Salvage carbon dioxide transoral laser microsurgery for laryngeal cancer after (chemo)radiotherapy: a European Laryngological Society consensus statement.

PURPOSE: To provide expert opinion and consensus on salvage carbon dioxide transoral laser microsurgery (CO2 TOLMS) for recurrent laryngeal squamous cell carcinoma (LSCC) after (chemo)radiotherapy [(C)RT]. METHODS: Expert members of the European Laryngological Society (ELS) Cancer and Dysplasia Committee were selected to create a dedicated panel on salvage CO2 TOLMS for LSCC. A series of statements regarding the critical aspects of decision-making were drafted, circulated, and modified or excluded in accordance with the Delphi process. RESULTS: The expert panel reached full consensus on 19 statements through a total of three sequential evaluation rounds. These statements were focused on different aspects of salvage CO2 TOLMS, with particular attention on preoperative diagnostic work-up, treatment indications, postoperative management, complications, functional outcomes, and follow-up. CONCLUSION: Management of recurrent LSCC after (C)RT is challenging and is based on the need to find a balance between oncologic and functional outcomes. Salvage CO2 TOLMS is a minimally invasive approach that can be applied to selected patients with strict and careful indications. Herein, a series of statements based on an ELS expert consensus aimed at guiding the main aspects of CO2 TOLMS for LSCC in the salvage setting is presented.

Long-term intubation and high rate of tracheostomy in COVID-19 patients might determine an unprecedented increase of airway stenoses: a call to action from the European Laryngological Society.

INTRODUCTION: The novel Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, may need intensive care unit (ICU) admission in up to 12% of all positive cases for massive interstitial pneumonia, with possible long-term endotracheal intubation for mechanical ventilation and subsequent tracheostomy. The most common airway-related complications of such ICU maneuvers are laryngotracheal granulomas, webs, stenosis, malacia and, less commonly, tracheal necrosis with tracheo-esophageal or tracheo-arterial fistulae. MATERIALS AND METHODS: This paper gathers the opinions of experts of the Laryngotracheal Stenosis Committee of the European Laryngological Society, with the aim of alerting the medical community about the possible rise in number of COVID-19-related laryngotracheal stenosis (LTS), and the aspiration of paving the way to a more rationale concentration of these cases within referral specialist airway centers. RESULTS: A range of prevention strategies, diagnostic work-up, and therapeutic approaches are reported and framed within the COVID-19 pandemic context. CONCLUSIONS: One of the most important roles of otolaryngologists when encountering airway-related signs and symptoms in patients with previous ICU hospitalization for COVID-19 is to maintain a high level of suspicion for LTS development, and share it with colleagues and other health care professionals. Such a condition requires specific expertise and should be comprehensively managed in tertiary referral centers.

Future Perspectives in Hypopharyngeal Cancer Care.

Recent advances in minimal access surgery have shown promise in the treatment of limited hypopharyngeal lesions. In spite of their functionally excellent results in individual patients, it currently remains unlikely that these approaches will gain a more major universal impact on hypopharyngeal cancer care. In advanced stage hypopharyngeal cancer, the use of the traditional radical surgery, such as laryngo-pharyngectomy, is no longer accepted by many patients. In recent years, most would rather opt for less mutilating treatment, preferring a non-surgical option. Patients, families and medical practitioners frequently ignore or misunderstand the associated mortality and morbidity consequence of such an approach. Although synergy between chemotherapy and radiotherapy enhances the efficacy of the treatment, chemo-radiation as currently used achieves a tumour response in < 80%, with relapses of the tumour during the follow-up period, indicating that surgery is the only effective treatment option as salvage. Advances in molecular research have improved our understanding of oncogenesis, tumour spread and the mechanisms of metastases. Innovative strategies have become available that manipulating tumours or the host to favour conditions receptive for disease eradication. These advances have gone through pre-clinical testing and are currently being used in early clinical trials using approaches such as replacement of defective genes, suicide gene therapy, and immunologic gene therapy. Precision oncology may eventually be able to predict which patients are more likely to respond to specific cancer therapies based on increasingly accurate, high-resolution biomarkers based on molecular diagnostics of individual tumours. Currently concentrating cancer treatment at specialised head and neck cancer institutions is likely to contribute faster and more sustained results at improving patient outcomes for hypopharyngeal cancer care than any individual innovation in surgery, radiation oncology or systemic treatment. Preventative work should continue by governments with the elimination of the preventable risk factors (abusive use of alcohol, tobacco and betel nut chewing) may reduce the incidence of the disease.

