Carbonic anhydrase IX, an endogenous hypoxia marker, expression in head and neck squamous cell carcinoma and its relationship to hypoxia, necrosis, and microvessel density.

Carbonic anhydrase IX (CA IX) is a transmembrane glycoprotein with an active extracellular enzyme site. We have shown previously that it was hypoxia inducible and may therefore be an endogenous marker of hypoxia. It is overexpressed in some tumors, particularly renal cell carcinoma. The aim of this study was to examine the expression and localization of CA IX in head and neck squamous cell carcinoma (HNSCC) and relate this to the location of tumor microvessels, angiogenesis, necrosis, and stage. Expression of CA IX was determined by immunoblotting in three HNSCC cell lines grown in normoxia and hypoxia (pO(2) 0.1%) and three paired tumor and normal tissue samples of HNSCC. Archived paraffin sections (79) of HNSCC were immunostained with antibodies to CA IX and CD34 to determine microvessel density (MVD). By double staining sections with CA IX and CD34, the distance between blood vessels and the start of CA IX expression and necrosis was calculated. CA IX was induced by hypoxia in all three HNSCC cell lines and overexpressed in HNSCC tumor tissue. Overexpression was localized to the perinecrotic area of the tumor on immunostaining, and the percentage area of the tumor expressing CA IX was significantly higher with more tumor necrosis (P = 0.001), a high MVD (P = 0.02), and advanced stage (P = 0.033) on univariate analysis and necrosis (P = 0.0003) and MVD (P = 0.0019) on multivariate analysis. The median distance between a blood vessel and the start of CA IX expression was 80 microm (range, 40-140 microm). CA IX is overexpressed in HNSCC because of hypoxia and is a potential biomarker for hypoxia in this tumor. Overexpression may help to maintain the intracellular pH, giving tumor cells a survival advantage and enhancing resistance to radiotherapy and chemotherapy. CA IX is a potential target for future therapy in HNSCC.

Hypoxia-inducible expression of tumor-associated carbonic anhydrases.

The transcriptional complex hypoxia-inducible factor-1 (HIF-1) has emerged as an important mediator of gene expression patterns in tumors, although the range of responding genes is still incompletely defined. Here we show that the tumor-associated carbonic anhydrases (CAs) are tightly regulated by this system. Both CA9 and CA12 were strongly induced by hypoxia in a range of tumor cell lines. In renal carcinoma cells that are defective for the von Hippel-Lindau (VHL) tumor suppressor, up-regulation of these CAs is associated with loss of regulation by hypoxia, consistent with the critical function of pVHL in the regulation of HIF-1. Further studies of CA9 defined a HIF-1-dependent hypoxia response element in the minimal promoter and demonstrated that tight regulation by the HIF/pVHL system was reflected in the pattern of CA IX expression within tumors. Generalized up-regulation of CA IX in VHL-associated renal cell carcinoma contrasted with focal perinecrotic expression in a variety of non-VHL-associated tumors. In comparison with vascular endothelial growth factor mRNA, expression of CA IX demonstrated a similar, although more tightly circumscribed, pattern of expression around regions of necrosis and showed substantial although incomplete overlap with activation of the hypoxia marker pimonidazole. These studies define a new class of HIF-1-responsive gene, the activation of which has implications for the understanding of hypoxic tumor metabolism and which may provide endogenous markers for tumor hypoxia.

Cause of death in patients with well-differentiated thyroid carcinoma.

OBJECTIVES: The aim of this study is to examine in detail patients dying of well-differentiated thyroid carcinoma. STUDY DESIGN: A retrospective chart review with follow-up. METHODS: Data were collected from 522 consecutive cases of differentiated thyroid carcinoma treated by one endocrinologist and four surgeons at Mount Sinai Hospital, Toronto, Ontario, Canada, from 1964 to 1999. RESULTS: Ten patients died as a direct result of thyroid carcinoma; 19 other deaths were unrelated. Five of 102 patients were men (5%) and 5 of 420 were women (1%); the median age at diagnosis was 68.5 years (range, 49-82 y). No cases were stage I; three, stage II; two, stage III; and five, stage IV. Pathologically papillary carcinoma was found in six of the patients who died, follicular carcinoma in three patients, and Hurtle cell carcinoma in one patient. The causes of death were local invasion or compression of the trachea in two cases and distant metastases in eight patients. Median survival was 3.5 years (range, 1 mo-20 y). CONCLUSIONS: All patients dying of well-differentiated thyroid carcinoma had neck nodes, extrathyroidal spread, or distant metastases at presentation and were older than 49 years of age. Many presented because of their distant metastases. Death resulting from local disease was unusual, with most patients dying of distant metastases.

Menière's disease: evolution of a definition.

In 1861 Prosper Menière separated patients with episodic vertigo, hearing loss and tinnitus from a group previously described as having apoplectiform cerebral congestion. He suggested the cause was disease within the semicircular canals (Menière, 1861). Over the years it became apparent that within this group there were a number of patients with characteristic signs and symptoms and in 1938 a pathological correlate was found in the form of endolymphatic hydrops. Descriptions such as Menière's 'disease', Menière's 'syndrome' and Menière's 'symptom complex' led to a confusing array of terms for this condition and monitoring of treatment results became difficult. In response to this in 1972 the American Academy of Ophthalmology and Otolaryngology Committee on Hearing and Equilibrium published a clear definition of Menière's disease and criteria for the reporting of treatment results, it was updated in 1985 and again in 1995. We describe the changes that have taken place as the definition of Menière's disease has evolved.

