Department of Head and Neck Surgery, UT MD Anderson Cancer Center, Houston, TX, USA Beth M. Department of Head and Neck Surgery, European Institute of Oncology, Milan, Italy Marco Guzzo, MD.
Introduction and Scope
Abstract Head and neck malignancies are among the most common in the world and constitute a major public health problem in most countries. Keywords Cancer • Head and neck • Upper aerodigestive tract • Mouth • Larynx • Nasopharynx • Tobacco • Alcohol • Nutrition • Human papillomavirus (HPV).
Epidemiology and Aetiology of Head and Neck Cancers
More than 90% of these are squamous cell carcinomas that arise in the mucosa of the upper aerodigestive tract (UADT). This, and the fact that survival rates in much of the world have improved little or nothing over several decades, underscores the need for effective primary and secondary prevention strategies—and for improved public policy to implement them.
History
SCC of the H&N are often aggressive in their biological behavior: patients with many of these cancer types have highly destructive disease above the clavicle, develop local (cervical) lymph node metastases early, develop distant metastases over time – even after effective local therapy, and a large proportion have recurrence of the primary lesion and/or develop a second primary neoplasm. We are now entering an era of individualized biotherapies for many cancers, based on an understanding of the precise molecular abnormalities within a given neoplasm, and of the patient's individual genetic polymorphisms, although such approaches have not yet been extensively tested.
Cancer Registries
SCC is strongly associated with certain environmental and lifestyle risk factors, especially tobacco use, smoking, and smoking. Comorbidities are common – especially respiratory and cardiovascular diseases – due to common risk factors, especially tobacco and alcohol abuse, and poor diet.
Why Collect Detailed Epidemiological Data?
The Global Scenario of Head and Neck Cancer: Differences by Country
In terms of countries, Sri Lanka has the highest incidence of oral cancer in the South Asian region. The incidence of cancer of the oral cavity, nasopharyngeal cancer, other cancers of the pharynx and larynx varies greatly (Table 1.1).
Differences by Sex
However, there is growing concern that commercial areca nut and tobacco products will contribute to future increases in the incidence of oral submucous fibrosis and subsequent oral cancer [11]. This is a very pleasant situation, which is common in many countries with advanced healthcare facilities, but is not reflected in most high-incidence countries elsewhere in the world.
Ethnic Variations
Age Distributions
Mortality Rates and Trends over Time
Mortality Trends by Birth Cohort
A study in Mumbai, India, indicated a decreasing trend in the incidence of oral cancer among Indian men, which it was suggested may be due to a decrease in the use of betel quid/pan and associated oral smokeless tobacco during this period [49] . Population-based survival rates around the world show little sign of improvement in recent decades, despite major improvements in treatment modalities.
Aetiology of Head and Neck Cancer
For men born in the nineteenth century and the first few decades of the twentieth. Part of the urban/rural difference in the incidence of head and neck cancer is related to atmospheric pollution.
Salivary Gland Neoplasms Epidemiology
In the developed world, leukoplakia is usually found between the fourth and seventh decades of life, in the developing world about 5–10 years earlier [155]. Extrapolation from these figures suggests that significantly more OSCC should have been reported in recent times, one possible reason being the underreporting of oral cancer cases in the developing world.
Aetiology of Salivary Gland Neoplasms
Therapeutic radiation, particularly to the head and neck region, has been associated with significantly increased risk [184, 185]. Exposure to silica dust and kerosene as a cooking liquid increased the risk of salivary tumors in a Chinese population [202], and an increased risk of parotid gland tumor was associated with exposure to nickel, chromium, asbestos, and cement dust [203].
Other Important Cancers of the Head and Neck: Malignant Melanoma
A concise summary of the situation with odontogenic tumors is in the WHO "Blue Book" of 2005 [169]. The experience of one US center has recently been described [220], with a useful review of the literature.
