HPV infection in squamous cell carcinomas arising from different mucosal sites of the head and neck region. Is p16 immunohistochemistry a reliable surrogate marker?

BACKGROUND: Human papillomavirus 16 infection has been proven to be associated with oropharyngeal squamous cell carcinomas (SCCs) and is probably the main reason of the reported increase in the incidence. The role of high-risk (HR) HPV for carcinogenesis of other sites in the head and neck awaits confirmation. With the aim to evaluate the prevalence of HPV infection and the reliability of different diagnostic tools in SCCs of different sites, 109 consecutive untreated head and neck SCCs were enrolled, and fresh tumour samples collected. METHODS: Human papillomavirus DNA was detected by Digene Hybrid Capture 2 (HC2). Human papillomavirus E6 and E7 mRNA were detected by NucliSENS EasyQ HPVv1. P16 expression was evaluated by immunohistochemistry. RESULTS: In all, 12.84% of cases were infected by HR genotypes and 1.84% by low-risk genotypes. Human papillomavirus 16 accounted for 87% of HR infections. The overall agreement between DNA and RNA detection is 99.1%. Although p16 expression clearly correlates with HPV infection (P=0.0051), the inter-rater agreement is poor (k=0.27). The oropharynx showed the highest HR HPV infection rate (47.6%) and was also the only site in which p16 immunohistochemistry revealed to be a fair, but not excellent, diagnostic assay (κ=0.61). CONCLUSION: The prognostic role of HR HPV infection in oropharyngeal oncology, with its potential clinical applications, underscores the need for a consensus on the most appropriate detection methods. The present results suggest that viral mRNA detection could be the standard for fresh samples, whereas DNA detection could be routinely used in formalin-fixed, paraffin-embedded samples.

Function Preservation in Head and Neck Cancers.

The treatment of head and neck cancers can have a significant impact on function and appearance, which results in impairment of quality of life. Various long-term sequelae of treatment include speech and swallowing difficulty, oral incompetence, trismus, xerostomia, dental caries and osteoradionecrosis. Management has evolved from single modality treatment of either surgery or radiation to multimodality treatment to attain acceptable functional outcomes. Brachytherapy, also known as interventional radiotherapy, with its ability to deliver high doses centrally to the target, has been shown to improve local control rates. Due to the rapid fall-off of the dose of brachytherapy there is better organ at risk sparing as compared with that of external beam radiotherapy. In the head and neck region, brachytherapy has been practiced in various sites, including the oral cavity, oropharynx, nasopharynx, nasal vestibule and paranasal sinuses. Additionally, brachytherapy has also been considered for reirradiation as a salvage. Brachytherapy can also be considered as a perioperative technique together with surgery. Close multidisciplinary cooperation is required for a successful brachytherapy programme. In oral cavity cancers, depending on the location of the tumour, brachytherapy has been shown to preserve oral competence, maintain tongue mobility, maintain speech, swallowing and the hard palate. Brachytherapy in oropharyngeal cancers has been shown to reduce xerostomia and also reduce dysphagia and aspiration post-radiation therapy. For the nasopharynx, paranasal sinus and nasal vestibule, brachytherapy preserves the respiratory function of the mucosa. Despite such an incomparable impact on function and organ preservation, brachytherapy is an underutilised technique for head and neck cancers. There is a strong need to improve brachytherapy utilisation in head and neck cancers.

Oral cavity defect reconstruction using anterolateral thigh free flaps.

BACKGROUND: It is estimated that about 92,000 new cases of oral cavity and pharyngeal cancer occurred in Europe in 2008. During the past 30 years in the USA and Western Europe, the prognosis for oral cancer has clearly improved thanks to the possibility of reconstruction with microvascular free flaps, resulting in broader and safer resections. The anterolateral thigh flap is now being increasingly employed for this goal. The aim of the present work is to evaluate the anterolateral thigh free flap in the reconstruction of oral cavity defects. MATERIALS AND METHODS: Between July 2004 and February 2009, we harvested 73 free flaps for the reconstruction of soft tissue defects in the oral cavity of 70 patients at our institution. The oncological and functional results in these 70 patients were evaluated, particularly in those patients reconstructed with anterolateral thigh (ALT) free flap. We also evaluated the quality of life using the FACT-H&N questionnaire. RESULTS: We observed no significant differences in functional and oncological results between patients reconstructed by ALT and patients reconstructed with other flaps. Swallowing may be more difficult in patients who undergo adjuvant irradiation. CONCLUSIONS: In our opinion, the very low morbidity at the donor site, great versatility, and very long pedicle make the ALT free flap the first choice for reconstructing soft tissue defects in the oral cavity (particularly mobile tongue).

