Bernard Lyons

Radiation with concurrent late chemotherapy intensification ('chemoboost') for locally advanced head and neck cancer.

The aim of this study was to review our experience with a treatment regimen that combined conventionally fractionated radiation therapy (70 Gy over 7 weeks) with chemotherapy (cisplatin and fluorouracil), given concurrently in the last 2 weeks of radiation therapy in patients with previously untreated advanced squamous cell cancer of the head and neck region.Twenty-eight patients, all but two having UICC stage IV disease, were treated at the Peter MacCallum Cancer Institute between November 1995 and April 1998. Planned chemotherapy consisted initially of continuous infusion at 10 mg/m(2) per day of cisplatin and 400 mg/m(2) per day of fluorouracil on days 1-5 of weeks 6 and 7 of a conventionally fractionated course of radiotherapy. After the first 14 patients, the dose of fluorouracil was reduced to 360 mg/m(2) per day because of acute toxicity.36.8 months), with an estimated 50% surviving at 2 years (CI, 29-71%). Sixteen patients (57%) developed confluent mucositis and 11 (39%) developed patchy mucositis. The median duration of mucositis for these 27 patients was 1.5 months. Seventeen patients (61%) required nutritional support for a median duration of 1.4 months. Fourteen patients (50%) had grade three skin reactions, and 12 (43%) had one or more other significant (Grade 3) toxicities, predominantly infective. Grade 3 late toxicity has been observed in three patients to date (three xerostomia, including one with severe depression), and one patient had chronic ulceration of the oral tongue (grade 4). This chemoradiation regimen achieved an excellent complete response rate and good locoregional control at 2 years in patients with a poor initial prognosis. Acute toxicity was significant but manageable. The regimen offers an alternative to surgery and postoperative radiation therapy in locally advanced head and neck cancer.

Differential mechanisms of CDKN2A (p16) alteration in oral tongue squamous cell carcinomas and correlation with patient outcome.

CDKN2A (p16) disruption is reported as a frequent event in head and neck squamous cell carcinomas that confers poor prognosis. We investigated the frequency of different potential mechanisms of CDKN2A inactivation in oral tongue squamous cell carcinomas (OTSCC) and their impact on patient outcome. From a cohort of 153 OTSCC patients, 131 formalin fixed paraffin embedded blocks of pre‐treatment primary tumours were suitable for further molecular analysis. We assessed CDKN2A (p16) levels by immunohistochemistry (IHC), promoter methylation status by methylation‐sensitive high resolution melting, mutation status by Sanger sequencing, gene copy number variation by fluorescence in situ hybridisation, and correlated these with patient outcome. We found that the majority of OTSCC did not overexpress p16 (110/116, 95%), assessed by IHC. The frequency of CDKN2A mutations was 20% (21/103), homozygous loss was 7% (7/97), hemizygous loss 31% (30/97), and promoter methylation was 18% (20/113). We found no evidence of these mechanisms in 24/106 (23%) p16 IHC negative tumours. No significant correlation was identified between any potential mechanism of CDKN2A inactivation and clinical features, including smoking status and age. There was a non‐significant trend for worse overall survival for p16 IHC negative patients versus positive patients (HR = 1.81, 95% CI = 0.44–7.47, p = 0.40). No relationship was found between mechanisms of CDKN2A disruption and patient outcome. In conclusion, we demonstrate that CDKN2A alteration is a frequent event in OTSCC tumourigenesis. However, no correlation was identified between different potential mechanisms of CDKN2A disruption and clinical characteristics or patient outcome.

