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Squamous cell carcinoma of the oral cavity and oropharynx have been used synonymously and interchangeably in the world literature in the context of head and neck cancers. As the 21st century progresses, divergence between the two have become more evident, particularly due to evidence related to human papillomavirus-associated oropharyngeal squamous cell carcinoma. As such, the American Joint Committee on Cancer recently published the 8th edition Cancer Staging Manual, serving as a continued global resource to clinicians and researchers. Through changes in staging related to T and N clinical and pathologic classifications, the new system is expected to influence current management guidelines of these cancers that have distinct anatomic and etiopathogenic characteristics. This article aims to review such impactful changes in a time of critical transition of the staging of head and neck cancer and how these changes may affect clinicians and researchers worldwide.

The most widely applied algorithm for human papillomavirus (HPV) detection in formalin-fixed, paraffin-embedded (FFPE) specimens of oropharyngeal head and neck squamous cell carcinoma (HNSCC) consists of p16INK4A immunostaining followed by PCR-based detection of high-risk HPV DNA on p16INK4A-immunopositive samples. However, in nonoropharyngeal HNSCC this algorithm fails, hampering correct interpretation of the prevalence and prognosis of HPV in these cases. In this study, we developed and validated a molecular HPV detection method for FFPE specimens of oropharyngeal and nonoropharyngeal HNSCC. Sectioning of FFPE blocks was circumvented by using punch biopsies from tumor-enriched regions of FFPE tissue blocks, and combined extraction was applied to obtain high-quality DNA and RNA from the punch biopsy. Next, PCR-based detection of HPV DNA was performed for 15 high-risk HPV types with subsequent detection of E6 mRNA for validation. The combined DNA/RNA FFPE test of tissue cores was assessed in well-characterized cohorts with known HPV status based on earlier work, that is, a cohort of oropharyngeal HNSCC (n= 80) and oral cavity HNSCC (n= 25), and reached an accuracy of 97% and 100%, respectively. In conclusion, our method is rapid, simple, and shows an excellent diagnostic performance for detection of HPV type 16. Ultimately, it can be applied for large cohort studies to determine the etiologic fraction and prognostic implication of HPV in nonoropharyngeal HNSCC.

Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite levels are within the reference range.

IMPORTANCE: Head and neck cancer (HNC) and its treatment may negatively alter neurocognitive and speech functioning. However, the prevalence of neurocognitive impairment among patients with HNC before treatment is poorly studied, and the association between neurocognitive and speech functioning is unknown, which hampers good interpretability of the effect of HNC treatment on neurocognitive and speech function. OBJECTIVES: To document neurocognitive functioning in patients with HNC before treatment and to investigate the association between neurocognitive and speech functioning. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of newly diagnosed patients with HNC before treatment using a large sample obtained in a nationwide, multicenter setting (Netherlands Quality of Life and Biomedical Cohort Study in Head and Neck Cancer [NET-QUBIC] project). MAIN OUTCOME AND MEASURES: Objective neuropsychological measures of delayed recall, letter fluency, and executive functioning, as well as patient-reported outcome measures on neurocognitive speech and functioning, were collected before treatment. RESULTS: In total, 254 patients with HNC participated (71.7% male), with a mean (SD) age of 62 (10) years. The response rate ranged from 81.9% (208 of 254) to 84.6% (215 of 254). Objective neurocognitive measures indicated that 4.7% (10 of 212) to 15.0% (32 of 214) of patients were initially seen with moderate to severe cognitive impairment. Mild to moderate impairment was found in 12.3% (26 of 212) to 26.2% (56 of 214) of patients. The most altered domains were delayed recall and letter fluency. Seven percent (15 of 208) of the patients reported high levels of everyday neurocognitive failure, and 42.6% (89 of 209) reported speech problems. Objective neurocognitive function was not significantly associated with patient-reported neurocognitive or speech functioning, but the results from patient-reported outcome measures were significantly correlated. CONCLUSIONS AND RELEVANCE: Results of this study demonstrate a high prevalence of impaired speech functioning among patients with HNC before treatment, which is in line with previous findings. A novel finding is that neurocognitive impairment is also highly prevalent as objectively measured and as self-perceived. Understanding the reason why patients with HNC are initially seen with neurocognitive impairment before the start of treatment is important because this impairment may complicate patient-clinician interaction and alter treatment adherence and because treatment itself may further worsen cognitive functioning. In addition, low self-perceived neurocognitive and speech functioning before treatment may decrease a patient’s confidence in communicative participation and perceived quality of life. Disentangling the associations between objective and patient-reported neurocognitive and speech functions is an important area for future research.