The role of radiotherapy in Kimura's disease: a multicenter systematic review of literature.

OBJECTIVE: From a clinical point of view, Kimura's disease is typically characterized by a subcutaneous mass occurring predominantly in the head and neck region. It occurs predominantly in young men of Asian descent, with a peak incidence in the second and third decades of life. However, KD has been also reported in other ethnic groups and in children. The most frequently used local treatments are surgical excision, radiotherapy, and surgical excision followed by radiotherapy. The aim of this multicenter systematic review is to highlight the available literature evidence about the outcome of RT in this setting. MATERIALS AND METHODS: A systematic review of any relevant literature in the principal medical databases, such as PubMed, Scopus and Cochrane library, was conducted. The inclusion criteria were original articles specifically reporting about KD and RT, including both prospective and retrospective studies. RESULTS: We were able to identify 11 studies, published from 1989 to 2021, eligible for inclusion in this review. Overall, data on 124 patients were recorded and are presented in this systematic review. The median recurrence rate, considering all patients, was 11% (ranging from 0% to 41.2%). In seven out of 11 studies, the relapse rate was less than 20%. Moreover, the relapse rate was 0% in four studies. CONCLUSIONS: The results of this multicenter systematic literature review show that evidence on RT of KD is limited and derives only from retrospective studies. In this setting RT seems to be well-tolerated and able to produce very high response rates in unresected lesions and reasonable results in terms of local control both as an exclusive and adjuvant treatment.

Correlation between musical aptitude and learning foreign languages: an epidemiological study in secondary school Italian students.

SUMMARY: The aim of this study was to assess if a correlation exists between language learning skills and musical aptitude through the analysis of scholarly outcomes concerning the study of foreign languages and music. We enrolled 502 students from a secondary Italian school (10-14 years old), attending both traditional courses (2 hours/week of music classes scheduled) and special courses (six hours). For statistical analysis, we considered grades in English, French and Music. Our results showed a significant correlation between grades in the two foreign languages and in music, both in the traditional courses and in special courses, and better results in French than for special courses. These results are discussed and interpreted through the literature about neuroanatomical and physiological mechanisms of foreign language learning and music perception.

IFN-γ and other serum cytokines in head and neck squamous cell carcinomas.

SUMMARY: Altered immune responses have been reported in head and neck cancer, and some of these responses have been associated with poor clinical outcomes. A multiple-array technology platform was used to simultaneously evaluate the levels of 25 cytokines. Pre-treatment serum levels were evaluated in 31 HNSCC patients and 6 healthy controls. The levels of 8 cytokines, specifically IL-1ra, IL-2, IL-5, IL-6, IL-8, IL-17, IFN-γ and IP-10, were significantly higher in patients than in controls. Among cancer patients we observed lower levels of IFN-γ and IL-7 in cases with nodal metastases compared to those with cN0 disease. We observed increases in the levels of some serum cytokines in HNSCC patients, as well as reductions in selected cytokines associated with regional progression. These findings provide an intriguing perspective on the development and validation of novel markers for follow-up evaluations and predictions of regional spreading in HNSCC patients.

Modelling tumour volume variations in head and neck cancer: contribution of magnetic resonance imaging for patients undergoing induction chemotherapy.

Primary tumour volume evaluation has predictive value for estimating survival outcomes. Using volumetric data acquired by MRI in patients undergoing induction chemotherapy (IC) these outcomes were estimated before the radiotherapy course in head and neck cancer (HNC) patients. MRI performed before and after IC in 36 locally advanced HNC patients were analysed to measure primary tumour volume. The two volumes were correlated using the linear-log ratio (LLR) between the volume in the first MRI and the volume in the second. Cox's proportional hazards models (CPHM) were defined for loco-regional control (LRC), disease-free survival (DFS) and overall survival (OS). Strict evaluation of the influence of volume delineation uncertainties on prediction of final outcomes has been defined. LLR showed good predictive value for all survival outcomes in CPHM. Predictive models for LRC and DFS at 24 months showed optimal discrimination and prediction capability. Evaluation of primary tumour volume variations in HNC after IC provides an example of modelling that can be easily used even for other adaptive treatment approaches. A complete assessment of uncertainties in covariates required for running models is a prerequisite to create reliable clinically models.

Predictive factors of neck metastases in laryngeal squamous cell carcinoma. Towards an integrated clinico-molecular classification.