Frequency of Fibroblast Growth Factor Receptor 1 gene amplification in oral tongue squamous cell carcinomas and associations with clinical features and patient outcome

OBJECTIVES Novel therapies are required for patients with recurrent or metastatic oral tongue squamous cell carcinoma (OTSCC). Fibroblast Growth Factor Receptor 1 (FGFR1) amplification frequently occurs in squamous cell carcinoma of the lung and represents a novel druggable therapeutic target in this and other malignancies. This study examined the frequency and clinical associations of FGFR1 amplification in OTSCC. MATERIALS AND METHODS The frequency of FGFR1 amplification determined by fluorescence in situ hybridization was evaluated in a cohort of 123 OTSCC patients. Associations of FGFR1 amplification with clinical characteristics and outcome were determined. RESULTS FGFR1 gene amplification was present in 9.3% (10/107) of cases and was significantly associated with smoking status (P = 0.03). FGFR1 amplification was seen more commonly in males (9/10 amplified cases male, P = 0.16) and there were no associations with age, stage, T stage, nodal status, alcohol history or performance status (all P>0.05). Outcome was not significantly different between FGFR1 amplified and non-amplified patients. CONCLUSIONS Copy number variations of the FGFR1 gene occur in a subset of OTSCC with approximately 10% of cases showing amplification of the gene. FGFR1 amplification may represent a therapeutic target in OTSCC.

Quantitative methodology is critical for assessing DNA methylation and impacts on correlation with patient outcome

BackgroundDNA hypermethylation is reported as a frequent event and prognostic marker in head and neck squamous cell carcinomas (HNSCC). Methylation has been commonly assessed with non-quantitative methodologies, such as methylation-specific PCR (MSP). We investigated previously reported hypermethylated genes with quantitative methodology in oral tongue squamous cell carcinomas (OTSCC).ResultsThe methylation status of 12 genes in 115 OTSCC samples was assessed by one or more of three quantitative analyses: methylation sensitive high resolution melting (MS-HRM), sensitive-melting analysis after real time-methylation specific PCR (SMART-MSP), and bisulfite pyrosequencing.In contrast to much of the literature, either no or infrequent locus-specific methylation was identified by MS-HRM for DAPK1, RASSF1A, MGMT, MLH1, APC, CDH1, CDH13, BRCA1, ERCC1, and ATM. The most frequently methylated loci were RUNX3 (18/108 methylated) and ABO (22/107 methylated). Interrogation of the Cancer Genome Atlas (TCGA) HNSCC cohort confirmed the frequency of significant methylation for the loci investigated.Heterogeneous methylation of RUNX3 (18/108) and ABO (22/107) detected by MS-HRM, conferred significantly worse survival (P = 0.01, and P = 0.03). However, following quantification of methylation levels using pyrosequencing, only four tumors had significant quantities (>15%) of RUNX3 methylation which correlated with a worse patient outcome (P <0.001), while the prognostic significance of ABO hypermethylation was lost. RUNX3 methylation was not prognostic for the TCGA cohort (P = 0.76).ConclusionsWe demonstrated the critical need for quantification of methylation levels and its impact on correlative analyses. In OTSCC, we found little evidence of significant or frequent hypermethylation of many loci reported to be commonly methylated. It is likely that previous reports have overestimated the frequency of significant methylation events as a consequence of the use of non-quantitative methodology.

Extraosseous osteoblastoma of larynx presenting with acute airway obstruction

OBJECTIVE We report the case of an osteoblastoma of the larynx arising from the vocal fold, which presented with acute airway obstruction and cardiopulmonary arrest. METHOD The histopathological findings, differential diagnoses and a novel method of treating laryngeal osteoblastoma, using transoral laser therapy, are discussed. RESULTS Benign osteoblastoma is a rare primary bone tumour usually presenting in young patients in the spine and sacrum. Its occurrence in the larynx is very rare, with only three similar case reports in the literature, none involving tumour arising from the vocal fold. Differential diagnoses must be considered and excluded using both histopathological and clinical features. Once the diagnosis is confirmed, successful treatment is achieved with surgical excision. CONCLUSION Osteoblastoma of the larynx is rare, and the clinical features can vary with the anatomical site of the lesion. The recommended treatment is surgical excision which, if available, may be achieved by transoral laser microsurgery. Due to its potential rapid growth, careful follow up is essential in order to detect recurrence.