Risk factors for oral squamous cell carcinoma in young adults – a comprehensive review of the literature. Diet and other risk factors for salivary gland cancer: a population-based case-control study.
Introduction
Future challenges remain in the correct interpretation of new findings and their wise and scientific application. Only then will we be able to influence the field of HNC, transforming prevention into the only form of cure.
Head and Neck Cancer Prevention
All the most important chemoprevention clinical trials reported in the scientific literature are critically presented and discussed and their impact on clinical practice is presented. The increased incidence of HPV-related cancers is linked to a change in sexual patterns in the overall population.
Natural History of Head and Neck Cancers Head and Neck Carcinogenesis
In fact, secondary primary tumors are among the leading causes of morbidity and mortality among patients cured of head and neck squamous cell carcinomas (HNSCC). Although screening is not equally successful for all HNCs, the premise is that early diagnosis can improve morbidity and mortality outcomes.
Precancerous Lesions
Despite the progress in molecular biology, there is still not a single reliable marker predicting malignant transformation [36, 37]. Regarding the oral cavity, the management of premalignant lesions of the larynx is controversial.
Precancer and Risk Markers for Cancer
The best chance for recovery should not be lost due to inadequate treatment and the therapy should be oncologically radical with maximal preservation of function. Despite substantial recent advances, there is significant morbidity associated with the nonsurgical therapy sometimes used to treat these conditions [56] while laser surgery appears to be the best treatment modality to meet the demands of oncologic radicalness and organ, as well as functional preservation.
Chemoprevention
Duration of the study Intervention of 3 months; follow-up = 6 months Patients included in the study Intervention = 24; placebo = 20. Duration of study Intervention = 12 months; follow-up = 60 months Patients included in study 170 after resection of oral leukoplakia.
Prevention of Neck Metastases
Chemoprevention trials are expensive because of the large study population required and the required duration of studies. Based on the negative experiences made with the CARET study, the psychological effects of information about possible negative study results (including the healthy population) should also be considered [121, 122].
HPV Infection
In the majority of studies, OSCC associated with HPV infection has a better outcome and a reduced risk of relapse and second tumors compared with HPV-negative tumors. Clinical trials to evaluate the effectiveness of the quadrivalent HPV vaccine (against HPV to protect against oral infection) are currently being developed.
Conclusions
Human papillomavirus infection as a risk factor for squamous cell carcinoma of the head and neck. Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma.
Squamous Mucosal Carcinogenesis
Malignancies arising from head and neck sites therefore differ in origin, morphogenesis, and biological behavior. Recently, great progress has been made in the molecular genetic characterization and understanding of head and neck tumorigenesis.
Histopathology
The histopathological classification remains the main reference for diagnosis and, to a large extent, malignancy grading. This chapter briefly presents the relevant pathomorphological and molecular features of the tumors at the most important head and neck sites for clinical management.
Cellular and Molecular Pathology of Head and Neck Tumors
The majority of leukoplakias develop in tobacco-using individuals, and their location and appearance vary depending on the geographic location and the manner and nature of tobacco use. E6 of HPV-16 binds to the p53 suppressor genes and therefore leads to uncontrolled proliferation of the oropharyngeal squamous mucosa.
Molecular Pathology Cellular Concept
They are classified based on their histological appearance into differentiated squamous cell carcinoma (WHO I) and undifferentiated carcinoma with lymphoid stroma (WHO II or III). The histological features of type I resemble well-differentiated squamous cell carcinoma, while types II and III are highly undifferentiated carcinoma with integrated lymphoid components.
Epigenetic Alterations
Studies of this gene and its major isotypes in HNSC indicate an important role in tumorigenesis, especially the DN isotypes. Overexpression of this isotype blocks differentiation and metastasis, promotes proliferation in HNS tumorigenesis and may be an attractive target for therapeutic intervention in a subset of patients with these tumors [ 27 , 28 ].
Genomic Studies
P63 has two different promoters, resulting in two different protein products, one retaining the transactivation domain (TA p63) and another lacking it (D(delta)Np63).