Our group has 25 years' experience in the use of molecular predictive markers in head and neck cancer, on a large patient population, enrolled from a single institution, with a long follow-up, and, most of all, homogeneous regarding histology (squamous cell carcinoma) and site (larynx). Among the most frequent malignancies in the US, cancers of the larynx and uterine corpus are the only types not showing an increase in 5-year Survival Rates over the last 30 years. As far as concerns laryngeal squamous cell carcinoma, we can identify several potential reasons for this failure, the most relevant probably lies in the neck. For this reason, a key issue in laryngeal oncology is to assess metastatic potential of squamous cell carcinoma at diagnosis. Nevertheless, the combination of clinical and histological parameters is not sufficiently reliable in the prediction of lymph node metastases. Molecular characterization, by the study of molecular predictive factors, is a clinical approach aimed to define homogeneous subgroups for clinical metastatic behaviour. Defining invasiveness by means of studies on selected molecular markers (among which the most reliable is probably Epidermal Growth Factor Receptor (EGFR)) may be useful in the choice of the most appropriate treatment on both T and on N.

Salvage total laryngectomy after conservation laryngeal surgery for recurrent laryngeal squamous cell carcinoma.

The aim of the present study was to evaluate the oncological efficacy of salvage total laryngectomy in patients who had previously undergone supracricoid partial laryngectomy or transoral laser microsurgery for treatment of laryngeal squamous cell carcinoma. We retrospectively reviewed the medical, surgical and pathological records of 35 patients who underwent salvage total laryngectomy after recurrence of laryngeal cancer (following supracricoid partial laryngectomy or transoral laser microsurgery). Kaplan-Meier survival curves as well as univariate and multivariate analyses of prognostic factors were performed. No statistically significant differences were seen comparing the supracricoid partial laryngectomy group with the transoral laser microsurgery group for overall survival and disease-specific survival at 3 years (OS = 38% vs. 52%, p = 0.16; DSS = 40% vs. 61%, p = 0.057) or locoregional control at 2 years (LRC = 40% vs. 54%, p = 0.056). A trend indicating worse survival and locoregional control for supracricoid partial laryngectomy patients emerged. Preservation of the osteocartilaginous frame in transoral laser microsurgery could hypothetically result in better salvageability of anterior recurrences with extralaryngeal spread.

Human papillomavirus infection and epidermal growth factor receptor expression in primary laryngeal squamous cell carcinoma.

PURPOSE: This study was designed to add new data about laryngeal carcinogenesis, a multistep process in which chemical and/or viral agents induce and promote successive alterations in growth factor-linked signal transmission pathways, genetic instability, and mutations in key genes involved in cell growth control. Epidemiological evidence suggests that human papillomavirus (HPV) infection may be associated with the development of laryngeal cancer. EXPERIMENTAL DESIGN: In this report, we have analyzed the prevalence of HPV infection and epidermal growth factor receptor (EGFR) expression in a series of 42 laryngeal squamous cell carcinomas by PCR with HPV consensus primers and by a radioligand receptor assay, respectively. RESULTS: HPV DNA was detected in 15 of 42 (35.7%) tumors, and it belonged almost exclusively to the highly oncogenic HPV-16, HPV-18, and HPV-33 genotypes. At analysis by Mann-Whitney nonparametric statistical test, EGFR level was found to be significantly higher in HPV-infected than in HPV-negative cases (T = 440; P = 0.002). EGFR overexpression (EGFR-positive status >6 fmol/mg protein, the arbitrary cutoff value chosen) was found in 20 of 42 (47.6%) tumors, and it was associated with HPV infection in a statistically significant extent (chi(2) = 4.686; P = 0.03). CONCLUSIONS: Viral oncoproteins have been shown to induce a perturbation of the cell response to signals for growth and differentiation; these findings confirm that enhanced EGFR expression and activation in laryngeal squamous cell carcinoma may occur also as a consequence of HPV infection and support the hypothesis of an involvement of HPV infection in laryngeal carcinogenesis.

Impact of microvascular free flap reconstruction in oral cavity cancer: our experience in 130 cases.

