Search

Purpose of review To summarize the most recent nuances in diagnosis, management, and prognostic stratification of carcinoma of unknown primary of the head and neck (CUPHN), in light of its recent re-assessment in the eighth edition of the TNM Classification Manual. Recent findings At least in Western Countries, most CUPHN are expected to be Human Papilloma Virus (HPV)-positive with an oropharyngeal origin. Their appropriate diagnosis starts with fine needle aspiration cytology and/or core biopsy of pathologic lymph node(s) with staining for p16 by immunohistochemistry and subsequent HPV detection by PCR. If these exams are negative (especially in Eastern Countries), in-situ hybridization for Epstein-Barr virus detection should be added. Thorough clinical examination should encompass white light videoendoscopy with the adjunction of bioendoscopic techniques (such as narrow band imaging). Radiologic workup (by CT, MR and/or PET) should be limited to cases that are persistently negative after comprehensive endoscopic evaluation. Invasive diagnostic procedures, such as unilateral or bilateral palatine tonsillectomy and base of tongue mucosectomy, may play a staging as well as a therapeutic role in CUPHN management. Summary Every effort should be made to identify and remove the primary site of a CUPHN: in doing so, possible subsequent de-intensification protocols by irradiation of the neck alone (with or without previous neck dissection according to the cN category, patient's risk profile, and general status) can be taken into consideration on a case-by-case basis.

Simple Summary CD8+ T lymphocytes are among the immune cells reputed to kill tumor cells. Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of infiltrating CD8+ T cells in a cohort of 30 HNSCC patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, we identified an intratumoral CD8+CD28- T cell subpopulation, which expressed markers of both exhausted (i.e., with impaired effector functions) and regulatory (i.e., exerting suppressive activities) cells. This suggests that in HNSCC effector T cells progressively undergo exhaustion and acquisition of regulatory properties, hampering their anti-tumor functions. Abstract Head and neck squamous cell carcinoma (HNSCC) has a poor clinical outcome despite the presence of a rich CD8+ T cell tumor infiltrate in the majority of patients. This may be due to alterations of tumor infiltrating CD8+ T cells. Here, we performed a characterization of HNSCC infiltrating CD8+ T cells in a cohort of 30 patients. The results showed that differential intratumoral frequency of CD8+CD28+ T cells, CD8+CD28− T cells, and CD8+CD28−CD127−CD39+ Treg distinguished between HNSCC patients who did or did not respond to treatment. Moreover, high PD1 expression identified a CD8+CD28− T cell subpopulation, phenotypically/functionally corresponding to CD8+CD28−CD127−CD39+ Treg, which showed a high expression of markers of exhaustion. This observation suggests that development of exhaustion and acquisition of regulatory properties may configure the late differentiation stage for intratumoral effector T cells, a phenomenon we define as effector-to-regulatory T cell transition.

A picture is emerging in which advanced laryngeal cancers (LCs) are potentially not homogeneous and may be characterized by subpopulations which, if identified, could allow selection of patients amenable to organ preservation treatments in contrast to those to be treated with total laryngectomy (TL). This work aims to analyze a multicentric cohort of T3-T4a LCs treated by upfront TL, investigating the clinical and pathological features that can best predict oncologic outcomes. A total of 149 previously untreated patients who underwent TL for T3-T4a LC at four institutions were analyzed. Survival and disease-control were considered as the main outcomes. A secondary end-point was the identification of covariates associated with nodal status, investigating also the tumor thickness. T and N categories were significantly associated with both overall and disease-specific survival. The number of positive nodes and tracheal involvement were associated with loco-regional failure, post-cricoid area invasion and extra-nodal extension with distant failure. Posterior laryngeal compartment involvement was not a significant prognostic feature, by either univariable and multivariable analyses. These results support the conclusion that laryngeal compartmentalization has no impact on survival in patients treated by upfront TL and the current TNM staging system remains a robust prognosticator in advanced LC.