Otoplasty: the problem of the deep conchal bowl.

The correction of prominent ears requires a logical approach to address each of the anatomical defects present while bearing in mind the overall shape of the ear. The two most common problems encountered are the lack of an antihelix and a deep conchal bowl. We describe a method of reducing the depth of the conchal bowl which avoids some of the problems previously encountered such as occlusion of the external auditory meatus and visible irregularity on the external surface of the pinna. Resection of the inferomedial part of the conchal bowl and thinning of the ponticulus allow realignment of the ear and prevent prominence of the antitragus. The ear is then secured with concha-mastoid sutures and the scapha-conchal angle can then be corrected to form an antihelix if necessary.

A modification to the brow incision for access to the anterior skull base and paranasal sinuses.

We present four cases where a brow incision was indicated for access to the anterior skull base and paranasal sinuses. We discuss the indications for this incision and present a modification of the incision, to improve cosmesis over the nasion.

Acute non-tuberculous retropharyngeal abscess in an adult. A case report and review of the literature.

Retropharyngeal abscesses in adults are very rare and usually secondary to chronic tuberculous cervical spine osteomyelitis. We report a case of Staphylococcus aureus septicaemia with multifocal abscesses and osteomyelitis of the cervical spine causing a retropharyngeal abscess. This presented as neck pain and dysphagia following a fall. In addition, we have reviewed related cases.

Enophthalmos secondary to maxillary sinus disease: single-stage operative management.

Maxillary sinus disease can lead to dehiscence of the orbital floor. Using endoscopic sinus surgery it is possible to simultaneously reconstruct the orbital floor and to assess and treat the underlying sinus disease.

Four cases of aggressive MRSA wound infection following head and neck surgery.

Four cases of serious MRSA wound infection following head and neck surgery have been identified. One patient died. At post mortem a mediastinal abscess containing MRSA was found to have eroded into the innominate artery causing fatal haemorrhage. The other three suffered serious wound infections, two requiring further surgery. Once MRSA had been identified they were treated with intravenous teicoplanin and all made a full recovery.

Is aortography in lower limb ischaemia still abused?

A study in 1980 revealed that 38% of aortograms performed in a series had been referred for inappropriate reasons and only 49% had been clearly indicated. Recommendations were made to reduce the number of inappropriate investigations. An audit has been carried out of the aortography referrals made in this unit recently. This has shown that, despite changes in the management of peripheral vascular disease in the intervening years, by following the recommendations made in the previous paper, the number of inappropriate aortograms has been reduced to a minimum. The recommendations are endorsed.

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.

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.

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.

A new short practical quality of life questionnaire for use in head and neck oncology outpatient clinics.

A new short questionnaire to assess the quality of life of head and neck patients has been designed at the University of Liverpool Head and Neck Oncology Department. The questionnaire is short, simple and can be easily completed by a patient whilst in the waiting room before consultation. It is filled in 6 months after completion of treatment and shows very good correlation with the standard long exhaustive questionnaires that are difficult to complete on every patient in a busy National Health Service clinic. The University of Liverpool questionnaire provides a simple score from 0%-100% which should prove valuable in the assessment of quality of care and help with decisions regarding treatment options in head and neck cancer patients.

Role of chest CT scanning in the management of patients presenting with head and neck cancer.

BACKGROUND: The detection of synchronous tumors, whether they be second primaries or distant metastases, in patients with head and neck carcinoma drastically affects prognosis and may alter management. Computerized tomographic (CT) scanning of the chest is an effective screening investigation in this group of patients, both in the detection of synchronous second primary tumors, the incidence of which in this study is 15%, and for accurate staging of metastatic pulmonary disease. The incidence of synchronous tumors in patients who are initially seen with head and neck squamous cell carcinoma (HNSCC) has been reported in large retrospective studies as being between 1% and 3%. These may be either second primary tumors or metastases, and the lung is the commonest site for both. METHODS: Eighty-one head and neck cancer patients (67 primary and 14 secondary referrals) treated at the Royal Liverpool University Hospital between 1994 and 1996 underwent CT scanning of the chest with ultrasound of the liver as part of their routine staging. The results were compared with standard chest x-rays also performed in each patient. RESULTS: Fourteen patients had pulmonary tumors detected on the chest CT scan. In 67 patients, the scan was negative. Patients with negative scans tended not to have neck node metastases (64%), whereas patients with positive scans were much more likely to have neck node metastases with negative necks present in only 36% of patients. Where multivariate analysis was carried out, there was a correlation between neck node metastases and positive CT scans of the chest (estimate = 0.5755, standard error = 0.3066, chi2(1) = 6.73, p .047). The sensitivity of chest x-ray compared with CT scan was only 21 % and the specificity 99%. The positive predictive value of a chest x-ray was 75% and the negative predictive value 86%. Intra-abdominal lesions were detected in two patients, one in the liver and one in the adrenal gland. In the latter patient, this was an isolated lesion, but in the former, the chest scan was also positive. In the 67 patients, who were initially seen at the Royal Liverpool Hospital (primary referrals), the incidence of synchronous tumors was 15%. CONCLUSIONS: Synchronous tumors, whether they be second primary tumors or distant metastases, are more common in patients initially seen with head and neck cancer than is realized, their incidence being significantly higher in those patients with cervical metastases. Computerized tomographic scanning of the chest is a more effective screening investigation than chest x-ray in this group of patients and is now used routinely in our department prior to undertaking major head and neck surgery.