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Spindle cell carcinoma is a rare neoplasm of the upper respiratory tract which occurs in adults, most commonly in the larynx. In the literature only one case of spindle cell carcinoma, located in the maxilla, has been reported in a child. We report the first presentation of a spindle cell carcinoma in a child, which was located in the parotid gland, together with the clinical course. The diagnostic challenge associated with this unusual disorder is elucidated, as well as the role of immunohistochemical and cytogenetic examination to define the nature of these lesions. [ABSTRACT FROM AUTHOR]

Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP-CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases.

Background: Warthin's tumors of the parotid gland are associated with smoking, whereas pleomorphic adenomas are not. Genetic polymorphisms in biotransformation enzymes, involved in detoxification of toxins and carcinogens in cigarette smoke, might modify the corresponding enzyme activity and influence detoxifying capacity. We hypothesize that these genetic polymorphisms may influence the individual risk for Warthin's tumor, but not for pleomorphic adenomas., Methods: Blood from 146 patients with benign parotid gland tumors and 437 controls were investigated for polymorphisms in several biotransformation enzymes. Based on these polymorphisms, patients and controls were divided according to predicted enzyme activity (low, intermediate, and high)., Results: Prevalence of predicted intermediate and high activity UGT1A7 and UGT1A6 genotypes was significantly higher in the patients with Warthin's tumors, but not in patients with pleomorphic adenomas, compared with healthy controls., Conclusion: Predicted intermediate and high activity UGT1A7 and UGT1A6 genotypes are associated with an increased risk for Warthin's tumor. © 2015 Wiley Periodicals, Inc. Head Neck 38: E717-E723, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: Chronic suppurative otitis media is a major cause of long-standing hearing impairment in many Sub-Saharan African countries., Methods: Attempts were made to optimise the pre-treatment process before mobile ear surgery for chronic suppurative otitis media in Wolisso, a semi-urban community in the Oromia region, and in Attat, a rural community in the Gurage region, both in the south-west of Ethiopia, between 2008 and 2010. This included special training for ENT nurses, and the use of a strict scheduling regime and improved topical treatment., Results and Conclusion: This strategy allowed effective middle-ear surgery to be carried out using simple means and with a mobile ear surgery team, the latter of which is only transiently but regularly on site.

The histopathology of premalignant laryngeal lesions does not provide reliable information on the risk of malignant transformation, hence we examined new molecular markers which can easily be implemented in clinical practice. Dual-target fluorescence in situ hybridisation (FISH) for chromosome 1 and 7 centromeres was performed on tissue sections of laryngeal premalignancies in 69 patients. Chromosome instability was indicated by numerical imbalances and/or polysomy for chromosomes 1 and 7. Additionally, immunostainings for p53, Cyclin D1 and (p)FADD expression were evaluated. Malignant progression was recorded. Eighteen patients with carcinoma in situ (CIS) were treated after diagnosis and excluded from follow-up. Chromosome instability was strongly associated with a high risk of malignant transformation, especially in lower grade lesions (hyperplasia, mild and moderate dysplasia; odds ratio = 8.4, p = 0.004). Patients with lesions containing chromosome instability showed a significantly worse 5-year progression-free survival than those with premalignancies without chromosome instability (p = 0.002). Neither histopathology nor the protein markers predicted progression in univariate analysis, although histopathological diagnosis, p53 and FADD contributed positively to chromosome instability in multivariate analysis. Chromosome instability is associated with malignant progression of laryngeal premalignancies, especially in lower grade lesions. These results may contribute to better risk counselling, provided that they can be validated in a larger patient set.