Salvage total laryngectomy (STL) is the most common treatment for recurrent laryngeal cancer after (chemo)-radiotherapy [(C)RT]. In this scenario, a higher rate of local wound complications, such as pharyngo-cutaneous fistula (PCF) and pharyngo-esophageal stenosis (PES), is generally expected. The aim of the present study is to evaluate outcomes using a standardized reconstructive protocol. Between 2009 and 2019, patients undergoing STL after (C)RT were collected at two referral hospitals with the objective of evaluating surgical outcomes using a standardized reconstructive policy based on the use of fascio-cutaneous free flaps as inlay patch grafts and a long-lasting salivary bypass stent. Fifty-five patients (mean age, 66 years; male-to-female ratio, 8:1) were included in the study. Previous treatments were RT in 22 (40%) patients, CRT in 21 (38.2%), and partial laryngeal surgery followed by adjuvant (C)RT in 12 (21.8%). Reconstruction was accomplished by radial forearm and anterolateral thigh free flaps in 16 (29.1%) and 39 (70.9%) patients, respectively. Flap success rate was 98.2%. Concerning postoperative complications, we encountered 3 PCFs (5.4%) and 1 PES (1.8%). The standardized reconstructive protocol analyzed herein granted significantly lower rates of PCF and PES after STL compared with data available in the literature.

Purpose Management of benign laryngeal stenosis (BLS) remains challenging even though transoral treatments in selected cases have shown satisfactory results, at least comparable to open-neck approaches, with reduced invasiveness. To date, no overall consensus has been reached on many issues. The aim of this study is to assess the effectiveness of a purely transoral treatment in a cohort of patients affected by BLS. Methods We evaluated 40 patients affected by BLS, treated by transoral surgery between 2013 and 2017. The European Laryngological Society classification for laryngotracheal stenosis was applied for the staging. Improvement in airway patency and quality of life was assessed by decannulation rate, Airway-Dyspnea-Voice-Swallowing (ADVS) score, Voice handicap index (VHI)-30, and Eating assessment tool (EAT)-10 questionnaires. Results Mean age was 61 years and M:F ratio was 1.4:1. Previous laryngeal surgery was the most common cause of stenosis (50%), followed by radiotherapy (20%), idiopathic etiology (12%), granulomatosis with polyangiitis (10%), and prolonged intubation (8%). Transoral treatment entailed an improvement in quality of life with a significant decrease in the VHI score (p p = 0.008), Dyspnea (p p N = 16) was 63%. Conclusions Transoral treatment of selected BLS managed by a team with high-level expertise in surgery and anesthesiology is associated with significant improvement of quality of life, especially with regard to voice and breathing functions.

Head and neck soft tissues sarcomas (HNSTS) are a heterogeneous group of rare tumours. The 8th edition of the TNM staging system (8TNM) considered these lesions separately for the first time. The aim of this study is to assess its effectiveness and identify the most significant prognostic factors for HNSTS. A retrospective survival analysis on 101 HNSTS operated between 1995 and 2015 at the National Cancer Institute of Milan was carried out. The variables considered were pathological stage (according to both the 7TNM and 8TNM), site, histotype, depth, grading, surgical radicality, (neo)adjuvant radiotherapy and/or chemotherapy. According to the 7TNM, the T category distribution was 35 T1a, 23 T1b, 11 T2a, and 32 T2b. Applying the 8TNM, the distribution changed to 19 T1, 18 T2, 35 T3, and 29 T4. Five-year overall and disease-specific survivals were 74.3 and 76.2%, respectively. Univariate analysis demonstrated an increased hazard ratio (HR) for deep lesions invading adjacent structures, high-grade, surgery with close/microscopically positive margins, and chemotherapy. Multivariate analysis confirmed an increased HR for deep location and size > 5 cm, G2–G3 tumours, and marginal surgery. No significant difference was found among T categories of the 8TNM. The present study underlines the negative prognostic impact of depth, size > 5 cm, high grade, and marginal treatment for HNSTS. Our results did not allow to validate the 8TNM staging system since, apparently, it was not associated with meaningful prognostic stratification. Further studies with wider multicentric cohorts should, however, be performed to obtain more powerful statistical data.

