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The fossa navicularis is an anatomical variant of the skull base thought to be a rare finding. It represents a bony depression in the skull base. The authors here report the case of a fossa navicularis magna in a 9-year-old female who had been treated for recurrent episodes of meningitis.A literature review was also done to highlight the unique features and clinical importance of this distinctive radiological skull base finding. The literature search covered papers from the 19th century up to 2018. Earlier authors described “fossa navicularis” as a very rare skull base finding. So far, only three cases of fossa navicularis with associated clival or intracranial infection have been reported in the literature. This is the fourth reported case, and the defect was closed endoscopically via a transnasal route. This morphological skull base anomaly should be considered in the differential diagnoses for an unexplained skull base infective pathology.Skull base surgeons should be aware of the existence of the fossa navicularis because of its clinical importance in rendering a prompt diagnosis and appropriate treatment.

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

Squamous cell carcinoma of mucosal sites in the head and neck (HNSCC) is the sixth most common cause of cancer worldwide, and despite advances in conventional management, it still has significant morbidity and mortality associated with both diagnosis and treatment. Advances in our understanding of the biological mechanisms underlying this disease have demonstrated a significant difference between human papillomavirus (HPV)-associated, HPV and tobacco associated, and HPV-negative disease. It remains important to further elucidate the biologic and genetic differences between HPV-associated and tobacco-associated disease, with the aim of earlier diagnosis through screening, and advances in management including the development of novel therapeutic agents. MicroRNAs (miRNAs) are small, non-coding RNAs that function as post-transcriptional regulators of gene expression, and have effects on almost every cellular function, and have potentially important applications to diagnosis, management and prognosis in HNSCC. Establishing a cellular miRNA expression profile for HPV-associated disease may therefore have important implications for the screening and treatment of this disease. This review summarises the current findings regarding miRNA expression in mucosal HNSCC, and focuses particularly on miRNA expression in HPV-associated tumours.

Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC. This results in an imbalance in the control of E2F-dependent targets such as SPHK1, which is derepressed and drives resistance to anthracyclines in HNSCC. Specifically, we show that (i) E2F7 is subject to exportin 1 (XPO1)-dependent nuclear export, (ii) E2F7 is selectively mislocalized in most of SCC and multiple other tumor types, (iii) mislocalization of E2F7 in HNSCC causes derepression of Sphk1 and drives anthracycline resistance, and (iv) anthracycline resistance can be reversed with a clinically available inhibitor of XPO1, selinexor, in xenotransplant models of HNSCC. Thus, we have identified a strategy to repurpose anthracyclines for use in SCC. More generally, we provide a strategy to restore the balance of E2F1 (activator) and E2F7 (inhibitor) activity in cancer.

Objectives/Hypothesis: To determine the feasibility of using a mouse tumor model as a microsurgical training tool for otolaryngology-head and neck surgery (OHNS) trainees.

Background Queensland, Australia, has the highest rates of cutaneous squamous cell carcinoma (SCC). Perineural invasion (PNI) is associated with reduced local control and survival. Methods A retrospective review of a prospective database of patients with clinical PNI from cutaneous SCC of the head and neck (SCCHN) treated with surgery and postoperative radiotherapy (PORT) between 2000 and 2011 and a minimum of 24 months follow-up. Patients were excluded if immunosuppressed, had non-SCC histology, or were treated palliatively. Results Fifty patients (mean age, 60 years) with median follow-up of 50 months were included in this study. A total of 54.8% of known primary tumors had incidental PNI. Ten percent had nodal disease at presentation. MRI neurogram was positive in 95.8%. Recurrence-free survival (RFS) at 5-years was 62%. Five-year disease-specific survival (DSS) and overall survival (OS) were 75% and 64%, respectively. There were no perioperative deaths. Conclusion This report demonstrates that long-term survival is achievable in patients with clinical PNI from cutaneous SCCHN after surgery and PORT.

Objectives To determine the rate of subsequent primary site failure in patients with head and neck squamous cell carcinoma of unknown primary (UKP HNSCC) in a region with a high prevalence of cutaneous squamous cell carcinoma, according to a pre-determined institutional policy. Secondary aims included regional and distant control, and overall survival. Material and methods Patients presenting between April 2005 and June 2016 to the Princess Alexandra Hospital Head and Neck Multidisciplinary Meeting with UKP HNSCC from either presumed mucosal or cutaneous sites treated with curative intent were eligible. Patients with presumed mucosal origin were treated with radiation therapy (RT) with or without chemotherapy, while patients with presumed cutaneous SCC were treated with surgery and post-operative RT with or without chemotherapy. Results A total of 63 patients met the inclusion criteria. Median follow up duration was 3.9 years (IQR 2.07-5.14). There were no subsequent primary site failures. The rate of nodal failure among presumed mucosal patients was 11.5%, and 8.1% among presumed cutaneous patients. The rate of distant metastatic failure was 11.1% among all patients. The estimated 5 year overall survival was 71.2% (95% CI 59.2–85.7%). Conclusion Treatment according to our pre-defined institutional policy for UKP HNSCC in a region with a high prevalence of cutaneous SCC appears to be safe and effective with low rates of mucosal primary emergence and nodal failure.