Larynx preservation with primary non-surgical treatment for loco-regionally advanced larynx cancer

Introduction: The objective of this paper was to review the results of primary non‐surgical treatment with the aim of larynx preservation for loco‐regionally advanced larynx cancer (LALC).

FUNCTIONAL OUTCOMES FOLLOWING TOTAL LARYNGOPHARYNGECTOMY

Background:  Despite increasing use of laryngeal preserving protocols, laryngopharyngectomy remains the gold standard treatment for locally advanced hypopharyngeal and upper oesophageal tumours and for salvage following failed chemoradiotherapy. Nevertheless, improved perioperative medical care and experience in reconstruction have reduced mortality and improved functional outcomes.

Post-nasal space oncocytoma : a different approach to a rare tumour

Oncocytomas are rare tumours that occur predominantly in the major salivary glands, particularly the parotid of older individuals. We present the exceptionally rare occurrence of an oncocytoma in the post-nasal space and its treatment for the first time via a Le Fort I osteotomy. The potential for local spread to the surrounding skull base makes it vital to achieve good oncological clearance. We found that this was possible using the Le Fort I technique and would recommend that this approach should be considered in future, when approaching such lesions.

A rare case of sinonasal ameloblastoma presenting with complete nasal obstruction.

A 73-year-old woman presented with a 3-month history of progressive nasal congestion and intermittent epistaxis but was otherwise systemically well. She had no significant co-morbidities and, in particular, no history of sinonasal disease or smoking. Examination revealed an expansive red polypoid mass clearly involving the right cheek and nasal cavity (Fig. 1). There was no suggestion of oral, ocular or neurological involvement. Imaging demonstrated an expansive and erosive soft-tissue mass originating in the right maxillary antrum extending posteromedially to almost completely obstruct the nasal cavity and nasopharyngeal air space (Fig. 2). Invasion into the orbit and metastatic disease were not evident. Initial biopsy suggested ameloblastoma and the patient went on to have a right total maxillectomy, ethmoidectomy with clearance of her right infratemporal fossa (Fig. 1). Subsequent reconstruction was with a vertical rectus abdominis myocutaneous flap. Histology confirmed the diagnosis of sinonasal ameloblastoma with no features of carcinoma (Fig. 3). Ameloblastomas are rare neoplasms of odontogenic epithelium, which almost always arise from the maxilla or mandible. Due to their high tendency to recur following surgical resection, they are of interest to surgeons. 2–10% of ameloblastomas are identified in extragnathic sites where the odontogenic apparatus is not normally found; theoretically, the result of an embryological aberration with

