for the old adage that whatever form of treatment is being used for the neck node should also be used for the primary site.

Radical radiotherapy for squamous cell carcinoma of the larynx, oropharynx and hypopharynx: patterns of recurrence, treatment and survival.

The present study investigates 1085 previously untreated patients with squamous cell carcinoma of the head and neck for factors that influence recurrence following treatment with definitive radiotherapy. In the second part of this study, those diagnosed with recurrence were studied with regard to treatment and were further analysed with regard to identification of prognostic factors which may affect outcome in the patient who actually develops a recurrence.