Objective To measure patient-perceived upper limb and neck function following neck dissection and to investigate potential associations between clinical factors, symptoms, and function. Study Design Cross-sectional. Setting Two tertiary hospitals in Brisbane, Australia. Subjects and Methods Inclusion criteria: patients treated with neck dissection (2009-2014).aged18 years, accessory nerve or sternocleidomastoid sacrifice, previous neck dissection, preexisting shoulder/neck injury, and inability to provide informed consent (cognition, insufficient English). Primary outcomes were self-reported function of the upper limb (Quick Disabilities of the Arm, Shoulder, and Hand) and neck (Neck Disability Index). Secondary outcomes included demographics, oncological management, self-efficacy, and pain. Generalized linear models were prepared to examine relationships between explanatory variables and self-reported function. Results Eighty-nine participants (male n = 63, 71%; median age, 62 years; median 3 years since surgery) reported mild upper limb and neck dysfunction (median [quartile 1, quartile 3] scores of 11 [3, 32] and 12 [4, 28], respectively). Significant associations were found between worse upper limb function and longer time since surgery (coefficient, 1.76; 95% confidence interval [CI], 0.01-3.51), having disease within the thyroid (17.40; 2.37-32.44), postoperative radiation therapy (vs surgery only) (13.90; 6.67-21.14), and shoulder pain (0.65; 0.44-0.85). Worse neck function was associated with metastatic cervical lymph nodes (coefficient, 6.61; 95% CI, 1.14-12.08), shoulder pain (0.19; 0.04-0.34), neck pain (0.34; 0.21-0.47), and symptoms of neuropathic pain (0.61; 0.25-0.98). Conclusion Patients can experience upper limb and neck dysfunction following nerve-preserving neck dissection. The upper quadrant as a whole should be considered when assessing rehabilitation priorities after neck dissection.

Perineural spread of tumour cells along cranial nerves is a severe complication of primary cutaneous squamous cell carcinomas of the head and neck region. While surgical excision of the tumour is the treatment of choice, removal of all the tumour is often complicated by the neural location and recurrence is frequent. Non-invasive immune treatments such as checkpoint inhibitor blockade may be useful in this set of tumours although little is understood about the immune response to perineural spread of squamous cell carcinomas. Immunohistochemistry studies suggest that perineural tumour contains a lymphocyte infiltrate but it is difficult to quantitate the different proportions of immune cell subsets and expression of checkpoint molecules such as PD-1, Tim-3 and CTLA-4. Using flow cytometry of excised perineural tumour tissue, we show that a T cell infiltrate is prominent in addition to less frequent B cell, NK cell and NKT cell infiltrates. CD8 T cells are more frequent than other T cells in the tumour tissue. Amongst CD8 T cells, the frequency of Tim-3, CTLA-4 and PD-1 expressing cells was significantly greater in the tumour relative to the blood, a pattern that was repeated for Tim-3, CTLA-4 and PD-1 amongst non-CD8 T cells. Using immunohistochemistry, PD-1 and PD-L1-expression could be detected in close proximity amongst perineural tumour tissue. The data suggest that perineural SCC contains a mixture of immune cells with a predominant T cell infiltrate containing CD8 T cells. Elevated frequencies of tumour-associated Tim-3+, CTLA-4+ and PD-1+ CD8 T cells suggests that a subset of patients may benefit from local antibody blockade of these checkpoint inhibitors.

Adoptive T cell therapy has emerged as a powerful strategy to treat human cancers especially haematological malignancies. Extension of these therapies to solid cancers remains a significant challenge especially in the context of defining immunological correlates of clinical responses. Here we describe results from a clinical study investigating autologous Epstein-Barr virus (EBV)-specific T cells generated using a novel AdE1-LMPpoly vector to treat patients with nasopharyngeal carcinoma (NPC) either pre-emptively in at-risk patients with no or minimal residual disease (N/MRD) or therapeutically in patients with active recurrent/metastatic disease (ARMD). Tolerability, safety and efficacy, including progression-free survival (PFS) and overall survival (OS), were evaluated following adoptive T-cell immunotherapy. Twenty-nine patients, including 20 with ARMD and nine with N/MRD, successfully completed T-cell therapy. After a median follow-up of 18.5 months, the median PFS was 5.5 months (95% CI 2.1 to 9.0 months) and the median OS was 38.1 months (95% CI 17.2 months to not reached). Post-immunotherapy analyses revealed that disease stabilization in ARMD patients was significantly associated with the functional and phenotypic composition of in vitro-expanded T cell immunotherapy. These included a higher proportion of effector CD8+ T-cells and an increased number of EBV-specific T-cells with broader antigen specificity. These observations indicate that adoptive immunotherapy with AdE1-LMPpoly-expanded T cells stabilizes relapsed, refractory NPC without significant toxicity. Promising clinical outcomes in N/MRD patients further suggest a potential role for this approach as a consolidation treatment following first-line chemotherapy.

Objectives:To assess the frequency of anterior pharyngeal pouch formation after total laryngectomy, and to discuss the causes and consequences of anterior pharyngeal pouch formation.Study design:A prospective, observational study of 43 patients undergoing total laryngectomy.Methods:Data collected included laryngeal defect closure type, tumour staging and demographic information. A barium swallow was performed on day 7–14 after surgery to assess for anterior pharyngeal pouch formation and fistula formation.Results:The incidence of anterior pharyngeal pouch formation was 47 per cent. Patients who did not have an anterior pharyngeal pouch on swallow imaging assessment were less likely to develop a pharyngo-cutaneous fistula. There was no statistically significant association between laryngeal defect closure type and anterior pharyngeal pouch formation.Conclusion:The anterior pharyngeal pouch is a dynamic phenomenon best investigated with a fluoroscopic swallow imaging study. Its causes are multi-factorial. Absence of an anterior pharyngeal pouch appears to confer protection against pharyngo-cutaneous fistula formation, hastening commencement of adjuvant therapy and an oral diet.

Background:Olfactory neuroblastoma is a rare sinonasal malignancy, with poorly defined treatment protocols. Management at a tertiary centre was retrospectively evaluated to inform future treatment and follow up.Methods:Cases treated with curative intent (2000–2014) were included. Data were collected, and overall and disease-free survival rates were calculated.Results:Eleven cases were identified, with a median follow up of 87 months. One patient was Kadish stage A, one was stage B, eight were stage C and one was stage D. The latter patient underwent chemoradiotherapy alone. The remaining patients proceeded to: endoscopic-assisted wide local excision (n = 2), anterior craniofacial resection (n = 4) or endoscopic craniofacial resection (n = 4). No patients had primary nodal disease or elective neck treatment. One patient had neoadjuvant chemoradiation. Six patients had post-operative radiotherapy; three received adjuvant chemotherapy. Two patients had late cervical node failure, and proceeded to neck dissection and post-operative radiotherapy. Two patients had late local recurrence. Ten-year overall and disease-free survival rates were 68.2 and 46.7 per cent, respectively.Conclusion:Longer-term follow up is supported given the incidence of late regional and local recurrence. Prophylactic treatment of cervical nodes in locally advanced disease is an area for further investigation.