Objectives: Good laryngeal exposure (GLE) is typically regarded as an essential prerequisite for transoral laser microsurgery (TLM). The Laryngoscore is a preoperative scoring system aimed at predicting glottic visualization through the laryngoscope using easy patient-derived parameters. However, the presence of subjective variables may hamper its reliability and reproducibility. The aim of the present study was to provide a validation of the Laryngoscore and to develop a revised mini-version of the same, called mini-Laryngoscore (mLS), which could allow even quicker, yet sufficiently accurate, preoperative prediction of GLE. Study design: Prospective cohort study. Methods: We prospectively evaluated 310 consecutive patients submitted to TLM between 2014 and 2017, grading each patient according to the variables considered in the Laryngoscore. Results: Among the 11 variables of the previous Laryngoscore, three were confirmed as statistically significant at validation: interincisors gap, thyromental distance, and upper jaw dental status. We chose these three variables as part of the revised mLS (ranging from 0 to 4). In our cohort, 30% of the patients obtained a score of 0, 57% a score of 1, 11% a score of 2, and 2% a score of ≥3. GLE was achieved in 97%, 85%, 65%, and 20% of cases, respectively. Conclusion: Our validation confirmed the predictive ability of the Laryngoscore. Furthermore, although composed of only three clinical parameters, the mLS was still able to convey useful information regarding the possibility of obtaining GLE. Level of evidence: 2 Laryngoscope, 129:1617-1622, 2019.

The optimal treatment for T3 laryngeal carcinoma (LC) is still a matter of debate. Different therapeutic options are available: Transoral laser microsurgery (TLM), open partial horizontal laryngectomies (OPHLs), total laryngectomy (TL), and organ preservation protocols (radiation therapy (RT) or chemo-radiation (CRT)). This study aimed to retrospectively evaluate oncologic outcomes of 104 T3 LCs treated by surgery or non-surgical approaches from January 2011 to December 2016 at a single academic tertiary referral center. Each case was evaluated by a multidisciplinary team (MDT) devoted to the management of head and neck cancers. We divided the cohort into two subgroups: Group A, surgical treatment (TLM, OPHLs, TL) and Group B, non-surgical treatment (RT, CRT). For the entire cohort, two- and five-year overall survival (OS) rates were 83% and 56%, respectively. The two- and five-year disease-free survival (DFS) rates were 75% and 65%, and disease-specific survival rates were 93% and 70%, respectively. The N category was a significant independent prognosticator for OS (p = 0.02), whereas Group B was significantly and independently associated with DFS (HR 4.10, p = 0.006). Analyzing laryngo-esophageal dysfunction-free survival as an outcome, it was found that this was significantly lower in higher N categories (p = 0.04) and in cases that underwent non-surgical treatments (p = 0.002). Optimization of oncologic outcomes in T3 LCs may be obtained only by a comprehensive MDT approach, considering that different treatment options have heterogenous toxicity profiles and indications.

Open partial horizontal laryngectomies (OPHLs) are well-established and oncologically safe procedures for intermediate&ndash, advanced laryngeal cancers (LC). T&ndash, N categories are well-known prognosticators: herein we tested if &ldquo, anterior&rdquo, vs. &ldquo, posterior&rdquo, tumor location (as defined in respect to the paraglottic space divided according to a plane passing through the arytenoid vocal process, perpendicular to the ipsilateral thyroid lamina) may represent an additional prognostic factor. We analyzed a retrospective cohort of 85 T3&ndash, 4a glottic LCs, treated by Type II or III OPHL (according to the European Laryngological Society classification) from 2005 to 2017 at two academic institutions. Five-year overall survival (OS), disease-specific survivals (DSS), and recurrence-free survivals (RFS) were compared according to tumor location and pT category. Anterior and posterior tumors were 43.5% and 56.5%, respectively, 78.8% of lesions were T3 and 21.2% were T4a. Five-year OS, DSS, and RFS for T3 were 74.1%, 80.5%, and 63.4%, respectively, and for T4a 71.8%, 71.8%, and 43%, respectively (p not significant). In relation to tumor location, the survival outcomes were 91%, 94.1%, and 72.6%, respectively, for anterior tumors, and 60.3%, 66.3%, and 49.1%, respectively, for posterior lesions (statistically significant differences). These data provide evidence that laryngeal compartmentalization is a valid prognosticator, even more powerful than the pT category.

