Significance of Lymph Node Metastasis in Cancer Dissemination of Head and Neck Cancer

Lymph node metastasis (LNM) in many solid cancers is a well-known prognostic factor; however, it has been debated whether regional LNM simply reflects tumor aggressiveness or is a source for further tumor dissemination. Similarly, the metastatic process in head and neck cancer (HNC) has not been fully evaluated. Thus, we aimed to investigate the relative significance of LNM in metastatic cascade of HNC using functional imaging of HNC patients and molecular imaging in in vivo models. First, we analyzed ¹⁸Fluorodeoxyglucose positron emission tomography (PET) parameters of 117 patients with oral cancer. The primary tumor and nodal PET parameters were measured separately, and survival analyses were conducted on the basis of clinical and PET variables to identify significant prognostic factors. In multivariate analyses, we found that only the metastatic node PET values were significant. Next, we compared the relative frequency of lung metastasis in primary ear tumors versus lymph node (LN) tumors, and we tested the rate of lung metastasis in another animal model, in which each animal had both primary and LN tumors that were expressing different colors. As a result, LN tumors showed higher frequencies of lung metastasis compared to orthotopic primary tumors. In color-matched comparisons, the relative contribution to lung metastasis was higher in LN tumors than in primary tumors, although both primary and LN tumors caused lung metastases. In summary, tumors growing in the LN microenvironment spread to systemic sites more commonly than primary tumors in HNC, suggesting that the adequate management of LNM can reduce further systemic metastasis.     

Overexpression of EMMPRIN Isoform 2 Is Associated with Head and Neck Cancer Metastasis

Extracellular matrix metalloproteinase inducer (EMMPRIN), a plasma membrane protein of the immunoglobulin (Ig) superfamily, has been reported to promote cancer cell invasion and metastasis in several human malignancies. However, the roles of the different EMMPRIN isoforms and their associated mechanisms in head and neck cancer progression remain unknown. Using quantitative real-time PCR, we found that EMMPRIN isoform 2 (EMMPRIN-2) was the only isoform that was overexpressed in both head and neck cancer tissues and cell lines and that it was associated with head and neck cancer metastasis. To determine the effects of EMMPRIN-2 on head and neck cancer progression, we transfected head and neck cancer cells with an EMMPRIN-2 expression vector and EMMPRIN-2 siRNA to exogenously modulate EMMPRIN-2 expression and examined the functional importance of EMMPRIN-2 in head and neck cancer invasion and metastasis. We found that EMMPRIN-2 promoted head and neck cancer cell invasion, migration, and adhesion in vitro and increased lung metastasis in vivo. Mechanistic studies revealed that EMMPRIN-2 overexpression promoted the secretion of extracellular signaling molecules, including matrix metalloproteinases-2(MMP-2), urokinase-type plasminogen activator(uPA) and Cathepsin B, in head and neck cancer cells. While MMP-2 and uPA have been demonstrated to be important mediators of EMMPRIN signaling, the role of Cathepsin B in EMMPRIN-mediated molecular cascades and tumorigenesis has not been established. We found that EMMPRIN-2 overexpression and Cathepsin B down-regulation significantly inhibited the invasion, migration and adhesion of Tca8133 cells, suggesting that Cathepsin B is required for EMMPRIN-2 enhanced cell migration and invasion in head and neck cancer. The results of our study demonstrate the important role of EMMPRIN-2 in head and neck cancer progression for the first time and reveal that increased extracellular secretion of Cathepsin B may be a novel mechanism underlying EMMPRIN-2 enhanced tumor progression in head and neck cancer.     

Paraganglioma of the Head and Neck: A Review

ObjectiveTo review the epidemiology, presentation, diagnosis, and management of head and neck paragangliomas.MethodsA literature review of english language papers with focus on most current literature.ResultsParagangliomas (PGLs) are a group of neuroendocrine tumors that arise in the parasympathetic or sympathetic ganglia. Head and neck PGLs (HNPGLs) comprise 65% to 70% of all PGLs and account for 0.6% of all head and neck cancers. The majority of HNPGLs are benign, and 6% to 19% of all HNPGLs develop metastasis outside the tumor site and significantly compromise survival. PGLs can have a familial etiology with germline sequence variations in different susceptibility genes, with the gene encoding succinate dehydrogenase being the most common sequence variation, or they can arise from somatic sequence variations or fusion genes. Workup includes biochemical testing to rule out secretory components, although it is rare in HNPGLs. In addition, imaging modalities, such as computed tomography and magnetic resonance imaging, help in monitoring in surgical planning. Functional imaging with DOTATATE-positron emission tomography, 18F-fluorodeoxyglucose, or 18F-fluorohydroxyphenylalanine may be necessary to rule out sites of metastases. The management of HNPGLs is complex depending on pathology, location, and aggressiveness of the tumor. Treatment ranges from observation to resection to systemic treatment. Similarly, the prognosis ranges from a normal life expectancy to a 5-year survival of 11.8% in patients with distant metastasis.ConclusionOur review is a comprehensive summary of the incidence, mortality, pathogenesis, presentation, workup and management of HNPGLs.     