Growth Factors and Signal Transduction Pathways
Studies of mutations in the hot spot exons of this gene have yielded negative results. Restoration of this pathway can lead to inhibition of PI3k phosphorylation and expression, which is responsible for radioresistance in HNSCC [ 50 ].
Structural Concept
Activation of these pathways plays an important role in the development and progression of HNSC. The activation of these pathways has been shown to lead to the downregulation of adhesion molecules (e.g. E-Cadherin) and elevation of surrogate mesenchymal markers (e.g. Vimentin.
Salivary Gland Tumors
The finding of the fusion transcript in both sporadic Warthin's tumor and MEC and associated tumors supports an early or etiological role in the development of a subset of these tumors. Cytogenetic studies of these tumors reported frequent alterations at chromosomes 6p, 9p and 17p, with the most consistent alteration at the 6q regions (Table.
Thyroid and Parathyroid Tumors Thyroid
Differential diagnoses of these tumors include sarcomatoid carcinoma of the upper aerodigestive tract, sarcoma, and melanoma. The most common location of these tumors is the lateral aspect of the upper 2/3 of the thyroid lobes, where high C-cell aggregation can be found.
Sinonasal and Skull Base Tumors
Oncogenomics/Proteomics of Head and Neck Cancers
Summary Head and neck cancer treatment has experienced major advances in surgical techniques, radiation therapy, chemotherapy, and molecularly targeted strategies over the years. Head and neck cancer represents an extremely heterogeneous disease with dysregulation of multiple interrelated cellular pathways, including differentiation, apoptosis, angiogenesis, and metastasis.
Oncogenomic Technologies
Human papillomavirus (HPV) may eventually serve as a putative marker for HNSCC, as it is more common in non-smokers and non-drinkers and these tumors have a better outcome independent of the specific therapy. Given the variety of molecular alterations found in these tumors, a greater understanding of the molecular basis of the biochemical pathways involved in carcinogenesis may facilitate diagnosis, drug discovery, and therapy for affected patients.
Proteomic Technologies
When the process is extended to many hundreds of samples, population-specific protein expression profiles can be derived that are characteristic of the tested group. However, the identified mass spectrum does not enable protein identification and none of the interactions are specific.
Oncogenomics of HNSCC
Many of the genes in the predictor set have previously been implicated in oral SCC. A large-scale gene expression analysis of the hypopharynx, a site associated with particularly aggressive behavior, found 119 genes that were highly differentially expressed between early and late tumors [18].
Proteomics of HNSCC Tumor Tissue Studies
Subsequently, they constructed knowledge-based networks, which revealed that integrin signaling and antigen presentation pathways were highly enriched in the dataset, and they found that chromosomal regions of 6p21, 19p13 and 19q13 had genomic alterations that were correlated with the nodal status of HNSCC. Serum studies have been widely used in studies of HNSCC due to the challenges of obtaining repeated tumor samples.
Challenges of Oncogenomics/
Five candidate biomarkers were validated and showed high sensitivity (90%) and specificity (83%) in detecting oral SCC. Finally, another study built on previous data indicating that IL-6 and IL-8 expression are uniquely associated with oral SCC.
Proteomics in HNSCC
A recent report showed that storage time may decrease the predictive performance of tissue samples [1]. In addition, studies vary in the heterogeneity of cell types included in the samples, ranging from 50%.
Conclusion and Future Directions
Genomic assessments of the frequent loss of heterozygosity region of 8p21.3-p22 in head and neck squamous cell carcinoma. Identification of a gene expression signature associated with recurrent disease in head and neck squamous cell carcinoma.
Genetics and Epigenetics of Head and Neck Cancer
One of the most consistent hallmarks of cancer is genomic instability, resulting from loss of function in DNA repair mechanisms. Also summarized are advances in molecular techniques that have contributed to our understanding of head and neck cancer development.