The aim of this study is to analyze the efficacy of a new modified pharyngoplasty technique with barbed sutures: barbed suspension pharyngoplasty (BSP).We enrolled patients affected by obstructive sleep apnea-hypopnea syndrome (OSAHS), having the main site of obstruction at the palatal and lateral pharyngeal walls, who refused or failed to tolerate CPAP therapy and underwent non-resective pharyngoplasty with barbed sutures between January 2014 and October 2017. Two surgical techniques with barbed sutures were used: barbed reposition pharyngoplasty (BRP) and BSP; the main characteristics of the latter are a double passage of the needle, each side, through the soft palate.Forty-two patients met the study inclusion criteria and were included in the analysis. Twenty-two patients underwent BRP and 20 BSP. Patients treated with both BRP and BSP achieved significant improvement in polysomnographic parameters: AHI, ODI, t90%, and daily sleepiness tested by the ESS questionnaire (p 0.001). There were no significant differences between groups considering gender, age, or severity of OSAHS (p 0.05). Outcomes were also comparable (p = 0.10) in the two groups; patients who underwent BSP had successful treatment in 100% of cases, compared to 86% with BRP, with a cure rate of 40% vs. 18%.BSP is a novel surgical technique that is effective in treating oropharyngeal collapse and can be tailored for patients with high collapsibility of the soft palate who might benefit from the palatal stiffness given by multiple passages of the suture inside it.

Early stage (T1-2, N0-1) oral squamous cell carcinoma (OSCC) has a generally favorable prognostic outcome. However, locoregional recurrences can occur in up to 30–35% of patients, and 20% will eventually die of disease. National and international treatment guidelines do not recommend the use of postoperative radiotherapy (PORT) in a setting of early OSCC, and highlight surgery alone as the standard single modality treatment. Notwithstanding, the negative prognostic impact of some adverse pathological features, such as perineural and lymphovascular invasion, poor differentiation, depth of invasion >4 mm, and presence of nodal metastasis, is well known. The advantages of PORT in such scenarios are still debated. The aim of this study was to review the more recent literature to provide evidence on the benefits of PORT in the context of early stage OSCC.

Non-resective pharyngoplasty techniques have been shown to be effective to treat oropharyngeal collapse in patients affected by obstructive sleep apnea-hypopnea syndrome (OSAHS). The aim of our study is to evaluate outcome predictors in a cohort of patients affected by OSAHS and treated with non-resective pharyngoplasty, including variation of pharyngeal measures at the end of the surgical procedure. A cohort of patients affected by OSAHS, with palatal or lateral pharyngeal wall collapse, who underwent non-resective pharyngoplasty, were enrolled between 2014 and 2017. Surgical procedures encompassed non-resective pharyngoplasty by expansion sphincter pharyngoplasty (ESP) or barbed antero-lateral pharyngoplasty with barbed reposition pharyngoplasty (BRP) or barbed suspension pharyngoplasty (BSP) techniques, eventually associated with nasal surgery. Pharyngeal measures were recorded intraoperatively and their variation at the end of the procedure was considered. Surgical success was evaluated at least 6 months after surgery with respiratory polygraphy and ESS questionnaire. Outcome predictors were examined by multivariable logistic regression and ROC curve analysis. Seventy patients met the study inclusion criteria. ESP, BRP, and BSP in a uni-/multilevel setting led to significant improvement of all respiratory polygraphic parameters and daily sleepiness (p

In the last decades, radiotherapy (RT) has become one of the cornerstones in the treatment of head and neck (HN) malignancies and has paralleled an increase in long-term patient survival. This lead to a concomitant increase in the incidence of radiation-induced sarcomas (RIS) of the irradiated field, with an annual rate up to 0.17%. The new techniques of irradiation do not seem to influence the risk of RIS of the HN (RISHN), which mainly develop within the middle-dose field. The median latency of RISHN after RT is 10–12 years and osteosarcoma is the most represented histotype, even though there is a high variability in time of occurrence and histological features observed. There is no clear evidence of predisposing factors for RISHN, and genetic findings so far have not revealed any common mutation. Early clinical diagnosis of RISHN is challenging, since it usually occurs within fibrotic and hardened tissues, while radiological findings are not pathognomonic and able to differentiate them from other neoplastic entities. Given the highly aggressive behavior of RISHN and its poor sensitivity to chemotherapy, radical surgery is the most important prognostic factor and the only curative option at present. Nevertheless, the anatomy of the HN district and the infiltrative nature of RIS do not always allow radical intervention. Therefore, a wise integration with systemic therapy and, when feasible, re-irradiation should be performed. Future findings in the genomic features of RISHN will be crucial to identify a possible sensitivity to specific drugs in order to optimize a multimodal treatment that will be ideally complementary to surgery and re-irradiation.