Infectious Complications in Head and Neck Cancer Patients Treated with Cetuximab: Propensity Score and Instrumental Variable Analysis

Background

To compare the infection rates between cetuximab-treated patients with head and neck cancers (HNC) and untreated patients.

Methodology

A national cohort of 1083 HNC patients identified in 2010 from the Taiwan National Health Insurance Research Database was established. After patients were followed for one year, propensity score analysis and instrumental variable analysis were performed to assess the association between cetuximab therapy and the infection rates.

Results

HNC patients receiving cetuximab (n = 158) were older, had lower SES, and resided more frequently in rural areas as compared to those without cetuximab therapy. 125 patients, 32 (20.3%) in the group using cetuximab and 93 (10.1%) in the group not using it presented infections. The propensity score analysis revealed a 2.3-fold (adjusted odds ratio [OR] = 2.27; 95% CI, 1.46–3.54; P = 0.001) increased risk for infection in HNC patients treated with cetuximab. However, using IVA, the average treatment effect of cetuximab was not statistically associated with increased risk of infection (OR, 0.87; 95% CI, 0.61–1.14).

Conclusions

Cetuximab therapy was not statistically associated with infection rate in HNC patients. However, older HNC patients using cetuximab may incur up to 33% infection rate during one year. Particular attention should be given to older HNC patients treated with cetuximab.     

Circulating Tumor Cells in Patients with Recurrent or Metastatic Head and Neck Carcinoma: Prognostic and Predictive Significance

Introduction

We investigated the frequency of detection and the prognostic and predictive significance of circulating tumor cells (CTCs) in patients with recurrent/metastatic (R/M) head and neck carcinoma (HNC) before starting systemic therapy.

Patients and methods

Using the CellSearch technology, CTCs were assessed prospectively in peripheral blood of 53 R/M-HNC patients. We performed spiking experiments to test the diagnostic performance of the CellSearch platform in identifying squamous carcinoma cells.

Results

CTCs were identified in 14 (26%) and 22 (41%) patients at baseline and at any time point, respectively. In univariate analysis ≥2 CTCs had a poorer prognostic role than 0–1 CTC. In multivariate analysis, the presence of one CTC or more was associated with a poor prognosis both in terms of progression-free survival (PFS) [Hazard Ratio (HR): 3.068, 95% confidence interval (CI): 1.53–6.13, p 0.002] and overall survival (OS) [HR: 3.0, 95% CI: 1.48–6.0, p 0.002]. A disease control after systemic therapy was obtained in 8% of CTC-positive patients as opposed to 45% in CTC-negative ones (p 0.03). The epidermal growth factor receptor (EGFR) expression was identified in 45% of CTC-positive patients.

Discussion

In conclusion, CTCs are detected in one out of three patients with RM-HNC. CTC detection is a strong prognostic parameter and may be predictive of treatment efficacy. The frequency of EGFR expression in CTCs seems to be lower than that expected in the primary tumor.     

Tooth Loss and Risk of Head and Neck Cancer: A Meta-Analysis

Background

Observational studies suggest an association between tooth loss and risk of head and neck cancer. However, whether tooth loss is an independent risk factor for head and neck cancer still remains controversial. The aim of this study is to assess the association between tooth loss and head and neck cancer risk.

Methods

Eligible studies were searched in PubMed and Embase databases from their inception to March 2013. A random-effects model or fixed-effects model was used to calculate the overall combined risk estimates.

Results

Eight case-control studies and one cross-sectional study involving 5,204 patients and 5,518 controls were included in the meta-analysis. The overall combined odds ratio for tooth loss and head and neck cancer was 2.00 (95% confidence interval, 1.28–3.14). Similar results yielded both in the moderate and severe tooth loss group. Sensitivity analysis based on various exclusion criteria maintained this significance with respect to head and neck cancer individually. Little evidence of publication bias was observed.

Conclusion

This meta-analysis suggests that tooth loss is associated with increased risk of head and neck cancer. This increase is probably independent of conventional head and neck cancer risk factors.     

Network Modeling Identifies Molecular Functions Targeted by miR-204 to Suppress Head and Neck Tumor Metastasis

Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1–22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases.     

