Staging Of Head And Neck Squamous Cell Carcinoma Research Articles

Role of 18F-FDG PET/CT in evaluating lymph node status in patients with head and neck squamous cell carcinoma.

The presence of cervical lymph node metastases (CLNM) at diagnosis is one of the most relevant negative prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC). The aim of this study was to analyse 2-deoxy-2[18F]fluoro-D-glucose (FDG) PET/CT findings for the identification of primary tumours and CLNM in a sample of patients affected by HNSCC. Moreover, a maximum standardised uptake value (SUVmax) threshold for the detection of CLNM was estimated. Clinical variables (i.e. smoking and alcohol habits), and tumour features (i.e. EBV and HPV positivity) were also evaluated in relation to FDG PET/CT findings. We retrospectively analysed patients who underwent FDG PET/CT for HNSCC staging between 2015-2020 at the University Hospital of Ferrara. All patients had cytological or histological confirmation of suspected cervical lymph nodes. In total, 65 patients were enrolled (53 males, 12 females, median age 65.7 years). CLNM of patients with smoking habit had significantly higher SUVmax values than those of patients with previous smoking habit and non-smokers (p = 0.04). p16 positive HNSCC demonstrated a trend for higher SUVmax values on CLNM, in comparison to p16 negative tumours (p = 0.089). ROC curve analysis identified 5.8 as the best cut-off value of SUVmax for the detection of CLNM (AUC = 0.62, sensitivity 71.4% and specificity 72.7%). FDG PET/CT is a useful tool to evaluate CLNM in patients with HNSCC, particularly in those with smoking habit and p16 positive disease. A SUVmax cut-off of 5.8, combined with the use of conventional radiological investigations, may represent a useful tool in the identification of CLNM.

Neoadjuvant low-dose radiotherapy, tislelizumab, combined with albumin-bound paclitaxel and cisplatin in resectable locally advanced head and neck squamous cell carcinoma (NeoRTPC02): The first-stage result from an open label, single-arm, two stage, phase II clinical trial.

6078 Background: Neoadjuvant immunotherapy and chemotherapy has been explored in phase I/II clinical studies in head and neck squamous cell carcinoma (HNSCC), confirming its safety and efficacy. However, the pathological complete response (pCR) / major pathological response (MPR) rate still needed for improvement. Recent studies revealed that low dose radiotherapy can overcome immunosuppressive tumors by reversing immune desertification when combining immunotherapy. Here, we conducted this clinical trial to explore the efficacy and safety of neoadjuvant low-dose radiotherapy, PD-1 inhibitor, combined with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma. Methods: This was an open-label, single-arm, phase II clinical trial. Patients with untreated, histologically confirmed HNSCC staging III-IVB were included. The eligible patients were scheduled to be administrated neoadjuvant low-dose radiotherapy (1GY/1F, D1, D2, D8, D15, Q3W), PD-1 inhibitor tislelizumab (200 mg D1, Q3W), combined with albumin-bound paclitaxel (100mg/m2, D1, D8, D15, Q3W) and cisplatin (25mg/m2, D1, D8, D15, Q3W) for two cycles. Radically surgical resection was planned to conduct 3-4 weeks after neoadjuvant therapy. The primary endpoint was pCR rate. The second endpoints consisted of MPR rate, objective response rate (ORR), R0 resection rate, safety, non-surgery-delay rate and quality of life. 25 patients will finally be enrolled in this study. Simon's two-stage design was adopted, and 10 patients should be included in the first stage. If 2 or more of the first 10 patients reached pCR, the second stage would be successfully entered. Results: By Jan 10, 2023, 10 patients were enrolled. 7 out of 10 patients successfully received the study regimen and finished the operation on schedule. Our primary endpoint of first stage was met. 4/7 (57%) patients achieved pCR at the primary site , 3/7 (43%) patients achieved MPR. The pCR/MPR rate was 100%. R0 resection rate was 100%. Totally 9 patients underwent MRI scan pre and post neoadjuvant therapy, and the assessment per RESCIST criteria were as follow: 0/9 (0%) CR, 6/9 (66%) PR, 3/9 (33%) SD. The treatment-related adverse events (TRAEs) were manageable. The most shared adverse events of grade 1/2 were anorexia (89%), anemia (89%) and nausea (66%). No surgical delay was observed. Conclusions: Neoadjuvant low-dose radiotherapy, tislelizumab, combined with albumin-bound paclitaxel and cisplatin contributed to an outstanding pCR/MPR rate of 100% (pCR rate of 57% and MPR rate of 43%) at present, and was generally tolerated in locally advanced HNSCC. The second stage is ongoing. Clinical trial information: NCT05343325 . Research Sponsor: BeiGene Co., Ltd. and CSPC Co., Ltd.