Genetic Principles in Carcinogenesis
When investigating the results of large-scale resequencing of sporadic human cancers, it also became apparent that the most common mutations observed were also in the DNA repair machinery. Silencing of certain tumor suppressor genes (TSGs), central to the development of many solid tumors, can occur in the absence of genetic alteration through abnormal methylation of CpG islands.
Oncogenes and TSGs
Inherited cancer susceptibility may be those rare single-gene autosomal recessive syndromes with greatly increased risk (ie, hereditary cancer syndromes) or multiple polymorphisms that more subtly affect susceptibility in the general population [ie. Such activation results in p53, which regulates growth by affecting cell cycle control at the G1/S junction, the "checkpoint" in the cell cycle.
The Multi-step Process of Carcinogenesis
Other oncogenes in HNSCC include D(delta)Np63-a(alpha), which belongs to the p53 family [12], and matrix metalloproteinases involved in proliferation and migration [13]. It is normally activated by stimuli that cause cellular stress, such as exposure to radiation and carcinogenic toxins.
The Genetic Progression Model
TSGs give cancer cells recessive loss of function and can be inactivated by genetic events such as mutation, deletions, or by epigenetic events such as DNA methylation or chromatin remodeling [ 15 ]. TSGs require both alleles to be altered before manifestation (i.e., homozygosity), unlike oncogenes, which can be activated by single-allele activation (i.e., heterozygosity).
Early Events: Loss of 9p21 Region (CDKN2A Locus)
RSSF1A may function as an effector molecule in the RAS-activated growth inhibitory signaling pathway and is inactivated by hypermethylation and allelic loss [ 31 ].
Later Events: 17p Loss
Hereditary Conditions Predisposing to HNSCC
The underlying cause of the disease is a mutation in the ATM gene (ataxia telangiectasia, mutated) located at 11q, a common deletion site in HNSCC [43]. The predisposition to cancer is mainly of the lymphoreticular system and is also associated with head and neck malignancies in younger patients [45].
Genetic Predisposition and Mutagen Sensitivity
Li-Fraumeni syndrome is a rare autosomal dominant syndrome characterized by a predisposition to cancers, including sarcomas, leukemia, and brain tumors. Lynch syndrome II has additional features than Lynch I and is associated with cancers outside the colon, including laryngeal cancer [51].
Techniques Used to Detect Genetic Changes in Cancer
Techniques have developed over time to improve the resolution of karyotype analysis and molecular cytogenetic technology such as fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) have increased the ability to identify genetic changes in cancer cells. This technology has been used to identify specific regions of gain, such as 8q22 and the LRP12 gene [29].
The Epigenetics of Head and Neck Cancer
Epigenetics: The Role of DNA Methylation, Histone Modifications and the Nucleosome
Gene repression induced by histone methylation and heterochromatin formation is easily reversible and common in cellular differentiation. Gene repression caused by DNA methylation leads to permanent gene silencing and is seen in various physiological and pathological processes such as imprinting and cancer [71].
Epigenetic Drivers of Carcinogenesis
The N-terminal tails of histones undergo a variety of covalent modifications such as acetylation, methylation and phosphorylation, which have an impact on conformation and subsequent gene expression. It is likely that the DNA methylation pattern of a cell may be the pattern used to reconstruct the epigenetic program after cell division.
Challenging the Genetic Paradigm
Many methylation events have been observed to occur in the promoters of genes not previously implicated in cancer and with no apparent mechanistic link. An alternative hypothesis is that some genes are targeted for methylation, and genes frequently methylated in cancer have been shown to have specific tri-methylation of lysine 27 on histone H3 in their nucleosomes [80].
Molecular Assay of Epigenetic Alterations in Cancer
However, advances in genome-wide methylation technologies have revealed that not all epigenetic events appear to occur in the expected TSGs. This suggests that cancer-targeted de novo methylation may be programmed by a predetermined epigenetic code that physiologically plays a role in marking embryonic genes for repression.
