Ketan A. Shah

Relation of a Hypoxia Metagene Derived from Head and Neck Cancer to Prognosis of Multiple Cancers

Affymetrix U133plus2 GeneChips were used to profile 59 head and neck squamous cell cancers. A hypoxia metagene was obtained by analysis of genes whose in vivo expression clustered with the expression of 10 well-known hypoxia-regulated genes (e.g., CA9, GLUT1, and VEGF). To minimize random aggregation, strongly correlated up-regulated genes appearing in >50% of clusters defined a signature comprising 99 genes, of which 27% were previously known to be hypoxia associated. The median RNA expression of the 99 genes in the signature was an independent prognostic factor for recurrence-free survival in a publicly available head and neck cancer data set, outdoing the original intrinsic classifier. In a published breast cancer series, the hypoxia signature was a significant prognostic factor for overall survival independent of clinicopathologic risk factors and a trained profile. The work highlights the validity and potential of using data from analysis of in vitro stress pathways for deriving a biological metagene/gene signature in vivo.

The relation between hypoxia-inducible factor (HIF)-1α and HIF-2α expression with anemia and outcome in surgically treated head and neck cancer

Hypoxia promotes tumorigenesis through the hypoxia‐inducible factor (HIF) pathway. There are 2 main homologues of the regulatory proteins, HIF‐1α and HIF‐2α, which have different effects in genetic knock‐out experiments. Anemia may contribute to hypoxia by reducing oxygen delivery, but it is not known whether this influences HIF‐α expression in tumors.

Relation of erythropoietin and erythropoietin receptor expression to hypoxia and anemia in head and neck squamous cell carcinoma.

Purpose: The use of erythropoietin in head and neck squamous cell carcinoma (HNSCC) has been associated with poor survival. This study examines the protein and mRNA expression of erythropoietin and erythropoietin receptor in HNSCC and their relation to hypoxia, hemoglobin (Hb), and clinical outcome. Experimental Design: The immunohistochemical expression of erythropoietin and erythropoietin receptor was assessed in 151 cases of HNSCC. Expression was compared with the hypoxia-dependent proteins hypoxia-inducible factor-1α (HIF-1α) and carbonic anhydrase-9 (CA-9) and correlated with clinical outcome. The mRNA expression of erythropoietin and erythropoietin receptor was measured in paired samples of HNSCC. Results: Erythropoietin and erythropoietin receptor were expressed in 95% and 99% of tumors, respectively. Using a weighed expression score, there was a positive correlation between erythropoietin and erythropoietin receptor expression (r = 0.18, P = 0.03). HIF-1α (r = 0.38, P < 0.01) and CA-9 (r = 0.26, P = 0.002) correlated with erythropoietin expression, but there was no correlation with erythropoietin receptor. No correlation was found between Hb and erythropoietin (r = 0.07, P = 0.36) or erythropoietin receptor (r = −0.02, P = 0.8), and no survival difference between high and low erythropoietin or erythropoietin receptor expression (P = 0.59 and P = 0.98, respectively). The mRNA expression of erythropoietin (P = 0.03) but not erythropoietin receptor (P = 0.62) was significantly increased in 11 paired samples of HNSCC. Conclusion:In vivo, the HIF pathway regulates erythropoietin at the mRNA level but not erythropoietin receptor expression in HNSCC. Anemia does not seem to influence the hypoxic microenvironment of tumors sufficiently to alter the expression of erythropoietin. The effects of exogenous erythropoietin may be acting via receptors expressed on tumor cells in vivo, or on vascular cells, which also express the pathway.

IGF-1R expression is associated with HPV-negative status and adverse survival in head and neck squamous cell cancer

Head and neck squamous cell carcinomas (HNSCC) are treated with surgery, radiotherapy and cisplatin-based chemotherapy, but survival from locally-advanced disease remains poor, particularly in patients whose tumors are negative for Human papillomavirus (HPV). Type 1 IGF receptor (IGF-1R) is known to promote tumorigenesis and resistance to cancer therapeutics. Here, we assessed IGF-1R immunohistochemistry on tissue microarrays containing 852 cores from 346 HNSCC patients with primary tumors in the oropharynx (n = 231), larynx (85), hypopharynx (28), oral cavity (2). Of these, 236 (68%) were HPV-negative, 110 (32%) positive. IGF-1R was detected in the cell membrane of 36% and cytoplasm of 92% of HNSCCs; in 64 cases with matched normal tonsillar epithelium, IGF-1R was overexpressed in the HNSCCs (P < 0.001). Overall survival (OS) and disease-specific survival (DSS) were reduced in patients whose tumors contained high membrane IGF-1R [OS: hazard ratio (HR) = 1.63, P = 0.006; DSS: HR = 1.63, P = 0.016], cytoplasmic IGF-1R (OS: HR = 1.58, P = 0.009; DSS: HR = 1.58, P = 0.024) and total IGF-1R (OS: HR = 2.02, P < 0.001; DSS: HR = 2.2, P < 0.001). High tumor IGF-1R showed significant association with high-tumor T-stage (P < 0.001) and HPV-negativity (P < 0.001), and was associated with shorter OS when considering patients with HPV-positive (P = 0.01) and negative (P = 0.006) tumors separately. IGF-1R was independently associated with survival in multivariate analysis including HPV, but not when lymphovascular invasion, perineural spread and T-stage were included. Of these factors, only IGF-1R can be manipulated; the association of IGF-1R with aggressive disease supports experimental incorporation of anti-IGF-1R agents into multimodality treatment programs for HPV-negative and high IGF-1R HPV-positive HNSCC.