Introduction The Union for International Cancer Control–American Joint Committee on Cancer TNM staging system for glottic squamous cell carcinoma (SCC) includes different types of lesions defined by the involvement of specific subsites in each T category. Our study aims to identify different subcategories according to tumor local extension and determine oncologic outcomes after treatment by transoral laser microsurgery (TLM) alone. Methods We retrospectively evaluated 410 patients affected by previously untreated pT1-pT3 glottic SCC treated by TLM alone from January 2005 to December 2015 at the Departments of Otorhinolaryngology—Head and Neck Surgery, Universities of Genoa and Brescia, Italy. All patients had at least 2 years of follow-up. Clinical, radiological, surgical, and histopathological data were reviewed and tumors divided into six subcategories: I, pT1a not involving the anterior commissure (AC); II, pT1b involving the AC; III, pT2 extending superficially to the supraglottis or the subglottis; IV, pT2 infiltrating the vocal muscle; V, pT3 involving the anterior paraglottic space; VI, pT2 or pT3 with vertical extension across the AC with/without involvement of the pre-epiglottic space. Recurrence-free survival (RFS), local control with laser alone (LCL), and organ preservation (OP) were defined as the primary oncologic outcomes. Results The 2, 5, and 10-year RFS for the entire series were 85.7, 80.3, and 73.8%, LCL rates 93.8, 92.1, and 89.6%, and OP rates 96.8, 95.9, and 93.5%, respectively. However, when comparing the rates of RFS, LCL, and OP for each subcategory, important differences emerged. In particular, subcategories V and VI showed a significantly increased risk of local recurrence [hazard ratio (HR) = 9.2 and 13.3, respectively]. These subcategories also had a significantly reduced probability to achieve LCL (HR: 73.6 and 93.5, respectively) and OP (HR: 6.4 and 8.1, respectively). Conclusion The present classification in subcategories allows introducing the concept of a three-dimensional map of isoprognostic zones in glottic SCC treated by TLM alone as a useful tool in its management by a multidisciplinary tumor board.

Introduction: Carbon dioxide laser coagulation during transoral laser microsurgery (TLM) for laryngeal cancer allows control of bleeding from vessels smaller than 0.5 mm. Therefore, larger arteries and veins must be carefully managed by clipping and/or monopolar cautery. The aim of this paper is to detail endolaryngeal vascular anatomy and identify areas of possible bleeding during TLM. Methods: We performed an anatomical study on a series of 11 fresh-frozen human cadavers. After injection of a bicomponent red silicone into the innominate, left common carotid, and left subclavian arteries, 22 hemilarynges were dissected, the course of the supraglottic, glottic, and subglottic vessels were traced after microdissection of the intervening structures, and their size measured at specific landmark points where such vessels are more frequently encountered during TLM. Results: Three vessels arising from the superior laryngeal artery were identified after its entry point at the level of the thyro-hyoid membrane: 1) the epiglottic artery (EA), documented in 100% of cases, and a common trunk dividing into two main vessels 2) the postero-inferior artery (PIA), present in 100% of the specimens, running downward and dividing in a posterior (pPIA) and anterior (aPIA) branches 3) the antero-inferior artery (AIA), present in 95% of our specimens, running downward to the anterior commissure (AC). Two transverse anastomotic networks (TANs) connected the AIA and PIA, both parallel to the vocal muscle, one lateral (present in 100% of cases), and another medial (91% of specimens). Finally, a fourth vessel supplying the glottic plane was found to be the endolaryngeal paracommissural branch of the cricothyroid artery (PCA), arising from the inferior laryngeal artery and emerging just below the AC, through the crico-thyroid membrane (reported in 100% of the specimens). This vessel anastomosed in 91% of cases with the AIA, through one or both of the TANs. Conclusion: The precise course of the endolaryngeal arteries, their relationships with adjacent structures, and size at specific landmark points have been herein described in order to provide surgeons with a map to guide them during the steep learning curve of transoral surgery of the larynx, with special emphasis given to TLM.