The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy.

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.

Background : Accurate segmentation of head and neck squamous cell cancer (HNSCC) is important for radiotherapy treatment planning. Manual segmentation of these tumors is time-consuming and vulnerable to inconsistencies between experts, especially in the complex head and neck region. The aim of this study is to introduce and evaluate an automatic segmentation pipeline for HNSCC using a multi-view CNN (MV-CNN). Methods: The dataset included 220 patients with primary HNSCC and availability of T1-weighted, STIR and optionally contrast-enhanced T1-weighted MR images together with a manual reference segmentation of the primary tumor by an expert. A T1-weighted standard space of the head and neck region was created to register all MRI sequences to. An MV-CNN was trained with these three MRI sequences and evaluated in terms of volumetric and spatial performance in a cross-validation by measuring intra-class correlation (ICC) and dice similarity score (DSC), respectively. Results: The average manual segmented primary tumor volume was 11.8±6.70 cm3with a median [IQR] of 13.9 [3.22-15.9] cm3. The tumor volume measured by MV-CNN was 22.8±21.1 cm3with a median [IQR] of 16.0 [8.24-31.1] cm3. Compared to the manual segmentations, the MV-CNN scored an average ICC of 0.64±0.06 and a DSC of 0.49±0.19. Improved segmentation performance was observed with increasing primary tumor volume: the smallest tumor volume group (<3 cm3) scored a DSC of 0.26±0.16 and the largest group (>15 cm3) a DSC of 0.63±0.11 (p<0.001). The automated segmentation tended to overestimate compared to the manual reference, both around the actual primary tumor and in false positively classified healthy structures and pathologically enlarged lymph nodes. Conclusion: An automatic segmentation pipeline was evaluated for primary HNSCC on MRI. The MV-CNN produced reasonable segmentation results, especially on large tumors, but overestimation decreased overall performance. In further research, the focus should be on decreasing false positives and make it valuable in treatment planning.

Various lymphoscintigraphic imaging protocols exist for sentinel node (SN) identification in early-stage oral cancer. This study aimed to evaluate the clinical value of performing additional late lymphoscintigraphic imaging.

To review the recent literature on health-related quality of life (HRQOL) in head and neck cancer (HNC) patients.

Micro-array expression profiling has been proposed to have predictive and prognostic value for patients with head and neck squamous cell carcinoma. A critical update of recent publications on this topic is presented.

OBJECTIVE To determine the effectiveness of repeated intracutaneous injections of botulinum toxin A to treat Frey syndrome. PATIENTS Between January 6, 1999, and July 1, 2005, 22 patients with Frey syndrome (12 men and 10 women) received repeated intracutaneous injections of botulinum toxin type A. MAIN OUTCOME MEASURES Before each treatment, the time since the previous treatment; the size of the affected area, as determined by a starch-iodine test; and subjective quantification of symptoms, as assessed by the previously used Frey Questionnaire Card, were recorded. RESULTS All patients underwent at least 3 treatments. Univariate analysis of variance showed a significant difference (P <.001) in the between-treatment interval. Univariate analysis of variance showed a significant difference in the size of the affected area in accordance with the number of treatments received (P <.001). The mean Frey Questionnaire Card score also decreased with repeated treatments. CONCLUSIONS In patients with Frey syndrome, repeated treatment with intracutaneous injection of botulinum toxin type A lowered subjective symptom scores, decreased the size of the affected area, and increased the duration of the effect.Arch Otolaryngol Head Neck Surg. 2009;135(3):287-290--