Salivary-Based Cell-Free Mitochondrial DNA Level Is an Independent Prognostic Biomarker for Patients with Head and Neck Squamous Cell Carcinoma.

Changes in the copy numbers of cell-free nuclear DNA (cf-nDNA) and cell-free mitochondrial DNA (cf-mtDNA) have shown promising diagnostic utilities among patients with head and neck squamous cell carcinoma (HNSCC). Considering the absence of objective prognostic tools for HNSCC surveillance, this study aimed to assess the utility of saliva-based cf-nDNA and cf-mtDNA in predicting the overall survival of patients with HNSCC. The study included ninety-four patients with a confirmed HNSCC diagnosis with a mean follow-up time of 32.04 months (±19.1). A saliva-based liquid biopsy was collected from each patient. A multiplex quantitative PCR was used to determine the absolute number of cf-nDNA and cf-mtDNA. The Kaplan-Meier estimator and Cox proportional hazards regression models were used to assess overall survival. The absolute copy numbers of cf-nDNA and cf-mtDNA were statistically significantly higher among the deceased patients than among the censored ones (p < 0.05). Individuals with elevated levels of cf-nDNA or cf-mtDNA were associated with a significantly poorer overall survival (p ≤ 0.05). A univariate analysis showed that only the absolute copy number of cf-mtDNA was the sole predictor of overall survival. However, the multivariate analysis showed that all the absolute copy numbers of cf-nDNA, the absolute copy numbers of cf-mtDNA, and the stage of HNSCC were predictors of overall survival. Our study confirms that saliva is a reliable and non-invasive source of data that can be used to predict the overall survival of patients with HNSCC, where cf-mtDNA levels act as the sole predictor.

Abdominal ultrasound in head and neck squamous cell carcinoma staging: yes or no?

Abdominal ultrasound is a diagnostic staging procedure for distant metastases in head and neck squamous cell carcinoma (HNSCC). However, currently performed abdominal staging procedures do not follow consistent standards. Therefore, this retrospective study on 498 patients aimed at investigating on abdominal ultrasound as a staging procedure in HNSCC. A retrospective analysis of 498 head and neck cancer patients treated in our Department of Head and Neck Surgery between 2008 and 2015 was performed. Disease-related data were collected over a mean follow-up time of 30.3months, and results of abdominal ultrasound were analyzed. 426 patients received abdominal ultrasound as a staging procedure. 7% (29) were suspicious for metastases. In 19 cases (66%), the detected abnormalities were masses of the liver. In four patients, abdominal metastases were confirmed at the time of initial diagnosis. 16 patients developed abdominal metastases in the course of the disease (on average 623days after initial diagnosis). 19 out of 20 patients with abdominal metastases had an N2/N3 cervical lymph node status. In this study, the negative predictive value of abdominal ultrasound for HNSCC staging was 99.03%, while the positive predictive value yielded 5.88% (N2/N3-patients). Only in patients with locally advanced lymph-node-status (N2/N3), abdominal ultrasound can be useful as a staging investigation to exclude abdominal metastasis in HNSCC patients. For N0/N1 patients, abdominal ultrasound might be dispensed. Of note, in case of a positive result, further diagnostic procedures are mandatory.

