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Objective: PTEN (phosphatase and tensin homologue deleted on chromosome 10), also referred to as MMAC1 (mutated in multiple advanced cancers) gene was recently identified as a putative tumor suppressor in a variety of malignant tumors. PTEN expression has been investigated in some squamous cell carcinomas (SCC) of head and neck. However, there is only little knowledge about laryngeal malignancies. Therefore, we examined PTEN product protein immunohistochemically in 30 consecutive laryngeal specimens from patients with laryngeal SCC and compared the results according to the clinicopathologic characteristics of the patients.Method: Surgical resection specimens of patients with laryngeal SCC were stained for PTEN protein using a primary rabbit polyclonal anti-PTEN antibody. Standard avidin-biotin immunohistochemical analysis was used to process the sections. The extent and intensity of PTEN staining in the specimens were compared according to the age and sex of the patients and localization, differentiation, size and stage of the tumor.Results: Out of 30 tumoral specimens (23 glottic and 7 supraglottic) 22 showed decreased PTEN staining intensity compared to the adjacent normal tissue. The extent of cytoplasmic PTEN staining was significantly less in supraglottic tumors (p < 0.05). When characteristics of the patients were analyzed according to the extent of cytoplasmic PTEN staining no difference was observed according to age, sex, measure, differentiation, T or N status.Conclusion: A significant decrease in the extent of PTEN staining was observed in supraglottic SCC. It could be worthwhile to test if PTEN expression is diminished in patients with more aggressive laryngeal tumors, with special attention to tumor localization in larger series. [ABSTRACT FROM AUTHOR]

Objectives: The study was intended to compare the outcomes for T1-T2N0M0 glottic squamous cell carcinoma with anterior commissure involvement who had undergone partial laryngectomy (PL) or radiotherapy (RT).Materials and Methods: We retrospectively analyzed 256 patients who were treated by RT (n = 70) or PL (n = 186). Patients received prophylactic irradiation of the neck in RT group whereas PL was not associated with lymphadenectomy. Propensity score matching (PSM) was used to eliminate the baseline variations.Results: The average age of the RT group (67 years) was significantly higher than that of the PL (59 years). Local recurrence was noted in 14 patients of the RT group and 22 of the PL. While regional recurrence was noted in only 1 patient of the RT group and 23 of the PL. After PSM, the 5-year overall survival (82.8% vs. 83.9%, p = 0.302), 5-year cancer-specific survival (88.3% vs. 89.7%, p = 0.793), 5-year local relapse-free survival (79.3% vs. 84.5%, p = 0.127) were not significantly different between two groups. However, 5-year regional relapse-free survival in the RT group was significantly better than that in the PL (100% vs. 87.1%, p = 0.014). In the PL group, infection, granuloma, laryngeal stenosis, chylous leakage, and pharyngeal fistula were reported in six, 11, 12, one, and two patients, respectively.Conclusions: RT resulted in comparable rates of survival, local control, and larynx preservation compared to PL. However, RT was associated with higher regional control rate. The complication rates were extremely low in RT group. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of the immune response to cancer is of increasing importance, with a determining role in the response to the treatments and prognosis of patients. In this work, we studied whether the immune response (local and systemic) can influence the treatment response and prognosis of patients with laryngeal and hypopharyngeal carcinoma receiving induction chemotherapy (ICT). We observed that the relationship between neutrophils and lymphocytes (NLR) in peripheral blood and PD-L1 expression in the tumor is related to ICT response and patient prognosis. The identification of new biomarkers related to the immune response may allow a better selection of treatments and the identification of potential therapeutic targets. Our goal was to assess the correlation of immune parameters with the response to induction chemotherapy (ICT) in head and neck squamous cell carcinoma (HNSCC) patients. Pretreatment biopsies from 64 patients with HNSCC that received ICT were assessed for PD-L1 protein expression and density of CD8+ and FOXP3+ tumor infiltrating lymphocytes (TIL). In addition, the neutrophil-to-lymphocyte ratio (NLR) was calculated from pretreatment whole blood counts. In total, 55% of cases exhibited PD-L1 combined proportion score (CPS) positivity (≥1% stained cells). PD-L1 CPS positivity correlated with a high density of both CD8+ (p = 0.01) and FOXP3+ (p < 0.001) TILs. There was no correlation between PD-L1 expression or TIL density and NLR values. In univariate analyses, the absence of PD-L1 CPS expression (p = 0.042) and a high NLR (p = 0.034) were significantly correlated with response to ICT. Neither CD8+ TIL (p = 0.99) nor FOXP3+ TIL densities (p = 0.71) were associated with response to ICT. In multivariate analysis, only a high NLR was associated with response to ICT (HR = 4.06, 95% CI = 1.06–15.5, p = 0.04). In addition, a high NLR was also independently associated with lower disease-specific (p = 0.03) and overall survival rates (p = 0.04), particularly in the subset of patients who received definitive surgical treatment. These results suggest that NLR could emerge as a predictive biomarker of response to ICT. [ABSTRACT FROM AUTHOR]