Background Transoral laser microsurgery (TLM) for early to intermediate laryngeal squamous cell cancer (SCC) can be technically challenging when adequate exposure of the posterior laryngeal compartment is required due to the presence of the orotracheal tube. The goal of our study was to analyze the efficacy of high frequency jet ventilation (HFJV) in achieving appropriate laryngeal exposure and safe oncologic resection of lesions located in such a position. Methods We reviewed the clinical records of 62 patients affected by Tis-T2 SCC of the posterior laryngeal compartment treated by TLM between 02/2012 and 12/2016. The cohort was divided into two groups according to the anesthesiologic technique used: Group A included patients treated using intraoperative infraglottic HFJV, while Group B encompassed patients treated by standard orotracheal intubation. The main outcome was postoperative surgical margin status. Group comparison analysis was performed. Results Significant difference in deep margin status was observed between the two groups: in Group A, the rate of negative deep margins was 86% compared to 56% in Group B (p = 0.04). A trend of better overall and superficial margin control was observed for patients treated using HFJV (Group A), although no statistical significance was achieved. Conclusion Use of HFJV during TLM allows easier and safer management of patients affected by Tis-T2 SCC of the posterior laryngeal compartment, reducing the rates of positive superficial and deep surgical margins.

The treatment of obstructive sleep apnoea syndrome (OSAS) is still a matter of debate; among the different therapeutic alternatives, both surgical and conservative, treatment with continuous positive airway pressure (CPAP) is considered the "gold standard". The recent scientific literature reports that even if CPAP represents an effective solution for sleep apnoeas, 12% of patients do not benefit from its use. In most cases, primary collapse of the epiglottis is responsible for failure. We developed a surgical technique that provides a stable support to the epiglottis without influencing its function during swallowing while preserving laryngeal anatomy and physiology. The procedure we propose is based on that conceived by Monnier for children affected by laryngomalacia. We analysed a group of 20 patients who underwent glossoepiglottopexy between January 2015 and September 2016 and compared data (AHI, ODI, t90, ESS, EAT10, etc.) collected before and 6 months after surgery to demonstrate the safety and effectiveness of our glossoepiglottopexy (GEP). The results allow us to consider GEP as a valid choice to treat adults who suffer from sleep apnoeas.Glossoepiglottoplastica con approccio trans-orale nel trattamento delle apnee ostruttive notturne nell’adulto.I dati della letteratura scientifica internazionale stabiliscono che almeno il 10% della popolazione adulta sia affetto da Sindrome delle Apnee Ostruttive nel Sonno (OSAS). Nonostante le numerose proposte terapeutiche, chirurgiche e non, che si sono susseguite negli anni, la ventiloterapia con C-PAP rappresenta ad oggi il gold standard per il trattamento di questi pazienti. Esiste comunque una percentuale di pazienti, stimata attorno al 12%, che non trae beneficio dalla terapia ventilatoria o che, addirittura, peggiora in corso di C-PAP; il collasso primario dell’epiglottide, ovvero quello dipendente esclusivamente da un’eccessiva lassità della cartilagine, verso l’aditus laringeo rappresenta la causa più frequente di insuccesso in questi soggetti. Sulla base di queste osservazioni abbiamo deciso di sviluppare una tecnica chirugica volta unicamente alla stabilizzazione dell’epiglottide che fosse conservativa e potenzialmente reversibile. La procedura che proponiamo prende spunto dall’epiglottoplastica proposta da Monnier per i pazienti pediatrici affetti da laringomalacia. Lo studio comprende 20 pazienti sottoposti a glossoepiglottoplastica tra Gennaio 2015 e Settembre 2016; diversi parametri (tra i quali AHI, ODI, t90, ESS, EAT10 ed altri) sono stati confrontati tra quelli registrati nel per operatorio e dopo 6 mesi di follow-up per valutare l’efficacia dell’intervento chirurgico. I risultati evidenziano come la glossoepiglottopessi rappresenti una valida possibilità di trattamento delle epiglottidi primarie responsabili della sindrome delle apnee ostruttive notturne nell’adulto.