Clinical Application of Epigenetics in Head and Neck Cancer
Epigenetic Biomarkers in HNSCC
Furthermore, it may be present in a relatively high percentage of tumors encountered (eg, cyclin A1 methylation in 50% of HNSCC in contrast to specific p53 mutations that are individually relatively uncommon. It may be possible to provide a prognostic evaluation of a tumor before definitive treatment by epigenetic analysis of the biopsy.
Epigenetically Directed Therapy in HNSCC
Loss of heterozygosity at 11q23 in head and neck squamous cell carcinoma is associated with recurrent disease. Summary The immune system plays a key role in the progression of head and neck cancer.
Immunology of Head and Neck Cancer
A better understanding of the important contribution of immune dysregulation and evasion to the development and evolution of head and neck cancer should lead to improved therapies and outcomes for patients. A better understanding of the important contribution of immune dysregulation and evasion to the development and evolution of head and neck cancer should lead to improved therapies and outcomes for patients.
Brief Overview of the Immune System
B Lymphocytes
T Lymphocytes
TH1 cells secrete IL-2, IFN-g, and TNF-a and are felt to be the most potent antitumor subtype. TH17 cells require TGF-b and IL-6 for differentiation and are defined by their production of IL-17.
Natural Killer Cells
The TH1 subset is responsible for most cell-mediated immune functions such as activation of CD8 T cells, inflammation and delayed-type hypersensitivity as well as the production of complement-activating IgG antibodies. The final subset of CD4 T cells is the regulatory T cell (Treg) originally defined as a CD4+CD25+Foxp3+ T cells.
Dendritic Cells
IL-17 is known to induce the production of several chemokines that attract proinflammatory cells, and IL-17 expression is greatly increased in autoimmune diseases [ 15 ]. Tregs are thought to be a reciprocal subtype to TH17 cells in that both are induced by TGF-b, but Tregs are immunosuppressive compared to TH17 cells which are proinflammatory.
Cancer Immunosurveillance and Immunoediting
Mice with genetically induced immunodeficiencies have been found to be more susceptible to both spontaneous and chemically induced tumors. The cancer immune surveillance hypothesis gave rise to the theory of cancer immunoediting, which is the idea that immune surveillance of cancers provides selective pressure on tumor cells and selects for cells that can evade the immune system.
Immune Escape and Immunosuppression in Head and Neck Cancer
The first was the discovery of the NK cell in the late 1970s, which appeared to provide innate immune protection against tumors [20]. Thus, SCCHN cells expressing HLA I and whole tumor antigen can evade T cell recognition through reduced expression of LMP2, TAP1, TAP2, and tapasin.
Myeloid-Derived Suppressor Cells
In other cancers there is extensive expression of HLA and tumor antigen, but without recognition by T cells. As mentioned, reduced expression of HLA molecules is protective against T cells, but increases NK cell-mediated cytolysis because the absence of HLA removes an important inhibitory signal for NK cells.
T Regulatory Cells
Cytokine levels are aberrant in SCCHN patients, indicating deregulation or dysregulation of cytokine pathways [ 62 ]. There is increased frequency of immunosuppressive regulatory immune cells and there is a global dysfunction of almost all facets of the immune system in SCCHN patients.
Inflammation and Cancer
In SCCHN patients, the frequency of Tregs is increased in the peripheral blood and among T cells that infiltrate the tumor and drain the lymph nodes, resulting in a state of immunosuppression. Also interesting was the finding that Treg numbers in SCCHN patients were greater after treatment than before treatment, indicating that oncological treatment increases Treg numbers [17].
Cancer Stem Cells
Angiogenesis is induced by NF-kB through the production of VEGF and several cytokines including TNF-a, IL-1, -6 and -8 are induced causing a positive feedback loop. It has also been suggested that NF-kB mediates resistance to chemotherapy and radiation treatment through regulation of GADD (growth arrest DNA damage) and glutathione-S-transferase [73].