From 70 patients with laryngeal cancer, pieces of mucosa were taken from the subglottis, the entrance to the sinus of Morgagni, and from the ventricular fold. There were 35 taken at the time of diagnosis and the other 35 were taken after radiotherapy. By means of an elective staining method and a whole mount technique, morphological and quantitative studies of the goblet cells were performed. The findings were compared with corresponding investigations of goblet cells in normal larynges. The significantly lower density in the subglottis than in the sinus of Morgagni and ventricular fold observed in normal larynges was not found in the two groups of cancer patients. Instead, there was a tendency to an equalization of the goblet cell density in all 3 laryngeal regions. In the irradiated group the goblet cell density was lower, in all 3 regions, than in the nonirradiated cancer group and in normal larynges. In the close vicinity of the cancer the goblet cell density was reduced, possibly because the cancer process had initiated metaplasia to an epithelium which was poor in goblet cells. Between the two cancer groups and normal larynges there were no morphological differences in the goblet cells. [ABSTRACT FROM AUTHOR]

In order to evaluate the expression of p53 protein in 28 premalignant and 40 malignant squamous cell proliferations of the larynx and its relationship to tobacco consumption, human papillomavirus infection and differentiation grade of the lesions, p53 expression was examined by means of a microwave post-fixation immunohistochemical method using the PAb 240 and PAb 1801 monoclonal antibodies. HPV infection was assessed by non-isotopic in situ hybridization (NISH) and polymerase chain reaction (PCR). A large proportion of carcinomas (77.5%) and dysplasias (61%) expressed p53. No difference was found between differentiation grades of the lesions regarding p53 detection (P > 0.1), but moderate or intense p53 expression was more frequent in the carcinomas (P < 0.05). A statistical correlation was found between cigarette consumption and both p53 detection and p53 staining intensity (P < 0.05 in each case). HPV study revealed HPV 16 and 18 infection only in carcinomas. The frequency was 28% and the physical state of the virus as demonstrated by NISH was integration into the genome. We observed an inverse relationship between HPV infection and p53 expression (P = 0.006). Our findings suggest that p53 overexpression is a common and early event which increases in frequency with progression of laryngeal squamous cell carcinoma. The expression of p53 is influenced by tobacco and high-risk types of HPV. [ABSTRACT FROM AUTHOR]

Simple Summary: Organ preservation protocols have become first line therapy for the majority of advanced laryngeal cancers. Unfortunately, up to one third of patients will develop recurrent disease requiring salvage surgery. These tumors tend to display aggressive features when compared to primary disease. The aim of this study is to identify genomic alterations associated with poor prognosis in the recurrent setting to guide precision therapy and identify potential targetable pathways. Here we show that mutations in the oxidation pathway, specifically the KEAP1-NFR2 pathway, predict survival in a cohort of patients undergoing salvage laryngectomy. Organ preservation protocols are commonly used as first line therapy for advanced laryngeal cancer. Recurrence thereafter is associated with poor survival. The aim of this study is to identify genetic alterations associated with survival among patients with recurrent laryngeal cancer undergoing salvage laryngectomy. Sixty-two patients were sequenced using a targeted panel, of which twenty-two also underwent transcriptome sequencing. Alterations were grouped based on biologic pathways and survival outcomes were assessed using Kaplan-Meier analysis and multivariate cox regression. Select pathways were evaluated against The Cancer Genome Atlas (TCGA) data. Patients with mutations in the Oxidation pathway had significantly worse five-year disease specific survival (1% vs. 76%, p = 0.02), while mutations in the HN-Immunity pathway were associated with improved five-year disease specific survival (100% vs. 62%, p = 0.02). Multivariate analysis showed mutations in the Oxidation pathway remained an independent predictor of disease specific survival (HR 3.2, 95% CI 1.1–9.2, p = 0.03). Transcriptome analysis of recurrent tumors demonstrated that alterations in the Oxidation pathway were associated a positive Ragnum hypoxia signature score, consistent with enhanced pathway activity. Further, TCGA analyses demonstrated the prognostic value of oxidation pathway alterations in previously untreated disease. Alterations in the Oxidation pathway are associated with survival among patients with recurrent laryngeal cancer. These prognostic genetic biomarkers may inform precision medicine protocols and identify putatively targetable pathways to improve survival in this cohort. [ABSTRACT FROM AUTHOR]

