[LARYNGEAL MALIGNANCIES IN ISRAEL - THE DIAGNOSIS, CLASSIFICATION AND TREATMENT OF NEUROENDOCRINE TUMORS].

INTRODUCTION: The larynx is the most common site of neuroendocrine tumors in the head and neck region. Tumors are divided morphologically into epithelial-derived tumors (carcinomas) and neural-derived tumors (paragangliomas). The classification of neuroendocrine tumors has evolved over the past two decades. OBJECTIVES: To investigate the incidence and histological types of laryngeal tumors in Israel. To evaluate laryngeal neuroendocrine tumors treated at a single tertiary referral center, while describing current classification and controversies. METHODS: Retrospective investigation was conducted of laryngeal tumors treated at Hadassah University Hospital between the years 2007 and 2016. Analysis was performed of all cases diagnosed in Israel between 2005 and 2014. Previous and current classifications of laryngeal neuroendocrine tumors were reviewed. RESULTS: Two hundred and twenty new laryngeal cancers were diagnosed on average annually in Israel during the study period. Squamous cell carcinoma consisted in most cases (95%); yet, no documentation of neuroendocrine tumors was noted. Three patients, in their fifties, were treated for laryngeal neuroendocrine tumors at Hadassah. Tumors consisted of paraganglioma, typical carcinoid and small cell neuroendocrine carcinoma. Investigation, treatment, outcome, and classification are described. CONCLUSIONS: This is the first description of laryngeal neuroendocrine tumors in Israel. The lack of clarity for diagnosis, documentation and classification of this rare, heterogenic group of tumors, described worldwide, was noted in Israel as well. A multidisciplinary team, including experienced pathologists, radiologists, head and neck surgeons and oncologists, is mandatory for providing the best patient care.

Does narrow band imaging improve preoperative detection of glottic malignancy? A matched comparison study.

OBJECTIVES/HYPOTHESIS: The primary suspicion for glottic malignancy during office laryngoendoscopy is based on lesion appearance. Previous studies investigating laryngeal use of narrow band imaging (NBI) are mostly descriptive. The additive value of NBI relative to white light (WL) requires further investigation. STUDY DESIGN: Observational matched study. METHODS: NBI was compared with WL images of 45 vocal fold lesions suspected for malignancy (21 carcinoma, 22 dysplasia, two benign). All images were presented randomly and evaluated by six independent otolaryngology specialists. The observers were asked to estimate lesion size, location, and pathology. The results for the two imaging modalities were compared with each other and with the final pathology. RESULTS: The observers estimated lesion size to be larger in the NBI images by an average of 9% (2.4 mm2 ; P =.04) compared to WL. In 64.6% of cases, the observers estimated similar pathology for NBI and WL. When there was a discrepancy, the estimated pathology was "malignant" in 24.3% by NBI, compared with 11.1% by WL. Overall, 44.7% of the lesions were estimated to be malignant by NBI, compared with 33.8% by WL (P =.001). The sensitivity and specificity rates for malignancy detection by NBI were 58.6% and 61.2%, respectively, compared to 48.7% and 76.1% by WL. CONCLUSIONS: Observers tend to estimate vocal fold lesions to be larger and more frequently suspect malignancy while assessing NBI images. Compared with WL, NBI demonstrates increased sensitivity and decreased specificity for detection of malignancy. Nevertheless, the specificity and sensitivity of NBI alone are considerably low. LEVEL OF EVIDENCE: 4 Laryngoscope, 127:894-899, 2017.

Salvage endoscopic angiolytic KTP laser treatment of early glottic cancer after failed radiotherapy.