Immune Mediators as Cancer Biomarkers
NF-kB also promotes tumor cell proliferation and expansion through regulation of a key cell cycle modulator, cyclin D1. The activation of NF-kB by inflammatory immune mediators demonstrates yet another subversion and exploitation of the immune system by cancer to promote key aspects of tumorigenesis and progression.
Head and Neck Cancer Immunotherapy
Tumor cell vaccines are similar to whole protein vaccines in that they are not HLA restricted and specific epitopes do not need to be known for their use. This is an extremely labor-intensive method in which dendritic cells are isolated from each patient and loaded ex vivo with tumor antigen.
Monoclonal Antibody-Based Immunotherapy of SCCHN
In addition to their ability to mediate ADCC, activated NK cells, specifically CD56bright NK cells [108] have also been shown to secrete cytokines, such as IFN-g, TNF-α, and chemokines, such as macrophage inflammatory protein (MIP) . -1a, MIP-1b and RANTES, which inhibit tumor cell proliferation, enhance antigen presentation and aid in T cell chemotaxis [103, 109]. Furthermore, IFN-g-secreting NK cells can be directly recruited to the lymph nodes to enhance the T cell.
Conclusion
Regulatory T cells and their prognostic value for patients with head and neck squamous cell carcinoma. Serum levels of tumor necrosis factor in squamous cell carcinoma of the head and neck.
Head and Neck Cancer
We have summarized the main life cycle events of HPV and EBV, the potential mechanisms of HPV- or EBV-mediated carcinogenesis, and the implications of HPV and EBV in head and neck cancer, with emphasis on the diagnosis, prognosis, and therapy of the disease. - peutic treatment. A mechanistic understanding of HPV-related HNSCC or EBV-related NPC would require in-depth analysis of these tumors using advanced molecular analysis technologies, which will then facilitate the development of preventive and therapeutic strategies for these diseases.
HPV and Its Life Cycle
Abstract The focus of this book chapter is to discuss the role of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) and Epstein-Barr virus (EBV) in nasopharyngeal carcinoma (NPC).
HPV and EBV in Head and Neck Cancer
As these epithelial cells divide and proliferate, the viral DNA also proliferates as a low-copy-number plasmid, carried in the nuclei of the daughter cells. Once the dead squames of the host epithelium are removed, the viral life cycle continues as the process begins again.
Mechanisms of HPV-Mediated Carcinogenesis
The E4 protein is found exclusively in the differentiating layer of host epithelial cells and promotes the collapse of the cytokeratin network. To compound this lack of knowledge, it may also prove difficult to separate the molecular mechanisms and etiological role of HPV in carcinogenesis from the many cofactors of the disease.
HPV in Head and Neck Precancer
Similarly, the exact role of E5 in carcinogenesis is not entirely clear, but it may play an important role in promoting HPV transformation and promoting the proliferation of HPV-infected cells [4]. However, the molecular mechanisms of HPV-induced carcinogenesis are still far from being fully understood, and further studies are needed.
HPV in Head and Neck Cancer
Although more than one type of HPV may be found in tumor samples, the low-risk HPV types found in most laryngeal papillomas differ from the high-risk HPVs in oropharyngeal SCCs. Similarly, the division between the types of HPV found in oropharyngeal and laryngeal SCCs is evident from the unequal distribution of HPV-16 and HPV-18, as previously mentioned.
Detection of HPV and Diagnosis of HPV-Positive HNSCC
However, a positive detection of HPV infection does not necessarily indicate the development of head and neck cancer. In this regard, the development of new molecular biomarkers (besides HPV DNA and proteins) for an improved diagnosis of HPV-positive HNSCC is also important.