Insight into Classification and Risk Stratification of Head and Neck Squamous Cell Carcinoma in Era of Emerging Biomarkers with Focus on Histopathologic Parameters.

Tumor-node-metastasis (TNM) staging system is the cornerstone for treatment planning of head and neck squamous cell carcinoma (HNSCC). Many prognostic biomarkers have been introduced as modifiers to further improve the TNM classification of HNSCC. Here, we provide an overview on the use of the recent prognostic biomarkers, with a focus on histopathologic parameters, in improving the risk stratification of HNSCC and their application in the next generation of HNSCC staging systems.

COMPARISON OF FEATURES AND OUTCOMES OF VERMILION LIP SCC WITH ORAL AND HEAD AND NECK CUTANEOUS SCC

<h3>Objectives</h3> Comparing features and outcomes of patients with skin, lip, and oral squamous cell carcinoma (SCC) and evaluating restaging lip cancer as skin cancer. <h3>Study Design</h3> All patients surgically treated at our center for vermilion lip SCC, oral SCC, and cutaneous head and neck (HN) SCC between January 2011 and December 2019 were retrospectively reviewed. <h3>Results</h3> 79, 125, and 620 cases were respectively included. Lip and oral SCC were similar regarding tumor diameter (<i>P</i> < .001), depth of invasion (<i>P</i> < .001), surgical margins (<i>P</i> = .01), T stage (<i>P</i> < .001), N stage (<i>P</i> < .001), AJCC stage (<i>P</i> < .001), perineural invasion (<i>P</i> < .001), and vascular invasion (<i>P</i> < .001). In total, 31 lip SCC cases were restaged applying cutaneous HN SCC staging system criteria, with a shift from stages I/II and T1/2 to stages III and T3, respectively. In Kaplan-Meier curves, there was a good distinction among staging curves for oral SCC and cutaneous SCC but not for lip SCC, in both staging models. <h3>Conclusions</h3> There are more similarities between lip SCC and cutaneous HN SCC than oral SCC, although both staging systems failed to distinguish categories in Kaplan-Meier curves.

An Investigation on Radiomics Feature Handling for HNSCC Staging Classification

The incidence of Head and Neck Squamous Cell Carcinoma (HNSCC) has been growing in the last few decades. Its diagnosis is usually performed through clinical evaluation and analyzing radiological images, then confirmed by histopathological examination, an invasive and time-consuming operation. The recent advances in the artificial intelligence field are leading to interesting results in the early diagnosis, personalized treatment and monitoring of HNSCC only by analyzing radiological images, without performing a tissue biopsy. The large amount of radiological images and the increasing interest in radiomics approaches can help to develop machine learning (ML) methods to support diagnosis. In this work, we propose an ML method based on the use of radiomics features, extracted from CT and PET images, to classify the disease in terms of pN-Stage, pT-Stage and Overall Stage. After the extraction of radiomics features, a selection step is performed to remove dataset redundancy. Finally, ML methods are employed to complete the classification task. Our pipeline is applied on the “Head-Neck-PET-CT” TCIA open-source dataset, considering a cohort of 201 patients from four different institutions. An AUC of 97%, 83% and 93% in terms of pN-Stage, pT-Stage and Overall Stage classification, respectively, is achieved. The obtained results are promising, showing the potential efficiency of the use of radiomics approaches in staging classification.