Bell's palsy is characterised by an acute onset of unilateral, lower motor neuron weakness of the facial nerve in the absence of an identifiable cause. Establishing the correct diagnosis is imperative and choosing the correct treatment options can optimise the likelihood of recovery.This article summarises our understanding of Bell's palsy and the evidence-based management options available for adult patients.The basic assessment should include a thorough history and physical examination as the diagnosis of Bell's palsy is based on exclusion. For confirmed cases of Bell's palsy, corticosteroids are the mainstay of treatment and should be initiated within 72 hours of symptom onset. Antiviral therapy in combination with corticosteroid therapy may confer a small benefit and may be offered on the basis of shared decision making. Currently, no recommendations can be made for acupuncture, physical therapy, electrotherapy or surgical decompression because well-designed studies are lacking and available data are of low quality.

Background: Transoral robotic surgery (TORS) is an accepted surgical treatment modality for patients with oropharyngeal squamous cell carcinoma (OPSCC). A prospective study was conducted to test patient selection for unimodality TORS in early OPSCC, with the primary endpoint being avoidance of adjuvant radiotherapy (RT) or chemoradiation (CRT) as per recommended guidelines. Methods: Patients underwent comprehensive evaluation including multidisciplinary team (MDT) review and staging (AJCC 7 th edition). Primary TORS was offered to patients with T1–2 lateralized tonsillar tumours, N0–1 with no extracapsular spread (ECS). Adjuvant RT or CRT were recommended if prespecified pathologic criteria were met, including close or positive margins, ECS and N2b disease. Results: Twenty-six patients underwent TORS, all with negative margins. Seven patients (26.9%) met one or more upstaging criteria, most commonly pN2b (5 patients, 19.2%) and close margin (3 patients, 11.5%). Five patients (19.2%) proceeded to adjuvant therapy with two patients declining further treatment. Conclusions: Single modality treatment of early tonsillar SCC utilising TORS is feasible amongst patients who undergo comprehensive evaluation including MDT review.

This article by the Perineural Invasion (PNI) Registry Group aims to clarify clinical and histopathological ambiguities surrounding PNI in non-melanoma skin cancer (NMSC). PNI is reportedly present in approximately 2–6% of cases of NMSC and is associated with greater rates of morbidity and mortality. The distinction between clinical PNI and incidental PNI is somewhat unclear, especially in regard to management and prognosis. One important objective of the PNI Registry is to develop a standardised method of classifying perineural invasion. Hence, in this article we propose a definition for PNI and for its sub-classification. This article also provides a critical analysis of the current literature on the treatment of incidental PNI by evaluating the key cohort studies that have investigated the use of surgery or radiotherapy in the management of incidental PNI. At present, there are no universal clinical guidelines that specify the acceptable treatment of NMSC exhibiting incidental PNI. Consequently, patients often receive surgery with varying wider margins, or radiotherapy despite the limited evidence substantiating such management options. It is evident from the existing literature that current opinion is divided over the benefit of adjuvant radiotherapy. Certain prognostic factors have been proposed, such as the size and depth of tumour invasion, nerve diameter, the presence of multifocal PNI and the type of tumour. The PNI Registry is a web-based registry that has been developed to assist in attaining further data pertaining to incidental PNI in NMSC. It is envisaged that this information will provide the foundation for identifying and defining best practice in managing incidental PNI.

BackgroundNonmelanoma skin cancer (NMSC) with perineural invasion (PNI) is most commonly seen in cutaneous squamous cell carcinoma of the head and neck (SCCHN). The cranial nerves are a conduit for skin cancer to reach the brainstem.

Background. The purpose of this study was to assess whether a positron emission tomography (PET)-directed policy remains appropriate for managing neck nodes (N3; >6 cm) in head and neck squamous cell carcinoma (HNSCC). Methods. All patients with N3 (>6 cm) HNSCC treated with definitive che- moradiotherapy (CRT) at our institution between 2005 and 2012 were included in the analysis. Patients underwent PET assessment before and 12 weeks after CRT. Neck dissections were performed for PET-avid resid- ual nodal abnormalities after complete response at the primary site. Rate of isolated nodal failure (INF) was the primary outcome.

Advances in the field of skull base surgery aim to maximize anatomical exposure while minimizing patient morbidity. The petroclival region of the skull base presents numerous challenges for surgical access due to the complex anatomy. The transcochlear approach to the region provides adequate access; however, the resection involved sacrifices hearing and results in at least a grade 3 facial palsy. An endoscopic endonasal approach could potentially avoid negative patient outcomes while providing a desirable surgical window in a select patient population.Cadaveric study.Endoscopic access to the petroclival region was achieved through an endonasal approach. For comparison, a transcochlear approach to the clivus was performed. Different facets of the dissections, such as bone removal volume and exposed surface area, were computed using computed tomography analysis.The endoscopic endonasal approach provided a sufficient corridor to the petroclival region with significantly less bone removal and nearly equivalent exposure of the surgical target, thus facilitating the identification of the relevant anatomy. The lateral approach allowed for better exposure from a posterolateral direction until the inferior petrosal sinus; however, the endonasal approach avoided labyrinthine/cochlear destruction and facial nerve manipulation while providing an anteromedial viewpoint. The endonasal approach also avoided external incisions and cosmetic deficits. The endonasal approach required significant sinonasal resection.Endoscopic access to the petroclival region is a feasible approach. It potentially avoids hearing loss, facial nerve manipulation, and cosmetic damage.

The temporal bone can be affected by primary or secondary malignancies. The latter are far more common. The complex anatomy of this region requires a thorough understanding in order to manage these lesions safely. Herein we present a brief description of the techniques used to resect malignant temporal bone lesions.