In this review we provide a complete overview of the existing sclerosing bone dysplasias with craniofacial involvement. Clinical presentation, disease course, the craniofacial symptoms, genetic transmission pattern and pathophysiology are discussed. There is an emphasis on radiologic features with a large collection of CT and MRI images. In previous reviews the craniofacial area of the sclerosing bone dysplasias was underexposed. However, craniofacial symptoms are often the first symptoms to address a physician. The embryology of the skull and skull base is explained and illustrated for a better understanding of the affected areas., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Hyperostosis cranialis interna (HCI) is an autosomal dominant sclerosing bone dysplasia affecting the skull base and the calvaria, characterized by cranial nerve deficits due to stenosis of neuroforamina. The aim of this study is to describe the value of several neurophysiological, audiometric and vestibular tests related to the clinical course of the disorder., Methods: Ten affected subjects and 13 unaffected family members were recruited and tested with visual evoked potentials, masseter reflex, blink reflex, pure tone and speech audiometry, stapedial reflexes, otoacoustic emissions, brainstem evoked response audiometry and electronystagmography., Results: Due to the symmetrical bilateral nature of this disease, the sensitivity of visual evoked potentials (VEPs), masseter reflex and blink reflex is decreased (25-37.5%), therefore reducing the value of single registration. Increased hearing thresholds and increased BERA latency times were found in 60-70%. The inter-peak latency I-V parameter in BERA has the ability to determine nerve encroachment reliably. 50% of the patients had vestibular abnormalities. No patient had disease-related absence of otoacoustic emissions, because the cochlea is not affected., Conclusion: In patients with HCI and similar craniofacial sclerosing bone dysplasias we advise monitoring of vestibulocochlear nerve function with tone and speech audiometry, BERA and vestibular tests. VEPs are important to monitor optic nerve function in combination with radiological and ophthalmologic examination. We do not advise the routine use of blink and masseter reflex., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Hyperostosis cranialis interna (HCI) is a rare autosomal dominant disorder characterized by intracranial hyperostosis and osteosclerosis, which is confined to the skull, especially the calvarium and the skull base. The rest of the skeleton is not affected. Progressive bone overgrowth causes nerve entrapment that leads to recurrent facial nerve palsy, disturbance of the sense of smell, hearing and vision impairments, impairment of facial sensibility, and disturbance of balance due to vestibular areflexia. The treatment is symptomatic. Histomorphological investigations showed increased bone formation with a normal tissue structure. Biochemical parameters were normal. Until today the disease has been described in only three related Dutch families with common progenitors and which consist of 32 individuals over five generations. HCI was observed in 12 family members over four generations. Patients are mildly to severely affected. Besides HCI, several bone dysplasias with hyperostosis and sclerosis of the craniofacial bones are known. Examples are Van Buchem disease, sclerosteosis, craniometaphyseal dysplasia, and Camurati-Engelmann disease. However, in these cases the long bones are affected as well. Linkage analysis in a family with HCI resulted in the localization of the disease-causing gene to a region on chromosome 8p21 delineated by markers D8S282 and D8S382. Interesting candidate genes in this region are BMP1, LOXL2, and ADAM28. Sequence analysis of these genes did not reveal any putative mutations. This suggests that a gene not previously involved in a sclerosing bone dysplasia is responsible for the abnormal growth in the skull of these patients.

Background: Combinations of genetic polymorphisms in biotransformation enzymes might modify the individual risk for head and neck cancer., Methods: Blood from 432 patients with head and neck cancer and 437 controls was investigated for genetic polymorphisms in 9 different phase I and II biotransformation enzymes. Analysis of the risk-modifying effect was performed according to predicted enzyme activities, based on genetic polymorphisms in the corresponding genes., Results: Combination of polymorphisms in COX-2 or EPHX1 with high activity polymorphisms in UGT1A1, UGT1A6, or UGT1A7 showed a risk-modulating effect in head and neck carcinogenesis, especially among heavy smokers and patients with laryngeal cancer. However, no additional effect for the combination of these polymorphisms was discovered when compared to the impact of polymorphism in UGT1A1, UGT1A6, and UGT1A7 individually., Conclusion: Predicted high activity polymorphisms in the phase II enzymes UGT1A1, UGT1A6, and UGT1A7 are associated with an increased risk of head and neck cancer., (Copyright © 2012 Wiley Periodicals, Inc.)

Background and Purpose: HCI is a unique autosomal-dominant sclerosing bone dysplasia affecting the skull base and the calvaria, characterized by cranial nerve deficits due to stenosis of neuroforamina, whereby the mandible is affected to a lesser extent. The aim of this study is to describe the specific radiologic characteristics and course of the disorder., Materials and Methods: CT scans of affected individuals within 1 family were analyzed and compared with scans of their unaffected family members and with an age- and sex-matched control group. Linear measurements were performed of the inner table, the medulla, and the outer table of different skull locations, and attenuation (density) measurements of the same regions were recorded. Neuroforamina widths were recorded as well., Results: There was significant thickening of the skull in the frontal, parietal, temporal, and occipital regions, which was mainly due to thickening of the inner table of the skull. The attenuation of the deposited hyperostotic bone was lower than normal cortical bone., Conclusions: HCI is the only genetic bone dysplasia known that is confined to the craniofacial area. The hyperostotic bone is less attenuated than normal cortical bone. The observed radiologic abnormalities explain the possible impairment of the olfactory, optic, trigeminal, facial, and vestibulocochlear nerves.