Detection of distant metastases and distant second primary cancers in head and neck squamous cell carcinoma: comparison of [18F]FDG PET/MRI and [18F]FDG PET/CT

PurposeThis prospective study aimed to compare the diagnostic performance of [18]FDG PET/MRI and PET/CT for the detection of distant metastases and distant second primary cancers in patients with head and neck squamous cell carcinoma (HNSCC).MethodsA total of 103 [18F]FDG PET/MRI examinations immediately followed by PET/CT were obtained in 82 consecutive patients for staging of primary HNSCC (n = 38), suspected loco-regional recurrence/follow-up (n = 41) or unknown primary HNSCC (n = 3). Histology and follow-up > 2 years formed the standard of reference. Blinded readers evaluated the anonymized PET/MRI and PET/CT examinations separately using a 5-point Likert score. Statistical analysis included: receiver operating characteristic (ROC) analysis, jackknife alternative free-response ROC (JAFROC) and region-of-interest (ROI)-based ROC to account for data clustering and sensitivity/specificity/accuracy comparisons for a score ≥ 3.ResultsDistant metastases and distant second primary cancers were present in 23/103 (22%) examinations in 16/82 (19.5%) patients, and they were more common in the post-treatment group (11/41, 27%) than in the primary HNSCC group (3/38, 8%), p = 0.039. The area under the curve (AUC) per patient/examination/lesion was 0.947 [0.927–1]/0.965 [0.917–1]/0.957 [0.928–0.987] for PET/MRI and 0.975 [0.950–1]/0.968 [0.920–1]/0.944 [0.910–0.979] for PET/CT, respectively (p > 0.05). The diagnostic performance of PET/MRI and PET/CT was similar according to JAFROC (p = 0.919) and ROI-based ROC analysis (p = 0.574). Sensitivity/specificity/accuracy for PET/MRI and PET/CT for a score ≥ 3 was 94%/88%/89% and 94%/91%/91% per patient, 96%/90%/91% and 96%/93%/93% per examination and 95%/85%/90% and 90%/86%/88% per lesion, respectively, p > 0.05.ConclusionsIn HNSCC patients, PET/MRI and PET/CT had a high and similar diagnostic performance for detecting distant metastases and distant second primary cancers.

UCHL1 promotes proliferation and metastasis in head and neck squamous cell carcinoma and could be a potential therapeutic target

The purpose of this study was to research the physiological roles of ubiquitin carboxyl-terminal esterase L1 (UCHL1) in head and neck squamous cell carcinoma (HNSCC). Ten HNSCC samples and matched normal oral mucosal tissues were collected. UCHL1 expression of these tissues was detected by the immunohistochemical staining and real-time quantitative polymerase chain reaction. The human HNSCC cell line HN6 UCHL1 knockout (UCHL1 KO) cell line was constructed using CRISPR/CAS9 gene editing and verified by western blotting. Wound healing assay, cell proliferation assay, cell invasion assay, and flow cytometric analysis of the cell cycle and apoptosis were applied to research the role of UCHL1 in HNSCC. Also, an RNAseq gene expression data set and HNSCC patient survival data from The Cancer Genome Atlas were analyzed. UCHL1 was highly expressed in HNSCC tissues compared with normal oral mucosal tissues (P=.032). A decreased proliferation (P < .0001), migration (P < .0001), and invasion (P = .0049) ability of HN6 cells was exhibited after knockout of UCHL1. However, HN6 UCHL1 KO cells showed no significant differences in the cell cycle or apoptosis. The progression, nodal metastasis status, and stage of HNSCC had a positive correlation with the expression of UCHL1. UCHL1 plays an important role in HNSCC, and we consider that targeting UCHL1 may be a feasible therapeutic strategy for HNSCC.