Tumors of the jugular foramen are rare and often benign. The surgical management of these conditions is often associated with considerable post operative morbidity. Complications include injury to the lower cranial nerves causing dysphagia and dysphonia, facial nerve paresis and loss of hearing. The POTS approach takes the vector of dissection from a lateral trajectory to a posterio-lateral trajectory. In the setting of the more posteriorly placed jugular foramen schwannomas this allows for resection and offers the opportunity for preservation of auditory and facial function.

Choosing the optimal approach to a given skull base tumor continues to be a matter of great debate. While endoscopy has revolutionized the management of various cranial base pathologies a thorough understanding of all approaches available to the skull base team is critical in order to properly manage these lesions. Herein, we present an overview of the most relevant approaches used to access the skull base. It is important for the skull base surgeon to be familiar with these approaches and understand what each approach can achieve.

Recent advances in endonasal endoscopy have facilitated the surgical access to the lateral skull base including areas such as Meckel's cave. This approach has been well documented, however, few studies have outlined transantral specific access to Meckel's. A transantral approach provides a direct pathway to this region obviating the need for extensive endonasal and transsphenoidal resection. Our aim in this study is to compare the anatomical perspectives obtained in endonasal and transantral approaches. We prepared 14 cadaveric specimens with intravascular injections of colored latex. Eight cadavers underwent endoscopic endonasal transpterygoid approaches to Meckel's cave. Six additional specimens underwent an endoscopic transantral approach to the same region. Photographic evidence was obtained for review. 30 CT scans were analyzed to measure comparative distances to Meckel's cave for both approaches. The endoscopic approaches provided a direct access to the anterior and inferior portions of Meckel's cave. However, the transantral approach required shorter instrumentation, and did not require clearing of the endonasal corridor. This approach gave an anterior view of Meckel's cave making posterior dissection more difficult. A transantral approach to Meckel's cave provides access similar to the endonasal approach with minimal invasiveness. Some of the morbidity associated with extensive endonasal resection could possibly be avoided. Better understanding of the complex skull base anatomy, from different perspectives, helps to improve current endoscopic skull base surgery and to develop new alternatives, consequently, leading to improvements in safety and efficacy.

Genomic instability underlies the transformation of host cells toward malignancy, promotes development of invasion and metastasis and shapes the response of established cancer to treatment. In this review, we discuss recent advances in our understanding of genomic stability in squamous cell carcinoma of the head and neck (HNSCC), with an emphasis on DNA repair pathways. HNSCC is characterized by distinct profiles in genome stability between similarly staged cancers that are reflected in risk, treatment response and outcomes. Defective DNA repair generates chromosomal derangement that can cause subsequent alterations in gene expression, and is a hallmark of progression toward carcinoma. Variable functionality of an increasing spectrum of repair gene polymorphisms is associated with increased cancer risk, while aetiological factors such as human papillomavirus, tobacco and alcohol induce significantly different behaviour in induced malignancy, underpinned by differences in genomic stability. Targeted inhibition of signalling receptors has proven to be a clinically-validated therapy, and protein expression of other DNA repair and signalling molecules associated with cancer behaviour could potentially provide a more refined clinical model for prognosis and treatment prediction. Development and expansion of current genomic stability models is furthering our understanding of HNSCC pathophysiology and uncovering new, promising treatment strategies.

Perineural invasion of head and neck skin cancer is a poorly understood and often misdiagnosed pathological entity. Incidental or microscopic perineural invasion is identified by the pathologist and often leads to confusion as to how the patient should be further treated. The less common but more aggressive clinical perineural spread presents with a clinical deficit, which is too commonly misinterpreted by the clinician. This review will try to clarify the terminology that exists in the literature and explore the mechanisms of invasion and spread. It will look at the recent advances in diagnosis and comment on the limitations inherent in current classification schemes. A review of outcomes will be included and current treatment strategies utilized discussed.

Objective To evaluate lateral temporal bone resection (LTBR) in the management of advanced cutaneous squamous cell carcinoma (SCC) with temporal bone invasion and patterns of failure. Methods This is a retrospective study of 35 patients undergoing lateral temporal bone resection for advanced cutaneous SCC at a tertiary care center between 1995 and 2006. Results The Pittsburgh tumor stage was T4 in 18 patients (51%), T3 in 5 (14%), T2 in 9 (26%), and T1 in 3 (9%). Clear margins were reported in 22 (63%) patients. Resection of the mandible and/or temporomandibular joint (TMJ) was required in 11 (31%) patients. Facial nerve involvement was seen in 10 (29%) patients. Survival outcomes at 2 and 5 years for overall survival were 72% and 49%; disease-free survival, 68% and 59%; and disease-specific survival, 79% and 62%, respectively. Pittsburgh T stage correlated significantly with disease-specific survival (p = 0.015) and margin status was significant for both disease-free survival (p = 0.0015) and disease-specific survival (p 0.001). Conclusions Surgery with curative intent is justified for cutaneous SCC invading the temporal bone with extended LTBR. Margin status was a significant predictor of outcome. Surgeons should plan preoperatively to achieve clear margins by extending the LTBR with possible nerve resection.

Squamous cell carcinoma (SCC) is the second most common cancer worldwide and accounts for approximately 30% of all keratinocyte cancers. The vast majority of cutaneous SCCs of the head and neck (cSCCHN) are readily curable with surgery and/or radiotherapy unless high-risk features are present. Perineural invasion (PNI) is recognized as one of these high-risk features. The molecular changes during clinical PNI in cSCCHN have not been previously investigated. In this study, we assessed the global gene expression differences between cSCCHN with or without incidental or clinical PNI. The results of the analysis showed signatures of gene expression representative of activation of p53 in tumors with PNI compared to tumors without, amongst other alterations. Immunohistochemical staining of p53 showed cSCCHN with clinical PNI to be more likely to exhibit a diffuse over-expression pattern, with no tumors showing normal p53 staining. DNA sequencing of cSCCHN samples with clinical PNI showed no difference in mutation number or position with samples without PNI, however a significant difference was observed in regulators of p53 degradation, stability and activity. Our results therefore suggest that cSCCHN with clinical PNI may be more likely to contain alterations in the p53 pathway, compared to cSCCHN without PNI.