GSTM3 A/B Polymorphism and Risk for Head and Neck Cancer: A Meta-Analysis

Background

Glutathione S-transferase M3 (GSTM3) is an important member of the GSTs that plays a critical role in the development of head and neck cancer (HNC). Several studies have investigated between the GSTM3 A/B polymorphism and risk of HNC, however, the results remain controversial. The aim of this meta-analysis is to evaluate the association between the GSTM3 A/B polymorphism and the risk of HNC.

Methods

All eligible case-control studies published up to July 2013 were identified by searching PubMed and Web of Science. The HNC risk associated with the GSTM3 A/B polymorphism was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively.

Results

Fourteen studies from ten publications with 2110 patients and 2259 controls were included. Overall, the GSTM3 A/B polymorphism was associated with a decreased risk of HNC using the dominant model, homozygote comparison model and heterozygote comparison model (OR = 0.82, 95%CI: 0.71–0.94; OR = 0.67, 95%CI: 0.49–0.94; and OR = 0.84, 95%CI: 0.73–0.97, respectively); besides, in stratification analyses by ethnicity, similar results were observed in Caucasian populations. Stratification by tumor site indicated that the GSTM3 polymorphism was associated with a decreased risk of laryngeal cancer under recessive model and homozygote comparison (OR = 0.52, 95%CI: 0.30–0.89; and OR = 0.50, 95%CI: 0.29–0.87, respectively); By stratifying source of control, decreased cancer risk was observed in hospital-based population under all genetic models (OR = 0.67, 95%CI: 0.56–0.81 for the dominant model; OR = 0.66, 95%CI: 0.46–0.95 for the recessive model; OR = 0.55, 95%CI: 0.37–0.83 for the homozygote comparison model, and OR = 0.70, 95%CI: 0.58–0.84 for the heterozygote comparison model).

Conclusions

This meta-analysis suggests that the GSTM3 A/B polymorphism may be an important protective factor for HNC, especially of laryngeal cancer and Caucasian populations.     

Tooth Loss and Head and Neck Cancer: A Meta-Analysis of Observational Studies

Backgroud

Epidemiological studies have shown that tooth loss is associated with risk of head and neck cancer (HNC); however, the results were inconsistent. Therefore, we conducted a meta-analysis to ascertain the relationship between tooth loss and HNC.

Methods

We searched for relevant observational studies that tested the association between tooth loss and risk of HNC from PubMed and were conducted up to January 30, 2013. Data from the eligible studies were independently extracted by two authors. The meta-analysis was performed using the Comprehensive Meta-Analysis 2.2 software. Sensitivity and subgroup analyses were conducted to evaluate the influence of various inclusions. Publication bias was also detected.

Results

Ten articles involving one cohort and ten case-control studies were yielded. Based on random-effects meta-analysis, an association between tooth loss and HNC risk was identified [increased risk of 29% for 1 to 6 teeth loss (OR = 1.29, 95% CI = 0.52–3.20, p = 0.59), 58% for 6 to 15 teeth loss (OR = 1.58, 95% CI = 1.08–2.32, p = 0.02), 63% for 11+ teeth loss (OR = 1.63, 95% CI = 1.23–2.14, p<0.001), 72% for 15+ teeth loss (OR = 1.72, 95% CI = 1.26–2.36, p<0.001), and 89% for 20+ teeth loss (OR = 1.89, 95% CI = 1.27–2.80, p<0.001)]. The sensitivity analysis shows that the result was robust, and publication bias was not detected.

Conclusions

Based on the current evidence, tooth loss is probably a significant and dependent risk factor of HNC, which may have a dose-response effect. People who lost six or more teeth should pay attention to symptoms of HNC, and losing 11 teeth or 15 teeth may be the threshold.     

Brain-Sparing Methods for IMRT of Head and Neck Cancer

Purpose

Radical radiotherapy for head and neck cancer (HNC) may deliver significant doses to brain structures. There is evidence that this may cause a decline in neurocognitive function (NCF). Radiation dose to the medial temporal lobes, and particularly to the hippocampi, seems to be critical in determining NCF outcomes. We evaluated the feasibility of two alternative intensity-modulated radiotherapy (IMRT) techniques to generate hippocampus- and brain-sparing HNC treatment plans to preserve NCF.

Methods and Materials

A planning study was undertaken for ten patients with HNC whose planning target volume (PTV) included the nasopharynx. Patients had been previously treated using standard (chemo)-IMRT techniques. Bilateral hippocampi were delineated according to the RTOG atlas, on T1w MRI co-registered to the RT planning CT. Hippocampus-sparing plans (HSRT), and whole-brain/hippocampus-sparing fixed-field non-coplanar IMRT (BSRT) plans, were generated. DVHs and dose difference maps were used to compare plans. NTCP calculations for NCF impairment, based on hippocampal dosimetry, were performed for all plans.