IgG levels in Human Papillomavirus Infection Associated with Clinical Stage of Head and Neck Squamous Cell Carcinoma

Background: Head and neck squamous cell carcinoma (HNSCC) is an invasive neoplasm of epithelial tissue in the head and neck and one of the etiologies of HNSCC is human papillomavirus (HPV) which maybe associated with the clinical stage of HNSCC. HPV infection in squamous cell epithelium produces specific IgG antibodies against HPV. IgG titer of HPV can help identify patients who are at risk for HPV-related cancers. This study aimed to explore the association between IgG titer of HPV with the clinical stages of HNSCC. Methods: The design of this study was analytic cross sectional, conducted at the Outpatient Clinic of Otorhinolaryngology-Head and Neck Surgery, Division of Oncology, Dr. Hasan Sadikin General Hospital Bandung period September-December 2017. Patients with HNSCC were recruited, and history was taken. Furthermore, histopathologic examination and HPV IgG serology examination was performed using the ELISA method. The HPV IgG levels were compared by stage and data were analyzed using the Shapiro Wilks test and Unpaired T test. Result: The HPV IgG was high in 75% (n=21) of HNSCC patients in the advanced stage and low in 25% (n=7) of patients in the early stage. There was a significant relationship between HPV IgG titer and early and advanced stage of HNSCC (p=0.001). Conclusion: The HPV IgG titer is related to the clinical stage of HNSCC indicating that the higher the HPV IgG level, the more advanced the clinical stage. Further study is needed to explore HPV IgG levels as a prognostic marker in HNSCC.

PERINEURAL INVASION AND WORST PATTERN OF INVASION AN IMPORTANT PREDICTOR FOR RECURRENCE AND NODAL METASTASIS

Background Prognostic implications for the head and neck squamous cell carcinoma (HNSCC) are related to many clinicopathologic parameters. Recent advancement in histopathologic assessment has led to the inclusion of perineural invasion (PNI) and worst pattern of invasion (WPOI) for staging and management of HNSCC as important prognostic parameters. Objective To assess the relationship of PNI and WPOI to lymph node metastasis including skip metastasis, risk of recurrence, and death in the patients with HNSCC. Methods Patients undergoing primary salvage surgery for HNSCC were enrolled in this prospective 1-year follow-up study from January 2019 to January 2020 (mean age 45.84 + 10.59 years). Clinicopathologic parameters of age, sex, size, site, staging, grading, histologic variant, depth of invasion, lymphovascular invasion, WPOI, extracapsular spread, nodal metastasis, recurrence, and skip lesions were assessed at a confidence level of 95% with a P value Results PNI was seen to be positive in 47.8% of cases and WPOI was seen in 70.2% of cases; in addition, 44.7% had positive nodal metastasis. Recurrence and death were seen in 10.6% cases and skip lesions in only 4.3%. A significant association was seen between PNI and recurrence (P = .02) and also between WPOI and nodal metastasis (P Conclusions WPOI is significantly related to nodal metastasis and PNI is significantly related to recurrence. Patients with PNI and WPOI are at increased risk of recurrence and nodal metastasis and will require aggressive treatment and management to improve prognosis.

Integrated analysis of deregulation microRNA expression in head and neck squamous cell carcinoma.

MicroRNAs (miRNAs) play critical roles in carcinogenesis and development of cancers. In this study, we analyzed the eccentrically expressed miRNAs in head and neck squamous cell carcinoma (HNSCC) tissues based on the miRNA-Seq data of HNSCC patients available in the Cancer Genome Atlas database. Aberrant expression of 2589 miRNAs was detected in HNSCC tissues (1128 downregulated and 1461 upregulated). The differential expression levels of the miRNAs were further validated by analysis of 25 HNSCC samples and paired control tissues and compared with the Gene Expression Omnibus database to determine the candidate miRNAs. Quantitative reverse transcription polymerase chain reaction was used to compare the expression of these candidate miRNAs between 22 fresh HNSCC tissue samples and 11 control samples. In addition, the relationship between the expression of these candidate miRNAs and Tumor, Node, Metastases staging of HNSCC was analyzed. Compared with the expression in control tissues, the levels of hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, and hsa-miR-99a-3p were significantly lower in HNSCC. According to the Cancer Genome Atlas dataset analyzed, all 4 miRNAs were shown to inhibit tumor progression (T stage), positive lymph node metastasis (N stage), and distant metastasis (M stage) in HNSCC. Kyoto Encyclopedia of Genes and Genomes analysis showed that genes regulated by these 4 miRNAs were enriched in certain pathways, including the transforming growth factor-β signaling pathway and the Hippo pathway. Enriched gene ontology terms mainly included regulation of transcription, cell proliferation, and apoptosis, which are well-characterized functions of miRNAs. Moreover, all 4 miRNAs inhibited the progression of primary tumors (T stage) and metastasis of regional lymph nodes (N stage). The top 4 aberrantly expressed miRNAs identified in this study have great clinical value in developing strategies for early diagnosis and treatment of HNSCC. More intensive studies are required to elucidate the mechanism underlying the roles of these miRNAs in HNSCC.