Natural History of Treated and Untreated Hypopharyngeal Cancer.

Patients with hypopharyngeal cancers frequently present at advanced stage and in poor general health status. Their natural history is characterised by diffuse local primary disease, mucosal and submucosal spread, early cervical nodal metastasis, and a relatively high rate of distant spread. By the time of initial diagnosis, some 60% of all hypopharyngeal cancer patients will be with stage IV disease, some 5% will present with distant metastases, and almost 40% will have a significant reduction in performance status. Less than 20% are diagnosed with a localised early stage disease. A long-standing social habit of excess of alcohol and tobacco usage leads to cancerisation and accounts for the multiple, synchronous primary malignant lesions that occur in many hypopharyngeal cancer patients. The natural history of untreated head and neck squamous cell carcinoma has infrequently been documented in the medical literature. However, without understanding the natural history of hypopharyngeal cancer, patient counselling and clinical management are difficult. Less than 20% of untreated patients survive for > 12 months and only a small proportion of patients will survive for more than 2 years after initial diagnosis. The natural course of the disease in patients treated for cure or, at least, for the relief of symptoms, is certainly more favourable than that of those who are not suited for, or not willing to accept the adverse effects of treatment. However, treatment results are still considerably less encouraging than those that are being reported for other sub-sites of the head and neck region. Among all head and neck cancer sites, 5-year age-standardised relative survival is currently the poorest for cancer of the hypopharynx and the highest for larynx cancers, 25 and 59%, respectively. Among the head and neck cancers, only hypopharynx showed a low outcome (25% at 5 years), with survival figures ranging between ≤30 (North Ireland and Italy) and 8% (Bulgaria). Recent studies from the United States indicate that overall 5-year survival rates for hypopharyngeal cancer have improved significantly in recent years, with the average survival being ≥40%.

Systemic Therapy, Palliation and Supportive Care of Patients with Hypopharyngeal Cancer.

Hypopharyngeal cancer patients have a very poor prognosis and limited therapeutic options. Seventy to eighty per cent of all hypopharyngeal cancer patients will require palliative and/or end-of-life care for incurable end-stage disease during the course of their illness. The overall proportion of hypopharyngeal cancer patients not qualifying for initial curative treatment, or requiring palliation and supportive care over time is higher than for any other subsite of the head and neck. Surgery and radiotherapy usually have a very limited role in this setting, while systemic therapy will usually compete with supportive care as the best approach. Advances in medicine and oncological treatments for the management of patients with recurrent head and neck cancer have given physicians the opportunity to prolong life where possible. However, this increase in survival might not be clinically meaningful if patients do not simultaneously experience palliative benefits, such as a reduction in symptoms and an improvement in their overall quality of life (QoL). The optimal outcome of palliative treatment is the control of symptoms with minimal treatment toxicities while improving QoL. It remains unclear if current palliative treatment options are better at improving QoL than the best supportive care. An intervention that results in insufficient or unacceptable functional status to the extent that the patient cannot achieve treatment goals - even in the course of prolonging life - is questionable. When used for palliative care purposes, surgery, chemotherapy and radiotherapy commonly have limited effectiveness in improving QoL. Moreover, if these treatments are not congruent with a patient's end-of-life goals, they could constitute low-value care.

Treatment Options for Hypopharyngeal Cancer.