Purpose: (18)F-Fluoride PET/CT is a relatively undervalued diagnostic test to measure bone metabolism in bone diseases. Hyperostosis cranialis interna (HCI) is a (hereditary) bone disease characterised by endosteal hyperostosis and osteosclerosis of the skull and the skull base. Bone overgrowth causes entrapment and dysfunction of several cranial nerves. The aim of this study is to compare standardised uptake values (SUVs) at different sites in order to quantify bone metabolism in the affected anatomical regions in HCI patients., Methods: Nine affected family members, seven non-affected family members and nine non-HCI non-family members underwent (18)F-fluoride PET/CT scans. SUVs were systematically measured in the different regions of interest: frontal bone, sphenoid bone, petrous bone and clivus. Moreover, the average (18)F-fluoride uptake in the entire skull was measured by assessing the uptake in axial slides. Visual assessment of the PET scans of affected individuals was performed to discover the process of disturbed bone metabolism in HCI., Results: (18)F-Fluoride uptake is statistically significantly higher in the sphenoid bone and clivus regions of affected family members. Visual assessment of the scans of HCI patients is relevant in detecting disease severity and the pattern of disturbed bone metabolism throughout life., Conclusion: (18)F-Fluoride PET/CT is useful in quantifying the metabolic activity in HCI and provides information about the process of disturbed bone metabolism in this specific disorder. Limitations are a narrow window between normal and pathological activity and the influence of age. This study emphasises that (18)F-fluoride PET/CT may also be a promising diagnostic tool for other metabolic bone disorders, even those with an indolent course.

Background: Sequence variants located at 15q25 have been associated with lung cancer and propensity to smoke. We recently reported an association between rs16969968 and risk of upper aerodigestive tract (UADT) cancers (oral cavity, oropharynx, hypopharynx, larynx, and esophagus) in women (OR = 1.24, P = 0.003) with little effect in men (OR = 1.04, P = 0.35)., Methods: In a coordinated genotyping study within the International Head and Neck Cancer Epidemiology (INHANCE) consortium, we have sought to replicate these findings in an additional 4,604 cases and 6,239 controls from 10 independent UADT cancer case-control studies., Results: rs16969968 was again associated with UADT cancers in women (OR = 1.21, 95% CI = 1.08-1.36, P = 0.001) and a similar lack of observed effect in men [OR = 1.02, 95% CI = 0.95-1.09, P = 0.66; P-heterogeneity (P(het)) = 0.01]. In a pooled analysis of the original and current studies, totaling 8,572 UADT cancer cases and 11,558 controls, the association was observed among females (OR = 1.22, 95% CI = 1.12-1.34, P = 7 × 10(-6)) but not males (OR = 1.02, 95% CI = 0.97-1.08, P = 0.35; P(het) = 6 × 10(-4)). There was little evidence for a sex difference in the association between this variant and cigarettes smoked per day, with male and female rs16969968 variant carriers smoking approximately the same amount more in the 11,991 ever smokers in the pooled analysis of the 14 studies (P(het) = 0.86)., Conclusions: This study has confirmed a sex difference in the association between the 15q25 variant rs16969968 and UADT cancers., Impact: Further research is warranted to elucidate the mechanisms underlying these observations.

Rationale, Aims and Objectives: A national guideline was proposed to enable shared care in hearing complaints and therefore to change patient flows. In this study the effect of this guideline is evaluated., Methods: From a total of 3500 patients with hearing complaints, consulting the Ear Nose and Throat Department of a large non-university hospital in the Netherlands in 2002, a random sample of 1000 patients was selected. Patient flow was simulated according to guideline criteria with as main outcome measures: the effect of the guideline on patient flow., Results: Simulation of the consensus guideline did not really alter patient flow, with 89% to 97% of the patients still being referred to the Ear Nose and Throat specialist or Audiological Centre. Age, ear operations in the past and asymmetric hearing loss are the most important factors determining whether a person is labelled as a patient in need of medical care., Conclusion: The present study emphasizes the importance of designing evidence-based guidelines for shared care., (© 2010 Blackwell Publishing Ltd.)

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility., Competing Interests: The authors have declared that no competing interests exist.