A great disappointment in head and neck cancer surgery is that 10–30% of head and neck squamous cell carcinoma (HNSCC) patients develop local recurrences despite histopathologically tumor-free surgical margins. These recurrences result from either minimal residual cancer (MRC) or preneoplastic lesions that remain behind after tumor resection. Distinguishing MRC from preneoplasic lesions is important to tailor postoperative radiotherapy more adequately. Here we investigated the suitability of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) using human Ly-6D (hLy-6D) transcripts as molecular marker to detect MRC in surgical margins.Submucosal samples of deep surgical margins were collected from 18 non-cancer control patients and 67 HNSCC patients of whom eight had tumor-positive surgical margins. The samples were analyzed with hLy-6D qRT-PCR, and the data were analyzed in relation to the clinicohistological parameters.A significant difference was shown between the group of patients with histopathological tumor-positive surgical margins and the non-cancer control group (p<0.001), and the group of patients with histopathological tumor-free surgical margins (p=0.001).This study shows a novel approach for molecular analysis of deep surgical margins in head and neck cancer surgery. The preliminary data of this approach for detection of MRC in deep margins of HNSCC patients are promising.

The common risk factors for oral and oropharyngeal cancer are tobacco smoking and alcohol consumption, and recently the human papillomavirus (HPV) was shown to be involved in a subgroup. HPV-positive and -negative carcinomas can be distinguished on basis of their genetic profiles. Aim of this study was to investigate patterns of chromosomal aberrations of HPV-negative oral and oropharyngeal squamous cell carcinomas (OOSCC) in order to improve stratification of patients regarding outcome. Thirty-nine OOSCCs were classified on basis of their genetic pattern determined by array comparative genomic hybridization (aCGH). Resulting groups were related to patient and tumor characteristics using the Fisher's exact test and in addition to survival with the Kaplan–Meier and log rank tests. Classification distinguished three groups, one characterized by hardly any chromosomal aberration (N=8) and another by a relatively high level (N=26), and one with a very high level (N=5) of chromosomal aberrations. This classification was significantly (p=0.003) associated with survival, with the best survival in the genetically ‘silent’ group and the worst survival in the most aberrant group. The silent profile was significantly (p<0.05) associated with wild-type TP53, an absence of alcohol consumption and a female gender. These carcinomas were negative for microsatellite instability. This classification of OOSCC was confirmed in an independent set of 89 oral carcinomas. In conclusion, the discovery of these new classes of oral and oropharyngeal cancer with unique genetic and clinical characteristics has important consequences for future basic and clinical studies.

The aim of this article is to examine the need for screening of endocrine dysfunction following treatment of head and neck cancer.

To look at the current published literature on squamous-cell carcinoma of the head and neck, at the microscopic level, and the implications of molecular and genetic research.

Objectives/Hypothesis:The detection of distant metastases during screening influences the choice of treatment in patients with head and neck squamous cell carcinoma. A previous study in the authors' institution showed that chest computed tomography (CT) scan was the most important screening technique. Different clinical risk factors in patients with head and neck squamous cell carcinoma for the development of distant metastases were identified.

Objectives:The aim of this retrospective study was to evaluate the prognostic significance of paratracheal lymph node (PTLN) metastases for tumor recurrence and survival for patients treated with total laryngectomy (TL) and PTLN dissection.

This paper reviews recent surgical contributions to the multidisciplinary approach to head and neck cancer treatment as well as published data on pertinent questions in the field.

Objective:To assess the results of the use of the free radial forearm flap in terms of objective morbidity and subjective patient response.

Identification of factors, especially comorbidity, that affect the incidence and severity of complications in head and neck cancer patients. One hundred patients with an oral/oropharynx carcinoma undergoing composite resection and microvascular soft tissue transfer were analyzed. Patient data and tumor and treatment factors were recorded. Comorbidity was graded by an Adult Comorbidity Evaluation 27 (ACE-27) test. Postoperative complications were scored according to their severity. Comorbidity score ACE-27 grade 2 or higher was present in 47% of patients, whereas 33% had a clinically important complication develop. A comorbidity score of ACE-27 grade ≥2 was a strong predictor for complications (p &lt; .001). There were no other predictors for postoperative complications. Comorbidity is of great importance for prediction of postoperative complications in head and neck cancer patients, especially an ACE-27 grade ≥2. It may be concluded from these results that prevention of complications should focus on comorbidities. © 2003 Wiley Periodicals, Inc. Head and Neck 25: 808–815, 2003