The surgical management of perineural spread of head and neck cancers has become an integral part in the contemporary treatment of this pathology. We now understand that tumour spreads within the epineurium and in a continuous fashion. We also can rely on the accuracy of magnetic resonance neurography in detecting and defining the extent of disease. With modern skull base techniques and a greater understanding of the anatomy in this region, specific operations can be designed to help eradicate disease. We review the current approaches and techniques used that enable us to better obtain tumour free margins and hence improve survival.

Since the mid-1960s surgeons have attempted to cure intracranial perineural spread (PNS) of cutaneous malignancies. Untreated patients with trigeminal PNS die from brainstem invasion and leptomeningeal disease. It was understood that resection with clear margins was potentially curative, but early surgical attempts were unsuccessful. The prevailing wisdom considered that this surgery failed to improve the results achieved with radiation therapy alone and was associated with high morbidity. However, with improved imaging, surgical equipment, and better understanding of cavernous sinus (CS) anatomy and access, contemporary surgeons can improve outcomes for this disease. The aim of this paper is to describe a technique to access the interdural compartment of the CS and treat PNS of cutaneous squamous cell carcinoma (cSCC) in the intracranial trigeminal nerve and ganglion. It is based on the experience of the Queensland Skull Base Unit, Australia in managing PNS of cutaneous squamous cell carcinoma of the head and neck (cSCCHN).

This article provides an overview of perineural spread of head and neck malignancy. It defines the problem and explores some of the unique features, which occur with this pathology. The expectation is for a better understanding of this extraordinary disease, hopefully leading to earlier diagnosis and for a more consistent reporting of results. It summarizes the topics to be covered in this special edition, which should leave the reader with a fairly complete understanding of the contemporary issues of perineural spread.

Perineural invasion (PNI) in cutaneous squamous cell carcinoma of the head and neck (CSCCHN) is associated with decreased survival. Large-nerve PNI presents with clinical signs and symptoms and/or magnetic resonance imaging evidence of cranial nerve involvement. We sought to determine which variables predict a worse outcome and to analyze patterns of failure.Case series with planned data collection.Tertiary care center.Patients with large-nerve PNI from CSCCHN between 1996 and 2006 were identified from a prospectively collected database. Clinical and demographic variables were recorded. Local control rates and survival analysis were performed using Kaplan-Meier curves.Thirty-six patients were identified (28 men and 8 women). The mean age was 61 years. Twenty-nine were treated with curative intent, and 7 received palliation. The mean follow-up was 35 months. Involvement of V3, disease zone, and the type of therapy were significantly associated with overall survival (P.05). The 5-year disease-free survival for patients by therapy was 50% for subcranial surgeries, 53.6% for skull base surgery, and 0% for radiation and palliative therapies (P.001). None of the patients treated with a skull base resection had a central recurrence, while all patients who received palliation had a central failure.Disease extent, type of therapy, and involvement of V3 are all significant predictors of survival in PNI from CSCCHN. We confirmed that the natural history of the disease is central progression and that this can be halted, if detected early enough, by a properly planned skull base resection.

Background. The purpose of this study was to present our prospectively evaluated positron emission tomog- raphy (PET)-directed policy for managing the neck in node- positive head and neck squamous cell carcinoma (NþHNSCC) after definitive radiotherapy (RT) with or without concurrent sys- temic therapy. Methods. One hundred twelve consecutive patients who achieved a complete response at the primary site underwent a 12-week posttherapy nodal response assessment with PET and diagnostic CT. Patients with an equivocal PET underwent a repeat PET 4 to 6 weeks later. Patients with residual CT nodal abnormalities deemed PET-negative were uniformly observed regardless of residual nodal size. Results. Median follow-up from commencement of RT was 28 months (range, 13-64 months). Residual CT nodal abnormal- ities were present in 50 patients (45%): 41 PET-negative and 9 PET-positive. All PET-negative residual CT nodal abnormalities were observed without subsequent isolated nodal failure. Conclusion. PET-directed management of the neck after definitive RT in node-positive HNSCC appropriately spares neck dissections in patients with PET-negative residual CT nodal abnormalities. V C 2011 Wiley Periodicals, Inc. Head Neck 00:000-000, 2011

6067Background: With results of chemo-radiotherapy de-escalation trials for Human Papillomavirus (HPV)-associated oropharyngeal carcinoma (OPC) pending, any reduction in toxicity may be offset by t...

Perineural invasion (PNI) in cutaneous squamous cell carcinoma of the head and neck (CSCCHN) is associated with decreased survival, particularly in patients with clinical signs of cranial nerve involvement. There is evidence to indicate that neural cell adhesion molecule (N-CAM) confers capability of PNI. We analyzed our own patient population to determine if N-CAM predicted clinical PNI in CSCCHN.Tissue from patients with CSCCHN and clinical PNI, who underwent surgery between 1998 and 2005, was immunostained for N-CAM. In addition, non-PNI CSCCHN and normal nerve sections were also stained. A section of neuroendocrine tumor was included in each slide as a positive control. In addition, most of the sections also had an "inbuilt control" in the CD56 positive natural killer T cells that formed part of the inflammatory reaction to the tumors.Tissue was available from 14 patients with CSCCHN and clinical PNI. The analysis was carried out in 14 patients without PNI and 4 normal nerves. N-CAM was not expressed in any of our PNI CSCCHN specimens or non-PNI controls. It was strongly expressed in the neuroendocrine tumors and positive in-built controls, as well as in normal nerve tissue.N-CAM expression did not predict neurotropism in our patient population. Additional studies are required to identify the cell surface markers expressed by CSCCHN which confer neurotropism capabilities.