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme which catalyses not only the glucuronidation of tobacco smoke carcinogens like benzopyrene, but also of the endogenous substrate bilirubin. Bilirubin for a long time was considered to be only a toxic waste product of hemoglobin degradation, but recent findings have shown that bilirubin is a potent antioxidant, which may play a protective role against cancer. We investigated whether a genetic polymorphism in UGT1A1 (UGT1A1*28), associated with a reduced UGT1A1 enzyme activity, may have a risk-modifying effect on head and neck carcinogenesis. Blood samples from 421 patients with oral, pharyngeal or laryngeal carcinoma, and 417 healthy controls were investigated for the UGT1A1*28 polymorphism. On the basis of the occurrence of this polymorphism, patients and controls were divided according to predicted UGT1A1 enzyme activity (low, intermediate, high). Logistic regression analysis showed a significant increased distribution of predicted high activity UGT1A1*1 polymorphisms among the patients (OR: 1.37; 95% CI: 1.02-1.83). Stratified analyses demonstrated that predicted high activity UGT1A1 polymorphisms were present even more significantly in patients with laryngeal cancer, older patients, heavy smokers and heavy drinkers. In conclusion, the predicted high activity UGT1A1*1 polymorphism, which results in lower serum levels of the endogenous antioxidant bilirubin, was associated with an increased risk of head and neck cancer., (Copyright © 2010 UICC.)

Aims: Oncogenic human papillomavirus (HPV) type 16 has been strongly associated with tonsillar squamous cell carcinoma (TSCC) and appears to be of prognostic significance. Because HPV+ TSCC also accumulates p16(INK4A), this cyclin-dependent kinase inhibitor has been proposed as a potential biomarker for HPV in clinical diagnosis. The aim of this study was to determine the prevalence of HPV in tumour-free tonsillar tissue and the value of p16(INK4A) overexpression in predicting its presence., Methods and Results: p16(INK4A) overexpression was detected by immunohistochemistry in tissue sections of tumour-free tonsils of 262 patients. They were treated for non-oncological reasons (snoring or chronic/recurrent tonsillitis) consisting of tonsillectomy. Genomic DNA isolated from these tissues was subjected to HPV-specific polymerase chain reaction (PCR) analysis. p16(INK4A) immunoreactivity was detected in 28% of samples in both crypt epithelium (49/177) and lymphoid germinal centres (52/187), which correlated with each other (P < 0.0001). No reactivity was observed in superficial squamous cell epithelium. HPV16 and 18 were detected by PCR analysis in 2/195 cases (1%), which, however, were negative on fluorescence in situ hybridization analysis and discrepant on p16(INK4A) immunostaining., Conclusions: No proof was found for the presence of HPV in tumour-free tonsil tissue, despite increased p16(INK4A) expression in a quarter of tonsil cases. Other mechanisms than HPV infection are therefore implicated in p16(INK4A) up-regulation.

Hyperostosis cranialis interna is a hereditary bone disorder that is characterized by endosteal hyperostosis and osteosclerosis of the calvaria and the skull base (OMIM 144755). The progressive bone overgrowth causes entrapment and dysfunction of cranial nerves I, II, V, VII, and VIII, its first symptoms often presenting during the second decade. This study analyzes the clinical course of 13 affected individuals of three related families (32 individuals). The disorder appears to have an autosomal-dominant transmission pattern. Facial and vestibulocochlear nerve dysfunction are most frequently reported. Surgical decompression of the accessible impaired cranial nerves is advised in the early symptomatic period or even in the presymptomatic period in high-risk individuals., ((c) 2010 Wiley-Liss, Inc.)

Background: UGT1A7 is an enzyme involved in the metabolism of (pre)carcinogens present in tobacco smoke. We investigated whether genetic polymorphisms in UGT1A7, with predicted altered enzyme activity, may have a risk-modifying effect on head and neck carcinogenesis., Methods: Blood samples from 427 patients with oral, pharyngeal, and laryngeal carcinoma and 420 healthy control subjects were investigated for UGT1A7 polymorphisms. Based on these polymorphisms, patients and controls were divided according to predicted enzyme activity (low, intermediate, high)., Results: Logistic regression analysis showed a significant increased distribution of predicted high activity UGT1A7 polymorphisms among the patients (OR:1.44; 95% CI: 1.07-1.93). Stratified analyses demonstrated that high activity UGT1A7 polymorphisms were even more significantly present in patients with laryngeal cancer, older patients, heavy smokers, and heavy drinkers when compared with the control subjects., Conclusions: Predicted high activity UGT1A7 polymorphisms were significantly associated with an increased risk of head and neck cancer., ((c) 2009 Wiley Periodicals, Inc.)

Unlabelled: Hyperostosis cranialis interna is an autosomal dominant disorder characterised by endosteal hyperostosis and osteosclerosis of the skull base and calvaria, leading to compression and dysfunction of cranial nerves I, II, VII and VIII., Case Report: We report the use of bilateral surgical decompression of the internal auditory canals to treat hyperostosis cranialis interna in an eight-year-old girl presenting with bilateral facial palsy due to hyperostosis cranialis interna., Intervention and Outcome: Using a middle fossa craniotomy approach, both internal auditory canals were unroofed and cranial nerves VII and VIII were decompressed, with a one-year interval between sides. The mimic function recovered. One year post-operatively, the right and left facial sides had been restored to House-Brackmann grades I and II, respectively., Conclusion: This is the first report of the use of surgical decompression of the internal auditory canal in a case of hyperostosis cranialis interna. Surgical decompression of the internal auditory canal is recommended therapeutically, but may also be performed prophylactically in younger patients with hyperostosis cranialis interna.