OBJECTIVES: Management of early glottic cancer subsequent to failed radiotherapy is challenging, especially in balancing oncological control and function preservation. Patients frequently have been incentivized against surgical management and thus have undergone radiotherapy as initial treatment. This history compounds the difficulty of discussions about surgical management after recurrence. Typically, endoscopic salvage has less morbidity than transcervical partial laryngectomy and is clearly desirable over total laryngectomy. However, there are appropriate concerns about the efficacy of endoscopic salvage and the overarching impact on larynx preservation and survival. Given our success with endoscopic angiolytic KTP laser treatment of previously nonirradiated T1 and T2 glottic cancers, we examined our results from treating similar-sized lesions after failed radiotherapy. METHODS: We performed a retrospective chart review of 20 patients from our cancer database who had undergone failed radiation therapy elsewhere for early glottic cancer and then underwent endoscopic angiolytic KTP laser treatment. RESULTS: Analysis of the geographic tumor recurrence of the 20 patients revealed T1a N0 M0 cancer in 4 patients, T1b N0 M0 cancer in 1 patient, T2a N0 M0 cancer in 1 patient, and T2b N0 M0 cancer in 14 patients. After KTP laser salvage treatment, 4 patients (20%) had local recurrence (all T2b) and required subsequent total laryngectomy, and 3 of these patients (15%) ultimately died of disease. The remaining 16 patients (80%) were free of disease at least 2 years after endoscopic salvage (average follow-up, 39 months). CONCLUSIONS: Our investigation provides preliminary evidence that angiolytic KTP laser salvage treatment of early glottic cancer is an effective treatment after failed irradiation. Studies with larger cohorts and longer follow-up will be necessary to establish incontrovertible evidence of its efficacy.

Voice outcomes for photoangiolytic KTP laser treatment of early glottic cancer.

OBJECTIVES: Surgery and radiotherapy routinely provide high cure rates in treating early glottic cancer. Therefore, key metrics for success are optimal voice outcome and preservation of future cancer treatment options. Remarkably, there is a paucity of pretreatment versus posttreatment voice outcome data. Angiolytic KTP (potassium titanyl phosphate) laser treatment of early glottic cancer with ultranarrow margins was initiated to better preserve vocal function. Given that effective oncological results have been achieved, it was hypothesized that this approach would also result in improved posttreatment measures of vocal function that more closely approximate historical norms than pretreatment values. METHODS: Pretreatment and posttreatment voice outcome data were obtained for 92 patients (64 with T1 cancer and 28 with T2 cancer) who underwent 532-nm KTP laser treatment of early glottic cancer in a study design in which each patient essentially served as his or her own control. The evaluations included objective measures (acoustic and aerodynamic) and patients' self-assessments of vocal function (Voice-Related Quality of Life; V-RQOL). A series of mixed analyses of variance were conducted for all vocal function measures, with tumor stage and depth of invasion as the between-subjects variables and time (presurgery versus postsurgery) as the within-subject variable. RESULTS: There were statistically significant (p < or = 0.05) postoperative improvements for acoustic (perturbation and noise-to-harmonics ratio) and aerodynamic (subglottic pressure and vocal efficiency) measures of vocal function, as well as for V-RQOL assessment. CONCLUSIONS: Comprehensive pretreatment and posttreatment voice measures in a large patient cohort demonstrated that the KTP laser significantly improved postoperative vocal function in patients with early glottic cancer. Furthermore, radiotherapy was preserved as an oncological treatment option.

High-force simulated intubation fails to dislocate cricoarytenoid joint in ex vivo human larynges.

OBJECTIVES: We assessed the likelihood of arytenoid dislocation during intubation through the application of controlled force. METHODS: Six cadaveric human larynges were mounted in an apparatus for simulating forcible collision with the arytenoid complexes. An endotracheal tube tip probe (ETTP) was used to push one arytenoid complex, and a non-slip probe (NSP) was tested on the other. Increasing pressure was applied until the probes either slipped or reached 5 kg of force. Dissection was then performed to assess the integrity of the cricoarytenoid ligament. The forces obtained by pushing an endotracheal tube against an electronic balance were measured to estimate the maximal possible intubating force. RESULTS: None of the ETTP or NSP trials disrupted the cricoarytenoid joint ligaments, and the joint never appeared to be dislocated. The mean maximal forces were 1.8 kg for the ETTP (after which, slippage consistently occurred) and 4.7 kg for the NSP. The mean maximal forces from an endotracheal tube pushed against a scale were 1.5 kg (without stylet) and 4.6 kg (with stylet). CONCLUSIONS: Arytenoid dislocation did not happen, and gross disruption of the joint capsule or ligament did not occur, even when the testing approximated the maximum force achievable under extreme conditions. Endotracheal tube insertion thus seems unlikely to cause arytenoid dislocation.

Safety and dosing of bevacizumab (avastin) for the treatment of recurrent respiratory papillomatosis.

