Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are unexpectedly heterogeneous in nature. Classical risk factors are smoking and excessive alcohol consumption, and in recent years, the role of human papillomavirus (HPV) has emerged, particularly in oropharyngeal tumours. HPV-induced oropharyngeal tumours are considered a separate disease entity, which recently has manifested in an adapted prognostic staging system while the results of de-intensified treatment trials are awaited. Carcinogenesis caused by HPV in the mucosal linings of the upper aerodigestive tract remains an enigma, but with some recent observations, a model can be proposed. In 2015, The Cancer Genome Atlas (TCGA) consortium published a comprehensive molecular catalogue on HNSCC. Frequent mutations of novel druggable oncogenes were not demonstrated, but the existence of a subgroup of genetically distinct HPV-negative head and neck tumours with favourable prognoses was confirmed. Tumours can be further subclassified based on genomic profiling. However, the amount of molecular data is currently overwhelming and requires detailed biological interpretation. It also became apparent that HNSCC is a disease characterized by frequent mutations that create neoantigens, indicating that immunotherapies might be effective. In 2016, the first results of immunotherapy trials with immune checkpoint inhibitors were published, and these may be considered as a paradigm shift in head and neck oncology.

The molecular landscape of head and neck cancer

Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours' aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.

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Clinical update on head and neck cancer: molecular biology and ongoing challenges.

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.

The Mutational Landscape of Head and Neck Squamous Cell Carcinoma

Cancer is a disease caused by the accumulation of genetic and epigenetic changes in two types of genes: tumor suppressor genes (TSGs) and proto-oncogenes. Extensive research has been conducted over the last few decades to elucidate the role of TSGs in cancer development. In cancer, loss of TSG function occurs via the deletion or inactivation of two alleles, according to Knudson's two-hit model hypothesis. It has become clear that mutations in TSGs are recessive at the level of an individual cell; therefore, a single mutation in a TSG is not sufficient to cause carcinogenesis. However, many studies have identified candidate TSGs that do not conform with this standard definition, including genes inactivated by epigenetic silencing rather than by deletion. In addition, proteasomal degradation by ubiquitination, abnormal cellular localization, and transcriptional regulation are also involved in the inactivation of TSGs. This review incorporates these novel additional mechanisms of TSG inactivation into the existing two-hit model and proposes a revised multiple-hit model that will enable the identification of novel TSGs that can be used as prognostic and predictive biomarkers of cancer.

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Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview.

Because most studies have focused on the intrinsic carcinogenic pathways of tumors, the underlying role of N6-methyladenosine (m6A) methylation in tumor immune microenvironment (TIME) remains elusive. Herein, we systematically explored the correlations of prominent m6A regulators with PD-L1 and immune infiltrates in 769 head and neck squamous cell carcinomas (HNSCCs; The Cancer Genome Atlas [TCGA] cohort, n = 499; GSE65858 cohort, n = 270). The PD-L1 expression evidently associated with m6A regulators. Two molecular subtypes (cluster1/2) were identified by consensus clustering for 15 m6A regulators. The cluster2 preferentially associated with favorable prognosis, upregulated PD-L1 expression, higher immunoscore, and distinct immune cell infiltration. The hallmarks of G2M checkpoint, mTORC1 signaling, and PI3K/AKT/mTOR signaling were remarkably enriched in the cluster1. A prognostic risk score was constructed using seven m6A regulator-associated signatures that represented an independent prognosis factor for HNSCC. Patients with low-risk score exhibited higher immunoscore and upregulated PD-L1 expression than patients with high-risk score. Consistently, m6A regulators showed the same influence on immune modulation and survival in external GSE65858 cohort. Further analysis revealed that m6A regulator-based signatures were implicated in TIME and their copy-number alterations dynamically affected the abundance of tumor-infiltrating immune cells. Collectively, our study elucidated the important role of m6A methylation in TIME of HNSCC. The proposed m6A regulator-based signatures might serve as crucial mediators of TIME in HNSCC, representing promising therapeutic targets in improving immunotherapeutic efficacy.

Comprehensive Analysis of the PD-L1 and Immune Infiltrates of m6A RNA Methylation Regulators in Head and Neck Squamous Cell Carcinoma.