Synchronous bilateral malignancy in the parotid glands is extremely rare. The English literature reveals nine case reports. The most common synchronous bilateral malignancies are acinic cell carcinoma. Epithelial-myoepithelial carcinoma is an uncommon neoplasm comprising 1% of all salivary gland tumours. In this case report, we describe, to our best of knowledge, the first case of a patient with a synchronous bilateral epithelial-myoepithelial carcinoma of the parotid gland. The clinical histopathological and immunohistochemical peculiarities are elucidated. Imaging studies like ultrasonography are mandatory for both parotid glands and upper necks in the clinical presence of a unilateral parotid gland tumour.

Background: Cyclooxygenase-2 (COX-2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of processes such as inflammation, cell proliferation, and angiogenesis, all relevant for cancer development. We investigated whether functional genetic polymorphisms in COX-2 may have a risk-modifying effect on head and neck carcinogenesis., Methods: Blood from 431 white patients with oral, pharyngeal, or laryngeal carcinoma and 438 white healthy controls was investigated for the presence of 2 functional promoter region polymorphisms (-1195A-->G and -765G-->C) in COX-2., Results: Logistic regression analysis did not show differences in COX-2 genotype distributions between patients and controls. Also no differences were found when stratified according to tumor localization, sex, or tobacco consumption., Conclusion: In contrast to earlier reports on the role of these COX-2 polymorphisms in mediating susceptibility to squamous esophageal carcinoma in a Chinese population, we could not demonstrate a risk-modifying effect in head and neck carcinogenesis in whites.

Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16(INK4A,) cyclin D1, pRb, p14(ARF), MDM2, p53, p21(Cip1/WAF1), and p27(KIP1). Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16(INK4A) overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14(ARF) (P<0.0001) and p21(Cip1/WAF1) (P=0.001), and downregulation of pRb (P<0.0001) and cyclin D1 (P=0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P=0.006), as well as for patients with T1-2 tumors (P<0.0001) or tumors showing low expression of cyclin D1 (P=0.028), presence of human papillomavirus and overexpression of p16(INK4A) (P=0.01), p14(ARF) (P=0.02) or p21(Cip1/WAF1) (P=0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21(Cip1/WAF1), were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21(Cip1/WAF1) and p14(ARF) overexpression and downregulation of pRb and cyclin D1. In particular p21(Cip1/WAF1) overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas.

Purpose: Patients with human papillomavirus (HPV)-containing oropharyngeal squamous cell carcinomas (OSCC) have a better prognosis than patients with HPV-negative OSCC. This may be attributed to different genetic pathways promoting cancer., Experimental Design: We used comparative genomic hybridization to identify critical genetic changes in 60 selected OSCC, 28 of which were associated with HPV-16 as determined by HPV-specific PCR and fluorescence in situ hybridization analysis and positive p16(INK4A) immunostaining. The results were correlated with HPV status and clinical data from patients., Results: Two thirds of OSCC harbored gain at 3q26.3-qter irrespective of HPV status. In HPV-negative tumors this alteration was associated with advanced tumor stage (P=0.013). In comparison with HPV-related OSCC, the HPV-negative tumors harbored: (a) a higher number of chromosomal alterations and amplifications (P=0.03 and 0.039, respectively); (b) significantly more losses at 3p, 5q, 9p, 15q, and 18q, and gains/amplifications at 11q13 (P=0.002, 0.03; <0.001, 0.02, 0.004, and 0.001, respectively); and (c) less often 16q losses and Xp gains (P=0.02 and 0.03). Survival analysis revealed a significantly better disease-free survival for HPV-related OSCC (P=0.02), whereas chromosome amplification was an unfavorable prognostic indicator for disease-free and overall survival (P=0.01 and 0.05, respectively). Interestingly, 16q loss, predominantly identified in HPV-related OSCC, was a strong indicator of favorable outcome (overall survival, P=0.008; disease-free survival, P=0.01) and none of these patients had a tumor recurrence., Conclusions: Genetic signatures of HPV-related and HPV-unrelated OSCC are different and most likely underlie differences in tumor development and progression. In addition, distinct chromosomal alterations have prognostic significance.