PD-L1 in Combination with CD8+TIL and HIF-1α are Promising Prognosis Predictors of Head and Neck Squamous Cell Carcinoma.

ObjectiveThe aim of this study was to evaluate the prognosis effect of PD-L1 in combination with CD8+ tumor-infiltrating lymphocyte (TIL) or HIF-1α in head and neck squamous cell carcinoma (HNSCC).MethodsA total of 63 patients who underwent surgical resection were included in this study. The level of PD-L1, CD8+ TIL, and HIF-1α was determined by immunohistochemical analysis. The survival of patients was evaluated by Kaplan–Meier analysis. The prognostic power of these parameters was evaluated by C-index.ResultsWe observed that the survival of patients, who had a high level of PD-L1 in tumor cells, was significantly shorter than those who had a low level of PD-L1. However, the survival of patients who had a high level of PD-L1 in tumor microenvironment was significantly longer than patients with a low level of PD-L1 in tumor microenvironment. In addition, high level of CD8+ tumor-infiltrating lymphocyte or low level of HIF-1α level suggests a better prognosis. Moreover, we observed that PD-L1 in combination with CD8+ tumor-infiltrating lymphocyte and HIF-1α could significantly improve the prognostic effect of current TNM stage.ConclusionThe results of this study suggest that the level of PD-L1, CD8+TIL, and HIF-1α are useful prognostic biomarkers for patients with HNSCC. Incorporating these biomarkers into current TNM stage of HNSCC improve the discriminatory capability of TNM stage.

Head and neck squamous cell carcinoma.

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.

Might anxiety disorders promote head and neck cancer development?

Cancer patients present a higher risk of experiencing anxiety disorders (AD). However, it is not clear if AD might be associated with cancer development. Thus, our study aimed to evaluate if AD might be related to head and neck squamous cell carcinoma (HNSCC) development. The combination of an applied animal basic study and a retrospective diagnostic case and control study in patients was performed. As a result, we obtained that stress reduced the locomotor activity of the animals in the group stress and stress + 4NqO (p < 0.0001). The stress showed no influence on the progression of neoplasia in mice. In the same way, the case group did not present differences in anxiety scores in comparison to control. Moreover, no association between HNSCC staging and anxiety scores was observed. In conclusion, our in vivo findings in humans and animals have shown that there is no relationship between AD and oral squamous cell carcinoma.

PD-L1 in combination with CD8+TIL and HIF-1α are promising prognosis predictors of head and neck squamous cell carcinoma.