Neuroendocrine Neoplasms of the Sinonasal Tract: Neuroendocrine Carcinomas and Olfactory Neuroblastoma

Neuroendocrine neoplasms (NENs) can occur in organs or tissues that do not contain neuroendocrine cells normally and do not necessarily imply embryologic derivation from the neuroectoderm; but rather reflect a shared phenotype characterized by the expression of multiple genes encoding both endocrine and neuronal features. NENs are rare in the sinonasal tract and are subdivided into epithelial and neural subtypes based on the presence of keratins or neurofilaments, respectively. Although relatively rare, neuroendocrine carcinomas (NECs) and olfactory neuroblastoma (ONB) are the most common neuroendocrine neoplasms of the sinonasal tract. The focus of this review is to highlight recent developments in the pathology of sinonasal NECs and ONB in light of the upcoming update of the World Health Organization (WHO) 2005 classification of tumors of the head and neck.

Clear Cell Odontogenic Carcinoma: A Rare Neoplasm of the Maxillary Bone

Clear cell odontogenic carcinoma (CCOC) is an extremely rare neoplasm, with only 74 cases in the English-language literature. It displays a propensity for the mandible, most commonly presenting in the fifth to seventh decades. Histopathologically, CCOC is characterized by sheets and islands of vacuolated and clear cells. The aggressive nature of CCOC was noted in its first description in 1985, although it was not formally classified as malignant by the World Health Organization until 2005. This report describes a case of CCOC presenting atypically in a young patient and at an uncommon site. The authors review the details of this case, outlining management strategies referencing their experience and that described in the other limited cases in the literature.

Parotid cancer treatment with surgery followed by radiotherapy in Oxford over 15 years

INTRODUCTION Primary parotid malignancies represent a rare diagnosis, making high-quality comparative research unfeasible. There is little U.K.-based evidence to guide practice. A review was therefore undertaken of a large series of patients treated by a multidisciplinary team in a National Health Service tertiary referral centre. PATIENTS AND METHODS Retrospective patient record review at the John Radcliffe Hospital in Oxford identified 401 patients who had undergone parotidectomy between 1995 and 2010, of whom 50 subjects were given a definitive diagnosis of primary parotid malignancy, treated with surgery and postoperative radiotherapy. Case notes, histology and imaging were reviewed by the study team. RESULTS The median follow up for the cohort was 60 months (range: 1-108 months). Facial nerve function was preserved in all patients undergoing partial or total conservative parotidectomy. Although histology showed microscopically close or positive margins in 82% of cases, all patients underwent postoperative radiotherapy and locoregional recurrence was identified in only two (4%) patients. CONCLUSIONS The data presented demonstrate a reasonable and practical multidisciplinary approach to a complex management problem. Facial nerve sparing surgery and postoperative radiotherapy result in good control of locoregional disease.

Fine needle aspiration

Fine needle aspiration test is a useful tool in the investigation of head and neck masses, be they of salivary gland, lymphoid, thyroid or other (branchial cyst) origin. Some practical aspects of this procedure are presented.

A Novel Approach to Chondrosarcoma of the Glenoid Fossa of the Temporomandibular Joint: A Case Report

Chondrosarcoma (CS) is a rare malignant tumor of cartilaginous tissue, with an incidence of 5% to 12% in the head and neck region. The maxilla and nasal and paranasal sinuses are most commonly affected. CS of the temporomandibular joint (TMJ) is extremely rare. Surgery remains the mainstay of treatment options. To our knowledge, this is the first report in the literature on CS arising from the glenoid fossa. We describe our surgical technique that allows immediate joint reconstruction and restoration of joint function.

Ewings sarcoma of the zygoma reconstructed with a gold prosthesis: a rare tumor and unique reconstruction.

INTRODUCTION Ewings sarcoma (ES) is a rare tumor, most commonly encountered within the long bones during the first 20 years of life. CASE REPORT We report the sixth case of ES of the zygoma, occurring in a 31-year-old male, and presenting a unique reconstructive opportunity. Diagnosis and preoperative planning were aided by CT/MR coregistration. Surgical reconstruction using 3D reconstructed CT images to produce an anatomically correct model provided the basis for a gold prosthesis construction. DISCUSSION Delayed definitive reconstruction provided opportunity for adequate tumor recurrence surveillance, and definitive histological diagnosis. The artefact produced on MR imaging from gold implants is minimal, permitting the unrestricted identification of potential future recurrence. CONCLUSION This case highlights the benefits of coregistration of radiological imaging, and custom-made gold prostheses providing the advantage of artefact-free MR imaging, which should be considered in patients requiring resection of zygomatic tumors and subsequent reconstruction.