Large nerve perineural spread represents a rare but potentially fatal form of metastasis for cutaneous malignancy most prevalent in the head and neck region. This often misunderstood and misdiagnosed condition is particularly prevalent in Queensland and is most commonly seen with squamous cell carcinomas. It is not known whether small nerve (incidental) and large nerve (clinical) represent a spectrum of the same disease processes but it is clear that the two have much different prognostic significance. An overview of large nerve disease will be discussed including which nerves are commonly affected and patterns of failure. Finally, current management regimes will be covered including staging of the disease and specific skull base techniques used for varying nerve involvement.

Objectives: We sought to examine the nature of fungal balls of the sphenoid sinus, in particular the exposure of adjacent skull base structures and the potential for surgical morbidity. Methods: We retrospectively reviewed our series of 17 cases of sphenoid sinus fungal balls seen between 1998 and 2005 with reference to their diagnosis, radiologic changes, histopathology, and surgical management. Results: Exposed structures included the pituitary fossa, cavernous sinus, and cavernous internal carotid artery, but this exposure did not result in an increase in perioperative complications. Sclerotic thickening of the sinus walls persisted, probably representing a chronic osteitis in response to concurrent bacterial infection. This appeared to be protective against further sinus wall erosions. Wall erosions did not heal. One patient demonstrated what appeared to be invasive fungal disease from a fungal ball. Conclusions: Sphenoid sinus fungal balls can occur with minimal symptoms in a mainly elderly population and require surgical removal. Sphenoid sinus fungal balls have a low rate of operative morbidity and should be effectively managed by transnasal endoscopic sphenoidotomy alone.

While human papillomavirus (HPV) is an accepted risk factor for oropharyngeal squamous cell carcinoma (SCC), its aetiological role in oral cavity SCC remains unclear. This study aimed to determine the HPV prevalence in an Australian population.DNA was extracted from 63 formalin-fixed paraffin-embedded tumour specimens histologically confirmed as SCC of the oral cavity, diagnosed during 2006-2012. Clinical data were extracted from medical records. HPV presence was determined by polymerase chain reaction. Positive samples were typed by sequencing. Immunohistochemistry was used to assess p16Five of the 63 tumours (8%) were positive for HPV DNA (three HPV-16 positive and two HPV-18 positive). Two tumours overexpressed p16This study has identified a low prevalence of high-risk HPV in Queensland, Australia.

Background:Chronic rhinosinusitis is characterised by persistent inflammation of the sinonasal mucosa. Multiple pathophysiological mechanisms are likely to exist. Previous research has focused predominantly on T-helper type cytokines to highlight the inflammatory mechanisms. However, proteins such as nuclear factor kappa B and transforming growth factor beta are increasingly recognised to have important roles in sinonasal inflammation and tissue remodelling.Objective:This review article explores the roles of T-helper type cytokines, nuclear factor kappa B and transforming growth factor beta in the pathophysiological mechanisms of chronic rhinosinusitis. An understanding of these mechanisms will allow for better identification and classification of chronic rhinosinusitis endotypes, and, ultimately, improved therapeutic strategies.

The objective of this study was to examine the effect of specific Protein kinase C (PKC) isoform re-expression in solid malignancies, particularly head and neck squamous cell carcinoma cell lines, and the impact this may have on treatment with known activators of PKC.The constitutive expression of PKC isoforms were determined in six head and neck squamous cell carcinoma (SCC) cell lines. Cytotoxicity of the prototypic phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) and the novel diterpene ester PEP005 was established. Viral transduction to re-express PKCβ isoforms in two of these cell lines was performed, and its effect on the sensitivity to the compounds was quantified.Tongue and hypopharyngeal SCC cell lines were resistant to both TPA and PEP005, with the concentration required to inhibit growth by 50% (IC50) being1,000 ng/ml. CAL-27 (tongue SCC) and FaDu (hypopharyngeal SCC) cell lines re-expressing PKCβI and -βII isoforms demonstrated IC50 of 1-5 ng/ml with TPA or PEP005.Re-expression of PKCβ in head and neck SCC cell lines leads to cells one thousand-times more sensitive to the cytotoxic effects of phorbol or diterpene esters in culture. This highlights the importance of the isoform in tumor progression and presents the potential benefit of these compounds in malignancies expressing the protein, and in combination therapy.

Objective:To assess nasal morbidity resulting from nasoseptal flap use in the repair of skull base defects in endoscopic anterior skull base surgery.Methods:Thirty-six patients awaiting endoscopic anterior skull base surgery were prospectively recruited. A nasoseptal flap was used for reconstruction in all cases. Patients were assessed pre-operatively and 90 days post-operatively via the Sino-Nasal Outcome Test 20 questionnaire and visual analogue scales for nasal obstruction, pain, secretions and smell; endoscopic examination findings and mucociliary clearance times were also recorded.Results:Sino-Nasal Outcome Test 20 questionnaire data and visual analogue scale scores for pain, smell and secretions showed no significant differences between pre- and post-operative outcomes, with visual analogue scale scores for nasal obstruction actually showing a significant improvement (p = 0.0007). A significant deterioration for both flap and non-flap sides was demonstrated post-operatively on endoscopic examination (p = 0.002 and p = 0.02 respectively).Conclusion:Whilst elevation of a nasoseptal flap in endoscopic surgery of the anterior skull base engendered significant clinical deterioration on examination post-operatively, quality of life outcomes showed that no such deterioration was subjectively experienced by the patient. In fact, there was significant nasal airway improvement following nasoseptal flap reconstruction.

To determine the feasibility of using a mouse tumor model as a microsurgical training tool for otolaryngology-head and neck surgery (OHNS) trainees.Animal study.We injected athymic nude mice with human cutaneous squamous cell carcinoma (A431 cell line) deep to the parotid region overlying the masseter muscle. We sacrificed the animals 1 to 3 weeks postinjection, once a visible tumor growth was confirmed. We then asked 10 OHNS trainees to excise the tumor with preservation of the facial nerves under a high-magnification dissecting microscope. The trainees graded the tasks in several areas of specific measures using a visual analogue scale (VAS) including 1) tumor texture, 2) surgical realism, 3) usefulness, and 4) difficulty of the task.Noticeable tumor growth occurred within 5 days following A431 cell injection and reached measureable size (0.5-1.5 cm) within 1 to 3 weeks. The tumor displaced the facial nerve laterally and medially, with few demonstrating infiltration of the nerve. VAS scores (± standard deviation) were 8.1 (± 1.7), 7.7 (± 2.5), 9.0 (± 0.9) and 6.6 (± 1.9) for tumor texture, surgical realism, usefulness, and the difficulty of the task, respectively.We demonstrate a novel, reliable and cost-effective mouse model for simulating tumor extirpation microsurgery with preservation of important neural structures. OHNS trainees have found this simulation model to be realistic, useful, and appropriately challenging.