e18545 Background: Currently, the tumor/node/metastasis (TNM) staging is the most widely used Head and neck squamous cell carcinoma (HNSCC) staging system. However, this classification only provides limit information for the prognosis of HNSCC. Recently, some studies suggest that the level of PD-L1 in tumor cells (TC-PD-L1) or in tumor microenvironment cells (TMC-PD-L1) is a promising biomarker for the prognosis of HNSCC patients. Therefore, in this study, we evaluated the prognostic value of TC-PD-L1, TMC-PD-L1, CD8+ TIL, HIF-1α. In addition, we investigated if incorporated these biomarkers into TNM stage could improve the prognostic value of TNM stage. Methods: A total of 63 patients who underwent surgical resection. The level of PD-L1, CD8+ TIL and HIF-1α was determined by immunohistochemical analysis. The survival of patients was evaluated by Kaplan-Meier analysis and Cox proportional hazards model. The prognostic power of these parameters was evaluated by C-index. Results: We observed that the survival of patients, who had high level of PD-L1 in tumor cells, was significantly shorter than those who had low level of PD-L1. However, the survival of patients who had high level of PD-L1 in tumor microenvironment was significantly longer than patients with low level of PD-L1 in tumor microenvironment. In addition, high level of CD8+ tumor-infiltrating lymphocyte or low level of HIF-1α level suggests a better prognosis. Moreover, we observed that PD-L1 in combination with CD8+tumor-infiltrating lymphocyte and HIF-1α could significantly improve the prognostic effect of current TNM stage. Conclusions: The results of this study suggest that the level of PD-L1, CD8+TIL and HIF-1α is useful prognostic biomarkers for patients with HNSCC. Incorporated these biomarkers into current TNM stage of HNSCC improve the discriminatory capability of TNM stage.

Genetic polymorphisms of the X‐linked transcription factor forkhead box P3 predispose to synchronous secondary primary malignancy (SPM) of esophagus in head and neck squamous cell carcinoma patients

AbstractPatients with head and neck squamous cell carcinoma (HNSCC) are prone to develop second primary malignancy (SPM) at the esophagus synchronously, especially those with increased forkhead box P3 (FOXP3) positive regulatory T (Treg) cell infiltration in tumor tissue. We tested whether FOXP3 genetic polymorphisms can be associated with Treg cell infiltration and synchronous SPM in HNSCC patients. HNSCC patients received screening esophagogastroduodenoscopy during 2008 to 2016 were enrolled consecutively. After excluding and matching cigarette smoking and alcohol drinking status, the final cohort went on investigation. Three tag single nucleotide polymorphisms (tag SNPs) of the FOXP3 gene (rs2232365, rs3761548, and rs3761549) were selected from the HapMap database and genotyped by RT‐PCR. FOXP3 immunohistochemistry was done to evaluate Treg cell amount in tumor tissues. A total of 270 male HNSCC patients were included, including 135 in the synchronous SPM (SynSPM group) and 135 in the HNSCC alone group. Compared with HNSCC alone group, synchronous SPM group had a HNSCC that was more commonly located at oro/hypopharynx (55.0% vs 39.6%, P = .012) and at earlier TNM stage with borderline significance (38.8% vs 29.0%, P = .124). In addition, carriage of G allele in rs3761549 of the FOXP3 gene significantly increased synchronous SPM risk (crude OR = 2.21, P = .009). After adjustment of HNSCC location and staging, rs3761549 G allele remained significantly associated with synchronous SPM risk (adjusted OR = 2.10, P = .024). Patients with G allele in rs3761549 also had higher FOXP3+ Treg cell infiltration in the tumor tissue than those with A allele (mean FOXP3+ cell number/mm2: 55.93 vs 36.39, P = .008). Male HNSCC patients with G allele in rs3761549 of the FOXP3 gene has a higher risk of synchronous SPM development and merit earlier screening endoscopy.

Genomics and precision surgery for head and neck squamous cell carcinoma.

The identification of the biological determinants that shape the response of tumors to medical therapies offers perspectives for better patient stratification and therapeutic targeting. Here, we discuss how genomics could help to improve the surgical treatment of head and neck squamous cell carcinoma (HNSCC). We examine the potential use of genomic analyses for: i) refining and standardizing the indications for surgery, ii) the choice of surgical procedure, and iii) the follow-up of patients with resected tumors. We highlight the studies that used genomics to explore the contribution of tumor biology to the outcome of surgery. We discuss the important developments that are challenging current surgical practice in HNSCC, such as neoadjuvant immunotherapy and the analysis of circulating DNA. Genomic analyses provide practical tools that could help improve the pathological diagnosis and staging of HNSCC, and increase the appreciation of the importance of tumor biology in the outcome of surgery. Identification of biomarkers will likely contribute to a move toward precision surgery of HNSCC, i.e. the personalization of surgical practice based on tumor biology.