Glomangiopericytoma: overview and role for open surgery

A 31-year-old woman was referred to our unit following an unsuccessful attempt to resect a lesion arising from her right maxillary sinus by functional endoscopic sinus surgery. The procedure was abandoned due to excessive bleeding. Results of the preliminary biopsy indicated glomangiopericytoma. Initial surgical presentation was with an 18th month history of intermittent right-sided headaches and dizziness. She had no symptoms suggestive of nasal obstruction, epistaxis or visual disturbance, and she was otherwise, systemically well. Her past medical history was unremarkable. Examination too was unrevealing with no facial asymmetry or cranial nerve abnormality, intact dentition and no visible mass on rhinoscopy. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a vascular lesion occupying the entire right maxillary sinus with extension medially into the nasal cavity, posteriorly into the masticator space and inferiorly into the alveolar process. There was no involvement of the orbital floor or evidence of regional spread of the disease (Fig. 1). She underwent right subtotal maxillectomy (Fig. 2) with anterolateral thigh flap reconstruction without incident and is scheduled for long-term follow-up. Sections showed an evenly cellular tumour with numerous thin-walled staghorn-type vessels. The tumour cells were plump spindle cells with clear to pale eosinophilic cytoplasm and ovoid nuclei with no evidence of nuclear atypia or increased mitotic activity. Immunohistochemistry showed the tumour cells were positive for smooth muscle actin and vimetin. They were negative for CD31, CD34, AE1/AE3, desmin and CAM5.2. Glomangiopericytomas are rare sinonasal tumours arising from modified perivascular glomus-like myoid cells, cells that likely share a cellular spectrum with glomus bodies. They have low malignant potential, behave indolently, and rarely metastasize but are prone to recurrence following resection. Prognosis is excellent with 5-year survival after surgery exceeding 95%. Also referred to as ‘sinonasal-type haemangiopericytoma’, ‘haemangiopericytoma-like intranasal tumour’ or ‘true haemangiopericytomas’, they should not be confused with the increasingly tenuous entity of ‘soft-tissue haemangiopericytomas’ which has been associated with a more aggressive natural history. First described in the 1940s, the concept of a ‘haemangiopericytoma’ – a soft tissue tumour thought to derive from pericytes anywhere in the body – has undergone steady deconstruction to the extent that now the term is increasingly recognized as a histological growth pattern identifiable in a range of un/related benign and malignant lesions and not a pathological entity in itself. This histological pattern is characterized by a rich vascular component consisting of variably thick-walled, branched, ‘staghorn’ vessels demonstrating perivascular hyalinization and is present in glomangiopericytomas. A number of histological and immunophenotypical features distinguish the glomangiopericytoma from other ‘haemangiopericytamalike’ tumours such as lobular capillary haemangioma, solitary fibrous tumour, leiomyoma and angiofibroma. The neoplastic cells are predominantly elongated, though they may be ovoid, in shape and grow uniformly in the submucosa, typically sparing the overlying respiratory epithelium. The nuclei are ovoid to spindle-shaped and rarely display any atypia, increased mitotic activity or necrosis. The cytoplasm is eosinophilic to clear and large with poorly definable borders (Fig. 3). Moreover, and at odds with the established nomenclature, only the glomangiopericytoma can be said to be of ‘true’ myoid (pericytic) lineage, possessing ultrastructural features of smooth muscle tissue and being immunoreactive to myogenic markers. Thompson et al. described the immunohistochemical profile of glomangiopericytoma as including reactivity to vimentin (98%), smooth muscle actin (92%), muscle specific actin (77%) and negative for CD34, CD31 and FVIII-Rag. Glomangiopericytomas are idiopathic, have a slight female preponderance and are more common among those in their sixth and seventh decade (mean 62.6 years); though, as in our case, it can occur much earlier (range 5–86 years). They constitute <1% of all sinonasal tumours and more commonly arise from the nasal cavity than the paranasal sinuses. Presentation is usually with a slowly progressive unilateral nasal obstruction, epistaxis and red, polypoid mass, and is indistinguishable from a range of benign and malignant sinonasal pathologies. Imaging too is non-specific and adds little to the diagnostic workup, showing a solid, soft tissue lesion on CT and MRI but is essential to surgical planning. Diagnosis therefore rests with biopsy. Treatment is with wide local excision though given the limited experience there is no consensus on margins. Endoscopic removal does have a role though we would like emphasize its inherent problems in managing glomangiopericytomas. Our case and a number of reports in the literature serve as reminders of the unpredictable bleeding risk associated with endoscopic resection of these highly vascular lesions. Furthermore, clear margins are paramount given that recurrence following surgery is a defining feature of the disease estimated to affect some 30% of patients. Therefore, an open approach where large, poorly accessible lesions are encountered is advised as it offers wide exposure and greater opportunity to minimize residual disease and control bleeding. There is no established role for adjunctive therapy but radiotherapy is recommended in the event of unclear margins. Neither it, nor metastatic spread, can be predicted histologically so long-term clinical follow-up is essential. Further surgery is warranted in the event of recurrence. IMAGES FOR SURGEONS