Patients with hypopharyngeal cancer are difficult to treat because they typically present with advanced disease, poor general health status and severe nutritional problems. Currently, treatment options for previously untreated and newly diagnosed hypopharyngeal cancer patients include surgery of the primary tumour and lymph nodes metastasis, radiotherapy, systemic medical treatment, including traditional chemotherapy and immunotherapy. Currently, a multimodal treatment approach is preferred using surgery, radiotherapy and systemic therapy with curative intent and best supportive care in patients considered unfit for curative treatment or patients presenting with distant metastatic spread. More detailed topics regarding the choice of treatment include biological and immunological host factors and their use for defining individualised cancer care, integration of novel therapies, integration of patient autonomy into clinical reasoning and dealing with patients' trade-offs between oncological outcome and individual quality of life, local availability of diagnostic therapeutic procedures and volume-outcome relationships for head and neck cancer surgery, radiotherapy and specialised supportive care. They also include considerations regarding potential delay between diagnosis and treatment, and between different treatment modalities within the frame of multimodal therapy. To date only one randomised trial comparing surgical versus non-surgical approaches has been published. Most randomised trials dealing with hypopharyngeal cancer compare different chemo- and radiotherapy regimen, but do not compare with a surgical approach. On the other hand, most studies on the results of surgery are best considered to be of low-quality case series. At the same time, many of the chemotherapy and radiation oncology studies in head and neck cancer include patients with different primary sites, where hypopharyngeal cancer patients when included usually account for a minority of the study population. Therefore, choosing the best treatment for an individual patient with hypopharyngeal cancer relies on personal experience and local expertise of the multidisciplinary team involved in the therapeutic process.

Effect of postoperative radiotherapy in pT1pN1cM0 and pT2p/cN0cM0 oropharyngeal squamous cell carcinoma.

OBJECTIVES/HYPOTHESIS: Consulting of patients with oropharyngeal carcinoma, classified as pT1pN1cM0 and pT2p/cN0cM0, about postoperative radiotherapy is a precarious task as data are lacking. The aim of this study was to evaluate the effects of postoperative radiotherapy for patients with intermediate-stage oropharyngeal carcinoma. STUDY DESIGN: Multicentric retrospective study. METHODS: This analysis was conducted at seven Austrian institutions and included data of patients treated between 2000 and 2012. A total of 81 patients with oropharyngeal squamous cell carcinoma were included, of whom 33 patients received postoperative radiotherapy. p16 status determined by immunohistochemistry was available in 68 patients. RESULTS: Median follow-up was 47.9 months. Postoperative radiotherapy showed no benefits in regard to overall survival (P = .701). In contrast, disease-free survival was significantly shortened in all patients without postoperative radiotherapy (P = .001). When dividing the cohort in dependence of p16, p16-positive patients did not benefit from postoperative radiotherapy regarding overall and disease-free survival (P = .934 and P = .102), whereas p16-negative patients showed improved disease-free survival after postoperative radiotherapy (P = .007). Multivariate analysis showed that outcome of postoperative radiotherapy is dependent on p16 status. CONCLUSIONS: In terms of disease-free survival, patients with p16-negative tumors may benefit from postoperative radiotherapy, whereas survival of p16-positive patients is good regardless of additional treatment. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1075-1082, 2018.

Nomenclature proposal to describe vocal fold motion impairment.

The terms used to describe vocal fold motion impairment are confusing and not standardized. This results in a failure to communicate accurately and to major limitations of interpreting research studies involving vocal fold impairment. We propose standard nomenclature for reporting vocal fold impairment. Overarching terms of vocal fold immobility and hypomobility are rigorously defined. This includes assessment techniques and inclusion and exclusion criteria for determining vocal fold immobility and hypomobility. In addition, criteria for use of the following terms have been outlined in detail: vocal fold paralysis, vocal fold paresis, vocal fold immobility/hypomobility associated with mechanical impairment of the crico-arytenoid joint and vocal fold immobility/hypomobility related to laryngeal malignant disease. This represents the first rigorously defined vocal fold motion impairment nomenclature system. This provides detailed definitions to the terms vocal fold paralysis and vocal fold paresis.

[Surgical treatment options in laryngeal and hypopharyngeal cancer]. / Indikationen zur chirurgischen Therapie von Larynx- und Hypopharynxkarzinomen.