(1) Background: Lymphoepithelial carcinoma of the hypopharynx and larynx is a rare tumor with fewer than 50 cases in the published literature. We present a literature review to discuss the clinical findings, viral or genetic associations, diagnostic challenges, histopathological findings and therapeutic aspects of the disease. (2) Methods: A comprehensive literature review was performed through MEDLINE/PubMed from 1968 to 2018. We identified 21 studies comprising 46 patients. Data on all the clinicopathological features, diagnostic modalities, treatment options and viral or genetic etiology were extracted and analyzed using SPSS. (3) Results: The mean age of presentation was 64 years (range 40–82 years) and mostly involved males. The supraglottis and pyriform sinus were the most commonly involved sub-sites, with surgery as the preferred treatment modality. The presence of the Epstein–Barr virus possibly directs a viral etiology. The incidence of cervical and distant metastasis was 54% and 21%, respectively. The median survival time was 30 months. (4) Conclusions: Lymphoepithelial carcinoma of the hypopharynx is an aggressive tumor with a strong predilection for regional and distant metastasis. Surgery, in combination with adjuvant therapy, provides promising results. Immunohistochemistry helps in differentiating LEC from other pathologies. [ABSTRACT FROM AUTHOR]

Aberrant SRC expression and activation is frequently detected in multiple cancers, and hence, targeting SRC has emerged as a promising therapeutic strategy. Different SRC inhibitors have demonstrated potent anti-tumor activity in preclinical models, although they largely lack clinical efficacy as monotherapy in late-stage solid tumors, including head and neck squamous cell carcinomas (HNSCC). Adequate selection and stratification of patients who may respond to and benefit from anti-SRC therapies is therefore needed to guide clinical trials and treatment efficacy. This study investigates the prognostic significance of active SRC expression in a homogeneous cohort of 122 human papillomavirus (HPV)-negative, surgically treated HNSCC patients. Immunohistochemical evaluation of the active form of SRC by means of anti-SRC Clone 28 monoclonal antibody was specifically performed and subsequently correlated with clinical data. The expression of p-SRC (Tyr419), total SRC, and downstream SRC effectors was also analyzed. Our results uncovered striking differences in the prognostic relevance of SRC expression in HNSCC patients depending on the tumor site. Active SRC expression was found to significantly associate with advanced disease stages, presence of lymph node metastasis, and tumor recurrences in patients with laryngeal tumors, but not in the pharyngeal subgroup. Multivariate Cox analysis further revealed active SRC expression as an independent predictor of cancer-specific mortality in patients with laryngeal carcinomas. Concordantly, expression of p-SRC (Tyr419) and the SRC substrates focal adhesion kinase (FAK) and the Arf GTPase-activating protein ASAP1 also showed specific associations with poor prognosis in the larynx. These findings could have important implications in ongoing Src family kinase (SFK)-based clinical trials, as these new criteria could help to improve patient selection and develop biomarker-stratified trials. [ABSTRACT FROM AUTHOR]

Discrimination of the etiology of arytenoid fixation in cT3 laryngeal squamous cell carcinoma (SCC) is crucial for treatment planning. The aim of this retrospective study was to differentiate among possible causes of arytenoid fixation (edema, inflammation, mass effect, or tumor invasion) by analyzing related signal patterns of magnetic resonance (MR) in the posterior laryngeal compartment (PLC) and crico-arytenoid unit (CAU). Seventeen patients affected by cT3 glottic SCC with arytenoid fixation were preoperatively studied by state-of-the-art MR with surface coils. Different signal patterns were assessed in PLC subsites. Three MR signal patterns were identified: A, normal; B, T2 hyperintensity and absence of restriction on diffusion-weighted imaging (DWI); and C, intermediate T2 signal and restriction on DWI. Signal patterns were correlated with the presence or absence of CAU and PLC neoplastic invasion. Patients were submitted to open partial horizontal or total laryngectomy and surgical specimens were analyzed. Pattern A and B did not correlate with neoplastic invasion, while Pattern C strongly did (Spearman's coefficient = 0.779, p < 0.0001; sensitivity: 100%; specificity: 78%). In conclusion, MR with surface coils is able to assess PLC/CAU involvement with satisfactory accuracy. In absence of Pattern C, arytenoid fixation is likely related to mass effect and/or inflammatory reaction and is not associated with neoplastic invasion. [ABSTRACT FROM AUTHOR]