The aim of this study was to investigate the oncological outcomes in patients affected by oral carcinoma treated with radical compartmental surgery followed by microvascular flap reconstruction. We conducted a retrospective analysis on a cohort of 130 patients. All patients underwent ablative tumour resection (compartmental surgery) followed by immediate reconstruction with free flaps and adjuvant chemoradiotherapy, when necessary according to our tumour board and international guidelines. Disease-specific survival (DSS) curves were obtained using the Kaplan-Meier method. Log-rank test and generalised Wilcoxon test were used to investigate the most important prognostic factors on 5-year DSS. A Cox proportional hazards model was constructed to provide hazard ratios or relative risks for individual variables. 88.5% of patients were affected by SCC. There were 46 (35.4%) women and 84 (64.6%) men in the sample with a mean age of 58.5 years. At the end of the follow-up period, 36 (27.7%) patients died, only 3 of which for other causes. The 5-year DSS rate was 67.8% (S.E. 4.9%). In univariate Kaplan-Meier analysis and in multivariate Cox regression model, seven variables were found to have a significant relationship with DSS: T (p = 0.026) and N (p = 0.0001) status, clinical stage (according to the UICC TNM Sixth Edition) (p = 0.007), margins of resection (p = 0.001), extracapsular spread (p = 0.005), recurrence of disease (p = 0.00002) and treatment modality (evaluated as surgery alone or surgery + RT/CHT) (p = 0.004). Our results confirmed findings already reported in the literature, and allowed us to conclude that compartmental surgery combined with free flap reconstruction can increase survival in oral cancer patients.

Contemporary role of pectoralis major regional flaps in head and neck surgery.

Countless disadvantages of the "old" pectoralis major have been listed while the amazing versatility of the free flap armamentarium gives the opportunity to suit the defect deriving from virtually every ablative head and neck surgery with a tailored reconstruction. Nevertheless, pectoralis major is still the "workhorse" for head and neck reconstruction in developing countries thanks to its ease of harvest, and minimal requirements in term of instrumentation. Furthermore, even in facilities with a high volume of reconstructions by free flaps, a certain number of pectoralis major flaps is still raised every year. The history, present role and current indications of the most widely head and neck reconstructive procedure ever has been reviewed.

Effects of the administration of epidermal growth factor receptor specific inhibitor cetuximab, alone and in combination with cisplatin, on proliferation and apoptosis of Hep-2 laryngeal cancer cells.

BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression and prognostic value in head and neck squamous cell cancer is the basis for targeting by anti-EGFR antibodies, which increase the efficacy of radiotherapy. In order to evaluate the best therapeutic schedule, the effects of cetuximab (C225) on Hep-2 cell proliferation, alone and in combination with cisplatin, were studied. METHODS: Hep-2 cells were treated with cetuximab alone or in combination with cisplatin. After determining cell viability with trypan blue, morphological features of apoptotic degeneration were analysed by fluorescence microscopy with Hoechst 33258 stain. RESULTS: Cetuximab alone mildly inhibited Hep-2 proliferation and showed no pro-apoptotic effects. When administered concomitantly with cisplatin, cetuximab synergistically increased inhibition of proliferation and apoptosis. CONCLUSION: The antiproliferative activity of cetuximab is consistent with its hypothesised role in inhibiting repopulation. However, the increase in the effects of pro-apoptotic agents induced by cetuximab may be even more relevant to its clinical effectiveness than the inhibition of repopulation.

Role of (18)F-FDG PET-CT in head and neck squamous cell carcinoma.

The role of PET-CT imaging in head and neck squamous cell carcinoma during pre-treatment staging, radiotherapy planning, treatment response assessment and post-therapy follow-up is reviewed with focus on current evidence, controversial issues and future clinical applications. In staging, the role of (18)F-FDG PET-CT is well recognized for detecting cervical nodal involvement as well as for exclusion of distant metastases and synchronous primary tumours. In the evaluation of treatment response, the high negative predictive value of (18)F-FDG PET-CT performed at least 8 weeks from the end of radio-chemotherapy allows prevention of unnecessary diagnostic invasive procedures and neck dissection in many patients, with a significant impact on clinical outcome. On the other hand, in this setting, the low positive predictive value due to possible post-radiation inflammation findings requires special care before making a clinical decision. Controversial data are currently available on the role of PET imaging during the course of radio-chemotherapy. The prognostic role of (18)F-FDG PET-CT imaging in head and neck squamous cell carcinoma is recently emerging, in addition to the utility of this technique in evaluation of the tumour volume for planning radiation therapy. Additionally, new PET radiopharmaceuticals could provide considerable information on specific tumour characteristics, thus overcoming the limitations of (18)F-FDG.

New insights into human papillomavirus-associated head and neck squamous cell carcinoma.