Prognosis of HPV-Positive HNSCC and Therapeutic Treatment
Early diagnosis of HNSCC is critical to reducing mortality from the disease and is the focus of much ongoing research in this area. Often it can be difficult to correctly diagnose HPV-positive HNSCC because there is such a wide variety of molecular tests, sampling methods, and oral specimens available that standardization of methods is a difficult task [28].
EBV and Its Life Cycle
The study also suggested that endogenous E7-specific immunity exists even in the presence of persistent virus-associated malignancy, perhaps due to immune cell escape of tumor cells from CTL recognition through downregulation of the expression of certain components of antigen processing machinery.
Mechanisms of EBV-Mediated Carcinogenesis
The EBNAs, LMPs and EBERs have been identified as the molecules of most interest in EBV-associated tumorigenesis. Because the BARF1 protein is found in serum, it may also prove to be a useful diagnostic biomarker in some patients with EBV-associated carcinoma.
EBV in Nasopharyngeal Precancer
The EBERs are small nuclear RNAs that are the most abundant RNAs in EBV-infected cells. Another oncogene that may play a role in EBV-associated carcinomas is the BARF1 gene, which has been shown to play an important role in growth promotion.
EBV in Nasopharyngeal Cancer
A recent study suggested that chromosomal losses affecting chromosome 3p occur at a preinvasive stage, early in the development of tumorigenesis. Early dysplastic lesions examined in this study supported the evidence that EBV infection indeed occurs after genetic changes in the cell, allowing a latent EBV infection to develop [59].
Detection of EBV and Diagnosis of EBV-Positive NPC
Of course, these controversial results warrant further studies to investigate the role of EBV in precancerous lesions of the nasopharynx. EBV DNA amplification by PCR provides another method for the detection of EBV DNA in blood, fluid or tissue samples [73, 76].
Prognosis of EBV-Positive NPC and Therapeutic Treatment
The main advantage of using in situ hybridization is its ability to localize EBV in the context of cytological and histopathological features of the tissue [ 56 , 73 ]. The detection of NPC is based on the patient's clinical history and a physical examination, but a definitive diagnosis requires a biopsy of the lesion.
Proteomics of HPV- and EBV-Associated Cancers
Cell therapy is another promising therapy for specific treatment against EBV-positive NPC, targeting the viral aspect of the disease. One of the possible functions of EBNA-LP is a cooperative induction with EBNA-2 of viral and cellular gene expression, including that of the genes for viral LMP-1 and cell cycle D2.
Summary and Future Perspective
Clonal proliferations of Epstein-Barr virus-infected cells in preinvasive lesions associated with nasopharyngeal carcinoma. Differential signaling pathways are activated in Epstein-Barr virus-associated nasopharyngeal carcinoma and Hodgkin lymphoma.
Head and Neck Cancer Staging and Prognosis: Perspectives of the UICC and the AJCC
Summary Head and neck cancer prognosis involves many dimensions of outcome that are governed by a wide variety of intra-patient and intra-tumor factors. In head and neck cancer, there is an increasing need to exploit new biological discoveries to enable changes in treatment and interventions in the clinic for this heterogeneous group of tumors.
The Principles of Staging in Head and Neck Cancer
Of central importance in the first edition of TNM were the classifications of head and neck cancer. Nowhere is this more evident than in the classification of the head and neck sites governed by the authors of this chapter who represent the UICC and the AJCC.
Recent Modifications to “TNM”
Relatively minor changes were made to the remaining T categories for different primary sites in the head and neck. Note: The term "Stage Grouping" is called "Anatomic Stage/Prognostic Groups" in the AJCC version of the classification [1].
The Future of TNM in Head and Neck Cancer
Can biomarkers play a role in the decision to treat clinically negative neck in patients with head and neck cancer. TNM-based staging groupings in head and neck cancer: application to hypopharyngeal cancer.
Biomarkers in Head and Neck Cancer
More and more molecularly targeted therapies are in preclinical and clinical evaluation in head and neck cancer. Potentially useful molecular markers in head and neck cancer also include the detection of viral DNA – human papillomavirus (HPV), mainly in oropharyngeal cancer, and Epstein-Barr virus (EBV) associated with nasopharyngeal carcinoma.