In Austria, around ten new cases of laryngeal cancer can currently be expected per 100.000 persons each year whereas three out of 100.000 men develope hypopharyngeal cancer. Among women, the incidence in both types of carcinoma is lower by a factor of around 5. All in all, the rate of new cases seems to have been constant or to have slightly decreased in the last few years. Approximately 70% of all laryngeal cancer are glottic cancer, that is to say originating from the vocal cords. About 30% are supraglottic tumours, true subglottic cancers are very rare. The majority of hypopharyngeal tumours originate from the piriform sinuses. Vocal cord tumours lead to a typical symptom that can be early detected: hoarseness. Thus, voice problems in adults that persist for several weeks should therefore always checked by laryngoscopy. This leads to there being a real possibility of early diagnosis of laryngeal cancer, which means that today, approximately 60% of all laryngeal tumours can be diagnosed in stage I or II according to UICC or as intraepithelial lesions (former carcinoma in situ). In glottic cancer about 75% are diagnosed in these early stages, whereas in supraglottic tumours the rate is only about 30% and in hypopharyngeal cancer it is less then 15%. Surgery, radiation therapy, chemo- or immunotherapy are the principal types of oncological treatments currently available. The following conditions generally need to be met for curative surgical treatment options: Local tumour, no systemic metastasis Tumour has to be resectable in healthy margins mortality/morbidity Surgery must not lead to unreasonable mutilation Lack of other therapeutic alternatives having an equal or lesser impact In the following pages, indications for the surgical treatment of laryngeal and hypopharyngeal cancer will be discussed and the results of surgical therapy will be summarised briefly.

Human papillomavirus-positive tonsillar carcinomas: a different tumor entity?

Human papillomavirus (HPV) infections are thought to be one of the causal factors in the development of head and neck squamous cell carcinomas (HNSCC), particularly in tumors arising from the Waldeyer's tonsillar ring. We screened 98 carefully stratified HNSCC and different control tissues for the presence of HPV DNA by nested polymerase chain reaction (PCR) specific for genital- and Epidermodysplasia verruciformis (EV)-associated HPVs and by HPV16-specific single step PCR. Typing was performed by direct sequencing and/or sequencing of cloned amplimers. On average HNSCC showed rather low HPV DNA prevalences; 18% of the oral cavity cancers, 8% of nasopharyngeal cancers, 25% of hypopharyngeal cancers and 7% of laryngeal cancers were HPV DNA positive. In contrast, HPV sequences could be detected in 45% of the oropharyngeal cancers, particularly tonsillar carcinomas (58%). Tonsillar carcinomas were significantly more likely to be HPV positive than tumors from any other site ( P<0.001). All tonsillar cancers contained oncogenic HPV types, predominantly HPV16 (13 of 14; 93%). Unaffected tonsils were available from two of these patients, but both tested negative for HPV DNA. Furthermore, no HPV DNA could be found in tonsillar biopsy specimens from control groups. Localization and load of HPV DNA was determined in HPV16-positive tonsillar carcinomas, their metastases and in unaffected mucosa using laser-assisted microdissection and subsequent real time fluorescence PCR. We demonstrated that the HPV genome is located in the cancer cells, whereas the infection of normal mucosa is a rare event. Quantification of HPV16 DNA in samples of seven patients yielded viral loads from 6 to 153 HPV DNA copies per beta-globin gene copy and the load values in both locations were roughly comparable. These loads are comparable with data shown for other HPV-associated lesions. Statistical evaluation of data related to clinicopathological parameters showed a significant correlation of the HPV positivity of tonsillar carcinomas with tumor grading ( P=0.008) and alcohol consumption ( P=0.029). Taken together our findings show a preferential association of HPV DNA with tonsillar carcinomas. Furthermore our results argue for HPV-positive tonsillar carcinomas representing a separate tumor entity, which is less dependent on conventional HNSCC risk factors.

Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus.