Histological grading of epithelial dysplasia in the oral cavity and oropharynx is used to predict the risk for cancer and to determine the treatment strategy. This grading, however, is subjective and not well reproducible. Recent publications have shown that molecular markers are promising in cancer risk assessment. The aim of the present study was to compare classical histological and molecular grading and to relate these to the proliferation rate by quantitative assessment of Ki‐67 staining. Forty‐three samples were analysed from the margins of patients who had undergone resection of their squamous cell carcinoma in the oral cavity/oropharynx. Three experienced pathologists performed the histological grading. With the consensus score, 12 samples were classified as normal and 31 as dysplastic (21 mild, six moderate, and four severe). Loss of heterozygosity (LOH) was assessed in the same samples with 15 microsatellite markers at chromosomes 3p, 9p, 17p, 8p, 13q, and 18q, and was present in 28 of the 43 samples. Twenty‐four of the 28 cases (86%) with LOH were classified as dysplastic and four as normal. All ten samples with moderate and severe dysplasia and 14 of 21 samples with mild dysplasia contained LOH. In four of 12 biopsies classified as normal, LOH was found. A very striking and significant difference of the Ki‐67 index was observed between LOH‐positive and LOH‐negative cases, 36.6 ± 11.1% versus 19.4 ± 2.8% positive cells, respectively. In mild dysplasia, 13 of 14 lesions containing LOH had a higher Ki‐67 index than all seven lesions without LOH. Thus, in the oral cavity/oropharynx, LOH is more frequently found in the histologically higher‐grade lesions (moderate dysplasia or worse) and in the lower grade lesions when a high proliferation rate is present. Assessment of proliferation with Ki‐67 is a better surrogate for LOH than histological grading. Copyright © 2003 John Wiley & Sons, Ltd.

The development of second primary tumors has a negative impact on the prognosis of head and neck squamous cell carcinoma. Previously, we detected genetically altered and tumor-related mucosal lesions in the resection margins in 25% of unselected head and neck squamous cell carcinoma patients (Tabor MP, Brakenhoff RH, van Houten VMM, Kummer JA, Snel MHJ, Snijders PJF, Snow GB, Leemans CR, Braakhuis BJM: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 2001, 7: 1523–1532). The aim of this study was to determine whether first and second primary tumors are clonally related and originate from a single genetically altered field. From 10 patients we analyzed the first tumor of the oral cavity or oropharynx, the 3-cm remote second primary tumor, and the mucosa from the tumor-free margins from both resection specimens. We compared TP53mutations and loss of heterozygosity profiles using 19 microsatellite markers at chromosomes 3p, 9p, 13q, and 17p. In all patients, genetically altered mucosal lesions were detected in at least one resection margin from both first and second primary tumor. Evidence for a common clonal origin of the first tumor, second primary tumor, and the intervening mucosa was found for at least 6 of 10 patients. Our results indicate that a proportion of multiple primary tumors have developed within a single preneoplastic field. Based on different etiology and clinical consequences, we propose that independent second primary tumors should be distinguished from second field tumors, that arise from the same genetically altered field the first tumor has developed from.

The objective of this study was to assess patency of the internal jugular vein following modified radical or selective neck dissection and microvascular flap reconstruction by power Doppler ultrasound and its impact on free flap survival. In 23 patients who underwent selective or modified radical neck dissection and microvascular flap reconstruction the patency of the internal jugular vein was examined by power Doppler ultrasound on the first post-operative day and after follow-up of at least four months. On the first post-operative day in one patient partial thrombosis was found, while in the other 22 patients the internal jugular vein was normal patent. During follow-up in 17 (74 per cent) patients a normal patent internal jugular vein was found, while partial and complete thrombosis were found in three (13 per cent) patients each. On the first post-operative day 22 of the 23 (96 per cent) free flap veins were visualized. There was no free flap loss during follow-up. Power Doppler ultrasound is a valuable diagnostic technique for determination of internal jugular vein patency and may be useful as screening method or in case of clinical suspicion of thrombosis to determine internal jugular vein patency. Late internal jugular vein thrombosis may probably not effect free flap survival due to neovascularization.

Cutaneous meningiomas are extremely rare tumours and their diagnosis is difficult. We describe the case of a patient who developed a paranasal swelling after head trauma and associated fractures in the same region years before. Histopathological examination of an incisional biopsy revealed the diagnosis of cutaneous meningioma. After one and a half years’ follow up, surgical excision was performed because of progressive growth of the tumour and associated aesthetic problems. Extracranial meningiomas can develop probably secondary to trapping of meningeal tissue after trauma. If there is no intracranial connection surgical removal can be considered.