Epidermal Growth Factor Receptor
EGFR overexpression has not been shown to correlate with efficacy of EGFR-targeted therapy in HNSCC and therefore does not serve as a predictive biomarker [ 11 , 12 ]. In preclinical studies, EGFR vIII mutation has been associated with poor response to anti-EGFR drugs, but it is not yet a proven predictive marker in the clinical setting of HNSCC.
PI3 Kinase/AKT Pathway and mTOR
IGFR/AKT Pathway
Src/STAT Pathway
The inactive state of NF-kB is maintained by the inhibitor of kappa beta (ikB), and activation requires proteasome activity. Activation of NF-kB results in the activation of receptors and signaling proteins, including IL-1/.
Cyclin D1
As a fast-acting transcription factor, NF-kB is normally converted from its inactive form to an active transcription factor in response to cellular attack. It may be useful not only for selecting therapies that specifically target increased NF-kB activation, but also for predicting response to cytotoxic agents and radiation.
Bcl-2
The list of inciting stimuli leading to activation and subsequent homo- and heterodimerization of NF-kB and its homologues is diverse and includes bacterial lipopolysaccharide, viruses and fungi as well as cytotoxic agents, DNA damage and radiation. In HNSCC cells, treatment with bortezomib down-modulates the expression of NF-kB-regulated genes cyclin D1, Bcl-XL and IAP-1, inhibits cellular proliferation and angiogenesis, and promotes apoptosis [ 48 , 49 ].
Paradoxically, Bcl-2 overexpression has been associated with improved outcomes in an HNSCC tumor's response to therapy, local control, time to progression, and survival, underscoring the lack of safety [58–60] .
Methylation
Description of Factors Associated
Tumor hypoxia, or the state of low oxygen, is a key factor for tumor progression and treatment resistance. Because hypoxic tumor cells are more resistant to ionizing radiation, tumor hypoxia has been recognized as a potential cause of failure in the treatment of human solid tumors with ionizing radiation, both in experimental models and in patients with various types of cancer, including head and neck cancer. (HNC).
Abstract Tumor hypoxia, or the state of low oxygen, is a key factor in tumor progression and resistance to treatment. The importance of hypoxia as a potential mechanism limiting the probability of cure rate in patients with HNC treated with radiation has been recognized [ 1 ].
Hypoxia in Head and Neck Cancers: Clinical Relevance and Treatment
Hypoxia occurs in solid tumors as a result of abnormal blood vessel formation, fluctuations in blood flow and increasing oxygen. Hypoxia is not only a major cause of treatment resistance, but also a potent stimulus for several critical tumor phenotypes.
Molecular Pathways Involved in Hypoxia
How to Detect Hypoxia in the Tumors
Techniques to Measure Tumor Hypoxia
One of the advantages of endogenous markers is that the levels of these proteins can be assessed on archival materials, allowing possible correlation with treatment outcomes. A potential drawback of these approaches is that these proteins may be regulated by factors other than hypoxia.
Hypoxia and Clinical Outcomes in Head and Neck Cancers
Absorption of Cu-ATSM is faster than that of 18F-FMISO, and the reported hypoxic to normoxic ratio is greater. One concern is that due to its lipophilicity, the early uptake and washout of Cu-ATSM is likely to be affected by regional blood flow, a major confounder with hypoxia [21].
Strategies to Overcome Hypoxia-Induced Treatment Resistance in Head and Neck
Predictive value of tumor oxygenation by pO2 histography in patients with advanced head and neck cancer. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of head and neck squamous cell carcinoma.
Roadblocks
Translational research is not unlike world peace, the meaning of which depends on who is asked. The discipline of head and neck oncology has a strong history of translational research and continues to expand and build on the foundation of scientific discovery.
Translational Research in Head and Neck Oncology