Recent analyses of head and neck squamous cell carcinomas revealed frequent infections by oncogenic human papillomavirus (HPV) type 16 in tonsillar carcinomas. Concerning involvement of risk factors, clinical course of the disease, and prognosis there are strong indications arguing that the HPV-positive tonsillar carcinomas may represent a separate tumor entity. Looking for a surrogate marker, which in further epidemiological studies could replace the laborious and expensive HPV detection and typing we analyzed p16 protein expression in 34 tonsillar carcinoma for correlation to HPV status and load of viral DNA. p16 has been shown to be of diagnostic value for clinical evaluation of cervical dysplasia. We found 53% of the tested tonsillar carcinomas to be HPV-positive. Fifty-six percent of all tumors tested were immunohistochemically positive for the p16 protein. In 16 of 18 of the HPV-positive carcinomas diffuse p16 expression was observed. In contrast, only one of the HPV-negative carcinomas showed focal p16 staining (P < 0.001). As determined by laser-assisted microdissection and quantitative real-time polymerase chain reaction, p16 expression correlated with the presence of HPV-DNA in the individual tumor specimens. Clinical outcome analysis revealed significant correlation of p16 expression with increased disease-free survival (P = 0.02). These data indicate that p16 is a technically simple immunohistological marker, applicable for routine pathological histology, and its prognostic value for survival is fully equivalent to HPV-DNA detection.

Olfactory changes at threshold and suprathreshold levels following septoplasty with partial inferior turbinectomy.

Partial inferior turbinectomy with septoplasty is routinely carried out for airway obstruction. However, its effects on the sense of smell have not been systematically evaluated. The aim of this prospective study was to evaluate the influence of septoplasty with partial inferior turbinectomy on threshold and suprathreshold olfactory acuity. The subjects were 30 patients undergoing septoplasty including partial inferior turbinectomy. Olfactory function was determined by the "Sniffin' Sticks," which allow the assessment of odor thresholds, odor discrimination, and odor identification. The patients rated both olfactory function and nasal airflow using visual analog scales. Nasal airflow was measured by anterior rhinomanometry. Multivariate analyses of variance for repeated measures were used to analyze the results before and after surgery (mean interval, 9.1 weeks). After operation, 87% of the patients had increased airflow, 80% had improved olfactory function in terms of odor identification, and in 70% odor discrimination was found to be improved - but only 54% had improved olfactory function in terms of odor thresholds. Surgery increased ratings of nasal airflow in 93%, and those of olfactory function in 77% (p < .001). Similarly, bilateral inspiratory nasal flow increased (p < .001) and olfactory function was improved (p < .001) after surgical treatment. However, this increase was most pronounced for suprathreshold tests, while it was moderate for odor thresholds (interaction "surgery" x "olfactory test," p = .001). The present investigation suggests that septoplasty in combination with inferior turbinectomy has a beneficial effect on olfaction, mainly on suprathreshold olfactory functions. This effect may be partly due to interactions between the increased perception of nasal airflow and cognitive factors involved in olfactory sensitivity. According to the present results and data from the literature, a moderate decrease of olfactory function appears to occur in as many as 20% of patients. However, anosmia seems to be an extremely rare complication of septoplasty and partial turbinectomy.

Intranasal volume and olfactory function.

The aim of this exploratory study was to identify the volume intranasal segments as they relate to parameters of olfactory function. Fifty healthy male volunteers (age range 22-59 years, mean age 28.5 years) were included. Olfactory function was measured by lateralized phenyl ethyl alcohol odor thresholds and odor discrimination, and by bilateral odor identification. Magnetic resonance imaging of the nasal cavity was performed immediately following olfactometry. To correlate the results of olfactometry with intranasal volume, each nasal cavity was divided into 11 segments. Significant correlations were found between the odor thresholds and volumes of the anterior part of the lower and upper meatus of the right nasal cavity. These results reveal that two nasal segments are important for inter-individual differences of odor thresholds in healthy subjects: (i) the segment in the upper meatus below the cribriform plate and (ii) the anterior segment of the inferior meatus. The latter finding is of special interest for nasal surgery, which allows modification of this volume through resection of the inferior turbinate and/or septoplasty.