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is an entity with peculiar clinical and molecular characteristics, which mainly arises from the reticulated epithelium lining the crypts of the palatine tonsils and the base of the tongue. The only head and neck site with a definite etiological association between persistent high-risk (HR) HPV infection and development of SCC is the oropharynx. HPV-positive malignancies represent 5-20% of all HNSCCs and 40-90% of those arising from the oropharynx, with widely variable rates depending on the geographic area, population, relative prevalence of environment-related SCC and detection assay. HPV-16 is by far the most common HR HPV genotype detected in oropharyngeal SCC (OPSCC), and the only definitely carcinogenic genotype for the head and neck region. Patients with HPV-induced OPSCC are more likely to be middle-aged white men, non-smokers, non-drinkers or mild to moderate drinkers, with higher socioeconomic status and better performance status than subjects with HPV-unrelated SCC. HPV-induced HNSCCs are often described as non-keratinizing, poorly differentiated or basaloid carcinomas, and are diagnosed in earlier T-category with a trend for a more advanced N-category, with cystic degeneration, than the HPV-unrelated carcinomas. HPV positivity is associated with better response to treatment and modality-independent survival benefit. Treatment selection in HPV-related oropharyngeal carcinoma is becoming a critical issue, and although there is no evidence from randomized, controlled trials to support a treatment de-escalation in HPV-positive SCC, some investigators argue that intensive combined modality strategies may represent an overtreatment.

A comprehensive approach to long-standing facial paralysis based on lengthening temporalis myoplasty.

Long-standing peripheral monolateral facial paralysis in the adult has challenged otolaryngologists, neurologists and plastic surgeons for centuries. Notwithstanding, the ultimate goal of normality of the paralyzed hemi-face with symmetry at rest, and the achievement of a spontaneous symmetrical smile with corneal protection, has not been fully reached. At the beginning of the 20(th) century, the main options were neural reconstructions including accessory to facial nerve transfer and hypoglossal to facial nerve crossover. In the first half of the 20(th) century, various techniques for static correction with autologous temporalis muscle and fascia grafts were proposed as the techniques of Gillies (1934) and McLaughlin (1949). Cross-facial nerve grafts have been performed since the beginning of the 1970s often with the attempt to transplant free-muscle to restore active movements. However, these transplants were non-vascularized, and further evaluations revealed central fibrosis and minimal return of function. A major step was taken in the second half of the 1970s, with the introduction of microneurovascular muscle transfer in facial reanimation, which, often combined in two steps with a cross-facial nerve graft, has become the most popular option for the comprehensive treatment of long-standing facial paralysis. In the second half of the 1990s in France, a regional muscle transfer technique with the definite advantages of being one-step, technically easier and relatively fast, namely lengthening temporalis myoplasty, acquired popularity and consensus among surgeons treating facial paralysis. A total of 111 patients with facial paralysis were treated in Caen between 1997 and 2005 by a single surgeon who developed 2 variants of the technique (V1, V2), each with its advantages and disadvantages, but both based on the same anatomo-functional background and aim, which is transfer of the temporalis muscle tendon on the coronoid process to the lips. For a comprehensive treatment of the paralysis, the eyelids are usually managed by Paul Tessier's technique to lengthen the levator muscle of the upper eyelid by aponeurosis interposition, combined with external blepharorrhaphy with Krastinova-Lolov's technique. Facial reanimation using lengthening temporalis myoplasty is a dynamic procedure that has its roots in the techniques of Gillies and McLaughlin. This method is a true lengthening myoplasty procedure using no intermediate grafts. In general, the results with a 1-stage combination of lengthening temporalis myoplasty and static correction of the lagophthalmos appear comparable with the major series in the literature using free microneurovascular transfers combined with cross-facial nerve grafts for longstanding peripheral monolateral facial paralysis. The obvious advantages of temporalis elongation myoplasty consist in its technical ease, a single step, low incidence of complications and markedly reduced operating time.

Synovial sarcoma of the parotid gland: a case report and review of the literature.

Parotid gland tumours are very heterogeneous, being benign in 80% of cases, and generally arising from epithelial cells. Nevertheless, a small group of non-epithelial tumours representing just 5% of all salivary gland neoplasms has also been reported, the most common of these being haemangioma, especially in children. However, lymphomas, neuromas, neurofibromas, lipomas and sarcomas can also be found. Synovial cell sarcoma is a high grade histological variety of sarcoma and is generally located near large joints and bursae of the lower extremities, such as knee, tendon sheaths and bursal structures. It is rarely found in the head and neck region due to its lack of synovioblastic tissue. Herewith, the case of a young female, affected by a synovial sarcoma of the left parotid gland, is presented and a review is made of the literature on this rare specific localization focusing on management and outcome.