Results

Significant reductions in hippocampal doses relative to standard plans were achieved in eight of ten cases for both HSRT and BSRT. EQD2 D40% to bilateral hippocampi was significantly reduced from a mean of 23.5 Gy (range 14.5–35.0) in the standard plans to a mean of 8.6 Gy (4.2–24.7) for HSRT (p = 0.001) and a mean of 9.0 Gy (4.3–17.3) for BSRT (p < 0.001). Both HSRT and BSRT resulted in a significant reduction in doses to the whole brain, brain stem, and cerebellum.

Conclusion

We demonstrate that IMRT plans for HNC involving the nasopharynx can be successfully optimised to significantly reduce dose to the bilateral hippocampi and whole brain. The magnitude of the achievable dose reductions results in significant reductions in the probability of radiation-induced NCF decline. These results could readily be translated into a future clinical trial.     

MIDA: A Multimodal Imaging-Based Detailed Anatomical Model of the Human Head and Neck

Computational modeling and simulations are increasingly being used to complement experimental testing for analysis of safety and efficacy of medical devices. Multiple voxel- and surface-based whole- and partial-body models have been proposed in the literature, typically with spatial resolution in the range of 1–2 mm and with 10–50 different tissue types resolved. We have developed a multimodal imaging-based detailed anatomical model of the human head and neck, named “MIDA”. The model was obtained by integrating three different magnetic resonance imaging (MRI) modalities, the parameters of which were tailored to enhance the signals of specific tissues: i) structural T1- and T2-weighted MRIs; a specific heavily T2-weighted MRI slab with high nerve contrast optimized to enhance the structures of the ear and eye; ii) magnetic resonance angiography (MRA) data to image the vasculature, and iii) diffusion tensor imaging (DTI) to obtain information on anisotropy and fiber orientation. The unique multimodal high-resolution approach allowed resolving 153 structures, including several distinct muscles, bones and skull layers, arteries and veins, nerves, as well as salivary glands. The model offers also a detailed characterization of eyes, ears, and deep brain structures. A special automatic atlas-based segmentation procedure was adopted to include a detailed map of the nuclei of the thalamus and midbrain into the head model. The suitability of the model to simulations involving different numerical methods, discretization approaches, as well as DTI-based tensorial electrical conductivity, was examined in a case-study, in which the electric field was generated by transcranial alternating current stimulation. The voxel- and the surface-based versions of the models are freely available to the scientific community.     

Periodontal Disease and Risk of Head and Neck Cancer: A Meta-Analysis of Observational Studies

Background

Many epidemiological studies have found a positive association of periodontal disease (PD) with risk of head and neck cancer (HNC), but the findings are varied or even contradictory. In this work, we performed a meta-analysis to ascertain the relationship between PD and HNC risk.

Methods

We searched the PubMed, Embase, and Cochrane Library databases for relevant observational studies on the association between PD and HNC risk published up to March 23, 2013. Data from the included studies were extracted and analyzed independently by two authors. Meta-analysis was performed using RevMan 5.2 software.

Results

We obtained seven observational studies involving two cohort and six case-control studies. Random-effects meta-analysis indicated a significant association between PD and HNC risk (odds ratio = 2.63, 95% confidence interval = 1.1.68 - 4.14; p < 0.001), with sensitivity analysis showing that the result was robust. Subgroup analyses based on adjustment for covariates, study design, PD assessment, tumor site, and ethnicity also revealed a significant association.

Conclusions

Based on currently evidence, PD is probably a significant and independent risk factor of HNC.     

Head and Neck Mycetoma: The Mycetoma Research Centre Experience

Mycetoma is a unique neglected tropical disease which is endemic in what is known as the “mycetoma belt”. The disease has many devastating impacts on patients and communities in endemic area and is characterised by massive deformity, destruction and disability. Mycetoma is commonly seen in the foot and hand and less frequent in other parts of the body. Mycetoma of the head and neck is a rarity and is associated with high morbidity and even mortality if not treated early. In this communication we report on 49 patients with head and neck mycetoma followed up at the Mycetoma Research Centre in Khartoum. Most of the reported patients had actinomycetoma and the majority were young adult males from mycetoma endemic areas in the Sudan. Most of them were students, farmers and workers. Prior to presentation the majority had long disease duration and the cause was multifactorial. Advanced disease with massive lesion, deformity and disability was the common presentation. There was no obvious history of local trauma, familial tendency or other predisposing factor identified in this group of patients. MRI and CT scan were the most accurate diagnostic tools to determine the disease extent. The treatment outcome was rather poor and characterised by low cure rate, poor outcome and high follows-up dropout. Such a gloomy outcome calls for structured and objective health education programs.