Australia is recognized as the non-melanoma skin cancer (NMSC) capital of the world with approximately 300,000 cases diagnosed annually [1]. NMSC with perineural invasion (PNI) is an aggressive feature, which carries a worse prognosis through higher rates of locoregional recurrence and reduced survival [2–5]. NMSC with PNI has been shown to be associated with a disease-specific survival at 3 years of 64 %, compared to NMSC without PNI of 91 % [6].

Squamous cell carcinoma (SCC) of the temporal bone is an aggressive malignancy. It presents as a primary tumour of the temporal bone arising in the middle ear or external auditory canal (EAC). Secondary invasion of the temporal bone occurs because of direct spread from a primary lesion of the pinna and its surrounds, or from cutaneous SCC (cSCC) metastasis to the first echelon lymph node bed. In Australia, SCC of the temporal bone typically presents from direct invasion from a cutaneous primary, or from metastatic spread from a cutaneous primary to the parotid lymph nodes abutting the temporal bone [1].

e17551 Background: Chemoradiotherapy (CRT) with 3 cycles (#) of high-dose cisplatin (HDC) (100mg/m2 weeks 1,4 & 7) and 70Gy over 7 weeks is associated with improved overall survival (OS) compared with radiotherapy (RT) alone in locally advanced OPC. Human Papilloma Virus (HPV) related tumours have superior outcomes and de-escalating treatment is a contemporary issue. Our study objectives were to determine if 2# HDC were non-inferior to 3#, how this was influenced by prognostic factors including stage, smoking history and p16 status, and to explore toxicity attributed to HDC. Methods: A single centre, retrospective analysis was undertaken for OPC patients who received CRT with HDC between Oct 2009 -Dec 2012. Those with distant metastatic disease or receiving induction chemotherapy were excluded. Data extracted included HPV and smoking status, tumour stage by 7thEd AJCC TNM and ICON-S classification, # HDC completed, toxicity and OS. Log-rank test was used for OS analysis. Results: 63, 96 and 4 patients received 3, 2 and 1 # HDC respectively. Median RT dose was 70Gy (range 66-70). 110 (67.5%) were p16 +, 28 (17.2%) were p16 negative and 25 (15.3%) unknown. 52 had omission of #3 HDC predominantly due to neutropenia (33%), nephrotoxicity (23%) and ototoxicity (12%). 19 had delays in #2 HDC resulting in omission of #3 due to completion of RT. There was no difference in OS between 3 #(mean OS (yrs)+/- SEM: 6.05+/- 0.22) or 2# HDC (5.70+/- 0.21) in all comers (p = 0.255). For RTOG0129 low risk p16+ patients, there was no significant difference (p = 0.896) between 3# (6.33+/- 0.24; n = 24) and 2# (6.18+/- 0.25; n = 44) HDC. Similar results were evident for ICON-S stage I for 3# (6.36+/-0.19; n = 25) vs 2# (6.30+/- 0.19; n = 42) HDC (p = 0.932). For RTOG 0129 intermediate risk p16 + OPC there was a significant difference (p = 0.017) in OS favouring 3# (6.29+/-0.22; n = 20) versus 2# (4.81+/-0.67; n = 10) HDC. For p16 negative patients there was no difference (p = 0.265) in OS between 3# (4.06+/-0.94; n = 9) and 2# (5.17+/-0.48; n = 22) HDC. Conclusions: This data suggests that cisplatin de-escalation does not confer inferior OS in low risk HPV related OPC. Significant toxicities with HDC influenced the ability to complete prescribed treatment.

6008 Background: We report on the first multi-centre randomized phase III trial of post-operative radiotherapy (PORT) vs post-operative chemo-RT (CRT) in high-risk cutaneous squamous cell carcinoma of the head and neck (cSCCHN) (NCT00193895). Methods: The primary objective was to determine whether there was a freedom from loco-regional relapse (FLRR) difference between patients randomly assigned to 60-66Gy (6-6.5 weeks) with or without weekly carboplatin (AUC 2) following resection of gross disease. Patients were stratified to high-risk nodal (either extracapsular nodal extension, intra-parotid nodal disease of any size or number, cervical nodal disease with ≥2 nodes or largest node > 3cm) or high-risk primary (T3-T4 or in-transit metastases). Patients with both features were stratified to the high-risk nodal group. Secondary objectives included disease-free survival (DFS), overall survival (OS) and acute & late toxicity (CTCAE V3). Results: 321 patients were randomly assigned between 2005-2014, with 11 not commencing treatment protocol due to disease progression or withdrawal of consent. Of the 310 patients commencing treatment protocol (157 RT and 153 CRT), 230 (74%) had high-risk nodal, 70 (22%) high-risk primary and 10 (3%) both. Median follow up was 60 months, median RT dose was 60Gy and 85% randomised to CRT completed 6 cycles of carboplatin. The 2- & 5-year FLRR (95% CI) for the RT arm was 88% (83-93%)/83% (77-90%) and for CRT 89% (84-94%)/87% (81-93%) (HR 0.85; 95%CI [0.46-1.55]; p = 0.59). The 2- & 5 year DFS (95% CI) for the RT arm was 78% (72-85%)/67% (60-76%) and for CRT 83% (77-89%)/73% (66-81%) (HR 0.85; 95%CI [0.55-1.29]; p = 0.43). The 2- & 5 year OS (95% CI) for the RT arm was 88% (83-93%)/76% (69-84%) and for CRT 88% (83-94%)/79% (72-86%) (HR 0.95; 95%CI [0.58-1.57]; p = 0.84). 134 (43%) experienced Grade 3/4 skin toxicity; 49% RT, 37% CRT (p = 0.039). 12 (3.9%) experienced Grade 3/4 subcutaneous fibrosis; 2.5% RT, 5.2% CRT. Conclusions: While surgery and PORT provided excellent FLRR with acceptable toxicity, the addition of weekly carboplatin did not improve outcomes in high-risk cSCCHN. Clinical trial information: NCT00193895.