OBJECTIVES: Increasing evidence supports the use of laryngeal injections of the antiangiogenic agent bevacizumab (Avastin) for the adjuvant treatment of recurrent respiratory papillomatosis (RRP). A recent prospective open-label investigation, approved by the US Food and Drug Administration, employing 12.5 mg of sublesional bevacizumab demonstrated single-site efficacy without complications; however, the safety of multiple-site injections and higher dosing has not yet been reported. The primary objective of this study was to report on the safety of increased doses of bevacizumab for the treatment of RRP. METHODS: Two cohorts of adult patients were evaluated. In the first group, a prospective analysis was performed on patients with a diagnosis of laryngeal RRP after t heir participation in th e initial clinical trial with a single-site lowerdose (7.5 to 12.5 mg). They received higher doses of sublesional laryngeal bevacizumab (15 to 50 mg total) with detailed physiologic, hematologic, and serum chemistry measurements performed before and after each bevacizumab injection. A second cohort of patients received sublesional laryngeal injections of bevacizumab (15 to 88 mg total) without physiologic measurements and underwent a retrospective analysis of reported complications. RESULTS: One hundred consecutive laryngeal injection sessions (office, 87; operating room, 13) with bevacizumab were performed in 43 patients, with a mean dose of 30 mg total per treatment (range, 15 to 88 mg). Sixty-three of the 100 sessions were accompanied by KTP laser photoangiolysis of the papilloma prior to bevacizumab injections. Eighteen patients (cohort 1) underwent detailed physiologic assessment, and no dysfunction was observed. There were no local or systemic complications of bevacizumab administration. The second group of 25 patients (cohort 2) also reported no significant local or systemic complications. Neither patient group was observed to have a local wound problem in the larynx. CONCLUSIONS: This investigation provides evidence that higher doses of bevacizumab are relatively safe in adult patients with laryngeal RRP. Further refinements in pharmacologic concentration and drug delivery will determine the optimal treatment regimens in the future.

Local injection of bevacizumab (Avastin) and angiolytic KTP laser treatment of recurrent respiratory papillomatosis of the vocal folds: a prospective study.

OBJECTIVES: Photoangiolytic laser treatment of recurrent respiratory papillomatosis (RRP) is effective, but does not reliably prevent recurrence. Therefore, sublesional injections of the antiangiogenic agent bevacizumab (Avastin) were given to assess the adjunctive effect on disease recurrence. Since bevacizumab is a new therapeutic modality for RRP, there were also primary safety objectives to determine whether there was a pegative impact on the voice and whether there were local or systemic complications. METHODS: A prospective open-label investigation was conducted in 20 adult patients with bilateral vocal fold RRP. The patients underwent planned 532-nm pulsed KTP laser photoangiolysis of bilateral glottal disease 4 times with an approximately 6-week interval between procedures. At each planned laser procedure, the vocal fold that on initial presentation had a greater volume of disease also underwent 4 serial sublesional bevacizumab injections (7.5 to 12.5 mg in 0.3 to 0.5 mL). A sham injection with saline solution was administered to the other vocal fold as a control. Disease resolution was compared between subjects' vocal folds, and objective measures of vocal function (acoustic, aerodynamic), as well as patients' self-assessments of vocal function (Voice-Related Quality of Life survey), were obtained. RESULTS: All 20 patients completed the study, and there were no local or systemic complications. After 4 injections, 3 of the 20 patients had no discernible disease in either vocal fold. Of the remaining 17 subjects, 16 had less disease in the bevacizumab-treated vocal fold despite starting with more disease. Only 1 of the 17 had more disease in the bevacizumab-treated vocal fold after 4 injections. Moreover, 7 of the 20 patients (35%) did not require a laser procedure in the vocal fold that had received 4 bevacizumab injections, as compared with 3 of the 20 vocal folds (15%) that were treated with laser alone. All of the vocal function measures displayed statistically significant posttreatment improvements, except for average fundamental frequency in the 3 female patients, in whom it fell below the normal range. CONCLUSIONS: This prospective investigation provided evidence that bevacizumab injections enhanced KTP laser treatment of glottal papillomatosis without systemic or local complications. Coupling the antiangiogenesis agent bevacizumab with KTP laser photoangiolysis is conceptually synergistic and scientifically promising since the mechanisms of action are complementary.