Background: We sought to expand upon preliminary data suggesting that metformin confers a survival benefit to patients with head and neck squamous cell carcinoma (HNSCC). Methods: A large-scale retrospective cohort study of all patients in Ontario diagnosed with squamous cancer of the larynx, hypopharynx, and nasopharynx between Dec 1st 2007 to Dec 1st 2012 was undertaken. The Institute for Clinical and Evaluative Sciences was accessed to obtain patient demographic, treatment and outcome information. We included patients on metformin at the time of diagnosis. Kaplan Meier methods and Cox Regression models were used. Results: Patients taking metformin at the time of diagnosis had a higher comorbid status but were otherwise similar to patients without metformin usage. Using multivariate analysis, neither overall survival nor disease specific survival was improved in patients on metformin (OS: HR 1.123, p =.338; DSS: HR 1.048, p =.792). Conclusions: No survival advantage was observed in patients with HNSCC taking metformin at the time of diagnosis. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate the benefit of induction chemotherapy followed by surgery in locally advanced unresectable stage IVb laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC). Methods: Data of patients with stage IVb LHSCC who received induction chemotherapy for the purpose of tumor resection between January 2007 and January 2016 were retrospectively collected. Definitive surgery with postoperative adjuvant therapy was performed in patients whose tumors became resectable (resectable group). Chemoradiotherapy, radiotherapy, or supportive care was considered in patients whose tumors remained unresectable (unresectable group). Results: Thirty-two patients were identified; the tumor resectability rate after induction chemotherapy was approximately 56%. The median overall survival (OS) rates of the resectable and unresectable groups were 20.0 months (range, 16.0–35.5 months) and 9.5 months (range, 6.0–15.0 months), respectively (p = 0.008). The estimated 2-year OS rates of the resectable and unresectable groups were 59.5% (95% confidence interval [CI], 33.2–78.3%) and 10.7% (95% CI, 1.1–35.4%), respectively (p = 0.008). The estimated 2-year disease-free survival (DFS) rates of the resectable and unresectable groups were 53.5% (95% CI, 27.9–73.6%), and 14.3% (95% CI, 2.3–36.6%), respectively (p = 0.009). On multivariate analysis, factors positively impacting OS and DFS in all patients were surgical resection, a laryngeal primary site, and induction chemotherapy with docetaxel, cisplatin, and fluorouracil. Conclusions: In advanced unresectable stage IVb LHSCC patients, surgical resection following induction chemotherapy appears to improve survival outcomes. [ABSTRACT FROM AUTHOR]

Background: The laryngeal framework provides a natural barrier preventing tumour spread to extralaryngeal structures. Transoral laser microsurgery (TLM) for laryngeal squamous cell carcinoma (SCC) may violate these boundaries, altering the pathways of tumor spread for potential recurrences. Our project objective is to describe laryngeal SCC recurrence patterns and overall survival in patients requiring total laryngectomy (TL) after TLM. Methods: Patients undergoing TLM for laryngeal SCC requiring salvage TL were identified from a prospective CO2 laser database containing all patients undergoing TLM for head and neck malignancies at the QEII Health Sciences Center in Halifax, Nova Scotia between March 2002 – May 2014. Surgical pathology reports were analyzed for tumor characteristics, extent of recurrence and invasion of local structures. Kaplan-Meier analyses were performed to evaluate overall survival, disease specific survival (DSS) and locoregional control. Results: Fifteen patients were identified from the database as receiving salvage TL for recurrent disease after initial TLM resection for laryngeal SCC. Final pathology reports demonstrated that 67% (10/15) of patients had thyroid cartilage involvement while 53% (9/15) of patients had cricoid cartilage involvement on salvage TL pathology. 33% (5/15) of patients had perineural invasion and 27% (4/15) had lymphovascular invasion. Mean and median follow-up times were 36.7 months and 26.8 months respectively (range 3.9–112.6). The Kaplan-Meier estimate for overall survival at 36 months was 40% post TL with a standard error (SE) of 13.6%. DSS was 47% (SE 14.2%), and locoregional control was 55% (SE 14.5%) post TL. Conclusions: Laryngeal recurrence sites following TLM seem to be consistent with historical data at known laryngeal sites of vulnerability. Treatment with TLM does not predispose patients to a lower rate of locoregional control and overall survival after total laryngectomy and salvage outcomes are consistent with literature values. [ABSTRACT FROM AUTHOR]