MiR-762 Promotes Malignant Development of Head and Neck Squamous Cell Carcinoma by Targeting PHLPP2 and FOXO4.

BackgroundHead and neck squamous cell carcinoma (HNSCC) is among the most common malignant tumors worldwide. This study, investigated the role of microRNA (miR)-762 in regulating HNSCC progression.Materials and methodsThe expression levels of miR-762 in HNSCC tissues were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Statistical analyses were performed to investigate the association of miR-762 with clinicopathological features in patients with HNSCC. Cell proliferation and migration were examined by cell counting (CCK-8) and IncuCyte assays. Target genes of miR-762 were screened using bioinformatics tools and microarrays, and confirmed using a luciferase activity reporter assay, qRT-PCR and Western blot analysis. Recuse experiments were performed to detect whether target genes mediated the effects of miR-762 on HNSCC cells. The in vivo effects of miR-762 were verified using tumor xenografts.ResultsHNSCC clinical specimens showed high expression levels of miR-762, which positively correlated with tumor-node-metastasis (TNM) stage and poor prognosis of HNSCC. miR-762 overexpression promoted the proliferation and migration of HNSCC cells in vitro. In addition, overexpression of miR-762 upregulated the expression of phosphorylated AKT (p-AKT) and mesenchymal markers (N-cadherin and vimentin), but suppressed epithelial marker (E-cadherin) expression. miR-762 also promoted HNSCC tumor growth in vivo. PH domain and leucine-rich repeat protein phosphatase 2 (PHLPP2) and Forkhead box O4 (FOXO4) were direct target genes of miR-762. HNSCC tissues had low expression levels of PHLPP2 and FOXO4, showing a negative correlation with miR-762 expression. Moreover, silencing of PHLPP2 and FOXO4 mimicked the tumor-promotive effects of miR-762 on HNSCC cells. Notably, overexpression of PHLPP2 and FOXO4 abolished the pro-tumoral function of miR-762 on cell proliferation and migration.ConclusionmiR-762 promotes HNSCC progression by targeting PHLPP2 and FOXO4. Therefore, miR-762 might be a potential diagnostic or therapeutic target for HNSCC.

KIR2DS4, KIR2DL2, and KIR2DS4del are linked with basaloid tumors, lymph node metastasis, advanced stage and metastatic risk in head and neck squamous cell carcinoma

BackgroundsOur previous study has suggested that KIR2DS1, 2DS5, 3DS1 and KIR2DL5 are associated with head and neck squamous cell carcinoma (HNSCC) development. The purpose of the current study was to investigate the possible association of killer cell immunoglobulin like receptors (KIRs) gene with the clinicopathological features of patients. MethodsWe reviewed the pathological reports of 285 pathologically confirmed cases of HNSCC and analyzed the association of KIR system with pathological characteristics. ResultsA significant increase was demonstrated in the carrier frequency of KIR2DS4 in conventional than basaloid type and a higher frequency of lymph node metastasis (LNM) in carriers of KIR2DL2 and individuals possess 5 inhibitory KIRs (iKIRs). We also observed a higher proportion of patients with advanced stage of HNSCC in carriers of KIR2DL2 and deleted variant of KIR2DS4. ConclusionIn HNSCC, KIR2DL2 is positively while KIR2DS4 is negatively associated with advanced stage. The higher proportion of LNM in carriers of KIR2DL2 and carriers of 5 iKIRs, suggested that inhibitory KIRs are associated with metastatic risk.