With current advances in medicine, many surgical methods have emerged for the reconstruction of soft and hard tissue defects of the head and neck. Current literature provides only a limited amount of evidence in studies addressing differences in quality of life for specific therapeutic measures in microvascular reconstruction. The validated University of Washington quality of life questionnaire version 4 (UW-QoL v4), a distress thermometer, and two questions addressing donor-site morbidity were sent to 134 patients at a tertiary care centre. All participants had undergone a type of microvascular reconstructive surgery of the head and neck. They were distributed into three groups according to the defect and type of treatment: defects reconstructed by soft-tissue microvascular tissue transfer, defects involving the hard tissue and treated by alloplastic reconstruction, and hard tissue defects receiving microvascular osseous reconstruction. A total of 82 patients completed the questionnaire in full and returned it. Patients from all the groups showed improved distress thermometer values postoperatively. Those who underwent osseous microvascular reconstruction had better functional items than those who had alloplastic reconstruction plates. Donor-site morbidity was rated low in all groups. Microvascular osseous reconstructive surgery might help to improve functional outcomes in patients with osseous defects more than alloplastic reconstruction.

Quality of life in patients with oral hard or soft tissue defects after reconstructive microsurgery.

Paget´s disease of bone is a common, progressive disorder with uncertain etiology. It results in the replacement of normal skeletal areas with highly vascularized, low density bone. The most frequent symptom is bone pain, which is a result of periostal irritation due to increased metabolic activity. However, the disease may run without any symptoms. In these cases, an abnormal radiograph or an elevated serum alkaline phosphatase can indicate the disorder. Most cases are discovered accidentally. The average age of patients at the time of diagnosis is about 50 years. Male individuals are preferentially diseased. Paget´s disease affects either single bone (monostotic) or many bones (polyostotic). It typically involves the pelvis, femur and lumbar spine rather than skull and tibia. In the head and neck area, the skull is the most frequently affected localization. Lesions of the mandible and maxilla are less common. For the therapy of active Paget´s disease, antiresorptive agents like bisphosphonates are effective drugs. Additional treatment with analgesic drugs, antiinflammatory and antineuropathic agents is recommended. We present a case of polyostotic Paget´s disease of the mandible and of the thoracic skeleton.

[Paget´s disease of the mandible: a differential diagnosis of the osteomyelitis of the jaw].

The original version of the above article contained a mistake in the presentation of one of the author names. Instead of Sirintawat Nattapong, it should be presented as Nattapong Sirintawat.

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Erratum to: Psychosocial acceptance of cleft patients: has something changed?

Dynamische Infrarot-Thermographie (DIRT) zur Darstellung der Kopfhautdurchblutung bei neurochirurgischen Eingriffen.

Purpose Excessive ear protrusion (prominauris) can negatively affect facial appearance. Because the concept of an ideal auriculocephalic angle is controversial, however, it is difficult to define when an obtrusive auricle requires surgical intervention. It is often assumed that angles exceeding 30° require corrective surgery. However, little is known about public perception of ear protrusion. This study aimed to assess perceptions of different degrees of auricular protrusion. Materials and methods We conducted an interactive panel survey. Male and female evaluators assessed digitally processed cloned images of a male and female model that depicted various ear protrusions ranging from 0° to 90°. Predictor variables were the sex of the evaluator, the sex of the clone and the extent of auricular protrusion. The outcome variable was the overall attractiveness of auricular appearance. Results Forty-four evaluators (students of dental medicine, mean age 25.43 years) participated in the study: 22 women and 22 men. The study results revealed sexual dimorphism, with the attractiveness of corresponding male and female clones rated differently. Male evaluators favoured female ear positions that fitted closer to the head; preferred alignments for female clones were: 18° (Mean) ± 9.38° (SD), p = 0.006; for male clones: 30° ± 7.94°, p = 0.003. Ear protrusion starts to negatively affect aesthetic appearance for male evaluators at positions of 42° ± 4.87° (female clone) and 54° ± 8.22° (male clone), p = 0.001. The panel of evaluators agreed to perceive angles of 21–24° ± 8.10° (female clones), ± 8.33° (male clones), as the ideal degree of protrusion in both sexes (p = 0.158). Conclusion In this study, perception of ear appearance depended on the sex of both the evaluator and the clone being assessed. Obtrusive ears were more readily accepted in male faces than in female ones. Nevertheless, the overall panel perception shows a preference for rather close fitting, unobtrusive ear alignments. For planning of corrective ear surgery, a target angle of approximately 22° can be considered as a desirable result.

Dirk Halama

Papers

Quality of life in patients with oral hard or soft tissue defects after reconstructive microsurgery.

[Paget´s disease of the mandible: a differential diagnosis of the osteomyelitis of the jaw].

Erratum to: Psychosocial acceptance of cleft patients: has something changed?

Dynamische Infrarot-Thermographie (DIRT) zur Darstellung der Kopfhautdurchblutung bei neurochirurgischen Eingriffen.

The ideal auricular protrusion - An interactive perceptual pilot study.