The aim of this study was to document the rate of pathologic neck disease in patients presenting with metastatic cutaneous squamous cell carcinoma (CSCC) to the parotid gland following parotidectomy and neck dissection in the clinically and radiologic negative neck.Case series with chart review.Tertiary referral center.The study involved a retrospective chart review from 1999 to 2008 of patients presenting with metastatic CSCC to the parotid at the Princess Alexandra Hospital, Brisbane, Australia.Eighty-one patients with metastatic parotid disease were identified. A total of 51 (63%) patients had no clinical or radiological evidence of cervical nodal disease. Forty-five patients (88%) were male, median age was 69 (range, 42-91) years, and the median follow-up was 16 (interquartile range, 9-44) months. Thirty-four of these patients underwent a parotidectomy and neck dissection with/without postoperative radiotherapy (RT). Occult pathological cervical nodal disease was found in 5 (14.7%) patients. Of those who received a neck dissection, 3 patients relapsed in the parotid, 1 in the neck alone, and 1 distantly.This series has shown that the rate of pathologically involved neck nodes in patients with metastatic CSCC to the parotid in the clinically node negative neck is low. Given many of these patients warrant postoperative RT to the parotid bed, an elective neck dissection may not be warranted as the parotid and neck may be treated in continuity with RT.

Queensland, Australia, has the highest rates of cutaneous squamous cell carcinoma (SCC). Perineural invasion (PNI) is associated with reduced local control and survival.A retrospective review of a prospective database of patients with clinical PNI from cutaneous SCC of the head and neck (SCCHN) treated with surgery and postoperative radiotherapy (PORT) between 2000 and 2011 and a minimum of 24 months follow-up. Patients were excluded if immunosuppressed, had non-SCC histology, or were treated palliatively.Fifty patients (mean age, 60 years) with median follow-up of 50 months were included in this study. A total of 54.8% of known primary tumors had incidental PNI. Ten percent had nodal disease at presentation. MRI neurogram was positive in 95.8%. Recurrence-free survival (RFS) at 5-years was 62%. Five-year disease-specific survival (DSS) and overall survival (OS) were 75% and 64%, respectively. There were no perioperative deaths.This report demonstrates that long-term survival is achievable in patients with clinical PNI from cutaneous SCCHN after surgery and PORT. © 2015 Wiley Periodicals, Inc. Head Neck 38: 824-831, 2016.

Summary Objectives The current study presents the long-term results from a study designed to evaluate a restaging positron emission tomography (PET) directed policy whereby neck dissections were omitted in all node positive head and neck squamous cell carcinoma (N + HNSCC) patients with PET-negative lymph nodes after definitive radiotherapy (RT), with or without chemotherapy. Methods A post-therapy nodal response assessment with PET and computed tomography (CT) was performed in patients who achieved a complete response at the primary site after definitive radiotherapy. Patients with PET-negative lymph nodes were observed regardless of residual CT abnormalities. Results One hundred and twelve patients, the majority of whom (83 patients, 74%) had oropharyngeal primaries, were treated on protocol. Median follow-up was 62 months. Negative and positive predictive values for the restaging PET was 97.1% and 77.8% respectively, with only one patient who was PET-negative after treatment experiencing an isolated nodal relapse. Conclusion PET-guided management of the neck following organ preservation therapy effectively spares neck dissections in patients with N + HNSCC without compromising isolated nodal control or overall survival.

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC). We assess the safety and tolerability of adoptive transfer of autologous cytotoxic T lymphocytes (CTLs) specific for the EBV latent membrane protein (LMP) in a patient with recurrent NPC. After infusion, the majority of pulmonary lesions were no longer evident, although the primary tumor did not regress.

Aims To determine prognostic factors for locoregional relapse (LRR), distant relapse and all-cause death in a contemporary cohort of locoregionally advanced oropharyngeal squamous cell carcinoma (OSCC) treated with definitive chemoradiotherapy or radiotherapy alone. Materials and methods OSCC patients treated with definitive radiotherapy between 2005 and 2010 were identified from a prospective head and neck database. Patient age, gender, smoking history, human papillomavirus (HPV) status, T- and N-category, lowest involved nodal level and gross tumour volume of the primary (GTV-p) and nodal (GTV-n) disease were analysed in relation to LRR, distant relapse and death by way of univariate and multivariate analysis. Results In total, 130 patients were identified, 88 HPV positive, with a median follow-up of 42 months. On multivariate analysis HPV status was a significant predictor of LRR (hazard ratio 0.15; 95% confidence interval 0.05–0.51) and death (hazard ratio 0.29; 95% confidence interval 0.14–0.59) but not distant relapse (hazard ratio 0.53, 95% confidence interval 0.22–1.27). Increasing T-category was associated with a higher risk of LRR (hazard ratio 1.80 for T3/4 versus T1/2; 95% confidence interval 1.08–2.99), death (hazard ratio 1.37, 95% confidence interval 1.06–1.77) and distant relapse (hazard ratio 1.35; 95% confidence interval 1.00–1.83). Increasing GTV-p was associated with increased risk of distant relapse and death. N3 disease and low neck nodes were significant for LRR, distant relapse and death on univariate analysis only. Conclusion Tumour HPV status was the strongest predictor of LRR and death. T-category is more predictive of distant relapse and may provide additional prognostic value for LRR and death when accounting for HPV status.

We describe a rare case of a surgically proven myxoma arising within the masticator space probably from a pterygoid muscle. The lesion showed characteristic hyperintensity on T2-weighted images and did not enhance following gadolinium.